Management of Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) — Helena Yu, MD

DR YU: Hello, everyone. Thanks for having me. This is Helena Yu. I am a thoracic medical oncologist at MSK (Memorial Sloan Kettering) in New York, and I am happy to be here to talk about the Year in Review: Management of Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer.

So the first study that we want to go over is Dr Jänne et al that was the final overall survival data for the FLAURA2 study, which was osimertinib plus chemotherapy in EGFR-mutant advanced non-small cell lung cancer.

So this, if you guys remember, is the first-line study where we looked at osimertinib, which is a third-generation EGFR TKI and our previous standard of care, and compared it to osimertinib plus chemotherapy, platinum plus pemetrexed, which is typically our second-line standard of care treatment, so combining those 2 lines up front. We had already learned earlier that there was a PFS benefit, a progression-free survival benefit, with the addition of chemotherapy of about 9 months, but now we see the survival benefit, so again almost a 10-month improvement in overall survival with combining those 2 active therapies as first-line therapy.

In terms of kind of conclusions or key takeaways from this study, I think, as I mentioned, it confirmed the progression-free survival benefit. I think some people adopted this regimen of chemotherapy plus osimertinib based on the PFS benefit, but I think a lot of us were waiting for this overall survival benefit. The toxicity is definitely more when you combine, obviously, platinum-based chemotherapy with osimertinib, and so we needed to know that it was definitely better than sequencing, and so I think seeing this clear overall survival hazard ratio benefit tells us that there’s something that we’re changing with the natural history of the cancer by giving those 2 different therapies up front rather than sequencing them.

And so I do think that this study convinced most people that chemotherapy with osimertinib should be the standard of care for most patients up front. I think of this as an opt out rather than an opt in strategy, where the default is to give osimertinib and chemotherapy to most people, and then for select patients, based on comorbidities or functional status or patient preference, we might opt out and give osimertinib, but you should be thinking about the combination for most people moving forward. And I think the other important thing is it changes the standard of care research going forward, so a lot of the different novel therapies in EGFR-mutant lung cancer now have to kind of sequence themselves to be after osimertinib and platinum-based chemotherapy because most people will get both of these regimens as first line moving forward.

A second kind of supporting study is looking at the exploratory overall survival but really focusing on poor prognostic subgroups. And this is an interesting kind of angle that both the FLAURA2 investigators, as well as the MARIPOSA investigators, so patients that got amivantamab and lazertinib up front, looked at these higher-risk features. And so some of the universal high-risk subgroups that all of these studies assess are patients that have active brain metastases at baseline.

We know that EGFR L858R-positive lung cancers do more poorly than exon 19 deletions, bone metastases, visceral mets like liver metastases, co-mutations in p53, which is about 60% of patients, and then detectable EGFR ctDNA at baseline. These are all potential risk factors, but I think important to note is that when you look at all of these about three quarters of patients will have at least 1 risk factor if not more, so when we talk about high-risk subgroups of EGFR-mutant lung cancer that actually includes more people than not. And this hazard ratio forest plot really just says that all of these higher-risk subgroups do seem to benefit from the addition of chemotherapy.

And again, this is just showing the benefit in all of these different subgroups for the addition of chemotherapy.

And so I think take-home points here is 1) that when we think about risk factors the majority of patients will have at least 1 high-risk feature in their lung cancer, so again we’re trying to say the majority should get combination therapy, and we might opt out of combination therapy for some patients. And then I think it just reinforces that even if patients have these features that are associated with poor prognosis they still benefit from escalation of therapy, so again I think reinforcing the default to be chemotherapy plus osimertinib for most patients.

This was a really interesting study. This is the NorthStar study, and this is looking at local consolidation therapy for patients with EGFR-mutant lung cancer. So this is taking patients that have metastatic Stage IV disease, it’s starting everybody on osimertinib, and if they have either a response or stable disease to osimertinib it’s then randomizing patients to either continuing osimertinib or adding in local consolidation therapy, which really practically means surgery or radiation. And this study really showed a benefit for patients with adding in local consolidative therapy to osimertinib.

And I think one of the interesting features is here on this study — on this page, where you can see that the majority of patients actually got radiation, but a sizeable minority were able to get pretty extensive surgeries, like lobectomies, in the Stage IV metastatic setting. And you can see that the patients with local consolidation therapy with osimertinib clearly had an improved progression-free survival, as well as an early look at overall survival that showed a benefit too. So this was clearly demonstrating that these local therapies can help people live longer and have disease-free — or progression-free intervals that are longer with using local therapy.

I think an important thing to point out is you have to be able to treat all sites of residual disease. So they looked at patients that had maybe 3-5 residual lesions, but if all of those lesions could be treated with either radiation or surgery versus if due to the nature of the disease or location only say 2 out of the 5 spots were able to be treated the benefit for local therapy was really only in people with complete local — local therapy. And so you can see that from the curves on the right side, where the median PFS if all sites were radiated or treated, was 28 months, versus only 14.5 months if you only spot treated some but not all of the disease. And that really is a median PFS that’s quite similar to osimertinib by itself.

So I think take-home points here is that local consolidation can help improve progression-free survival. I thought an important point is people with polymetastatic disease, so significantly more than 5 sites of disease at initial diagnosis, can be rendered oligometastatic with osimertinib. So even for patients that initially you’re not considering local therapy, after that first scan and seeing significant response to osimertinib and only a few residual sites of disease, you could consider local therapy in those patients.

And then only — to remember, again, that only if all patients — if all sites of disease can be treated with local therapy that’s the only time that I consider local therapy for Stage IV disease. If say 1 spot is unable to be treated with local therapy then I tell people that continuing osimertinib and not undergoing local therapy might be the best course of action. But I do think that that’s practice changing already to consider for patients in terms of consolidative local therapy.

I mentioned this previously. This is the MARIPOSA study that looks at amivantamab and lazertinib. Amivantamab is an EGFR/MET bispecific antibody. Lazertinib is a third-generation EGFR inhibitor, similar to osimertinib. And this is first-line treatment for EGFR-mutant lung cancer.

And similar to the FLAURA2 study the overall survival was positive, where there was an improvement in overall survival of using amivantamab and lazertinib up front compared to osimertinib. The one thing that I want to point out, and that shows — is illustrated in the subsequent treatment figure on the right, is patients on the osimertinib arm, very few of them, only 3 of them, received subsequent amivantamab. So in some ways this is an overall survival benefit of getting amivantamab at any point versus getting it in the first line — versus not getting it at all.

So I think that’s one thing to think about, because as I’m sure you all are aware, amivantamab can be combined with chemotherapy in the second-line setting and also shows both a PFS and OS benefit. So I think one question that comes from this data is we know amivantamab is active, it’s just a matter of should we be using it in the first-line setting or the later-line setting.

And then similar to the FLAURA2 study it looks at different features of both the disease and patient population but does show a survival benefit for patients, whether they have brain metastases, what type of EGFR mutation they have, again, in these different subgroups.

And so bottom line for this study is again showing both a PFS and OS benefit with amivantamab and lazertinib that’s maintained in the various higher-risk subgroups. And I think there’s really no question that amivantamab is an active drug. The really only question to consider is whether to use it in the first-line setting or whether to use it in the later-line setting. Amivantamab does have EGFR- and MET-related side effects, and so we have to think about first-line treatment, where you’re on a drug for 2-3 years, you want a therapy that is not only effective but also has reasonable side effects for patients to stay on the drug for that period of time.

So PALOMA, the different PALOMA studies, also very interesting, and they came out, and we got a new approval this year for subcutaneous amivantamab. So amivantamab, that EGFR/MET bispecific antibody, was initially an intravenous formulation that needs to be given in a loading fashion, where patients have to get a split dose for the first dose, then weekly dosing for a month, then moving to every-2-week dosing. So this is utilizing subcutaneous amivantamab in a similar fashion.

So this was really just an equivalence study, where it was looking at subQ amivantamab in the situations where we would be giving intravenous amivantamab and really shows that the patient population that receives amivantamab in this study versus previous amivantamab studies was quite similar. And then the other thing that this study did was when you give amivantamab and lazertinib together there is an increased risk of venous thromboembolic events, so either DVTs or pulmonary emboli. And so this study gave prophylactic anticoagulation and was able to lower the risk of VTEs, so I think that was an example of prophylaxis decreasing side effects of the regimen.

And so unsurprisingly the subcutaneous amivantamab actually does lead to less infusion reactions. About two thirds of patients will have an immediate hypersensitivity reaction to intravenous amivantamab, but that rate is significantly lowered with the subQ formulation.

It also requires less chair time and seems to have at least comparable efficacy to the intravenous formulation, with some data looking at overall survival suggesting that there might even be increased efficacy with the subcutaneous formulation compared to the intravenous formulation. However, subQ administration does not change the EGFR- and MET-directed cutaneous toxicities, so those are similar. And then, again, prophylactic anticoagulation reduces the rate of venous thromboembolic events, so important to do that if you’re thinking about the amivantamab and lazertinib combination.

So this was a similar study, again, but focusing on patients of subcutaneous amivantamab but focusing on patient satisfaction as well as resource utilization.

And so this is really just saying that the time that the health care professional is with the patient, the chair time in the infusion suite, and the participants kind of satisfaction with treatment are all tilted towards the positive, so less time with the patients, less time in the treatment chairs and increased satisfaction when giving the subcutaneous formulation. And that really makes sense because it’s less time in the hospital or clinic, right, and more time for patients to be doing the things that they want to do outside of the clinic or hospital.

So again, I think it’s — this is, I would say, the new standard of care immediately with the approval, which just happened in the last year, so personally I’m moving all of my patients that were on intravenous amivantamab to the subcutaneous formulation. And I’ve already heard feedback from patients, where obviously it’s cutting their time in clinic by half, and we really have seen no negative effects. And so this is, I think, a new standard of care as well.

Next we’re going to segue to datopotamab deruxtecan. So this is one of those antibody-drug conjugates. Specifically, it’s a TROP2-directed antibody-drug conjugate. You might recognize the deruxtecan backbone. This is a cousin of trastuzumab deruxtecan, which is the HER2 ADC, or patritumab deruxtecan, which is the HER3 ADC. They all have different antibody portions, but they have the same chemotherapy payload.

So this was looked at initially in all comers with non-small cell lung cancer in the TROPION-Lung01 study, but when they looked at what subgroup seemed to have the most benefit it looked like patients with actionable gene alterations. And so the TROPION-Lung05 study, which was published in the last year, really focused and enrolled only patients with different actionable gene alterations, and that includes EGFR mutations, but also ALK, ROS1, RET, MET exon 14, BRAF, MET amplification, and looked at the efficacy of datopotamab deruxtecan as later-line treatment for these patients. And so here you can see the waterfall plot, where you can see that most patients did have benefit with datopotamab deruxtecan, and that benefit was durable, with a reasonably long progression-free survival as well.

So again, this is a study that focused on looking at Dato-DXd in patients with AGA-positive lung cancer after chemotherapy and after targeted therapy. About half of the patients had EGFR-mutant lung cancers, and actually when looking at the different mutation subgroups the group that had the highest efficacy was actually EGFR-mutant lung cancer, so an overall response rate of 44%, a median PFS of 5.8 months. And so this is the study — or 1 of the 2 studies that supported the accelerated approval of datopotamab deruxtecan in patients with EGFR-mutant lung cancer after EGFR TKI and after chemotherapy. So this was an FDA accelerated approval that was given last year.

Similarly, this is the pooled analysis for datopotamab deruxtecan and now focusing solely on patients with EGFR-mutant lung cancer. And so this is combining 2 studies, TL-05, which is the study that I just mentioned of Dato-DXd in patients with AGA-positive lung cancer, and then also pooled patients from TROPION-Lung01, so that was the large study in non-small cell lung cancer, but they took out the patients that had EGFR-mutant lung cancer.

So a total of 117 patients with EGFR-mutant lung cancer were treated with Dato-DXd. You can see the different summary of mutation types. I think a really important point to bring up, which a lot of people are unaware of: patients with EGFR exon 20 insertions were treated and also patients with uncommon or atypical EGFR mutations, like G719 or L861, were also treated. And so it has a wider label than osimertinib or amivantamab and lazertinib, so different mutation types were treated. And again showed benefit in terms of tumor shrinkage as well as progression-free survival.

So I think this is the 2 studies, the pooled analysis that ultimately led to the FDA accelerated approval of Dato-DXd and again showed a response rate of 43%, a median PFS of 5.8 months. And I think a really important thing to note is that this approval, the FDA label, also includes patients with uncommon EGFR mutations and exon insertions. So if you have a patient that was on amivantamab and chemotherapy for an exon 20 insertion first line, and they end up having progression after sometime on treatment, datopotamab deruxtecan is a treatment that you could consider for that patient, or similarly a patient with an uncommon exon 18 mutation, like a G719 that’s treated with afanitib, then given chemotherapy, you can think of datopotamab deruxtecan for that patient as well.

So the COMPEL study. I think this was a study that might have gone a little bit under the radar but I think is an important practice-changing study. This is a study that looked at continuation of osimertinib after first-line osimertinib progression when starting platinum-based chemotherapy for patients.

And so this was an important study that took patients that had progression on first-line osimertinib that was not central nervous system progression, so no progression in the brain but systemic progression, and they were planning on switching to chemotherapy, and half the patients received chemotherapy alone, platinum/pemetrexed, and half the patients continued osimertinib along with chemotherapy. They wanted to see whether continuing the osimertinib enhanced the benefit.

And I think this is an important contrast to earlier studies, where we looked at say gefinitib or erlotinib with chemotherapy, and those studies were negative. Where the IMPRESS study, where we continued gefinitib with chemotherapy after progression on first-line gefitinib, was actually negative, but here, in contrast, we actually see a significant benefit in progression-free survival with continuing osimertinib. So you can see osimertinib plus chemotherapy the median PFS was 8.4 months versus only 4.4 months if you stopped the osimertinib and just continued with chemotherapy.

And this led to improvements in both systemic progression and also CNS progression. And there was some additive toxicity with continuing osimertinib, with a little bit more kind of anemia, but really otherwise actually looked to be pretty comparable in terms of toxicity, so not significantly worse with continuing the osimertinib.

So I think this is a very important study. I think one thing to note is that the study was stopped early due to slow accrual, so they didn’t have as much statistical power to really be behind the different results that they had, but separating that there was improvement in both median progression-free survival, as well as CNS progression-free survival and non-CNS progression-free survival with continuing osimertinib.

So in terms of a bottom line, if I’m starting chemotherapy after first-line osimertinib, and someone’s progressed on first-line osimertinib, I’m either continuing the osimertinib or I’m considering amivantamab or adding amivantamab, but I actually would not proceed with chemotherapy alone.

So I do think this is practice changing, saying that continuing some sort of EGFR inhibitor along with chemotherapy is clearly additive. And then again, I think especially for patients that have active CNS disease that’s well controlled on osimertinib and maybe only having systemic progression I would definitely — that would be a person that I would think about continuing osimertinib to maintain the CNS control but adding in chemotherapy to address the systemic progression. So I think an important practice-changing study.

And then with these antibody-drug conjugates one question is whether we should continue the EGFR TKI in these situations, as well, partly to have better CNS control, which we know osimertinib is a highly penetrant — CNS-penetrant EGFR inhibitor but also to see if there are additive effects. And so I did already tell you guys about datopotamab deruxtecan, which is the novel TROP2 ADC that was recently approved, and this study looked at combining that with osimertinib after osimertinib progression.

And this was a subgroup or a cohort in the ORCHARD study, which tested different treatments after first-line osimertinib progression and then looked at 2 different doses: osimertinib at the full dose of 80 mg daily, but looked at Dato-DXd at the 4 mg/kg dosing every 3 weeks and the 6 mg/kg dosing every 3 weeks. You can imagine or understand that there would be some added — additive toxicity or increased toxicity with the higher dose, where they did see higher rates of stomatitis or mucositis, as well as some higher rates of ILD or pneumonitis and ocular toxicities with the higher dose, but they did also see higher efficacy with the 6 mg/kg dosing. And so I think the bottom line for this study — or these results really are that the combination is doable but there is additive toxicity, there is better efficacy with the higher dose of Dato-DXd, and there are ongoing studies looking at this combination.

So there is a TL-15 study, which is TROPION-Lung15, that is looking after osimertinib progression seeing whether standard chemotherapy, platinum/pemetrexed, versus Dato-DXd by itself versus Dato-DXd with osimertinib, which of those has better efficacy in that second-line setting. So we will be able to kind of definitively see whether osimertinib added to Dato-DXd is additive, but I think this is already a study that tells us that it’s safe and doable.

And then I think finally we’re going to talk about MET inhibitors, including savolitinib, which is a novel MET inhibitor, with osimertinib for patients with MET-amplified or MET-positive lung cancer after first-line osimertinib or a first-line TKI. And so we know that about 15 — up to 30% of patients will have some degree of MET amplification or MET positivity after first-line osimertinib, and already off label there are some series that have looked at adding in a MET inhibitor to osimertinib and showing benefit for these patients that have MET-positive lung cancers.

And so this SACHI study was a randomized study that was done all in China that looked at patients after progression on an EGFR TKI giving them chemotherapy, like platinum/pemetrexed, or targeting the MET amplification by giving savolitinib and osimertinib. And this showed, as you can see from the Kaplan-Meier curve, that there was a clear improvement in PFS of using the targeted therapy for these patients that had MET-positive lung cancer after EGFR TKI. And so you can see that the progression-free survival was better, 8.2 versus 4.5 months, and also the toxicity was pretty comparable. And of course this is an all-oral/oral regimen compared to intravenous chemotherapy.

And so again, I think one thing that is interesting is globally some people are still using first- or second-generation EGFR TKIs, and so interestingly they saw that the use of this combination was actually better in people that got first- or second-generation TKIs not that went from first or second to third to this regimen, so the earlier in the disease that this treatment is given does seem to be better.

And then also an important thing to note is that treatment discontinuation was relatively low at 8%. But I think what this tells us is that if patients have MET amplification that’s identified after EGFR TKI that this is a valid actionable biomarker, and we do expect that this regimen of savolitinib and osimertinib, they’re certainly seeking approval in this setting.

And this is — to end, this is a global study, the SAVANNAH study, that looked at that same combination, savolitinib and osimertinib, but in a global population.

I think 1 interesting thing with MET positivity is that the cutoffs are not uniform, or the diagnostic assay that’s used is not uniform, and so some of these studies use MET IHC 3+, and so that’s looking at immunohistochemistry and looking at the degree of expression and in the number of cells, so greater than 50% of cells having high-level expression. Some of these studies use FISH, which is looking for MET amplification, and then some, like the SAVANNAH study, are using a combination of both.

And so initially the cutoffs were lower, MET IHC 3+ in 50%, and MET FISH 5+, but when they used this lower cutoffs actually the efficacy was pretty kind of moderate or not great, where the median PFS was 2.8 months, and the overall response rate was 9%. So they did increase the cutoffs to MET IHC 3+ and 90% or having a FISH 10+, and when they did that higher cutoff, which does mean less patients were positive, they did see better efficacy.

And then one other thing to note is they actually looked at savolitinib by itself versus savolitinib plus osimertinib, in the bottom curve, and you can see that you do need to continue the osimertinib, where if you just gave the MET inhibitor and not osimertinib the median PFS was 2.7 months compared to 7.6 months if you used the combination.

So I think what this study tells is that, again, that this combination of savolitinib and osimertinib is effective but that you really need a high cutoff of probably IHC 3+ and 90% or FISH actually 10+. With the lower cutoff the efficacy was lower and less than standard platinum-based chemotherapy. But with the higher cutoff the patient population that’s eligible is going to be smaller, but you’re going to see greater efficacy. And then again you need to continue the osimertinib because the savolitinib by itself is not effective.

Other Relevant Topics in EGFR-Mutant NSCLC (eg, Nonmetastatic Disease, Exon 20 Insertion Mutations, Novel Agents) — Suresh S Ramalingam, MD

DR RAMALINGAM: Hello everyone. I'm Dr Suresh Ramalingam, medical oncologist at Emory Winship Cancer Institute. I'm delighted today to discuss with you some of the recent advances in the treatment of EGFR-mutated non-small cell lung cancer. So these are the things that we will cover in this presentation.

EGFR-mutated lung cancer accounts for about 15% of all patients with lung cancer in the Western patient population, specifically the non-small cell lung cancer patient population. So we're going to talk about some of the recent advances when it comes to managing EGFR-mutated lung cancer for patients with early-stage disease. And then I'll shift gears, talk about more advanced stage settings where we have some new salvage therapy options for patients who develop acquired resistance to EGFR-mutated, EGFR tyrosine kinase inhibitors. And then I'll shift gears in the last part, talk about EGFR exon 20 mutation, which is another subset of EGFR-mutated non-small cell lung cancer where we're seeing some exciting new developments in terms of novel approaches to treat this patient subset. And then we will have time for questions.

So let me start with early-stage non-small cell lung cancer. We know that patients with Stage I, II and III non-small cell lung cancer are considered candidates for surgical resection. In the era of immunotherapy, we're now using chemo plus IO in the neoadjuvant setting, or we do surgery and then use chemo and IO in the postoperative or adjuvant therapy setting? How do we manage patients with EGFR-mutated early-stage non-small cell lung cancer? We're going to talk about the neoadjuvant osimertinib data that was just presented last year at ASCO.

So this is the NeoADAURA trial. These are patients with Stage II and IIIA, IIIB non-small cell lung cancer. They have EGFR exon 19 or exon 21 mutations. And these are all patients who are candidates for surgery. And this study, the NeoADAURA study, was conducted primarily to ask the question, where does neoadjuvant osimertinib come in? So there were 3 arms to the trial. In one group, the control group, patients were treated with carboplatin or cisplatin with pemetrexed, standard chemotherapy. The second group received osimertinib as monotherapy for 9 weeks. And the third group received both chemo and osimertinib for 3 cycles, approximately 9 weeks. After that, patients went on for surgery. And after surgery, the patients were given investigator choice of adjuvant treatment. And over 90% of the patients in this study went on to receive osimertinib in the postoperative or adjuvant therapy setting.

The primary endpoint was to look at major pathological response, which is defined as almost 90% reduction in tumor, pathologically speaking. So what you're left with, in the sample that was resected, is less than 10% tumor tissue. And that constitutes major pathological response. Of course, if there is no tumor seen, then that's called a complete pathological response.

So this study has reported the early results. And here is the primary endpoint. There were about 120 patients per arm in the trial. The major pathological response was 26% for osi plus chemo, 25% for patients treated with osimertinib and 2% for patients in the control group. So the primary endpoint was met for both osimertinib-containing arms.

Neoadjuvant therapy resulted in a statistically significant improvement in major pathological response. The question is, what about complete pathological response? That was lower, about 10% in the osimertinib-containing groups and practically 0 in the chemotherapy-alone group. So giving 9 weeks of osimertinib by itself or with chemo resulted in a significant improvement in major pathological response in this trial. Now these results are still early. We don't have the overall survival results yet. When one looks at disease-free survival, there appears to be a favorable trend. So based on this now, we can say there is a role for osimertinib. We obviously want to wait for the survival results.

But at this time point, where does this fit in into my clinical practice? Well, when I have a patient with N2 positive EGFR-mutated lung cancer, that's Stage IIIA disease, I would use chemo osi for 3 cycles before surgery. If the patient has Stage II disease and they are candidates for up-front resection, I would do the surgical resection, then give them adjuvant chemo, and then give them adjuvant osimertinib according to the ADAURA trial. So that's my current treatment standard. Of course, as the mature results of the study report, we will wait to see how this changes the overall treatment approach for early-stage EGFR-mutated lung cancer.

Now, I mentioned the role of adjuvant osimertinib. That was based on the results of the ADAURA trial, which randomized patients after surgery to osimertinib or placebo after patients also having received chemotherapy if they are appropriate candidates. And in this trial, there was not only an improvement in disease-free survival, but also a significant improvement in overall survival for patients treated with osimertinib. And those results from the ADAURA trial resulted in FDA approval of osimertinib for 3 years post-surgery in EGFR exon 19 and 21 mutated patients.

The question always is, is 3 years appropriate therapy? Is there a way we can use biomarkers, specifically the MRD or ctDNA information to guide who should get adjuvant therapy or not? And that was reported in the MRD analysis done for patients who participated in the ADAURA trial. So patients had baseline tumor samples available. They had longitudinal blood samples available. And based on that, they were eligible for MRD analysis. So this was a tumor-informed assay, which means both the tumor and the baseline sample were initially studied for a set of mutations, and the longitudinal blood samples were evaluated for those baseline events.

What did we learn from this MRD analysis? I'll walk you through the results. First, when you look at all the patients who completed surgery before randomization, whether they got placebo or not or osimertinib, it doesn't matter. This is baseline pretreatment. You can see on your left that only 8% of the patients had baseline MRD detectable, 92% of the patients did not have baseline detectable MRD. However, a lot more patients beyond the 8% who had baseline MRD developed disease recurrence down the course of follow-up. Which means, if you do have detectable ctDNA or MRD positivity, it is a bad prognostic sign. The tumor is highly likely to recur. But that does not mean the other side of the coin is true. If you are MRD-negative, it does not mean one is out of the woods. They still need follow-up and adjuvant therapy. That's the first point we learned.

The second thing. After treatment, what happened to these patients? When we looked at patients in the placebo group, nearly 70% of them either became MRD-positive or developed radiological disease progression. Whereas in the osimertinib treated group of patients, 75% of the patients did not have radiologic disease or MRD positivity. About 25% developed progression based on MRD or radiographic criteria.

But even among those in the osimertinib arm that progressed, if you break them down, nearly two-thirds of them progressed within 12 months of discontinuing the 3 years of therapy. In other words, patients get 3 years of therapy and they stop, and that immediate 12 months after they stop is when most of the recurrences happen, be it MRD-positive. Only 8% of the patients developed an MRD or a disease recurrence event while on treatment with osimertinib. So this tells us that continuation of osimertinib may be needed well beyond 3 years, though that was not the scope of what this trial was specifically designed to answer.

So what can we conclude from this? MRD assessment can be helpful. If it's positive, it definitely makes the case for continuing the adjuvant therapy. If it's negative, we're not at a point where we can tell the patients that you're out of the woods. We still need adjuvant therapy. We still need to follow them closely. So more to come on this. At this point, I would not use MRD to make treatment decisions outside of a clinical trial setting.

Now let me switch gears, talk about surgically unresectable, still early-stage disease. These are patients with locally advanced disease who are treated with chemotherapy and radiation. This was the design of the LAURA trial. We know that for an all-comer population, if they don't have an EGFR mutation, we give them chemotherapy and radiation for locally advanced disease, and then we give them 1 year of durvalumab or immunotherapy, and that results in improved overall survival. But if the patients have an EGFR mutation, durvalumab is not helpful. In fact, the question then is what is the role of EGFR inhibition in this setting.

That was the question we asked through the LAURA trial. Patients with locally advanced unresectable disease, they all got standard chemo RT, concurrent chemo RT, some had sequential chemo RT. And if they did not progress, within 6 weeks of completion of the chemo radiotherapy, they were randomized to osimertinib or placebo. And here we gave osimertinib continuously. We did not stop the therapy after a defined duration. It was given until patients either developed progression of disease or were no longer able to tolerate therapy.

And in this trial, we showed that there was a significant improvement in progression-free survival, close to 40 months for osimertinib compared to only about 5 and a half months for placebo. This resulted in FDA approval of osimertinib, and it's now considered standard of care in locally advanced non-small cell lung cancer for patients with exon 19 or 21.

We recently reported the updated survival results. The key question is, will this result in improved survival? What you see here are not mature data. There's only 31% maturity, but the trend towards overall survival is seen for patients treated with osimertinib. The hazard ratio is 0.67. This is not statistically significant at this point. In fact, the full survival analysis will occur after 60% maturity.

But these are encouraging results in that patients treated with osimertinib appear to have a favorable survival outcome. Now keep in mind that according to the trial, patients in the placebo group who had disease progression or recurrence were allowed to cross over and receive osimertinib. And in fact, 80% of the patients in the control group crossed over and got osimertinib. And to me, that's what makes these survival results encouraging. Despite the high level of crossover, we're still seeing a favorable survival trend. So we'll wait for the mature data, but at present, this further reinforces the notion that for patients with locally advanced EGFR exon 19 or 21 mutated lung cancer, giving chemoradiation and then osimertinib as consolidation is now the new standard of care.

Now we also looked at MRD to see what we can learn on the LAURA trial, just like we discussed the ADAURA results. So this was an even more sensitive assay that we used for samples from the LAURA study. We looked at the tumor samples from patients, and then we followed blood longitudinally to look for MRD-assessable disease. Now, what did we find? Again, here again, I'll start with the pie chart you see on your left side.

Nearly 56% of the patients, after completing chemoradiotherapy, regardless of whether they were in the osimertinib or placebo group subsequently, this is before randomization, after chemo RT, had disease in the form of MRD. Fifty-six percent were MRD-positive after chemo RT. This tells us that chemo RT by itself is not completely curing these patients. Forty-two percent of the patients did not have MRD or were MRD-negative at baseline. Now what happens over the course of treatment? The curves on the right side show the outcomes with osi versus placebo in patients with MRD positivity at baseline and those with MRD negativity at baseline. And in both of these groups of patients, you see a significant improvement in outcome for patients treated with osimertinib. In fact, the only difference you can see here is in MRD-negative patients, the control group did a little better. The median PFS was 11 months. In MRD-positive group, the control group had median PFS of less than 6 months.

So osimertinib improves outcomes regardless of MRD-positive or negative status, which is key. And I would also point out that the high proportion of MRD positivity after chemoradiation suggests that micrometastases happens very early on in this patient population.

So, in locally advanced non-small cell lung cancer, again, I would not use MRD status assessment outside of a clinical trial because it doesn't tell you who to treat and who not to treat or how long to treat. It just shows that this is a biologically aggressive disease. A lot of patients recur specifically in the brain, and that's where osimertinib plays a big role in reducing progression in the brain and also in other parts of the body. So that's why this is now the standard of care.

Now let me switch gears and talk about metastatic EGFR-mutated lung cancer. We know that third generation EGFR TKIs are used in the front-line setting. And we know that unfortunately practically every patient will develop acquired resistance to first-line therapy.

Now we have some options when it comes to second-line therapy for these patients. For a long time, platinum-based chemotherapy was the standard of care. Now we have a variety of approaches emerging, so we can start thinking, not necessarily fully implement in clinical practice, treatment decisions based on mechanism of resistance. So we're seeing on the research setting a variety of mechanism-based approaches emerging, and that results in patients either getting a fourth-generation TKI or a MET-targeted approach if their MET amplification is driving resistance, or if they have an aberrant fusion gene like they can develop in ALK fusion, then using a specific directed therapy based on the mechanism of resistance for that particular patient can help treatment.

Then there are a variety of mechanism-agnostic approaches, such as using chemo or chemo plus amivantamab and datopotamab, which has recently been approved. So there are mechanism-agnostic approaches that are being developed.

I want to today focus on some of the mechanism-agnostic approaches where we've seen new data in the past year or so. I'll start with ivonescimab.

Ivonescimab is a monoclonal antibody that targets PD-1 and VEGF and it has shown promising data in a variety of settings. So the HARMONi Phase III trial was done to look at using ivonescimab in combination with chemotherapy compared to placebo plus chemotherapy in the control group. These are for patients who progressed on third-generation EGFR TKI. And this trial enrolled approximately 450 patients.

The primary endpoint was overall survival with a co-primary endpoint of progression-free survival. This trial was reported at the World Conference on Lung Cancer last year. And you see the overall results. The progression-free survival was improved, 4.4 to 6.8 months. Hazard ratio was 0.52, statistically significant. And the survival results were favorable, not statistically significant. The chemo plus ivonescimab group had 16.8-month median and 14 months for the chemo plus placebo group. And the hazard ratio here was 0.79. Even though the p-value was very promising, it was not statistically significant. There were no unexpected adverse events. Because it blocks VEGF, we see some VEGF-related adverse events, and because it blocks PD-1, we see some PD-1-related adverse events.

But overall, this trial shows that ivonescimab could be used in combination with chemotherapy in the second-line setting. We are waiting for FDA decision on this regimen. This trial included a high proportion of patients from China and a smaller proportion of patients from the West. So the specific ability of this trial to tease out the benefit in both patient populations in a robust manner is somewhat limited by the study design. But regardless, we will wait to see what the next steps are with this combination.

The other treatment that I want to talk about is the OptiTROP-04 study that involves a new antibody-drug conjugate. This is called sacituzumab tirumotecan. This antibody-drug conjugate targets TROP2. And this payload is a TOPO I inhibitor. This trial was done exclusively in China, and this was a randomized trial of sacituzumab tirumotecan given intravenously at a dose of 5 mg every 2 weeks compared to standard chemotherapy after patients developed acquired resistance to third-gen or first or second-gen TKI with negative T790 disease.

This was reported in the New England Journal of Medicine very recently, and this trial showed really promising and exciting results. Here you see the progression-free survival data, 4.3 in the control group of platinum-based chemo versus 8.3 months for patients treated with sacituzumab. And this one had a hazard ratio of 0.49. And in the overall survival Kaplan-Meier curve, once again you see a hazard ratio of 0.6, very exciting, favoring Sac-T. And the median overall survival had not been reached for the experimental arm compared to 17.4 months in the control group. The adverse events seen with Sac-T are summarized in the bottom of your slide.

Stomatitis is the most common side effect you see. It's seen in about 65% of the patients. Five percent of them have Grade 3 events. So we have to be mindful of this and manage this prophylactically. But this study has resulted in further development of Sac-T in non-small cell lung cancer, specifically in EGFR-mutated disease. So we'll wait to see how this trial done in China compares to efficacy of this drug in Western patient populations when those studies are conducted.

Lastly, let me switch gears and talk about EGFR exon 20 insertion mutation. This is a group of patients where the standard TKIs we use for exon 19 and 21 don't have robust efficacy. In fact, the standard of care for first-line treatment is the combination of chemotherapy and amivantamab.

Amivantamab is an antibody that targets both MET and EGFR. And we have seen from the PAPILLON trial that using chemo plus amivantamab compared to chemo alone results in a median PFS improvement from 6.7 months to 11.4 months. This is now approved by the FDA for first-line therapy, and it has been published.

The main side effects with amivantamab are infusion reaction and skin rash. Now there is also a subQ formulation of amivantamab that has been approved by the FDA recently that would significantly mitigate infusion reaction and skin rash is managed with a variety of supportive care measures that are helpful.

More recently, we learned about the patient-reported outcomes in the PAPILLON trial. This was reported by Dr Paz-Ares and they looked at physical functioning and global health status for patients in both groups of the trial. And they noted that nearly 77% of the patients remained free from symptomatic progression with chemotherapy and amivantamab combination compared to only 60% with chemotherapy alone at 12 years. So, the efficacy benefit is correlated with patient-reported outcomes improvement for patients treated with chemo and amivantamab, which further reinforces the value of this regimen in patients with EGFR exon 20 insertion mutations.

We've also seen a new FDA approval for a small molecule, sunvozertinib, in this patient population, and that was based on the results of the WU-KONG1B trial. This is the trial design.

This is a 2-arm trial where patients with locally advanced metastatic non-small cell lung cancer with a confirmed EGFR exon 20 insertion were enrolled. Patients had received prior platinum-based therapy, and the randomization was to 2 cohorts. One was 200 mg per day of the drug. The other was 300 mg per day administered orally on a continuous dosing. And the primary endpoint for this trial is response rate.

So, what did we learn? We learned that for patients treated with sunvozertinib, the response rate was very robust at about 46% for the 200-mg dose and almost similar, 47% for the 300-mg dose. The median PFS was approximately 8 months. When they looked at efficacy based on whether or not the patients had prior amivantamab, there was a difference. Patients who had not seen amivantamab had nearly 50% response rate. Patients who had seen prior amivantamab had about a 40% response rate for the 300-mg dose and a 25% response rate with the 200-mg dose.

We also saw that patients without prior baseline brain metastases had over 50% response rate, whereas those with prior brain mets had a lower response rate. What were the side effects? Diarrhea, increase in blood creatinine phosphokinase and anemia. These are the 3 most common Grade 3 events. And generally, with supportive care measures, it did not lead to treatment discontinuation or dose reduction. So sunvozertinib is approved in patients who had progressed on prior platinum-based therapy.

What about new developments? There's also another drug knocking on the door, zipalertinib. This is also an orally administered tyrosine kinase inhibitor specific for EGFR exon 20 insertion. The trial design here is shown in this slide. Patients who had documented mutation were given 100 mg bid of zipalertinib. One cohort of patients were those who had received prior platinum-based chemotherapy without prior EGFR exon 20 targeted drugs, and another group of patients had received prior platinum and also prior amivantamab or exon 20 targeted drugs.

So this trial also showed very promising results. When you look at the response rate, it's about 35%, and the median duration of response is nearly 9 months. For patients who had prior platinum-based chemo without another exon 20 targeted therapy, the efficacy results were even better. Response rate was 40%, whereas for patients who had been treated previously with an exon 20 targeted drug and also amivantamab, the response rate was about 25%, still respectable, and the median duration of response was about 8 and a half months.

The adverse events are shown in the lower part of your slide. Paronychia, skin rash and diarrhea being the more common side effects. You do see some stomatitis. Most of them are Grade 1 or 2 in severity. When you look at Grade 3 events, anemia is the most common Grade 3 event.

This drug also showed activity against brain. That has been reported as well by Dr Piotrowska and colleagues. So, zipalertinib is an exon 20 insertion targeted tyrosine kinase inhibitor that has robust response rates in patients who progress on prior platinum-based therapy and also has activity against brain metastases.

So, overall, I think we're seeing some significant advances in the treatment of EGFR-mutated non-small cell lung cancer, both in patients with the common mutations, exon 19 and 21, and the uncommon, specifically the EGFR insertion 20 mutations. With the availability of these new advances for treatment of our patients, making sure that we understand their optimal dose, potential side effects, managing the side effects in a prophylactic manner, whenever applicable, will result in better treatment outcomes and better patient tolerance. So, I'll stop there, and thank you very much for your attention.