Evaluation, staging and typical disease management approaches for patients with locally advanced non-small cell lung cancer (NSCLC)

This transcript was edited lightly for clarity and to reflect the preferences of the faculty presenter.

DR RIMNER: The workhorse is still PET-CT staging, and MRI of the brain is absolutely critical in these patients to rule out metastatic disease. And invasive mediastinal staging I think is important to anyone for any questionable nodes or PET-avid nodes.

In my practice, I especially pay attention that the PET scan is up to date. So if a PET scan is older than 6 weeks, I repeat it at the time of simulation for treatment planning. That’s been demonstrated to have advantages in more accurate targeting of the tumor from a radiation perspective. And you do pick up about 10% or so patients that you upstage at the time of repeat PET scan. So this is just characteristic of locally advanced disease, where there’s a fair number of microscopic or systemic disease that declares itself in a relatively short period of time.

DR LOVE: Could you maybe go through a typical clinical scenario where a patient with locally advanced disease ends up having surgery?

DR RIMNER: At our institution pretty much any patient who’s young, fit, so where there are no objections from an operability perspective are being considered for it, especially if they have single-station N1 and/or N2 involvement with a resectable primary mass, ideally with a lobectomy. Those would be ideal candidates for the surgery approach. So patients that have somewhat limited Stage IIIA disease. We generally would shy away from resection when a pneumonectomy might be necessary to achieve a gross total resection or when there’s multistation N2 or even suspicion for N3 disease, of course.

DR LOVE: Could you talk about your approach in the neoadjuvant setting for a typical patient with Stage IIIA lung cancer?

DR RIMNER: Yes, just a very, very standard type of Stage IIIA patient would be someone with, let’s say, a lung adenocarcinoma without a driver mutation that comes in with a right upper lobe mass, T2 mass in the right upper lobe and a right paratracheal lymph node, maybe a questionable right hilar node. So it would be consistent with N2 disease in 1 single lymph node station in the right paratracheal space.

So those patients we would typically see by all the disciplines, and typically we would recommend neoadjuvant chemotherapy. Typically, if we can, we would confirm the nodal involvement by EBUS or bronchoscopy with a biopsy of the right paratracheal lymph node. And then if this was a lung adenocarcinoma, our general approach is a platinum/pemetrexed approach with 4 cycles. We do assess the response every 2 cycles with a CT scan. And then that would be followed by surgical resection, typically in a case like this with a right upper lobectomy and mediastinal lymph node dissection. And then if the lymph node is still positive at the time of surgery under pathology examination, we would offer that patient postoperative radiation therapy to the right paratracheal space and the right hilum where the bronchus was taken off.

Selection and dose of postoperative radiation therapy (RT)

DR LOVE: Could you talk a little bit about the way you approach the radiation therapy in that situation, the technique that you utilize at Memorial, and what are some of the other radiation oncology approaches?

DR RIMNER: In postoperative radiation therapy, we typically treat to a dose of 50.4 to 54 Gy in 28 to 30 fractions. We target only the involved nodal levels. We don’t do what is called elective nodal irradiation, meaning we don’t treat the entire mediastinum. We don’t treat nodal levels that are not involved or are found to be uninvolved at the time of surgical dissection. We will typically cover the ipsilateral hilum, because that’s where the transitioning lymphatics are running to the N2 nodes, and it’s usually not a very big difference in terms of expanding the field to cover that space.

We’ll typically use a 3D or IMRT technique with daily image guidance. The 3D versus IMRT approach depends a little bit sometimes on insurance clearance, unfortunately. And there’s no absolute right or wrong. Really, what the bottom line is is that the lung constraints and the normal tissue constraints have to be met no matter which technique you use. And that is certainly part of the treatment planning and can be well evaluated with both modern radiation delivery techniques.

DR LOVE: Any comments on other techniques of radiation therapy in this situation, including proton beam?

DR RIMNER: Yes. Proton beam radiation is, of course, an exciting novel therapy. It’s not, to my knowledge, been prospectively evaluated specifically in the postoperative setting. We are working on a study like that. In my mind, proton therapy might be actually a really good technique for the mediastinum. Some of the challenges of proton therapy in thoracic radiation oncology have to do with respiratory motion and significant tissue density differences. And many of those issues are not as significant when we talk about targeting the mediastinum.

The advantage of proton therapy is that the beam comes in from one direction and stops at a certain point, or you can make it stop. And then any tissue that is distal to that stopping point will receive no radiation dose. So it’s an ideal technique when there’s a little bit of space between the target and the organ that we are trying to avoid, so that we can stop the beam right in between.

So, for instance, the spinal cord we could completely avoid with postoperative radiation therapy with proton beam. Maybe more importantly, it would be really nice in some scenarios — and that depends on where the target would be located — but would be really helpful to avoid the esophagus and the lungs more effectively with proton radiation if there is enough space in between the area that needs to be targeted and those organs.

DR LOVE: Do you do proton beam therapy at Memorial?

DR RIMNER: Our proton radiation center is built and should be fully operational in June 2019.

DR LOVE: How do you see that fitting into your practice, if at all?

DR RIMNER: So I think it will really add another tool to our practice. It is a New York Proton Consortium, so it’s not just Memorial. It’s a consortium of several academic institutions that are working together. But we, of course, have a significant interest and portion in it. We are planning to design, and we are in the process of designing trials, because we would like to really use this as an academic opportunity to treat as many patients as possible and monitor them in a prospective fashion.

So, for instance, the postoperative RT question that we just discussed would be an ideal one. Each organ site or disease team has a list of trials that they would like to do, that they are designing for the center. That should be up and running by the time the center opens.

DR LOVE: Any other new or evolving radiation techniques that are used in the community that you want to comment on?

DR RIMNER: It’s a little bit unclear what the role is of stereotactic radiation in locally advanced lung cancer. Obviously, that has revolutionized early-stage lung cancer. It plays an increasing role in oligometastatic lung cancer, and that, oftentimes, is actually a scenario that we end up with in the locally advanced patient population.

So as I said earlier, when we repeat a PET for restaging, it’s not uncommon that one detects 1, 2 or 3 early, early metastases. And so generally, oligometastatic disease is defined as less than 5 metastases. And that is somewhat arbitrary. But in those scenarios, stereotactic radiation therapy does play an increasing role. It has been shown in 2 studies last year that it results in a progression-free and an overall survival benefit when we treat all sites of disease with aggressive local therapy, such as surgery, or of stereotactic radiation. And that will be an increasing indication for that.

Stereotactic body RT (SBRT) versus surgery for patients with early-stage NSCLC

DR LOVE: I see that you actually were part of a paper just published in The Journal of Thoracic and Cardiovascular Surgery, not one that I usually read — there was actually a meta-analysis of stereotactic body radiation versus surgery for patients with lung cancer. Can you talk about what you looked at there and what you found? I guess that was for localized disease.

DR RIMNER: Yes, that was for early-stage disease. That’s right. That’s an ongoing question, where the borderline resectable patients, where is the right line between offering surgery versus stereotactic radiation therapy. I come from the perspective that stereotactic radiation really has dramatically improved what we can offer, from a radiation perspective. It’s changed our local control rates from about 60% to the 90% range, and that’s a gigantic jump in long-term local control.

So we now have a tool that really is a fair rival to surgical resection and is really an alternative, when before it wasn’t really an alternative. It was really only an option for anyone who was completely inoperable. And with more tools available, of course come questions on where to draw the right line.

I think what is clear is that both surgical resection and stereotactic radiation therapy, also known as stereotactic body radiation therapy (SBRT) or stereotactic ablative body radiation (SABR), both of those acronyms are being used — result in very high local control rates. If there’s a difference between surgery and SBRT, it’s likely in the 5% to 10% range, and that includes local control as well as progression-free survival.

So there are multiple randomized studies ongoing that will really have to be the benchmark or will really have to be studies that we need to go by to solve this question. I don’t think any meta-analysis or retrospective large analysis can really replace that, as they are not Level 1 evidence. But what we see is that surgery and SBRT are remarkably close in outcomes.

DR LOVE: Where I heard it mainly discussed is in patients who are elderly or too ill to have surgery. Is that the main situation where it’s used?

DR RIMNER: Yes, at this point in time that is really the main target population. Patients who are clearly inoperable or patients where surgery is considered to be quite risky and that are considered borderline resectable and then a few patients who prefer a nonoperative approach.

I’m not of the opinion that we should offer stereotactic radiation therapy as standard of care for resectable and clearly operable patients. I think that would be premature. But as I said, it’s, for the first time, a real alternative for the patients that are at high risk for surgery.

Case: A man in his mid-70s, a former smoker, with Stage IIIC adenocarcinoma of the lung receives durvalumab consolidation after chemoradiation therapy (CRT)

DR LOVE: So let’s get into the issue of chemoradiation for locally advanced disease and particularly, as you mentioned, the new development in terms of the use of consolidation and checkpoint inhibitors, and maybe to get into that we could hear about your 74-year-old man.

DR RIMNER: So that one was a pretty typical standard patient with locally advanced disease as we see them now. The patient was a 74-year-old. Had a history of hypertension, diabetes and coronary artery disease. Had a recent CABG and had Stage IIIC disease with bilateral mediastinal involvement and had right supraclavicular lymphadenopathy.

DR LOVE: He was a smoker?

DR RIMNER: Yes, he was a smoker. He did not have an actionable mutation. He had quit smoking, so he was a former smoker.

DR LOVE: Right. And what actually brought him to see a physician? Was he symptomatic?

DR RIMNER: Yes. He had developed a cough. He had a pneumonia that then was treated and cleared but in the process of the workup was found to have a mass and mediastinal lymphadenopathy.

DR LOVE: What did the initial workup of this man show?

DR RIMNER: There was a CT scan that showed a left upper lobe mass, mediastinal fullness and then on CT scan a right supraclavicular lymph node as well.

DR LOVE: And did he have chronic lung disease?

DR RIMNER: Not officially diagnosed, but after many decades of smoking, I think it’s fair to assume that. He had mostly cardiac disease from his smoking.

DR LOVE: Can you talk about his workup and biopsy? How was that done? And what did it show?

DR RIMNER: Yes. So he had a core needle biopsy of the left upper lobe mass that showed a lung adenocarcinoma. There were no actionable driver mutations. He did not have metastatic disease on a PET scan that followed the CAT scan of the chest. He had no metastatic disease on MRI of the brain. And because he had bilateral mediastinal and contralateral supraclavicular disease, he was started on definitive concurrent chemoradiation. He was not a surgical candidate because of the extent of the disease, as well as his cardiac comorbidities.

Optimal design of the radiation treatment field; mitigation of RT-associated side effects

DR LOVE: Can you talk a little bit about specifically the fields that you designed and the treatment that you gave to him?

DR RIMNER: So we, again, do not do any elective nodal radiation. We treat the disease that is there that is PET-CT guided. So what we do is, we outline what we call the gross tumor volume, the GTV. We always obtain a 4D-CT scan at the time of simulation to measure any respiratory movement and account for that in a so-called ITV. Then we add a margin for microscopic extension, which is on the order of 7 to 8 millimeters, which is based on radiologic and pathologic correlative studies. And then we add a 5-mm margin for what we call set-up error, just because no patient can lie perfectly still on the table. So those are some typical margin expansions.

We, as I said, do not treat with elective nodal radiation fields. It’s been shown that the risk of failing in nodes that are not initially involved when we take this approach is less than 10%. It’s on the order of 5% to 7% when a patient is PET staged, and that is generally considered an acceptable risk, but in return, to avoid significantly increased side effects, mostly esophagitis and pneumonitis, by treating smaller fields.

In these cases we always use an IMRT technique. It’s not really possible to meet normal tissue constraints without an IMRT technique. We do daily 2D kV imaging to verify the set-up positioning. We do weekly cone beam CTs to verify any marked soft tissue changes during the treatment that may require replanning or readjustment of the treatment fields. Luckily, that does not happen too often, but once in a while we may have to adjust it — for instance, if there was a lung collapse or a pleural effusion or things that really could change the dosimetry. But in addition to that, it also just gives us a sense on how the tumor responds to the treatment and whether things are going as planned.

DR LOVE: Could you talk a little bit about what happened as you treated him?

DR RIMNER: So he was doing remarkably well. We were actually a little bit nervous about his recent CABG that he was just recovering from, but he really tolerated the treatment remarkably well. He had some mild esophagitis towards the end of the 6 weeks. He did not develop pneumonitis, which is usually not happening that early on anyway. The main side effect during the treatment is really fatigue, esophagitis, skin irritation. And because of the esophagitis, oftentimes dehydration or decreased oral intake, which can further weaken the patient. But he did actually remarkably well with just a little bit of supportive medications to help with his swallowing.

DR LOVE: So in his situation, and I don’t know whether he actually is the kind of the person who asked you more detailed information, but with the conclusion of this treatment, what would you estimate his prognosis to be, his chance of developing recurrence, metastatic disease and death? And can you talk a little bit about the history of what’s been going on to try to improve the outcome that preceded this big trial with the durvalumab? What had been done up until that time? But how would you have seen his prognosis at that point, assuming — before we had this other new approach?

DR RIMNER: Yes. So for the last 20, 30 years, we have tried to make really inroads in locally advanced lung cancer with different radiation techniques. And I think what we’ve achieved the most is decreased side effects by shrinking the fields, by using more conformal radiation techniques, by avoiding organs at risk in a better way and also defining better how much radiation organs at risk can take and how much we need to restrict them.

Results of the Phase III RTOG-0617 trial evaluating carboplatin/paclitaxel in combination with standard- versus high-dose conformal RT, with or without cetuximab, for Stage III NSCLC

DR RIMNER: Much time and effort has been invested in dose escalation on the radiation side. There were several institutional trials, including our institution, where we tried to escalate the dose to 70, 80, even 90 Gy. And the initial results were quite promising but were somewhat biased by smaller tumors being treated to higher doses. And that can more easily, safely be achieved than if one treats a typical Stage IIIB or IIIC patient, like the patient that we just discussed, in whom it’s likely not safe to treat to such high doses.

This was followed by a large, randomized, Phase III trial, RTOG-0617, which compared 60 Gy versus 74 Gy, and showed that the higher-dose arm did not result in better overall survival. In fact, the high-dose arm was associated with worse survival and, even more surprisingly, even worse local control. Now, there’s many reasons one can speculate why that might be: technical reasons, quality control reasons, et cetera. One of the factors that came out was cardiac radiation dose, which was correlated with survival, which is not completely clear yet what the pathophysiology behind that is. But what became clear was that just going to a higher dose on a general prescription basis, meaning everybody should get 74 Gy no matter how large the tumor is or what it involves, is probably a little too simplistic of an approach and does not work. So 60 Gy remains the standard of care in terms of the radiation dose. We don’t know whether there is an optimal dose between 60 and 74 Gy, but 74 Gy was certainly worse than 60 Gy in RTOG-0617.

Similar efforts have been done on the medical oncology side with adding more chemotherapy either before concurrent chemoradiation or after concurrent chemoradiation for consolidation or maintenance, and those also have failed. They all showed increased toxicity but no improvement in survival.

DR LOVE: I think that RTOG trial also looked at cetuximab, the anti-EGFR antibody. I think it was during the chemoradiation, was it not?

DR RIMNER: Yep.

DR LOVE: And I guess in a way to try to sensitize it, or that seemed to fail also.

DR RIMNER: Yes, there were some early-phase data that suggested that cetuximab may have a role, and obviously EGFR plays a role in lung cancer. And that was really at a time where the whole mutational landscape was still being discovered and the driver mutations and the erlotinib and the TKI landscape really evolved. So I think it was an early idea. The trial started in 2006. So cetuximab was added as a third and fourth arm to compare each of the radiation dose arms with and without cetuximab. And that failed as well. That did not show any significant difference. It was also not a selected patient population for EGFR overexpression or anything like that.

DR LOVE: I don’t know if this man asked you for some ideas in terms of numbers, in terms of likelihood that he was going to develop recurrence in metastatic disease. If he did, or even if he didn’t, what numbers would you have given him?

DR RIMNER: I’m generally very cautious with numbers because it can be very misleading — not that numbers are not real, but when talking to patients I generally caution that a number is only an average number. It does not give a specific prognosis for an individual. If, let’s say, someone has a 90% chance of surviving but is in the unlucky 10%, that doesn’t help you that 90% of the other patients do well, because you were in the unlucky 10%. And the other way around: If your chance of doing well is only 10% but you are one of the lucky 10%, that does not affect you that 90% of people in your situation don’t do well.

But generally, the median survival is on the order of 2 to 3 years. That is, I think, consistent across more recent trials. And I still tell patients that the long-term chances that they will be completely without lung cancer recurrence were, if they really asked me numbers, on the order of 30% with more modern chemoradiation, and that’s really changed with the addition of adjuvant durvalumab, which you alluded to.

Role of RT in enhancing tumor immunogenicity

DR LOVE: So let’s get into that a little bit. And I was really curious about the relationship between radiation therapy and tumor immunogenicity and the old abscopal effect that people have always loved to talk about. Can you kind of go through that?

DR RIMNER: Yes. So I think at this point it’s clear that radiation does play a role in harnessing the immune system. It does play a role in changing the tumor microenvironment and allowing the immune system to infiltrate the tumors. It does play a role in exposing antigens to the immune system. And possibly or probably making immunotherapies more effective.

We’re in the process of figuring out in what way they are best combined, these therapies. And the durvalumab study was one of the first ones to really demonstrate a significant effect.

The abscopal effect was actually initially observed many decades ago but really got a lot of attention when this case report came from our institution and was published in The New England Journal, where a patient was treated with melanoma on anti-CTLA-4 therapy and did not respond. The patient developed a paraspinal lesion that required radiation treatment. And after being treated with radiation, the patient started to respond to the anti-CTLA-4 therapy that he hadn’t responded to before, and not only in the lesion that was treated with radiation but even in lesions that were not treated with radiation.

And so the idea is that the radiation changed something that made the tumor more recognized by the immune system, that the immune system could attack the tumor in other locations other than the irradiated lesion.

DR LOVE: Although what’s really interesting about your case is, obviously they got a checkpoint inhibitor, so it wasn’t — when I think about the abscopal effect, I don’t know if traditionally it was something where you spontaneously saw benefit outside the radiation field or in conjunction with therapy, but now you're talking about in conjunction with immunotherapy.

DR RIMNER: Right. That was really the interesting part of that case, that a patient who had stopped responding or not responded very well to immunotherapy, after the radiation therapy started responding. And what my colleagues did really nicely was, they had collected correlatives, and they could demonstrate that the activated T cells went up. The myeloid-derived suppressor cells went down. So they really could correlate a change in some of the components of the immune cells that correlated with a response, which was fascinating.

DR LOVE: Anything that we know in terms of the timing, the optimal timing of radiation and immunotherapy in terms of when it might be most synergistic?

DR RIMNER: That’s the Holy Grail question right now. There’s a lot of studies going on in that space. We don’t have a final answer yet. The most convincing data is in the adjuvant setting after concurrent chemoradiation in Stage III disease. That’s from the durvalumab study. That’s the most robust and prospective and largest study of its kind. But there are a lot of studies ongoing where we are trying to combine stereotactic radiation, for instance, with immunotherapy, either with immunotherapy given for a few cycles before the radiation, sort of emulating that case report that was presented, or doing radiation first followed by immunotherapy. All of those are unanswered questions, as well as what is the optimal radiation dose and fractionation to really maximize the immunotherapy response.

Avoiding safety concerns with the combination of CRT and immune checkpoint inhibitors

DR LOVE: So you cited the PACIFIC trial that looked at durvalumab in the consolidation setting in terms of, let’s say, radiation and immunotherapy synergy, and we’ll get into a little bit about what in the data makes you think it’s actually synergistic as opposed to, let’s just say, additive.

But before we even get into that, let me ask you, were you involved in the PACIFIC trial specifically? Do you put patients on it, or any involvement there?

DR RIMNER: No, we did not have it open. At our institution at the time we had a competing study, so, therefore, we did not have it open at the time.

DR LOVE: Okay. Can you kind of talk a little bit about the initial concerns about safety in the situation of using immunotherapy after chemoradiation, specifically in the lung?

DR RIMNER: Yes. Actually, not just in that setting, but in general, there was a lot of concern on the side of pharmaceutical industry, of combining radiation with checkpoint inhibitors for lung cancer, mostly because of the rare but severe pneumonitis that had been observed with checkpoint inhibitors alone, and that made many companies very gun shy to try and combine it with radiation.

Now, I think some of that has to do with just a lack of knowledge on how radiation works and what radiation pneumonitis looks like and how we can control the dose and how we can predict the risk of pneumonitis, which would allow for some control when combining 2 new modalities and trying to minimize the risk and avoiding safety issues with a new combination, which, obviously, the industry is concerned about. But what so far has come out is that there’s no clear increased risk, in terms of the risk of pneumonitis, when combining radiation and immunotherapy.

We and others have looked at this retrospectively just in patients that have been treated on various immune checkpoint inhibitor protocols and needed palliative radiation to the chest as part of their treatment, and we did not see any trace in risk of pneumonitis or other toxicities, intrathoracic toxicities, when we looked at these given at the same time or further apart in a sequential fashion.

Activity and tolerability of pembrolizumab after RT in patients with NSCLC on the Phase I KEYNOTE-001 trial

DR RIMNER: Similarly, there was a paper in Lancet Oncology published by my colleague Dr Shaverdian, who looked at one of the KEYNOTE studies and found that when radiation was given at a variable time point before pembrolizumab, there was no increase in toxicity and maybe an improvement in progression-free survival, which may be a synergy but may also just be an effect of radiation being effective in its own right.

And then lastly, on the PACIFIC trial, there was no clear signal that the durvalumab arm had a higher risk of severe pneumonitis compared to the placebo arm. Both were about 3% Grade 3 and higher pneumonitis — that was the rate in both arms. In the lower grades there was a slight numerical increase in the durvalumab arm, but it did not reach statistical significance.

DR LOVE: In these initial looks at patients who had radiation and checkpoint inhibitors, in addition to the fact that it seemed like it was safe, particularly as it relates to the lung, was there any evidence, even cases, that looked like there might be some synergy? Stories like your patient who didn’t respond and then responded — was anything like that picked up?

DR RIMNER: Not in our retrospective series, but it’s also really hard to reconstruct that in a retrospective fashion. By now there are multiple case reports in the literature.

I do believe that there is such a thing as an abscopal effect. I don’t think it happens at the frequency that it’s hyped as, given these very exciting case reports. We don’t understand yet what triggers an abscopal effect in some patients and why it does not happen in others. Those are all questions that we would love to have an answer to but have not fully understood yet.

PACIFIC trial: Efficacy and tolerability of durvalumab after CRT for patients with unresectable Stage III NSCLC

DR LOVE: So we’ve been talking about the PACIFIC trial. Can you kind of talk about specifically the patients that were focused on, where the trial was done and what they actually saw?

DR RIMNER: Mm-hmm. So these were all unresectable Stage III patients treated with concurrent chemoradiation. They accrued like a whirlwind within a year, more globally, to a large degree, in Asia. And it was a placebo-controlled, randomized trial. It was a 1:1 randomization, and half of the patients received adjuvant durvalumab after completion of concurrent chemoradiation, and the other half received placebo. And what they found was a 20% progression-free survival improvement from about 35% to 55% at 1 year, and last year it was also reported that this translated into a 10% overall survival benefit. And that’s really the biggest jump in survival outcomes that we have seen in Stage III lung cancer over several decades. And that’s why there was a lot of excitement. It’s been incorporated in the NCCN guidelines and really changed practice or standard practice for this patient population.

DR LOVE: Can you talk a little bit more — you’ve been referring to this issue of the tolerability, particularly as it relates to the potential for pneumonitis. Globally, what was seen, in general, in terms of how the patients tolerated durvalumab? This is for a year. It’s really adjuvant treatment. You don’t have specific disease you’re treating. You’ve already treated with chemoradiation therapy.

What was seen in general with tolerability? And what you, yourself, have observed in your own practice in terms of tolerability.

DR RIMNER: So generally it’s been reasonable in terms of tolerability. Although in the PACIFIC trial, there was a range during which you could start durvalumab from right at the end of chemoradiation to up to 6 weeks. They actually initially had only a 2-week window to start adjuvant durvalumab and then expanded it to 6 weeks to make it more practical and feasible.

There was no clear difference in terms of duration of adjuvant durvalumab given or timing of starting durvalumab with the risk of pneumonitis. They did observe a little bit of a higher risk in Asian patients for reasons that are not quite clear. And those are just hypothesis-generating observations that will have to be further looked into.

There was no clear correlation with radiation dose and risk of pneumonitis, but there was a relatively tight radiation range that was used anyway. So maybe there was just not enough spread of the dose to really get a statistical difference there.

DR LOVE: Do these patients typically have imaging after the chemoradiation and before they start durvalumab? And when you do image a patient at that point, what do you see?

DR RIMNER: Yes. So that’s a very controversial question. The PACIFIC trial actually enrolled patients after completion of concurrent chemoradiation and required only that patients did not progress at the time. In some ways that possibly biased the study a little bit towards excluding the worst players, the ones that progressed right after or even during chemoradiation, but the results are very similar to other trials, so I think they still hold up.

The problem with that is that there was no quality control on the radiation dose, no quality control or very minimal data collected on the chemotherapy, and so it’s not clear how these factor in. In a way, the study was still quite convincing, just because it was such a convincing result, but it was not by design but in a way a little bit lucky that had such a great result.

In terms of how do we image these patients, that’s a somewhat unsolved question. We have a consensus within our disease management team that we image a patient within 2 to 4 weeks from the end of radiation with a CT scan, and if there’s no clear, obvious disease progression, we offer them durvalumab if they’re candidates for durvalumab. But it’s definitely changed the way we follow these patients. Because traditionally we would only get imaging 3 months after concurrent chemoradiation, because in the beginning there’s a lot of inflammation and the tumor has certainly not responded fully to the treatment yet. It continues to respond over many months. So it’s definitely changed that approach.

DR LOVE: What do you see in the lung fields when you look at them after completion of radiation therapy?

DR RIMNER: Not too much. Some acute inflammation or inflammatory signs can be seen, but the dense fibrosis really develops a little bit later after radiation, in the 2- to 6-month range after the end of radiation, and that has not fully developed by the time we image them between concurrent chemoradiation and durvalumab.

Activity of durvalumab after CRT; diagnosis and management of pneumonitis associated with durvalumab/CRT

DR LOVE: So maybe we can hear a little bit more about what happened to your patient, because this 74-year-old man actually did receive durvalumab. So what happened there?

DR RIMNER: Yes. So the patient had a good response to concurrent chemoradiation. Did not progress. There was a partial response. That’s actually pretty good to be seen that soon after chemoradiation and, therefore, was offered consolidation durvalumab. After 5 months on durvalumab, he did develop some shortness of breath that was unclear whether that was radiation related or durvalumab related and needed a prolonged 8- to 10-week course of prednisone. But with that, he cleared it. It never got out of control. It was actually quite manageable. And he’s currently NED and being followed observantly.

DR LOVE: What was seen on imaging when he developed this shortness of breath?

DR RIMNER: Some fibrosis near the radiation field. Nothing uncommon. I don’t decide on whether a patient has pneumonitis, radiation pneumonitis, based on imaging only. It really remains a clinical diagnosis. Patients can have a lot of radiographic changes on their scan and no symptoms, and patients can have very severe symptoms and very minimal radiographic changes. So it’s really not a good marker by itself to go by whether something is radiation pneumonitis or not.

DR LOVE: So can you describe a scenario that, from your point of view, let’s say a patient is on durvalumab, where you’d be pretty sure it’s radiation pneumonitis and then a scenario where you’d be pretty sure it’s related to durvalumab. And what’s the difference in how you manage them?

DR RIMNER: We’re never really pretty sure. That’s the challenge with this, because there’s no diagnostic test to distinguish durvalumab-induced pneumonitis. We have clues. I think one of them is timing. If it is in the time frame that we think radiation pneumonitis could occur, somewhere between 2 and 6 months after the end of radiation, that would be a typical time course for radiation pneumonitis.

In order to answer that question, I do pay attention a little bit to the radiographic changes that we see on imaging. If it is in the radiation field, that points a little bit more towards being radiation related. If there were no changes at all, or if there was a very diffuse picture, I would be more concerned about an infection or durvalumab-related pneumonitis.

If there was bilateral inflammatory changes clearly outside of the radiation field, that would make us think more that it’s more durvalumab related. But there’s no real way to answer it.

Essentially, the only saving grace is that we treat them both pretty much the same. We manage them pretty much the same with prednisone, tapered slowly over 8 to 10 weeks. At least that’s the radiation pneumonitis regimen. Sometimes our colleagues in medical oncology taper a little bit faster. But it’s really in radiation oncology tapered based on the patient’s symptoms and not too quickly in order to avoid rebound symptoms.

DR LOVE: Do we know that corticosteroids are helpful in recovery from radiation pneumonitis?

DR RIMNER: Yes. So the symptomatic relief is quite quick, yes. So typically, we see symptomatic relief of shortness of breath and cough within 3 to 5 days after initiating prednisone. We typically start at 40 mg daily, and then we taper it, as I said, based on symptoms and make sure that symptoms don’t rebound.

Ongoing Phase II trial evaluating the activity and safety of nintedanib with prednisone for the treatment of radiation pneumonitis

DR RIMNER: There is a question on how long lasting these effects are and what the long-term damage to the lungs is in patients that have had pneumonitis. We’ve looked at our own data and found that about half of the patients that have had radiation pneumonitis have subsequent recurring pulmonary complications or exacerbations over the following 12 months. Because of that, we have a randomized trial open combining nintedanib with prednisone in order to try and avoid or minimize the long-term effects of a patient having experienced radiation pneumonitis. Essentially trying to prevent the inflammatory phase transitioning into the fibrotic phase that then has long-term implications on pulmonary functions. It’s a drug that has been approved for IPF, idiopathic pulmonary fibrosis, and has been very promising in that space.

DR LOVE: What is the drug?

DR RIMNER: Nintedanib. It’s a TKI.

DR LOVE: Nintedanib.

DR RIMNER: Yes.

DR LOVE: Yes, it’s a VEGF TKI?

DR RIMNER: Yep. It’s actually a multityrosine kinase inhibitor. It inhibits the VEGF access, the FGF access. So PDGF access, so multiple accesses. It’s not a very specific TKI. It’s not been too successful as an oncology drug, but it’s been actually really successful as a pulmonary drug.

DR LOVE: Really!

DR RIMNER: And is actually FDA approved for IPF.

DR LOVE: Wow! Hmm.

DR RIMNER: Yes.

DR LOVE: So you use it in patients who are having radiation pneumonitis?

DR RIMNER: Correct. So we have a prospective trial ongoing for patients who have developed radiation pneumonitis —

DR LOVE: Huh!

DR RIMNER: — and it’s a randomized study comparing nintedanib and prednisone versus prednisone alone, which is the standard of care.

DR LOVE: Wow! That is really fascinating. Did they get any TKI side effects? Is it that kind of dosing?

DR RIMNER: They can. It’s at 150 mg BID.

DR LOVE: Wow! Amazing. Huh!

DR RIMNER: And they can have some diarrhea. They can get some fatigue, some nausea. I have not seen any severe inflammatory reactions of internal organs, which have been described in these patients. Luckily, we have not observed that yet.

DR LOVE: That’s interesting. I know your colleague Matt Hellman, the medical oncologist. I remember he wrote a paper about pneumonitis related to the checkpoint inhibitors in people with lung cancer.

DR RIMNER: Right.

DR LOVE: Which is really tricky in general, not just in terms of locally advanced or in durvalumab. Has nintedanib been used for checkpoint inhibitor pneumonitis?

DR RIMNER: Not to my knowledge.

DR LOVE: Is there any reason to think it would work?

DR RIMNER: There’s no reason to think it wouldn’t work.

DR LOVE: Do they know why it works in IPF, in radiation pneumonitis?

DR RIMNER: We don’t know yet that it will work in radiation pneumonitis. That’s why we do the study.

DR LOVE: Got it. Okay.

DR RIMNER: But in IPF, it’s been demonstrated. There was a New England Journal article in 2012.

But I think it’s more of a question in the Stage IV setting for checkpoint inhibitor-induced pneumonitis, how to combine it with other drugs. That’s actually a question that is being examined in a few other trials. But as of now, it’s only clear that in a limited number of drugs it’s safe to combine it. But for many drugs, we don’t know yet whether it’s safe to combine it.

Incidence of pneumonitis with CRT alone and with the addition of durvalumab

DR LOVE: So given the fact then in a patient like your patient who has multiple other comorbidities, it may be difficult to really figure out why somebody’s having shortness of breath, but globally, considering everything, how often do you have to use corticosteroids following chemoradiation? Let’s just put the durvalumab aside. Just in general, baseline, how often do you use it?

DR RIMNER: The risk of Grade 2 or higher pneumonitis after standard concurrent chemoradiation is 15% in our hands. And in most institutions it’s somewhere between 15% and 20%, in that range.

DR LOVE: And is it higher when you give durvalumab?

DR RIMNER: Not according to the PACIFIC study. It was numerically higher at Grade 2, not even numerically higher at Grade 3 and higher. That was 3% for both arms. Grade 2 and higher was numerically a little bit higher in the durvalumab arm. But I don’t think we have treated enough patients yet to have our own experience.

We just submitted an abstract on our early experience with new durvalumab approach. And in that we did not see any clear increase in pneumonitis. But the numbers are still too small.

Survival outcomes and duration of consolidation therapy with durvalumab

DR LOVE: So you mentioned that maybe globally a patient like this maybe would have a 70% chance developing metastatic disease and dying of their lung cancer. In your own mind, do you see durvalumab — and, of course, we don’t know for sure yet — but do you see durvalumab as improving the cure rate?

DR RIMNER: So when you look at the survival curves, there is a tail, which is what makes us all very excited. We haven’t seen a tail like that for a long time. Obviously, we need longer follow-up, longer-term follow-up. The published survival data are all within the 1- to 2-year range. We don’t have 5-year data yet. So we’re all very hopeful that it will translate into a real cure or an increase in cure in these patients. The tail is at least suggesting that. But I think it’s a little premature to say that.

DR LOVE: Any data to suggest that my shortening the course of durvalumab, so instead of giving a year you end up giving 8 months or 4 months, any suggestion that it impairs the outcome in terms of efficacy?

DR RIMNER: No. We don’t know what the right answer is there. Actually, when you look at the PACIFIC trial, most patients did not receive all 12 months of durvalumab. It’s either because they had side effects or because of logistical issues or because they didn’t want to continue. And that is actually a debate for designing upcoming trials, what the right duration is. And the debate goes in both directions — some argue for shorter courses, because most patients received actually a shorter course, and that’s what the data is based on. Some argue that if it works well, why not continue beyond 1 year if a patient tolerates it well and has good disease control.

We don’t know the answer to that at this point. We just know that this study was done with 1 year of adjuvant or up to 1 year of adjuvant durvalumab. And that’s what we have at this point.

I think there will be multiple studies coming down the road with variable time frames of adjuvant immune checkpoint inhibition, and, hopefully, that will give us an answer. We are designing some ourselves.

DR LOVE: So thinking about what you’re saying, we know that, let’s say, 15% of these people are going to have steroid-requiring pneumonitis-related radiation therapy, and yet you may not know whether it’s that or durvalumab. So I assume these people are going to have the durvalumab held? Do you ever restart it?

DR RIMNER: So I make that decision in conjunction with my medical oncology colleagues. I think it depends on the clinical picture and the severity. Generally if someone has really had a severe about of pneumonitis, we’ll be cautious in just restarting it if we really think it was drug related.

We have 1 patient who developed pneumonitis after just a single dose of atezolizumab, and the patient really wanted to go back on it, but we were quite cautious about doing that. So we don’t know what the right answer is. I think it can be tried cautiously again, but there certainly is a risk.

Ongoing evaluation of immune checkpoint inhibitors with concurrent RT with or without chemotherapy

DR LOVE: So I’m not aware there’s another Phase III trial, at least reported, looking at consolidation with a checkpoint inhibitor. But can you talk about what other research has been done looking at checkpoint inhibition in the postchemoradiation situation?

DR RIMNER: In the postchemoradiation situation, that is the one study that is published. What people are doing now is trying to move up durvalumab or other checkpoint inhibition into the concurrent setting. So trying to start it with the initiation of chemoradiation or replacing chemotherapy with immune checkpoint inhibition. We have a study that will open soon on radiation therapy and durvalumab in lieu of chemotherapy. And this is for the poor KPS patients who are not even candidates for concurrent chemoradiation because, actually, concurrent chemoradiation is only for the fittest of the unresectable patients. But there’s a large patient population that has to be treated with either radiation alone or sequential chemoradiation, because it would be too aggressive and too risky to treat them with concurrent chemoradiation, even before the advent of durvalumab. And so those patients have an even worse prognosis with an even higher rate of distant metastases and disease progression. And these patients are really in need of an improved outcome.

So we are starting a trial where we do durvalumab concurrently with radiation without chemotherapy, getting rid of chemotherapy, in that patient population. And we’re hopeful to see a progression-free survival benefit there.

DR LOVE: There have been studies — I know they’re not randomized that I know about, but there have been, I think, Phase II studies looking at other checkpoint inhibitors in patients getting pembrolizumab, for example. What do we know about other checkpoint inhibitors?

DR RIMNER: No. On the one hand, we think of them all having this similar mechanism of action. On the other hand, there are definitely differences observed in response, also in the neoadjuvant setting, as well as in the tolerability. So these are open questions. We don’t know yet how they stack up against each other.

Activity of immune checkpoint inhibitors in the neoadjuvant setting

DR LOVE: What about the use of neoadjuvant checkpoint inhibitors prior to radiation therapy? There’s been some really exciting work out of your institution, Jamie Chaft, et al, looking at — I was really stunned. I mean, they gave these people — I think they were resectable patients that they gave 2 doses of a checkpoint inhibitor. Were you involved with that?

DR RIMNER: Not directly. Obviously, that’s a medical oncology study. But I work very closely with Jamie Chaft on multiple other projects.

DR LOVE: Can you kind of talk about from your point of view what they saw there and what you thought about it?

DR RIMNER: Yes. They definitely saw a remarkable number of complete or near-complete responses at pathologic examination, more than we typically anticipate with chemotherapy. However, the numbers are small, and the endpoint of these studies were safety first, not an efficacy endpoint.

So while we are very excited about these numbers and these indications, we have to be cautious and will need to be followed up with larger-scale studies. But still, I think it’s very intriguing to see the kind of responses that we see in the neoadjuvant setting with, as you said, just very few doses of immune checkpoint inhibition, which, then again, relates to the question, how many doses do we need to give even in the adjuvant setting to get an immune response? This suggests, the neoadjuvant studies suggest that you get a response quite early and quite robustly.

From a radiation perspective, there was no concurrent radiation in the preoperative setting. And if anything, it would decrease the number of patients needing postoperative radiation therapy if they really clear their mediastinum completely, or at least that is an open question that needs to be addressed. We don’t know how to integrate port in that scenario.

Selection of the optimal dose and technique of RT for locally advanced NSCLC

DR LOVE: Any other research initiatives going on with locally advanced lung cancer that involve checkpoint inhibitors, or anything else that you’re excited about?

DR RIMNER: So there are other studies looking at different doses and fractionations of radiation with immune checkpoint inhibition. Within the NRG oncology group is a hypofractionated design with 4 Gy x 15 fractions comparing that to the standard 2 Gy x 30 fractions. Those are some questions that are being explored.

There are several trials in the early-stage setting following SBRT for Stage I or II lung cancer, where adjuvant immune checkpoint inhibition is being added in order to prevent disease progression. Because even in those patients, there’s about a 25% to 30% risk of disease progression, even in patients who present with a small 1-cm or 1.5-cm lung nodule without nodal involvement. And even in that patient population, we need to do better.

DR LOVE: I’m sure you see a lot of patients who’ve been seen by other doctors, who’ve been treated by other radiation oncologists. Any — I’m not going to say “mistakes,” but things that you see people doing that maybe you don’t do or that you think could be done better?

DR RIMNER: I still see a fair amount of older technique being used.

DR LOVE: Really?

DR RIMNER: 3D conformal radiation with cone downs when I see patients coming from elsewhere. I still see some people pushing the radiation dose beyond 60 Gy. Some people using smaller doses per fraction and dragging it out loner, which also, I think, is not advisable. I think it’s quite clear that the standard should be 2 Gy x 30, at least in the United States.

So those are some of the things that I still observe. Stereotactic radiation still has not been rolled out in all places for early-stage lung cancer. It’s still being underutilized in the oligometastatic setting. Those are 2 other areas where we can do better.

I think that the last point is maybe just a difference in how we practice. We just, as I said earlier, use relatively little preoperative chemoradiation, and to a degree that’s institutional preference. There’s not a lot of data to say that you can absolutely not do that or that’s absolutely a worse approach. It’s just not been our approach at MSKCC.

DR LOVE: You’d mentioned a couple of times now treating oligomets. What are some of the sites that you treat and the sites that you’re most successful with?

DR RIMNER: Yes. So in our department, we actually have subspecialized services for that.

DR LOVE: Wow.

DR RIMNER: We have a service for metastatic disease. We have a spine service for spine SBRT led Dr Yamada. We have a CNS team that treats all the brain SRS. So we really split it up amongst ourselves. I, obviously, do the lung SBRT, also for oligometastatic disease from other primary histologies that has spread to the lung. So I treat some of these, but not all of these patients.

DR LOVE: Any comments on treating adrenal mets? How often do you do it? What kind of success do you have with it?

DR RIMNER: We do, and I have treated them myself as well. Sometimes our GI colleagues treat some of those.

They can be treated with image-guided or stereotactic techniques. We usually treat them in 3 to 5 treatments. I think it’s important in that area to pay attention to the bowel very closely, because that is probably the one organ that can see some severe toxicity if one is not careful. So it’s important to delineate the bowel very carefully and make sure that that stays within clear and strict constraints to avoid perforations or bleeding or severe toxicities. But it can be very successfully used and save the patient from having to undergo an adrenalectomy.

Case: A woman in her early 70s with unresectable Stage IIIB adenocarcinoma of the lung and a KRAS mutation receives CRT followed by durvalumab

DR LOVE: So let’s finish out hearing about maybe a couple more of your cases. How about this 72-year-old lady? This is an interesting case.

DR RIMNER: That was another patient with unresectable Stage IIIB adenocarcinoma. Her disease was quite extensive, with a T4N3N0 tumor encasing the left pulmonary artery. It was KRAS mutant, and there was a 20% PD-L1 expression. She was treated with standard concurrent chemoradiation with carboplatin and pemetrexed and 60 Gy standard dose and 30 fractions.

DR LOVE: Can I just ask, did the encasement of the pulmonary artery in any way affect the way you approached the case?

DR RIMNER: Not from a radiation perspective. But if she didn’t have multiple nodal stations involved, that would have been the make or break between what might have been considered resectable disease. But that is a decision that we always do in conjunction with the surgeon. We don’t decide for the surgeon what is resectable, just like they don’t decide for us what can be radiated or not.

DR LOVE: So what happened there?

DR RIMNER: So she completed chemoradiation. She did well. And then a few weeks after recovery from the chemoradiation, she started on durvalumab. She was one of the unfortunate women who developed an infection, pretty severe pneumonia with sepsis, and even an empyema that had to be drained. But she recovered from that, and she’s currently NED and just being monitored observantly.

DR LOVE: When did she develop this infection?

DR RIMNER: About 4 months after chemoradiation.

DR LOVE: So she was on the durvalumab at that point?

DR RIMNER: She had gotten 4 doses, yes. So 8 weeks.

DR LOVE: What was your interpretation of what happened? Do you think it was a complication of durvalumab or had nothing to do with it?

DR RIMNER: It’s hard to say. These things can happen, even with chemoradiation. They don’t happen frequently. But I think it points to the need to have a multidisciplinary team who knows how to also address complications. Even with standard chemoradiation there’s a 2% to 3% mortality risk actually in most studies. This is not an easy treatment. It’s not an easy clinical scenario to deal with. Lung cancer is an aggressive disease that can have a lot of ramifications, and patients are sick. So it’s hard to say whether it was the durvalumab itself or it would have happened even without the durvalumab.

Clinical experience with the use of durvalumab after CRT

DR LOVE: I mean, as you mentioned, chemoradiation is difficult to go through. So these people are maybe not in the same condition they are when they start. At the point that they’re starting durvalumab, what have you observed in terms of quality-of-life impact on top of that of the durvalumab? Do you think it adds fatigue or any quality-of-life issues at all?

DR RIMNER: Yes, it does. I think overall, generally speaking, the immune checkpoint inhibitors have been tolerated quite well. But when patients develop side effects on them, they can be quite severe. So it’s often either you do really well and you have very little side effects, or when you have them it can be quite severe. But in terms of quality of life, the other factor that really affects patients is having to come in every 2 weeks. So there’s different regimens that are being explored now every 4 weeks or — that’s another open question: How frequently do you have to deliver it? But coming in every 2 weeks for an indefinite amount of time or a year’s time is a long time. So that’s definitely a quality-of-life factor for patients.

DR LOVE: How many patients do you think you’ve had who received durvalumab in postconsolidation?

DR RIMNER: About 40 at our institution.

DR LOVE: Really? Wow!

DR RIMNER: Over the last year since it became standard.

DR LOVE: Hmm. And when a patient asks you, based on your own experience and what you’ve read from the data, what is the likelihood that somebody is just going to cruise through the year without any problems?

DR RIMNER: I would say about 60%, 70% of patients do well without major issues. And another 30% have some issues that we can address and get them through. Maybe another 5% or 10% with more severe side effects that require hospitalization or so.

DR LOVE: I was talking to a doc who’s an oncology fellow — she’s the chief fellow at North Carolina — and I was just thinking about the fact that I don't know if people realize who haven’t been in the field for a long time how frustrating it was with locally advanced lung cancer. I mean, so many things were tried and really nothing, zero worked at all until this, really. I mean, that was the way I was seeing it.

DR RIMNER: Yes. We have not made really any progress since 2 or 3 decades at least. I mean, there’s an old study that looked at radiation at 40 rads back then, 40, 50 and 60 rads, and that showed a dose response. So 60 rads became the standard, and we’re still at 60 Gy.

So yes, from just a pure dosing perspective, not much has happened other than improvement in technique and trying to minimize side effects. But until the arrival of adjuvant durvalumab, in terms of disease control and survival, we haven’t moved the needle very much until this trial.

Case: A woman in her mid-50s with Stage III adenocarcinoma of the lung and an EGFR mutation receives adjuvant osimertinib

DR LOVE: So let’s finish out hearing about your 55-year-old lady here. One of the things about her that I think is interesting, and we haven’t talked about yet, is the issue of patients with targetable mutations. You mentioned your other 2 patients didn’t, but this patient looks like they had an EGFR tumor mutation. So what happened with her?

DR RIMNER: Right. So she was treated with neoadjuvant atezolizumab on a protocol. Then she underwent surgery per protocol. She had N2 involvement and received adjuvant chemotherapy because of that.

DR LOVE: Could I just ask, just out of curiosity, how did she do on the atezolizumab neoadjuvantly?

DR RIMNER: She did well.

DR LOVE: Did she respond?

DR RIMNER: Although she was one of the few that didn’t respond.

DR LOVE: Did not respond. Interesting.

DR RIMNER: So even though, as we said earlier, many patients responded really well. She was one of the people who did not have a good response. And, therefore, was treated with standard chemotherapy and radiation therapy in the adjuvant setting in a sequential fashion.

And then the question was, because she had an EGFR mutation, should she go on adjuvant TKI or not? And that’s a controversial question that is posed to our medical oncology colleagues. But as you know, there were trials investigating adjuvant TKI, and they had a progression-free survival benefit but did not translate into an overall survival benefit. And so believers do offer it and nonbelievers don’t offer it.

DR LOVE: Your pulmonary oncologists actually are, I think, the most proactive, I think, about using adjuvant TKIs in this situation. Most people don’t do it outside a trial setting. But it seems like it’s not uncommon for your group to do it.

DR RIMNER: No. I mean, we believe that if you have a genetic driver and you have a drug that works for that driver mutation that there’s a benefit to that. Our institution was one of the first to really move that field forward. So yes, we’re believers.

DR LOVE: Yes. It’s so controversial. It comes up all over oncology. You never know what to do. We just had the SOLO-1 trial looking at a PARP inhibitor in ovarian cancer. Everybody knew it was going to be positive, but nobody did it until they saw the data. But your group’s maybe a little bit more proactive.

Can you talk a little bit about how you designed her ports and the treatment you gave her in the adjuvant setting after she had surgery?

DR RIMNER: Yes. That was a very standard port field. The right level 4 lymph node was involved as well as the subcarinal node and several right hilar nodes. So we covered the right level 4, the subcarinal space and the right hilum with the radiation field.

DR LOVE: So this also brings up the issue of what you do with people with targetable mutations who aren’t resectable. And there are a lot of things that have been discussed. One thing maybe we ought to comment on is, there were patients with targetable mutations in the PACIFIC trial. And it looked like they benefited as well. I’m kind of curious, was that your take? And are you giving durvalumab to — for example, this patient had had chemoradiation and was not resectable?

DR RIMNER: So in those patients our medical oncology colleagues will weigh the risks and balances between that, putting them on durvalumab versus a TKI in the adjuvant setting. We now routinely obtain the PD-L1 expression. They’ll look at what comorbidities they have. Do they have contraindications for a TKI or for an immunotherapy? And then they will decide based on those factors.

DR LOVE: That’s really interesting, because in the rest of the country, they’re kind of deciding about durvalumab or not, because, like, the TKIs are off the table, because most people aren’t doing it. But your people kind of choose. Do they ever do both? Would they give a TKI and during the check — the durvalumab?

DR RIMNER: I have not observed them do that, no.

DR LOVE: Yes, that seems like it might be a little bit out of bounds there.

Increased RT precision with the merging of MRI and a linear accelerator

DR LOVE: Anything that we haven't talked about today that you want to comment on? Any other thing that you talk about with radiation oncologists as it relates to lung cancer that we haven’t talked about?

DR RIMNER: Something that happens in the radiation oncology community is the MR-linear accelerator. So that’s maybe a new tool that is becoming a little bit more available — MR-guided therapy that is particularly helpful in areas that have targets within soft tissues, where CT has limitations in terms of imaging capabilities and really identifying the target. So we have an MR simulator. We are getting an MR-linear accelerator within this year. And we are planning to do trials on that.

In the thorax it’s particularly challenging, because MR is very sensitive to motion, degradation of the images. But at the same time, if we can get it to work, which is what we’re working towards, it would allow monitoring of the tumor location in real time during the treatment, because you could actually see the tumor move as the patient breathes on the table. And that would provide an unprecedented level of precision if we can make that work.

And in the mediastinal and perihilar areas, it would like be most beneficial as well, because those are the areas that are not well seen on, let’s say, a cone beam CT, which can visualize a nodule in the peripheral lung quite well, but the mediastinum or the esophagus or the mediastinal structures are much harder to see on cone beam CTs.

Case: A woman in her mid-60s, a never smoker, with locally advanced, unresectable adenocarcinoma of the lung and an EGFR exon 18 tumor mutation receives CRT followed by consolidation durvalumab

DR LANGER: A 64-year-old previously healthy never smoker, mild cough, presented about a year ago — she was diffident, but someone suggested getting an x-ray, and lo and behold, there was a vague shadow in the right upper lobe. Her exam was completely normal. She underwent a CT scan, which showed a fairly central 3.5-cm right upper lobe mass that seemed to be kissing, if not invading, the mediastinum. It also showed a somewhat juicy 2-cm pretracheal lymph node. Of course, the latter was not evident on the plain film.

So she underwent a bronchoscopy and endobronchial ultrasound, which confirmed adenocarcinoma in the N2 node. Special stains were positive for TTF-1. And she underwent the standard workup for anybody with putative locally advanced non-small cell. She had a PET scan, which fortunately showed no evidence of extrathoracic tumor, and a brain MRI was negative.

And you could argue that’s all the workup you need, but inevitably in this day and age where frequently they’re not always doing PD-L1 testing and molecular testing. And, in fact, her PD-L1 came back completely negative. And her molecular markers, unsurprisingly, since she was a never smoker, proved positive for EGFR mutation. It was actually not one of the standard ones. It was an atypical but still actionable mutation, exon 18.

Clinical significance and prognostic relevance of microsatellite instability testing in the management of lung cancer

DR LANGER: And all other markers were negative, including TMB and MSI, were either negative or low.

DR LOVE: Now, just to clarify for our audience, TMB and MSI?

DR LANGER: TMB is tumor mutation burden. Certainly in advanced disease, higher mutation burden is associated with greater sensitivity to checkpoint inhibitors, particularly the combination of ipi/nivo. Its implications in locally advanced are completely unclear. And, of course, very recently pembro has a stand-alone indication that’s disease agnostic but based on microsatellite instability. So genomic instability, which is a bit more common in colorectal cancer, but, in fact, can be seen in just about any malignancy.

DR LOVE: Just out of curiosity, not to get too far off, but I’ve heard people say that MSI testing now should be done in anyone with a metastatic solid tumor. I’ve heard other people say anybody with metastatic adenocarcinoma. What’s Penn’s policy about that?

DR LANGER: Definitely metastatic adenocarcinoma. I think it’s still relatively rare in squamous, so you could make a blanket statement that except for PD-L1 testing, there’s not a good strong indication to do molecular testing in squamous. So if you get a never smoker or a remote former smoker, regardless of histology I would still do full molecular testing. And most of the send-out reports, there are many companies that are doing this now, will include MSI as part of their assays.

Risk of recurrence after concurrent CRT for patients with Stage III NSCLC

DR LOVE: So you started her on concurrent chemoradiation therapy. Which regimen did you utilize?

DR LANGER: I used a tried and true one I’ve been using now for over 20 years, actually probably closer to 25 years: weekly paclitaxel and carbo. She was offered enrollment in a Phase III trial comparing photon beam standard radiation to proton beam but declined that. There were some logistical issues that precluded her going on that trial. And she finished a full course. She got 66 Gy.

We could argue whether 60 Gy is the standard or whether we should go higher. Certainly pushing the doses up to 74 Gy or higher has not panned out. We had a major Phase III study, 0167, that actually showed a survival decrement with higher doses using conventional photon radiation.

And she had a modest response. I wouldn’t call it a PR, but at least some shrinkage. The node clearly shrank. There were no other signs of tumor. Certainly no evidence of disease progression.

DR LOVE: So before you go on, I’m kind of curious. I don’t know whether she asked you this question, but if she had, or if a patient were to ask you who had this clinical situation, at the completion of the chemoradiation that she had, what would be your estimate for the chances she is going to have recurrent disease in the future?

DR LANGER: So up until PACIFIC, I would have guesstimated somewhere between a 65% and 75% chance of having a recurrence, either locoregionally or distantly. And the brain is often a sanctuary site, which is rather unfortunate. We’ll discuss PACIFIC a little bit more, but those numbers have improved, clearly, at least broadly.

Now, she’s probably in a better prognostic group. She is female. She is a never smoker. Her tumor burden, not mutation burden but actual tumor burden, is relatively low. She’s got a smaller primary and a single apparent node. And she’s tolerated treatment. So the numbers I quoted are really the broad numbers, but I would be a bit more optimistic about her chances.

Improvement in progression-free and overall survival with the addition of consolidation durvalumab after CRT for patients with Stage III NSCLC on the PACIFIC trial

DR LOVE: And just out of curiosity, what would you estimate her risk is if she were able to receive durvalumab? Assuming she was, let’s say, a typical patient.

DR LANGER: That is a big debate, and that was actually a dilemma we wrestled with. There was no PD-L1 positivity. She did have an EGFR mutation. And you actually analyzed the second publication of PACIFIC. That group, the group that did not have PD-L1 expression, did not seem to have a survival benefit. In fact, the hazard ratio’s in the wrong direction. It was about 1.3, although the confidence intervals were overlapped in unity.

So on the face of it, one could perhaps make an argument that this could be deleterious. It may not be advisable. But you’ve got to remember, this was a post-hoc exploratory analysis. The overall trial had well over 700 patients. The group that had zero expression, it was a small minority. It was probably about 150, 160 overall. And well over 40% of patients did not have testing for PD-L1, so I’m not sure I’m going to hang my hat on that. And at least the overall study was strikingly, frankly, astoundingly positive, both for PFS and OS.

So we actually had this conversation. This individual is extremely well informed. She certainly knew her way around medical articles. And we had a frank debate — folks in this day and age would call shared decision-making. And we mutually opted to proceed. I’d have to state flat out that in people with the PD-L1-positive tumors, I embrace PACIFIC with enthusiasm. In those who are negative, there’s certainly a degree of ambivalence.

DR LOVE: So in the majority of patients who do have some PD-L1 expression, if you just look at it globally, and let’s just put aside the EGFR mutation for a second, you said that globally you’re looking at 65%, 75% risk of relapse, maybe a little bit less in this lady, how much do you see, would you estimate, did you tell her — do you think that would decrease?

DR LANGER: For all comers, at least on PACIFIC, it’s about a 10% to 11% absolute improvement in survival, at least at 2 years. Now, we do have maturing data, and we have a 2-year survival rate of about 66% versus 55%. And it should be noted that the majority of recurrences in locally advanced usually occur in the first 2 to 3 years. So I’m sure the overall survival would be a lot less than 66%, but we’re talking a reasonable chance of 40%, 50%. I mean, these are unprecedented numbers. It could be lower, but at least the trajectory of the curves looks fairly promising.

DR LOVE: I guess the other kind of way to look at data in these kinds of situations in addition to absolute changes is relative risk reduction. What globally, in your own mind, do you visualize is a relative risk reduction and risk for recurrence and death?

DR LANGER: So I think at least the metric I use now in locally advanced and, frankly, in advanced disease, I want to see a maximum hazard ratio of 0.75, 0.80, and the PACIFIC data at least fall within that range. The PFS data are a bit more impressive. But ultimately, at the end of the day it’s the OS data that’ll, I think, govern usage.

We’ve gone 25, 30 years without a single positive trial in locally advanced non-small cell. And it’s not for lack of trying. And here, in one fell swoop we have a strikingly positive trial, and I have to admit that I was one of the skeptics.

DR LOVE: No, I remember when it first came out and you were saying, wow, that’s a big bump in progression-free survival, but let’s hold out and see about survival — but it seemed like a lot of people, even you, I think, jumped on board even before you saw the survival data, because it was such a dramatic impact on relapse.

DR LANGER: Not quite with the enthusiasm that some of my colleagues had. I mean, some immediately jumped on board as soon as the study came out, and certainly when the approval came out. I was a little bit more hesitant, although I have to confess, probably offered it to the majority of folks who were eligible for durvalumab, even before the survival data came out. But there was still that element of doubt. And I don’t know if you want me to go through it, but there are still a lot of criticisms for this trial.

Role of immune checkpoint inhibition in the treatment of locally advanced NSCLC with an EGFR tumor mutation

DR LOVE: Before we get off into that, let’s just finish out with her case, because there are a couple of other things I wanted to bring up about her, specifically before we get into the paper.

So one other question I was thinking about is in general, up until now, or up until this came out, were you giving postchemoradiation consolidation? Because you gave paclitaxel/carboplatin. Did you give it afterwards?

DR LANGER: Yes, I did. I generally gave 2 cycles of pac/carbo, either every 3 weeks or what I call the Belani regimen, weekly, days 1, 8 and 15 every month for 2 cycles. And that had really become my standard, probably for the past 15, 18 years.

DR LOVE: But in this lady, did you give her that before she started the durvalumab?

DR LANGER: No, I did not. The clinical trial, at least, stipulated the initiation of the checkpoint inhibitor within 2 to 6 weeks of completion of the chemoradiation without concurrent chemo, and since that study construct, that schema actually generated the data we’ve observed in the 2 New England Journal papers. I felt fairly strongly I wasn’t going to deviate from the way it was given.

DR LOVE: So this patient, another issue was that this patient had an activating tumor mutation, EGFR mutation, and there’s been debate about whether checkpoint inhibitors are helpful in patients with these mutations. But this was one trial, the PACIFIC trial, where they actually looked at that, and it kind of looked like those patients benefited. Was that your take?

DR LANGER: The numbers are really tiny. You go back to the original paper, it was about 42, 45 patients out of well over 700. Maybe a slight trend toward benefit. The confidence intervals were really wide, so they overlapped unity, and you have to go to the second paper into the supplements to actually find the survival outcomes for the EGFR mutants. And they don’t even have a forest plot. The numbers are way too small.

So I think we’re in unchartered territory, and again, for the same reason that I’d argue to at least consider durvalumab in PD-L1-negative, I’d make the same argument, in this setting at least, for EGFR mutant. I am absolutely certain had this patient had metastatic disease, I would not offer a PD-L1 inhibitor. Even if the PD-L1 had been positive, in the face of an EGFR activating mutation.

DR LOVE: Right, and there, I think, people are using targeted therapy before even thinking about checkpoint inhibitor.

DR LANGER: Absolutely.

Perspective on the use of EGFR tyrosine kinase inhibitors in the adjuvant or neoadjuvant setting for patients with locally advanced NSCLC and EGFR tumor mutations

DR LOVE: Another aspect of this, in terms of the EGFR tumor mutation, is, I believe that at one point there was an Intergroup trial looking at patients with locally advanced disease with activating tumor mutations and using targeted therapy before chemoradiation to shrink it down. And I always thought that was a great idea, but I guess the trial ended.

DR LANGER: Died. Lack of accrual. We think that mutations, or at least molecular aberrancies, are perhaps a little bit less common in earlier-stage disease than locally advanced. And that trial certainly did not accrue. It was the ALLIANCE trials, both ALLIANCE and the then RTOG, now NRG group, together comparing erlotinib to placebo for 3 months followed by definitive treatment. Actually, it was erlotinib followed by definitive treatment versus definitive treatment. And for the ALK-positive group, a similar design of crizotinib followed by definitive treatment versus standard definitive treatment.

And there was just no saving that trial. I had problems with that trial. I think the design sounds wonderful, but the TKIs only work as long as you give them. And 3 months may be insufficient. And for that matter, I have difficulty with the ongoing adjuvant trials, which restrict its use to 2 years. We know then in one of the trials done in resectable disease, the SELECT trial, as soon as they stopped the treatment at 2 years, there was a sudden drop in progression-free survival.

So I’m worried about the use of TKIs in this setting, at least for the majority of patients with locally advanced non-small cell. Probably 70% to 80% have no activating mutation. And there the only agent that’s been proven to benefit is checkpoint inhibitor, in this case durvalumab.

DR LOVE: So I don’t want to get too far off on this, but what about the patient who has bulky disease, the idea of maybe shrinking it down short term before chemoradiation? Is that something you ever do?

DR LANGER: Not typically. There have been studies in the precheckpoint era where we compared induction therapy followed by concurrent versus concurrent up front, and it really didn’t show any added benefit. Plus, you’re delaying the definitive curative modality, which is still the radiation or chemoradiation combination. I will do it in select patients if the radiation oncologist tells me the field is just too big and they’re just going to cause major toxicity and I really need a debulking. Then we’ll certainly initiate it. And then in certain frail patients who may not be up to concurrent chemoradiation we may choose that approach, either chemotherapy first followed by radiation or, if they are in better shape at that point, concurrent chemoradiation.

DR LOVE: And I guess also, as long as you brought it up, we should just briefly touch on where we are with adjuvant use of TKIs in these people with targetable lesions. You referred to that. And I know the trials are out there, either in the adjuvant early setting or even in the locally advanced setting. And I guess the one thing that you were mentioning about maybe the need of using long-term therapy is that it seems like now that you have osimertinib out there, that’s going to be a lot more achievable than it was with the prior generation of TKIs in terms of tolerability. Is that your take? That most patients will be able to get through long-term osimertinib, a couple years, maybe even more?

DR LANGER: I think so, but ironically, the ongoing, at least, cooperative group prospective randomized Phase III trial, the ALCHEMIST trial, is using the older generation of drugs. They were initiated in another era, so erlotinib versus placebo, now observation for up to 2 years in the EGFR mutants and then crizotinib initially versus placebo, now observation for up to 2 years in the ALK-positive.

I think if we had redesigned those studies now, it would be osimertinib versus observation, and, of course, alectinib for the ALK-positive group. There are separate prospective trials that are assessing osimertinib in the EGFR mutant in the adjuvant setting. And all of these trials, I believe, call for a minimum of 2 years of treatment.

Initial diagnostic workup and disease management for patients with locally advanced NSCLC

DR LOVE: Another question I have is, you described what happened in terms of how this patient was worked up and managed, particularly diagnostically. I’m kind of curious what your take is as you see patients coming in who’ve been managed elsewhere, for second opinions, whether there are any, let’s say, misperceptions or things that people are doing out there, whether it’s in the community or not, surgeons, rad oncs, that maybe are different from what you do.

DR LANGER: I think there’s a tendency to err on the side of molecular testing even though we haven’t proven in resectable or locally advanced disease that the institution of any of the TKIs really makes a difference in terms of survival. I consider it a research question. I certainly wouldn’t fault someone for testing. It’s good to know those answers in case the patient relapses, and then you know what to do at that point.

I still see this tendency — 2 problems: number 1, to assume that if a node’s present, it’s positive. We’ve seen plenty of patients where there appears to be a fairly juicy node on CT scan, even positive node on PET. We biopsy it, and it’s completely negative. It’s infiltrated with lymphocytes. You should not deny the patient an opportunity for curative resection simply on the basis of a CT scan or PET. The pathologic workup is absolutely essential.

And then the second issue that comes up: The patient has locally advanced disease. They start chemoradiation, and a multidisciplinary conference convenes and they decide, let’s see what happens at 45 Gy. Have they responded sufficiently? Maybe we can consider surgery. That decision needs to be made up front. If it’s going to be trimodality, you should know that a priori before you initiate the combined modality approach and not make that decision midway through the treatment. If you interrupt chemoradiation for any amount of time, a week, 2 weeks, you are reducing that patient’s survival chances.

RTOG-1308: An ongoing Phase III trial of photon versus proton CRT for patients with inoperable Stage II to Stage IIIB NSCLC

DR LOVE: So I wanted to get your take on the issue of checkpoint inhibitors in locally advanced disease, but 1 other question, again about this patient. I was intrigued by the fact that she was offered a trial of proton versus photon therapy. That’s really interesting. Can you talk a little bit more about the trial? And also what your take is on proton therapy and lung cancer.

DR LANGER: I think protons certainly have a potential role, particularly for larger central tumors. Remember, this is a way of really regulating the radiation dose within tissue depth. When you’re using standard photons, you get the same dose through and through. The same dose that hits the skin hits adjacent normal lung, hits the tumor and then hits adjacent lung going back out. Whereas with the protons, you can regulate that dose. You can actually concentrate that dose at the level of the tumor and then have an abrupt drop off. So at least in theory, protons can limit or reduce the collateral damage that happens to adjacent normal tissue.

And there’re 2 upshots of that: number 1, potentially less toxicity. And in selected patients, and this doesn’t really apply here, you can envision folks with small tumors where you really may be able to increase the radiation dose safely beyond standard doses — beyond 60 or 66 Gy.

So this particular study is a head-to-head comparison. It was initiated through the then RTOG, now NRG cooperative group. The only comparison is the nature of the radiation. It’s the same chemo. All these folks have unresectable locally advanced.

And I believe the doses are more or less the same. So it’s a true comparison of different technologies.

And with all the hype that proton therapy gets, you’d think, oh, my goodness, it must be better. It has to be better. But we have no proof. At least in locally advanced disease, we have yet to actually show prospective randomized data that documents an enhanced outcome with protons. And I think for that reason this trial is critically necessary.

DR LOVE: So I’m guessing you have access to proton therapy off trial?

DR LANGER: Correct.

Role of proton beam RT in the treatment of locally advanced NSCLC

DR LOVE: So I’m kind of curious, I heard this story about this patient, and she had the travel issue, but I’m kind of curious how people respond to that randomization. I’m going to guess a lot of people would rather just get treated with protons.

DR LANGER: Or their insurance denies it and they get photons. It’s a very tough trial to accrue, unfortunately. And I personally have equipoise. As a medical oncologist, I don’t really have a preferred approach. And I think the question is important enough that it needs to be addressed in a Phase III trial. Remember, we’re talking about very expensive technology that requires a cyclotron — it requires equipment that’s not standardly available.

DR LOVE: Yes, and update me on that in terms of the amount of space that the current proton, you know, setups have. I know initially they were big spaces. Is that still the case?

DR LANGER: I believe it’s either 2 or 3 football fields —

DR LOVE: That’s big.

DR LANGER: — to actually have sufficient space for the cyclotron. And, fortunately, where I work, at the University of Pennsylvania, the setting is above the former footprint of the Philadelphia Convention Center. And that area was big enough to accommodate this. The 1 downside, it’s very close to a river, the Schuylkill River. And unfortunately if it rains heavily and there’s flooding, there’s a real risk that this entire complex, which, of course, is underground —

DR LOVE: Wow.

DR LANGER: — could get flooded. But it’s a little bit unusual. Many proton centers are actually remote from the main cancer centers. The patients have to travel back and forth. Ours is explicitly on site. The patients just go up an elevator to get their chemo.

DR LOVE: I thought that now they’re moving towards smaller spaces being required, but I don’t know too much about that.

DR LANGER: Apparently yes, but I don’t know enough about the more recent technology to comment on it intelligently. At least traditionally it was a huge amount of space.

DR LOVE: Right now, if the patient has insurance, in what situations do you encourage them to do — is it a different experience for them? Do they — same time?

DR LANGER: No. Not really. A little bit more set-up time, but the actual treatments don’t take that much longer. So from the patient perspective, it feels very similar.

DR LOVE: Are there any clinical situations where you say, “Hey, you know, if your insurance covers this, maybe we ought to do this.”

DR LANGER: We frequently end up doing that. And we have a separate in-house study to accommodate those patients who frankly decline going on the randomized trial.

DR LOVE: That’s interesting.

Rationale for the combination of RT and immune checkpoint inhibitors

DR LOVE: So let’s get into this issue of checkpoint inhibitors in terms of locally advanced disease — what we know about it. Not just the PACIFIC trial, but other agents that are being looked at, other trials that are being looked at.

Maybe you can begin, though — I was interested in some of the background for this whole idea of using checkpoint inhibitors near or close to radiation therapy. I was talking with Dr Rimner about the old abscopal effect and whether that’s for real. But can you talk from your own point of view about the rationale for this kind of strategy?

DR LANGER: I think there’s at least 2 to 3 rationales: (1) We can see upregulation of PD-L1, which is the target of the checkpoints, particularly the interaction between T cells and tumor. So at least in theory, it can potentiate the capacity of the checkpoints to fight tumors. We also see release of tumor antigen and inflammatory cytokines with any sort of radiation. For that matter, you see that with chemo as well. And that, in turn, will stimulate the immune system.

So at a very simple level, there is potential synergy between radiation, chemo and the checkpoint inhibitors. And certainly that has been borne out in advanced disease, where we have several studies now in treatment-naïve non-small cell, but squamous and nonsquamous showing a survival benefit for checkpoint inhibitors plus platinum-based chemo versus chemo alone. So whether or not we believe this is going to happen, at least clinically, prospectively Level 1 data shows that it’s, in fact, translated into a survival benefit.

Risk of pneumonitis with CRT

DR LOVE: So as these trials were getting underway, I know another major issue was the issue of toxicity tolerability, and specifically lung cancer and specifically in patients who might have coexisting comorbidities, the question of whether there was going to be pneumonitis. Can you talk a little bit about, first of all, what the baseline is in terms of what you see when you use chemoradiation, including in older patients in terms of risk of pneumonitis and the time period that it rolls out over?

DR LANGER: So usually pneumonitis, if it’s going to occur, will be anywhere from 6 weeks to about 6 months after the conclusion of the chemoradiation. So it’s not an immediate side effect the way esophagitis is. Esophagitis typically occurs 3, 4, 5 weeks into treatment. It peaks at the end of treatment and then improves over the ensuing months. This is a delayed issue.

Pneumonitis is actually fairly common, but Grade 3 is not. So Grade 1 or higher rates are 20%, 30%, 40%, but Grade 3 or higher is usually single digits. And I think one of the amazing and frankly unexpected observations from the PACIFIC trial was that there was virtually no increase in pneumonitis. It was about 4.5% overall. There’s a separate prospective Phase II trial of pembrolizumab in the same setting, where the Grade 3 and higher pneumonitis rate was 6.5%. it was maybe marginally higher. But I would still argue at acceptable levels.

You’ve got to remember, though, to get onto these trials, patients had to have gone through the chemoradiation. They had to be fit enough. Certainly if they had active pneumonitis at the time they’re being assessed, they probably were not enrolled. So some of this may be a self-fulfilling prophesy.

Design and results of the Phase III PACIFIC trial of durvalumab after CRT for unresectable Stage III NSCLC

DR LOVE: Maybe we can talk a little bit about the data that’s out there, beginning with the PACIFIC trial. If you could just kind of provide a broad overview of what you think the key points were in the design of the trial and then go through the key points in terms of the results.

DR LANGER: So PACIFIC was a 2:1 randomization postdefinitive chemoradiation with durvalumab for up to a year versus placebo. Patients had to have locally advanced disease. They had to have gotten at least 2 cycles of a platinum-based chemo regimen and a fairly low minimum dose of radiation. I think most of us would at a minimum give 60 Gy. In this particular trial, it was 54 Gy. So some would argue that perhaps the chemoradiation was, in some cases, suboptimal.

But it was a slice of clinical reality. It was a global trial, and it really tried to accommodate clinical treatment as it existed throughout the world.

The results were, to be blunt, were fairly shocking. There was a 3-fold increase in progression-free survival. The control arm was 5.6 months. In the investigational arm, the durvalumab arm was 16.8 months. So you do the math. That’s unprecedented. We’ve not see that before in locally advanced disease. And when you looked at sites of progression across the board, whether it was lung, extracranial, metastatic sites or brain, for that matter, it was about a 40% to 50% reduction in the incidence of recurrence or metastases.

So many folks, based on that, assumed that survival would be better. And I thought it would be, but I hadn’t seen the data yet. But the presentation in October of 2018, by Scott Antonia, I think, put all that to rest. And, in fact, there was this major PFS benefit translated into an overall survival benefit of about 10% or 11% absolute increase at 2 years, with a clear-cut significant p-value.

There are still some flaws to the trial. The trial did not mandate PET imaging at the get-go. In North America, at least, a PET is a standard part of the workup. PETs are used as part of simulations. And we know that when we do a PET, even in patients who ostensibly have locally advanced disease, 10%, 15%, 20% of these patients will have otherwise occult metastases that are detected by PET.

So those folks actually go onto the trial. And think about it: two thirds of those folks got durva, and one third got placebo. Of course the checkpoint’s going to do better than nothing.

So I was concerned that that might have helped contribute to the survival advantage, and to this date we have no data on the percentage that had PET at baseline simply because that wasn’t collected as part of the case report forms.

The other issue is, the control arm probably underperformed historic controls. Median PFS was 5.6 months. The only comparable trial was the vaccine trial, called the START trial, where the PFS and the placebo control arm was about 8, 8 and a half months. So not a major difference, but still some difference. Nevertheless, the data certainly stand then, and it’s completely changed our therapeutic approach in locally advanced disease.

In North America it’s approved across the board, regardless of PD-L1 levels. But intriguingly in the EU, the approval is restricted to PD-L1-positive at 1% or higher. And I think that’s partly borne out of a need to contain cost.

DR LOVE: What about other toxicity? I should mention, I guess, your patient elected to be treated, and she’s currently being treated. She’s at 9 cycles? Or where is she now?

DR LANGER: At least when I last saw her, which was about 2 months ago. She’s roughly about halfway through treatment, tolerating it extraordinarily well.

Monitoring and management of the toxicities associated with immune checkpoint inhibitors

DR LOVE: And what other issues arise in this setting and other settings when you give checkpoint inhibitors? What are some of the common toxicity issues? And what types of screening do you do? Do you do thyroid tests preventatively? How do you approach monitoring for toxicity?

DR LANGER: You basically take an organ and add “itis,” and you can get any toxicity that’s caused by these checkpoint inhibitors. Obviously the biggest concern in the setting of locally advanced disease where radiation’s been used to the chest is pneumonitis. But those rates have been a lot lower, as I mentioned, than we anticipated. But you still need to be on the lookout for other inflammatory sequelae.

And I routinely check thyroid functions, pretty much every time I get a scan, so at least every 3 to 4 cycles. Sometimes I just do it every cycle, just so I don’t forget to do it. It’s not difficult. The TSH is an easy test to add to the general blood work.

And I would guesstimate, in my experience, and this isn’t specific to durva, but to checkpoint inhibitors in general, I’m seeing at least 15% to 20% incidence of hypothyroidism, predominantly hypothyroidism. One case of hyperthyroidism.

We see adrenal insufficiency, so when a patient develops unexpected fatigue or lassitude, it’s important to do a cortrosyn stimulation test. And we sometimes see hypogonadism. Any part of the pituitary adrenal axis can be affected. And I’ve had some patients, men in particular, have astoundingly low testosterone levels. And that’s very easy to remedy. And it’s not just a matter of libido or virility. These folks are extremely fatigued. So all of these, hypothyroidism, hypoadrenalism, hypogonad, can translate into just general nonspecific symptoms of lassitude.

I’ve seen other oddball toxicity. I’ve seen uveitis. I’ve seen nephritis. So again, a simple history and basic lab work will detect these problems.

DR LOVE: Can you imagine the number of people I’ve interviewed about checkpoint inhibitors the last few years? And I’ve never heard anybody say hypogonadism. Never heard it.

DR LANGER: Let me be the first.

DR LOVE: That is really amazing. Wow!

DR LANGER: You look for it, you’ll find it. Again, how often is it definitely due to checkpoint inhibitors? If you don’t have baseline you don’t know, but I’ve detected it.

DR LOVE: Also something very treat —

DR LANGER: It’s documented. It’s definitely documented.

DR LOVE: I mean, something very treatable.

DR LANGER: Absolutely.

DR LOVE: And yet never heard it. So wow, that is fascinating. Very interesting. So this patient, nothing whatsoever. Zero. No toxicity. Nothing whatsoever.

DR LANGER: Remarkably well. Doing quite well. Very pleased. Very gratified. Her scans continue to show evolution of radiation change. It’s unclear if she has any viable tumor at this point.

Use of durvalumab for patients with preexisting autoimmune disease and for transplant recipients

DR LOVE: I was going to ask you whether in a completely asymptomatic patient if there are any things that you can see on imaging in the lung that would get you to not start durvalumab. You know, from the radiation therapy. My understanding is, you kind of always see something. Is there anything that, in an asymptomatic patient, would have you turn back?

DR LANGER: I think if the patient starts out before treatment, before the chemoradiation, with preexisting interstitial lung disease, that’s the kind of patient I’d have second thoughts about enrolling, either on a clinical trial or using durvalumab empirically. So you really need to look at the initial entry criteria of the PACIFIC trial and see who is allowed on.

I’m a little bit less strict about folks with prior autoimmune disease. If they had a remote history of, say, rheumatoid arthritis or Crohn’s disease, again, we’ll have the same shared decision-making discussion. For the most part, I’ve plunged ahead.

DR LOVE: As you as you’re bringing that up, what about people with prior transplants? For example, renal transplants?

DR LANGER: Definitely not heart or liver. You’ve only got one of those. Kidney is, again, a discussion. I have done it once. You run the risk of rejecting the allograft, but at least with kidneys you can go to dialysis. You can’t easily get a new heart or liver.

DR LOVE: And, of course, I think it’s really a lot different, though, in the metastatic than locally advanced setting, where you have some people who are going to be cured without it, just with chemoradiation, but...

DR LANGER: My threshold would definitely be higher in locally advanced. I think I would hold off probably and just revert to my standard treatment.

Results from the Phase II Hoosier Cancer Research Network LUN14-179 trial of consolidation pembrolizumab after CRT for unresectable Stage III NSCLC

DR LOVE: So you referred to the pembro single-arm initiative. I’m curious — if you could talk a little bit about that. What do we know about pembro right now?

DR LANGER: We know that it behaves very similarly to durvalumab. There was the Hoosier Oncology Group trial that took folks that were enrolled, the same sorts of patients that were enrolled on PACIFIC, who had completed chemoradiation and gave them essentially a year’s worth of pembro in the same setting. Here, I think ultimately they will be able to generate some preexisting PET data, since the trial was done in North America. Though that’s not yet been forthcoming.

But the final outcomes are remarkably similar. Only about 40% of patients were able to complete the full year. So that’s an important point. Both in the PACIFIC trial and in the Hoosier Oncology Group trial, the majority of folks did not make it the full year. The median number of cycles, I believe, in the Hoosier Oncology Group trial, was about 13, so about 9 months total. There was an incremental response rate in both the PACIFIC trial and in the HOG trial, the Hoosier Oncology Group trial.

DR LOVE: There’s no incremental, because there was no comparison in Hoosier Group comparing to historical.

DR LANGER: That’s true, but in PACIFIC there was, and clearly the continued further response was higher in the durva arm. And it seemed to match the data for durva.

Progression-free survival, again, was in the 15-, 16-month range. So pretty close to what was seen in PACIFIC. And 1- and 2-year survival numbers, almost identical.

So it remains to be seen. I personally don’t think one checkpoint inhibitor is necessarily going to be better than any other in this setting. I think the crucial question, the question that we’re asking at Penn and Robert Wood Johnson in Ohio and the folks at MD Anderson are asking is, can you give it concurrently with chemoradiation, then follow as consolidation? We have data that shows at least so far it’s safe. We don’t have any long-term efficacy data.

Ongoing investigation of anti-PD-1/PD-L1 immune checkpoint inhibitors for locally advanced disease

DR LANGER: And the folks at MD Anderson have looked at atezo in the same setting and again have shown relative safety. No obvious major increase in pulmonary toxicity, and 1- and 2-year survival rates that are at least as good, maybe a tad better, than we’ve seen with the PACIFIC trial. But it’s going to take a Phase III trial to truly define the role of concurrent checkpoint inhibitors and chemoradiation.

But yes. It’s an embarrassment of riches, but you know what, it’s better to have more choices and options.

DR LOVE: Absolutely. Absolutely. Is there a Phase III trial of pembro or one of the other things cooking? Or are we going to be with durvalumab data for a while?

DR LANGER: I think we’re going to be with durvalumab for a while, but there are several trials cooking, so stay tuned. The problem is, it’s going to take a while for these trials to read out. So at least for the foreseeable future, at least, I would guess, for the next year or two into 2020, durva is going to be the standard.

DR LOVE: So I want to get into some of your other cases, but 1 other toxicity issue I was just curious about, because I’ve heard that a fair number of people on checkpoint inhibitors have dermatologic problems, supposedly low grade. Did this woman have any dermatologic problems? And what do you see?

DR LANGER: She’s escaped dermatologic problems. But I do see a fair amount of rash, usually torso, sometimes face. Probably about 20%, 25%, generally low grade, treatable with topical steroids or with diphenhydramine. A fair number of folks get diffuse pruritus without rash. So again, one of the “itises.” So basically probably a symptom of very dry skin. The rash is a bit different from what we’ve seen with tyrosine kinase inhibitors. It’s not the classical acneiform rash. We don’t see onychonycia or digital fissuring. And it usually dissipates over time.

Case: A man in his mid-80s, a former heavy smoker with multiple comorbidities, is diagnosed with locally advanced squamous cell carcinoma of the lung with a high PD-L1 TPS (tumor proportion score)

DR LOVE: So let’s go through some of your other cases, sort of variations of this theme. I was curious whether you had many patients, because I had heard that you see, on occasion, older frail patients who really aren’t chemo candidates, but you want to try to palliate them with radiation therapy. I asked if you had any patients. You said not many, but you came up with this 86-year-old man. What about him?

DR LANGER: So this was a fellow who was clearly too frail for concurrent chemoradiation. And it’s always a bit of a dilemma how to address these folks. He was a former heavy smoker, and I mean a really heavy smoker, 3 packs per day for over 60 years. If you do the math, that’s 180 pack-years. Many comorbidities, as you’d expect with somebody that smoked that much. Coronary artery disease. He had a defibrillator. He had low-grade renal insufficiency with a creatinine of about 2, 2.5. Pretty severe COPD.

Presented with cough and shortness of breath and a transient episode of hemoptysis. And initially his primary doctors just thought it was a COPD exacerbation. But he ended up on x-ray having a fairly large left upper lobe mass. And you can imagine this type of patient. They arrive in clinic. They’re in a wheelchair. They’re on oxygen. He was just on 2 liters. They’re unable to get up on the exam table. You have to do a wheelchair exam. That sort of patient is not a candidate for combined modality therapy.

Diffuse wheezing and rhonchi. Generously he was a PS2. He was probably closer to a PS3.

So big mass, 7 centimeters, invading the left mainstem bronchus. He was able to tolerate a bronch EBUS, although even that was questionable, and that showed squamous cell. And, of course, the procedure itself was complicated. He ended up having transient respiratory insufficiency. He had to go to the ICU. He required a nonrebreather for about 48 hours and then high-flow O2, and he was ultimately discharged on a higher rate of oxygen flow, on 4 liters.

So even the diagnostic workup in this population can be hazardous. So the question was what to do. He was having symptoms. He was clearly more short of breath from this mass. It was invading the main stem bronchus. It was causing hemoptysis.

So he got essentially a palliative course of radiation, 30 Gy in 10 fracs — about a 2-week course. And a month later he improved. He was back down to 2 liters. His shortness of breath was better. The hemoptysis had died down. Basically, we returned him to his prediagnostic baseline, which was still all his comorbidities. And the mass had shrunk. It hadn’t disappeared, but it was down to about 3 to 4 cm. And we look back, and lo and behold, his PD-L1 was positive at 80%.

DR LOVE: Eighty percent.

DR LANGER: Yes.

DR LOVE: What’s his current situation?

DR LANGER: So the question was whether to watch and wait or start pembro. Even though he did not have metastatic disease, I had no delusions that we had given him curative therapy. We have not. We have given him really a palliative course of therapy. He’s improved, and we are currently still debating with the patient. He’s a relatively recent patient. We’ve outlined the potential toxicity.

Still a bit leery about giving pembro to somebody with so much baseline respiratory insufficiency. Did not have interstitial lung disease, but he has fairly severe COPD. So any sort of respiratory compromise could just put him off the brink. He could end up in the ICU and on a ventilator. But he is right now leaning toward it. We’ve not yet started it.

Use of liquid biopsies to detect targetable tumor mutations in patients with lung cancer

DR LOVE: So a couple questions about these kinds of situations. I assume that you can’t make a diagnosis of cancer by liquid biopsy?

DR LANGER: Not yet, but I think that day is coming. So if you have a high suspicion, for some reason the tumor’s inaccessible and you do a liquid biopsy and you find somatic mutations that are specific to cancer, for instance, EGFR mutation, you’ve got a de facto diagnosis. I mean, you’ve got a mass. You’ve got a liquid biopsy that shows molecular abnormalities that are specific for cancer. Obviously if you see a BRCA1, that could be a germline mutation, but a somatic mutation could very well be specific for cancer.

So the gold standard, of course, is still tissue or cytologic biopsy. But I foresee a time when we’re going to substitute liquid biopsy.

In small cell you can actually find circulating tumor cells. So there you can truly see the cancer in the blood in extensive-stage disease. But this sort of person with squamous cell might have had a high TMB but could have had other reasons for that, too.

DR LOVE: What about KRAS? Do you see that in people without cancer?

DR LANGER: I’m not 100% sure. I think you can see it in white cells.

DR LOVE: Hmm.

DR LANGER: But generally not. But again, that’s much more common in nonsquamous. It’s the most common mutation that exists, about 25% to 35%. But sadly, it’s not yet actionable. We’re clearly trying. So I guess if somebody had a cancer and had KRAS, had p53, had other mutations, you could make a circumstantial diagnosis, but I’d still want the tissue.

DR LOVE: So I’m curious whether when you saw the PD-L1 level of 80% you thought to yourself, “Hmm, if I’d known that at the beginning, maybe I would have tried it before even giving him radiation therapy.”

DR LANGER: Possibly, yes.

DR LOVE: I mean, what’s the chance you would actually have a good response with the PD-L1 level of 80%?

DR LANGER: Fifty percent or higher. The response rates are 40% to 50%.

DR LOVE: Yes. Interesting.

DR LANGER: So a pretty good chance actually.

DR LOVE: And same thing as we were talking about before. Of course him, he was a heavy smoker, but if you had a very, very frail patient for other reasons, or age or whatever, who had an EGFR mutation like this —

DR LANGER: Oh, for sure I would’ve have given him a TKI. With the heavy smoking history, that wasn’t likely.

DR LOVE: Right.

DR LANGER: And particularly with the histology. But in other scenarios, absolutely. He would have gotten osimertinib.

Case: A man in his mid-50s, a former smoker, is diagnosed with Stage IIIA mixed adenosquamous carcinoma of the lung with TTF-1 and p40 tumor mutations

DR LOVE: You mentioned before this issue of surgery in people with Stage III disease. Let’s hear about your 55-year-old man.

DR LANGER: Sure. So I have a gentleman. This is actually sort of a composite patient.

Former smoker, pack per day, 20 years, right inguinal herniorrhaphy, was found to have a right lower lobe mass, and that’s typically how curative lung cancer is found. Five centimeters on x-ray. On subsequent CT scan, it looked larger. It was about 62 x 58 mm. The scan was otherwise negative.

Had a transthoracic biopsy that showed adenocarcinoma. It was positive for TTF1 and p40, so right there, suspicion of a mixed histologic picture. PD-L1 was 30%, and the molecular and fusion panels were completely negative — so EGFR, ALK, all negative.

PET scan showed intense uptake in the right lower lobe but was negative in the mediastinum and hilum. And the brain MRI showed nonspecific vascular changes. There was no evidence of mets.

You could make an argument in the absence of any uptake on both CT scan and PET to just go ahead and do the surgery and do a lymph node dissection at the time of surgery. But this was a big primary. This wasn’t a 2- or 3-cm primary. This was 6 centimeters, so he actually underwent a bronch EBUS and, lo and behold, at level 4 on the right, ipsilateral to the tumor, same histology, a mixed adenosquamous.

So he was no longer an N0 but an N2, a T3N2, minimum IIIA. The new staging system he may actually be worse, but it’s still somebody that you would approach with combined modality.

And he was begun on concurrent chemo with etoposide/platinum on a protocol with proton beam to 54 Gy and then had surgical resection. And final path showed a major pathologic response. The tumor itself was only about half the size, but less than 10% was viable, and major pathologic response is defined by at least 90% eradication of viable tumor. And probably as important, or even more important, all the lymph nodes were negative. So he had no obvious residual nodal disease. So he was downstaged, effectively, to a T2aN0.

And so the question always comes up in this sort of patient, do you give them additional adjuvant treatment? Should you give them more chemo? Remember, he only got 2 cycles of etoposide/platinum. Do you put him on a regimen that would be specific for the squamous or nonsquamous element? And is there a role for durvalumab in this situation? And the answer to all 3 questions is completely unknown.

DR LOVE: So I’m kind of curious what you actually did, though.

DR LANGER: This guy was beat up, was not eager to get more treatment, even though I was leaning in favor of giving him more chemo, figuring that he really hadn’t had a full course of adjuvant treatment. But there again, I have no proof. There was mostly adeno left, so I probably would have given him pem/platinum if he was at all willing.

There is no proven role for durvalumab here. Now, you could extrapolate. You could argue, in locally advanced unresectable, it shows a survival advantage. It’s gotta show a survival advantage in resected disease. We have zero data. And with this degree of radiation in the preop setting, I think for me personally it’s a bridge too far.

DR LOVE: Hmm. Interesting. Are there situations in patients who have surgery where you would consider durvalumab?

DR LANGER: Possibly in patients who do not have R0 resection, so we knew that they had residual tumor. We gave them concurrent chemoradiation. Or gross residual, I’d probably go ahead with chemoradiation then assume at best they’re a de facto Stage III with residual tumor and give them durva at that point. If they’ve had a full resection, the highest nodes are negative, the margins are clear, I just don’t quite have the comfort level yet.

Perspective on the use of anti-PD-1/PD-L1 antibodies as neoadjuvant therapy for patients with NSCLC

DR LOVE: So I’m kind of curious about the issue of neoadjuvant checkpoint inhibitors. I believe there are trials in locally advanced disease that are incorporating that strategy, and I know there’s data in the resectable situation because it was already published, and I think I talked to the Memorial people as they were doing it, at least that was with 1 trial. And it’s really interesting. So can you tell me what we know right now about neoadjuvant checkpoint inhibitors?

DR LANGER: It’s pretty exciting. The Memorial folks — and they weren’t doing this on their own, they were doing it with other institutions — took resectable patients and gave them a few cycles of nivolumab up front. And here again, we see this sort of desynchrony between radiographic response and pathologic response. Forty percent or more had major pathologic responses, but the actual objective radiographic response was only about 19% or 20%.

And some of these folks had hardly any viable tumor left. And this was just with a couple of doses of checkpoint inhibitor. No radiation. No chemo. Did not seem to exacerbate the perioperative morbidity or affect resectability. And, of course, it’s attractive.

You’re giving systemic treatment up front, and the main reason these folks die is because of systemic metastasis. So you’re starting the systemic therapy immediately, in an intact vasculature and healthier patients, so they’re much more likely to tolerate the treatment.

The downside is, you’re still delaying the definitive curative modality. Last I checked, surgery cures a lot more folks than any adjuvant or neoadjuvant treatment.

More intriguingly, I think, is this trial from Spain by Provencio and colleagues. It’s called the NADIM trial, N-A-D-I-M. And they actually added nivo to standard chemo — to pac/carbo regimen — and specifically targeted folks with IIIA disease. So these are not Stage Is or IIs, but folks with a little bit more locally resectable IIIA, but still locally advanced.

And their response rates were astounding. The radiographic response rate was something like 70%. The major pathologic response rates of greater than 90% eradication of tumor, less than 10% viability, was 80%. It was an astounding number. And the path CR rate was close to 60%. I’ve never seen data of that sort.

Certainly with chemotherapy alone, the best data I’ve ever seen was an old study by Boetticher and colleagues back in the early aughts looking at docetaxel and platinum, where the path CR rate was something like 20% or 25%. So it was literally double.

So needless to say, there are multiple prospective Phase III trials comparing chemo alone versus plus a checkpoint inhibitor in the neoadjuvant setting. And I think those trials will probably unfurl themselves in the next 18, 24 months, maybe sooner if they’re really positive.

DR LOVE: I don’t know why, but for some reason it’s just really striking when you hear — I guess we’ve been associating checkpoint inhibitors with metastatic disease so much it’s kind of hard to get oriented towards — but if you think about it, first-line checkpoint inhibitors shrink tumors, no doubt about it.

I was interviewing Matt Hellmann from Memorial. He had one of those patients on the trials, a woman in her 70s, resectable lesion. Gave her 2 doses — I think it was nivo. They went in there. They didn’t find any viable tumor. Like you said, some necrotic stuff. So he didn’t know what to do about adjuvant chemo. So he didn’t give it to her, but I guess you don’t really know what to do in that situation.

DR LANGER: If it was smaller than 3 or 4 cm, I probably wouldn’t have given it either. But if the baseline tumor was bigger than 4 cm, I probably would have offered the adjuvant chemo. I don’t feel confident enough just in the immunotherapy alone at this point to simply rely on that.

What’s really interesting is, retrospectively, major pathologic response seems to correlate with better outcome, as you’d guess. And we certainly have seen this in breast cancer. But we’ve never proven it in lung cancer. It’s all retrospective data. So these trials that are ongoing will either prove or disprove that notion.

DR LOVE: I was mentioning before about bladder cancer and the 5 checkpoint inhibitors. They have neoadjuvant data there. And again, I think, like, 40%, 50% path CRs. Like, that is bladder cancer. For that matter, the other thing that’s really wild about bladder, I don’t know if you know about that is, they give it to people with noninvasive bladder who’re resistant to BCG. And it seems to cause benefit, which is really wild.

DR LANGER: Comparatively speaking, I’d rather do a few cycles of a checkpoint inhibitor than get my bladder instilled repeatedly with BCG or mitomycin or other therapies.

DR LOVE: Also in terms of neoadjuvant therapy, getting cisplatin, some of the bladder regimens are pretty rough, and —

DR LANGER: That’s for sure.

DR LOVE: — so if that works out, it’s going to be a lot better for patients.

Case: A man in his early 70s, a current smoker, with adenosquamous carcinoma of the lung and a KRAS mutation receives SBRT

DR LOVE: I asked if you had any patients who had primary radiation therapy to primary lung lesions. I’m just kind of curious how that plays out in your practice, since we have a radiation oncology audience here. Maybe we can talk about your 70-year-old patient.

DR LANGER: So this was a gentleman from West Philly, 30 pack-year smoker, multiple comorbidities, including COPD, diabetes, hypertension, CAD. Again, a herniorrhaphy, found to have an incidental left lower lobe mass on chest film. CT scan confirmed a 3.5-cm lesion. And also suggested perhaps some hilar adenopathy. At least a hilar node was enlarged.

He had a core biopsy of the left lower lobe mass that showed a mixed adenosquamous. Intriguingly, his KRAS mutation was positive. And because we had some suspicion that he had central nodal disease, he underwent a bronch EBUS. And that was completely negative. So at least clinically he was T2N0.

DR LOVE: What kind of shape was he in when you kind of look at him functionally?

DR LANGER: Certainly good enough for radiation. Not good enough for surgery. His FEV1 was really marginal. It was good enough to exist without oxygen, but he was the kind of patient where if you operated he’d almost definitely end up on the supplemental O2.

And his remaining workup was completely negative. So this sort of patient now is standardly treated with stereotactic radiation. And he completed it in 5 fractions — Monday, Wednesday, Friday, Monday, Wednesday.

And at 6 and 12 months, he’s doing fine. Tumor’s decreased. He has the typical post-SRS radiation changes. Sometimes even in this setting, you can sometimes see clinical pneumonitis, although it’s pretty rare.

And we’re just following him. I mean, he has so many other comorbidities that you’d be hard pressed to put him through a major thoracic operation.

By the same token, his tumor was smaller than 4 centimeters. There was no nodal involvement. In my mind, no indication for adjuvant chemo or adjuvant checkpoint inhibitors.

DR LOVE: From your point of view, do you think there’s generally efficacy equivalence between stereotactic and surgery?

DR LANGER: My gut says yes. My brain says I don’t know. Certainly in an unresectable patient, you have no choice. It’s the standard approach. But in resectable or marginally resectable, that is not truly known. There have been a number of Phase III efforts that have tried to compare surgical resection to stereotactic radiation. They’ve all failed. They lacked accrual.

There is one ongoing effort, and I think it’s very important. It’s being done through the VA. It’s called the VALOR trial, and I think Drew Moghanaki is the principal investigator. In the interest of full disclosure, I’m on the data safety monitoring committee that is trying to replicate that trial. And so far, it’s accruing. The VA population tends to be different from the general public. It remains to be seen if it’s going to accrue adequately, but it’s definitely ahead of the other trials. And I personally think it’s an extraordinarily important question, particularly in these folks with marginal resectability.

Optimal approach to RT for patients with locally advanced NSCLC

DR LOVE: Any other comments specifically relevant to radiation oncologists? Any new developments in lung cancer that you think are particularly relevant to radiation oncologists? Any suggestions for improvement based on interactions, things you don’t like they do, if there’s any?

DR LANGER: I think most of them have learned their lessons, as have the medical oncologists, that you don’t tackle any of these patients without a multidisciplinary tumor board.

Anybody who’s going to be even considered for combined modality, you’ve got to sit down, a priori, with the medical oncologist, with the surgeons if you think there’s any potential role for surgery, frankly, with the pulmonologist. We have interventional pulmonologists at our institution who are critical to making sure these patients get through their treatment. And that multidisciplinary approach is super critical.

Everett Vokes has said this, and I will reiterate it: The best form of radiation in locally advanced disease is chemoradiation. Combined modality therapy is still the standard. And now, of course, we have the prospect of trimodality if we consider checkpoint inhibitors yet another modality. I think we’ve got to be sensitized to the notion of continued close surveillance after the chemoradiation to make sure horrible side effects aren’t occurring, particularly pneumonitis.

So far, the clinical trials say the rates aren’t very high. Personally, my experience with pneumonitis is a little bit higher than I’ve seen objectively on the clinical trials. And again, I’m probably treating a broader population, some of whom might not have been candidates for those trials.

And then finally, I think we have to abandon this notion that more is better. Certainly, the RTOG-0617 showed with conventional radiation that 74 Gy not only was not better than 60 Gy, it was worse. We had higher toxicities and lower survival.

So we’ve got to be very careful and deliberative about how the radiation is given, and it really does require a major therapeutic alliance with the other modalities, and, of course, with their physicist. And, I think, for the most part, radiation oncologists who are used to treating locally advanced non-small cell have all this down pat. But those lessons need to keep going.

DR LOVE: You mentioned that trial looking at higher dose. I actually asked Dr Rimner about it, because I’d heard about it lately. And I was asking him, I’ll ask you if you have any hypothesis about why patients did worse with higher dose. Did they have more toxicity, or was it something else?

DR LANGER: Some more toxicity. I think the V5 to the level of radiation that went to the heart was higher, and there may have been some delayed cardiopulmonary toxicities that may or may not have been attributed to the combined modality. And there were also some inadvertent imbalances in the baseline demographics of the study that actually favored the lower-dose arm.

But the bottom line is, just an empiric escalation in the dose does not benefit patients. It seems to cause more mayhem than benefit. But a full analysis still needs to be done. I think one of the other theories was that perhaps they had a rougher time getting all the chemo in, although I’m not sure that’s panned out.

DR LOVE: Anything else you want to add to what you’ve said today?

DR LANGER: Just it’s imperative we get folks on clinical trials, and the checkpoint inhibitors are here to stay. I still want to see an analysis based on PET imaging. I’ve yet to see that.

And, importantly, in this regard with the PACIFIC trial, we need to see the patterns of recurrence. We’ve seen the sites, but if there’s a lung recurrence, is that happening in field? Is it regional? Is it out of the field? I don’t have any sense of that, and I think that may help determine how we go forward with future treatments.