Management of Metastatic EGFR Mutation-Positive NSCLC — Enriqueta Felip, MD, PhD

DR FELIP: So hello, everyone. My name is Enriqueta Felip. I’m a medical oncologist working at Vall d’Hebron University Hospital in Barcelona, Spain, and it’s a real honor for me to participate in this program. I’m going to review the most updated information about the management of patients with metastatic EGFR mutation-positive non-small cell lung cancer.

I’m going to start with a trial — with a study with analysis presented during the World Conference in San Diego from FLAURA2. As you know, FLAURA2 is a trial in first line in patients with sensitizing EGFR mutations comparing carboplatin/pemetrexed plus osimertinib versus osimertinib alone. These trials show longer progression-free survival with the combination of chemotherapy plus osimertinib when compared to osimertinib, with a hazard ratio of 0.62. In the second overall survival interim analysis there was a trend towards an improvement in overall survival with the combination of chemo plus osimertinib, with a hazard ratio of 0.75 that was not statistically significant at the time of presentation.

So during the World Conference … presented the impact of baseline tumor burden defined as the number of metastatic anatomical sites and PFS in the patients included. So overall they presented the PFS for those patients with lower than 3 metastatic anatomical sites or 3 or more metastatic anatomical sites.

First, I would like to remember that for those patients with CNS metastases at the study entry the median PFS with chemo plus osimertinib was 24.9 months, with osimertinib alone 13.8 months, with a hazard ratio of 0.47. And for those patients without CNS metastases at baseline the hazard ratio favoring the combination of chemo plus osimertinib. It was 0.75.

So here is the data presented during the World Conference for those patients with at least 3 metastatic sites at baseline chemo plus osimertinib was associated with a median PFS of 25 months. With osimertinib the median PFS was 16.4 months with a hazard ratio of 0.57. For those patients with less than 3 metastatic sites at baseline the hazard ratio with chemo plus osimertinib was 27.9 months, with osimertinib monotherapy 30.5 months, so no main differences in the median PFS, although the hazard ratio was 0.75. Perhaps also to mention that for those patients with intrathoracic disease only the median PFS was 26 months with chemo plus osimertinib, and it was not reached with osimertinib monotherapy, with a hazard ratio of 0.97.

So here my take-home messages from this trial. So we know that chemo plus osimertinib is one of the approved treatments in first-line patients with EGFR mutations. However, the mechanisms for the observed clinical benefit with the combination are not currently clear. It is possible that the combination overcomes intertumor heterogeneity. In this trial, in FLAURA2, the PFS benefit appeared to be most pronounced among patients with brain metastases at baseline.

And I would like to remember that brain scans were performed at the screening in all the patients and at the time of progression in all the patients. In the study, PFS benefit was observed with osimertinib plus chemotherapy versus osimertinib alone in patients with high tumor volume. And I think it’s important that there was no PFS difference in those patients with only intrathoracic disease, with a hazard ratio of 0.97. I understand that this is a subset analysis, but these are the results presented.

Also analyzing the FLAURA2 trial I would like to highlight the study analyzing the potential mechanisms of resistance and also the impact of the baseline p53 comutations. So again, in this trial there were a number of analyses performed by NGS in ctDNA at diagnosis and also at disease progression, and the p53 mutations were analyzed in tumor samples.

So the first message is that when the authors analyzed the mechanisms of acquired resistance in both treatment arms, osimertinib or chemotherapy plus osimertinib, the mechanisms of acquired resistance were pretty similar. So it was the presence of the C797S mutation in approximately 7% to 10% of the patients. There were also MET amplifications in approximately 10% of the cases and other molecular alterations such as even BRAF V600, KRAS mutation and also fusions. So the message is that there were no differences between the 2 treatment arms in the mechanisms of acquired resistance, and also there were no novel resistance mechanisms detected in plasma for those patients with these samples at the resistance time.

And also, as mentioned, p53 was also analyzed in the tissue at diagnosis if the patient was included in the FLAURA2 trial. Here, 141 samples were analyzed, and when the authors presented the results for those patients with p53 wild-type at baseline the median PFS with chemo plus osimertinib was not reached, with osimertinib monotherapy it was also not reached. For those patients with concomitant p53 mutation in the tumor the median PFS with chemotherapy plus osimertinib was 27.6 months, with osimertinib monotherapy 27 months, with a hazard ratio of 0.67.

So again, this is the FLAURA2 in first-line treatment of patients with EGFR mutations. My take-home messages are the following: In this updated plasma analysis the acquired resistance mechanisms remain similar between the 2 treatment arms, osimertinib or osimertinib plus chemotherapy. No new acquired resistance mechanisms were observed. And the p53 comutations seemed more prognostic than predictive.

Now I would like to discuss a paper published in Journal of Clinical Oncology by Dr Pasi Jänne about the CNS frequency of osimertinib with or without chemotherapy in EGFR-mutated patients in this FLAURA2 study. We have discussed the results of this trial, so we know that in the FLAURA2 trial progression-free survival was longer with chemo plus osimertinib when compared to osimertinib in the group of patients specifically with CNS metastases. In this group the median PFS with chemo plus osimertinib was 24 months, 13.8 months with osimertinib alone, with a hazard ratio of 0.47. And in this publication the authors present the additional data on CNS efficacy with osimertinib, including the CNS progression-free survival.

So in the full analysis set the CNS progression-free survival was longer in the chemotherapy plus osimertinib arm versus the osimertinib arm, with a hazard ratio of 0.58. At 24 months there are 74% of patients in the chemo plus osimertinib arm that were CNS progression free compared to 54% in the osimertinib arm.

And there was also a subgroup of patients with brain metastases evaluable. This is the CNS evaluable analysis group, and in this group also the CNS progression-free survival was longer with chemo plus osimertinib when compared to osimertinib, with a hazard ratio of 0.40. Also there was an analysis of the cumulative risk of CNS progression in the CNS full analysis set, and disease progression was higher for those patients treated with osimertinib in monotherapy.

And also some data on the depth of the response. You can see the waterfall plots. The patients in the combination arm, chemo plus osimertinib, had a greater depth of response compared with those in the monotherapy arm, and overall the response rate in these patients is around 60% to 70%.

So more data of the CNS efficacy in patients included in the FLAURA2. And again, as a summary, overall in all patients there was a brain scan at baseline, and in 84% of the patients a brain MRI was obtained. In this analysis I would like to highlight that the scans were assessed by a neuroradiologist according to the independent review committee. And again, among the 222 patients with baseline CNS metastases, osimertinib plus chemotherapy had an improvement in the CNS progression-free survival compared with osimertinib, supporting the analysis of this combination in those patients with CNS metastases at diagnosis.

And then there is another publication, also this year in Journal of Clinical Oncology, that is a Phase II analyzing osimertinib 80 mg, that is the usual dose, in patients with EGFR mutations with leptomeningeal metastases. I would like to mention that this trial was performed in patients with EGFR mutations treated with first-line — or first- or second-generation EGFR/TKIs and then progression. So a large number of patients with leptomeningeal disease showing median PFS of 12 months and a medial overall survival of approximately 15.6 months.

And also you can see the response here according to the independent review committee, and according to the RANO criteria it was a response rate in 51.5% of the cases, and we have discussed, with the median PFS of 11.2 months.

So this is the publication in JCO in August analyzing this dose of osimertinib, 80 mg, in patients with leptomeningeal metastases. I think the results and efficacy was pretty good. However, as recognized by the authors in the discussion, there is an important limitation that is that in this trial patients were included after first- and second-generation EGFR/TKIs, and we know that now the standard of care in first line are third-generation EGFR/TKIs or other combinations. And perhaps another important point is that there are some pharmacokinetic analyses in this trial, and there were all trials showing that perhaps in these patients double dose of osimertinib, 160 mg, may help. However, this study supports the standard osimertinib dose even in patients with leptomeningeal metastases.

Let’s move on to the other combination that has been analyzed and approved in the first-line setting of patients with EGFR mutations, the MARIPOSA trial, so the combination of amivantamab plus lazertinib. In the MARIPOSA trial patients with activating mutations, EGFR, treatment naïve, were randomized to receive the combination of amivantamab plus lazertinib, osimertinib or lazertinib. Lazertinib was analyzed in this study to determine the action of these components, which was a requirement by the FDA.

So we know that this trial — we knew that this trial was positive for progression-free survival. This was presented at ESMO 2023 in Madrid, but this year during the World Conference there was an update in data presented. So in this update we have seen that the intracranial progression-free survival was longer with amivantamab plus lazertinib when compared to osimertinib. It was also a longer intracranial duration of response with the combination of ami plus lazer. The time to treatment discontinuation was also longer with the combination when compared to osimertinib, but also the time to subsequent therapy longer with amivantamab plus lazertinib, and also the PFS2, so the time from the inclusion until the progression after the first subsequent therapy was longer in the ami plus lazer arm when compared to the osimertinib arm.

During the World Conference there was also an updated overall survival analysis. There was a longer overall survival with ami plus lazer when compared to osimertinib. At that time, this was numerically longer, with a hazard ratio of 0.77, although it was still not statistically significant. However, we have seen in a recent press release by the company that in the final analysis the overall survival is positive, favoring the combination of amivantamab plus lazertinib, and also they mentioned that this is statistically significant and meaningfully positive. So we need to see these results in the future meeting, but according to the press release the improvement in median overall survival with ami plus lazer is expected to exceed 1 year.

So again my take-home messages from this presentation. So I’m discussing what was presented in San Diego, so after a longer follow-up data continued to favor first-line amivantamab plus lazertinib over osimertinib, with a promising overall survival trend in patients with EGFR mutations. We have seen that the overall survival curves separate early and widen over time, favoring the combination. We have discussed also the press release, and I think also there is a scientific rationale to give this combination because we are addressing potential mechanisms of resistance to osimertinib, blocking EGFR and also MET.

It’s true that with the combination there is a high incidence of adverse events, and the toxicity management of this combination is relevant. And again, the data supports the combination as first-line treatment in patients with EGFR mutations.

And also during the World Conference analyzing the same study there was a presentation about the patient-relevant outcomes and overall the summary is that the time to symptomatic progression is longer with the combination when compared to osimertinib, and the quality of life was maintained in both treatment arms. We know that the combination has more toxicity, but the quality of life was not affected.

So again, this was the presentation about patient-relevant outcomes from MARIPOSA, and the main points, in my opinion, is that the amivantamab plus lazertinib combination delays symptomatic progression compared to osimertinib. And probably symptomatic progression as a patient-relevant outcome is important for the patients. And quality of life was maintained in both treatment arms, and overall the increased adverse events from amivantamab plus lazertinib did not meaningfully impact patients’ health-related quality of life.

I had the privilege to present during the ASCO Meeting and also to publish with all the coauthors in the Annals of Oncology the combination analysis in the MARIPOSA trial for those patients with poor outcomes. So overall in this study, the MARIPOSA, patients — all patients had EGFR mutation. But also in the literature we know that there are a group of patients with poor prognosis, and these are the patients with brain metastases, with liver metastases, with concomitant p53 comutation at baseline, and also those patients with detectable ctDNA at baseline.

So during ASCO we presented the analysis, the comparison between amivantamab plus lazertinib versus osimertinib in these patients with poor prognosis. So for those patients with a history of brain metastases ami plus lazer improved progression-free survival when compared to osimertinib, with a hazard ratio of 0.69. It’s true that also there is an improvement in PFS for those patients without a history of brain metastasis with the combination.

Also, for those patients with concomitant p53 comutation at diagnosis there was an improvement with the combination when compared to osi, with a hazard ratio of 0.65. For those patients with detectable EGFR mutation at baseline in the plasma sample also longer PFS with the combination when compared to osimertinib, with a hazard ratio of 0.68. And also, for those patients without clearance of EGFR mutation at week 9, for this group of patients without clearance the combination of amivantamab plus lazertinib improved progression-free survival when compared to osimertinib.

So the summary is that even in the patients with poor prognosis, those are the patients with brain metastases, liver metastases, detectable EGFR mutation at plasma, concomitant p53 comutations and detectable EGFR mutation at baseline, in all these subgroups the combination of ami plus lazer improved progression-free survival when compared to osimertinib.

And these are the summary of our presentation at ASCO. So we have detected that approximately 50% of patients with EGFR mutations at diagnosis had concomitant p53 comutations, and approximately 70% of the patients who had detectable EGFR mutations had shedding, and we are able to detect in liquid biopsy. We have seen that ami plus lazer improved median PFS versus osimertinib in all high-risk subgroups, so overcomes the effect of these negative prognostic factors. However, it is also true that the combinations also benefit those patients without these high-risk prognostic features.

I think it was important that at ESMO Dr Benjamin Besse presented the mechanisms of acquired resistance to first-line amivantamab plus lazertinib versus osimertinib in these analyses in the MARIPOSA study. And again, the results show that amivantamab plus lazertinib reduced the incidence of acquired MET amplification and also reduce the incidence of EGFR resistance mutations when compared to osimertinib, so supporting also the mechanism of action of amivantamab.

It seems that perhaps the HER2 amplifications were slightly higher for those patients receiving the combination. And also, this is based on liquid biopsy, but there is no biopsy to determine the small cell lung cancer transformation, but overall the patients with p53/RB1 loss that were related to small cell lung cancer transformation were less common for those patients treated with amivantamab plus lazertinib. And also, the authors presented that osimertinib had a higher frequency of complex resistance mutations than amivantamab plus lazertinib.

So again, the summary of this presentation. Using ctDNA, NGS analysis, ami plus lazer reduced the incidence of MET amplification and also EGFR-resistance mutations when compared to osimertinib monotherapy, there was a low rate of p53 and RB1 loss that is associated with small cell lung cancer transformation, and also I think it’s the confirmation of the scientific rationale of the combination that is trying to proactively address the mechanisms of resistance to osimertinib blocking EGFR and MET.

A few words about the MARIPOSA-2 trial. This is in the second-line scenario. It was previously presented at ESMO and updated by Dr Popat during the ESMO Meeting. Patients previously treated with osimertinib were randomized to receive chemotherapy or chemo plus amivantamab. There is also another arm of chemo plus lazertinib plus amivantamab, and this was updated during the ESMO Meeting.

And again, in the overall survival there was a trend towards an improvement in the overall survival for those patients receiving chemo plus amivantamab when compared to chemo alone, with a hazard ratio of 0.73. although it was not statistically significant, still it was not the case, and the trial is ongoing and will proceed to final overall survival analysis. And also all the other endpoints analyzed benefitted also the combination of chemo plus amivantamab second line when compared to chemotherapy alone.

So again, the summary of this presentation from Dr Popat about the MARIPOSA-2. At the second interim analysis there is a promising overall survival trend favoring ami plus chemo in the postosimertinib setting. There was also an improvement in time to symptomatic progression, time to treatment discontinuation, time to subsequent therapy, and also PFS2. But this is a scenario in which we will have a lot of Asians, so there would be a possibility, perhaps, to give targeted combinations in the presence of fusions or BRAF V600. We have also antibody-drug conjugates and also the possibility probably in the future of chemotherapy plus bispecific antibodies.

And finally, I think this is the last presentation by Dr Leighl at ASCO and also published in Journal of Clinical Oncology in patients treated with lazertinib plus amivantamab. It was the PALOMA-3 comparing the subcutaneous amivantamab presentation versus the intravenous amivantamab presentation. The primary endpoint was PK, and it was a noninferiority design, and it demonstrated that the subcutaneous administration was not in favor when compared to intravenous from the PK objective. But it was important that the response rate was exactly the same with the subcutaneous amivantamab or intravenous presentation. Progression-free survival and duration of response, there were no differences. And interestingly there was a trend towards an improvement in overall survival with the subcutaneous administration when compared to intravenous presentation.

Importantly, there was a decrease in adverse events with the subcutaneous administration. The infusion-related reactions were observed only in 13% of the patients in the subcutaneous arm versus 66% in the intravenous arm. And also, the VTE, the venous thromboembolic events, were less common for those patients with the subcutaneous formulation. For those patients with prophylaxis, in the subcutaneous arm, VTEs were seen in only 7% of the cases.

So I would like to mention, and this was discussed by Dr Jessica Leighl at ASCO, I think the summary is that the subcutaneous amivantamab demonstrated a PK noninferiority. There are a number of advantages in safety. There is reduced rates of infusion-related reactions and VTEs, and it’s not inferior in efficacy. And there is this intriguing signal for improved overall survival that needs further investigation.

The hypothesis is that perhaps the impact of subcutaneous administration on lymphatic absorption and immune stimulation may help, but I think that is something that requires other analysis.

So I think in the future the subcutaneous formulation of amivantamab could be an interesting option in the clinical practice.

And finally, a few words in immunotherapy. I think with the anti — with pembrolizumab and nivolumab no clear activity of the combination of chemo plus nivo or pembrolizumab after osimertinib resistance. And probably I think here the future could be the bispecific anti-VEGF and anti-PD-1 antibodies in combination with chemotherapy.

So I think these are the summary of the presentations that in our opinion changed the standard of care for patients with metastatic EGFR mutations. Very pleased to participate in this initiative. Thank you.

Other Relevant Topics in EGFR Mutation-Positive NSCLC, Such as Nonmetastatic Disease, Exon 20 Insertion Mutations and Novel Agents — Helena Yu, MD

DR YU: Thank you so much for having me, Neil. My name is Helena Yu. I'm a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center in New York, and I am very happy to be here presenting to you different relevant topics that relate to EGFR-mutant lung cancer with exciting new data from 2024.

So the first study that I will go over is the use of neoadjuvant osimertinib for early-stage resectable disease. And so this was a really interesting investigator-initiated study that took patients with early-stage, anywhere from Stage I to IIIA, EGFR-mutant lung cancer that was amenable to surgical resection. All patients received a short course, 1 to 2 months of single-agent osimertinib without chemotherapy and then underwent surgical resection if appropriate. The primary endpoint of the study was major pathologic response rate, which is established endpoint in the early-stage setting that correlates with survival and outcomes. And in total, 27 patients were accrued on this study. The demographics of patients accrued, really was in line with what we see for EGFR-mutant lung cancer, predominantly female, significant minority of patients that were Asian. And you can see from the clinical stage of the patients, the different stages were pretty well represented but the major did have Stage II or III disease.

And I think these results were really striking where the expectations were not met. The major pathologic response rate was surprisingly low at 15%. And if we put this into context, the major pathologic response rate that we've seen with chemotherapy is somewhere — or chemotherapy/ immunotherapy in the recently presented neoadjuvant studies, really ranges from the 30% to 40% range. So this is far below what we see even for chemotherapy monotherapy. So this was striking in terms of results.

So kind of the different conclusions I made from the data, of course both the major pathologic response rate and the pathologic complete response rate were quite low. One of the questions that was raised is, possibly is this due to the short treatment time? The osimertinib was only given for 4 to 8 weeks. And so perhaps there needs to be more time to see cytotoxic response. But I think what the main kind of conclusion is, is that chemotherapy may be an important component of neoadjuvant treatment for EGFR-mutant lung cancer, where there is a clear benefit with cytoreduction that a short course of osimertinib does not seem to get.

This is a little bit in contrast with what we've seen in terms of the incredible benefits of adjuvant osimertinib. So based on the ADAURA study, 3 years of adjuvant osimertinib has been approved for some time. And we see really striking, both disease-free survival benefit, but an overall survival benefit as well. And so something about prolonged dosing of osimertinib does seem to lead to curing of more cancers and cytotoxic benefit, but interesting that we didn't see it in the neoadjuvant setting.

I think the study that we're really awaiting is the NeoADAURA study. And so that study schema is up on the screen on the top. And it is a 3 arm study, where we are — the study does enroll osimertinib monotherapy but importantly, there's a chemotherapy and a chemotherapy osimertinib arm. So I think this is going to be the definitive study to see whether osimertinib adds to chemotherapy in that neoadjuvant setting. And I would just say, for these patients for the present time, without having the NeoADAURA data, my standard of care practice is to do neoadjuvant chemotherapy and then surgery and then adjuvant osimertinib in the backend. But that might change with this NeoADAURA study.

The other data that we saw last year was the ADAURA Minimal Residual Disease Analysis. And so the ADAURA study, as I just mentioned, is an adjuvant study looking at the 3 years of adjuvant osimertinib. And they did a lot of different correlative analyses, including using a tumor-informed minimal residual disease assay. And so that was tested prior to, right at enrollment of the study, prior to surgery, after surgery and then serially after surgery while on osimertinib. And you can see they have a really robust dataset of more than 200 patients that had serial MRD analysis. I think importantly, on the top right, you can see the baseline MRD status, where the majority of patients were MRD negative prior to going — after surgery but prior to going on adjuvant osimertinib. And then you can see the MRD lead time. So this is how soon before radiologic or clinical progression was the MRD assay able to detect residual disease. And that lead time was about 5 months. And then finally, when looking at patients who received adjuvant osimertinib, it's interesting to note that most of the patients that had recurrent disease, either by MRD or clinical progression, actually had that after they completed their 3 years of adjuvant osimertinib. And so again, stating that the recurrences happened predominantly after osimertinib was discontinued. And that also raises the question, should we be giving longer or indefinite osimertinib for these surgically resected patients? And so I think this is good supportive data and I ultimately think that these MRD assays will likely, number 1, help inform adjuvant therapies, and 2, might actually help us decide how long to continue adjuvant therapies for certain patients. So we'll see more data to come on that.

The next study that came out last year that was really transformative was the LAURA study. The LAURA study is looking at osimertinib after chemoradiation. And so this took patients with Stage III nonresectable but locally advanced EGFR-mutant lung cancer that underwent concurrent chemoradiation as definitive treatment without progression, either during or following chemoradiation, and then randomized patients 2 to 1 to receive osimertinib daily versus placebo. And importantly for this study, treatment was indefinite until progression. And so there was no set timeframe where this adjuvant therapy was received, but really was indefinite until a patient progresses. Primary endpoint was PFS by BICR. And here you really see a marked benefit with the adjuvant osimertinib after chemoradiation, where the hazard ratio is 0.16, so perhaps even greater than what we see with surgically resected cases with adjuvant osimertinib. And you can see there's prevention of both distant and local progression with osimertinib versus placebo.

One of the big issues or sort of points that were brought up with this study though, is that this was a really high-risk group of patients. And so one of the concerns is only about half of patients got PET scans prior to study enrollment. And so a real question is, is this just telling us that osimertinib works for metastatic disease? Even when looking at patients that had CNS metastases, 10% had baseline CNS metastases and so at least 10% had metastatic disease prior to study enrollment. And so I think that is a real question as to whether, if there was kind of more standard of care up to date staging prior to study enrollment, whether we would see such a marked benefit. But 1 thing that I think it does raise, or a point that it raises, is should we be giving osimertinib indefinitely for these locally advanced cases? And a lot of us were, you know, brought up the question about whether for surgically resected disease as well, whether a prolonged or longer course of osimertinib would be beneficial. But I think that the, as of now, take home from these studies is really that osimertinib has become the standard of care, adjuvant therapy after definitive therapy, for all locally advanced EGFR-mutant lung cancers, whether they receive radiation or surgery.

The next compound that we'll discuss is patritumab deruxtecan. So patritumab deruxtecan is a HER3-directed antibody-drug conjugate. It's in the deruxtecan family of ADCs, which also includes trastuzumab deruxtecan and datopotamab deruxtecan. So all of them have the same chemotherapy payload. We've now seen data from several of these patritumab deruxtecan studies.

So the first one is the Phase I dose escalation study. And what was reported last year was the longer-term follow-up data from that Phase I dose escalation. Since that Phase I dose escalation, we've also seen the registrational Phase II study, looking at a very large number of patients who received the recommended Phase II dose of 5.6 mg/kg every 3 weeks of patritumab deruxtecan. And so we have established the response rate of around 30% and the median PFS of about 5.5 months in a large dataset of patients with EGFR-mutant lung cancer after osimertinib and after platinum-based chemotherapy. So with longer follow-up of the Phase I study now, with several years of follow-up, the main points are that the progression-free survival and the OS are updated but consistent with prior reports where we're seeing a median progression-free survival of 6.4 months and median OS of 16.2 months.

Importantly, as we've all been looking for biomarkers for these different ADCs, there was a retrospective look at HER3 expression and its potential correlation with response to HER3-DXd. And you can see here that there really was no way — HER3 expression did not distinguish responders from non-responders, where there was completely overlapping HER3 expression among responders and non-responders. And I think part of the challenge is that all patients had some degree of HER3 expression. And so, I think, there's more and more thought that actually very little of the protein cell surface antigen is required for antibody binding. And so I think 1 main point that you'll hear me say over and over is, perhaps the patient selection or biomarker is actually oncogene driven lung cancer. And so a lot of these ADCs are now focused on EGFR-mutant lung cancer that are kind of currently in development.

Other findings from that longer follow-up is a suggestion that maybe patients with EGFR-independent resistance had higher response rates to pat/deruxtecan. And so EGFR-independent resistance are patients that had MET amplification, KRAS alterations, acquired ALK fusions, I think just, again, reinforcing that these ADCs do seem to be effective amongst patients with diverse mechanisms of resistance to osimertinib. And then we saw the first data on acquired resistance to antibody-drug conjugates, specifically HER3-DXd.

So one of the questions with antibody-drug conjugate drug resistance is, will patients develop resistance to the antibody component of the ADC or the payload? And I think the initial data from HER3-DXd really suggests both. So with sequencing of both plasma and tumor tissue, when available, of patients with acquired resistance to HER3-DXd, some of the alterations we found included a HER3 frameshift mutation that inactivated and kind of led to lack of dependence on HER3 signaling. And we actually also saw an acquired alteration in the TOP1 gene, which is the topoisomerase gene. So I think that sort of explains to us that we can see resistance to both the antibody and the payload, and understanding a patient's individual resistance is going to be important because if somebody has acquired HER3 alteration after HER3-DXd treatment, they still might respond to, say, trastuzumab deruxtecan because they don't necessarily have resistance to the payload but actually the antibody. And so hopefully we'll see more and more data about acquired resistance to ADCs and how that should fit into clinical sequencing of the different ADCs.

So in terms of where patritumab deruxtecan is in development, the confirmatory Phase III study was a study that took patients after first-line osimertinib and then randomized patients 1 to 1 to either platinum-based second-line chemotherapy or HER3-DXd, with the primary endpoint being progression-free survival. We did see a press release back in September that stated that pat/deruxtecan demonstrated statistically significant improvement in PFS compared to platinum-based chemotherapy, so positive results via PFS. We haven't yet seen the full data but this is encouraging to hear.

And then in terms of where HER3-DXd is in development, in June of last year, we heard that pat/deruxtecan received a complete response letter from the FDA based on their BLA submission. And so what we heard was that the FDA did not have any issues with the efficacy or safety data with patritumab deruxtecan, but rather the complete response letter was a result of inspection findings at the third-party manufacturing facility. And so we don't have updated data as to when this will be resolved, but we do expect that patritumab deruxtecan will likely be approved in the future.

So another agent, ADC, that we've heard a lot of data in the last year, is datopotamab deruxtecan. So datopotamab is, again, in that deruxtecan family of ADCs, and it's a TROP2-directed ADC. And so 1 of the studies that we saw was results of TROPION-Lung05. And so this was a study that focused on actionable gene-altered lung cancers. You can see from the pie chart on the top right the breakdown of the different AGAs that were included in TROPION-Lung05, but really included patients with genomic alterations that received targeted therapy, but also that received cytotoxic chemotherapy as well. And so the — in total 137 patients were treated. The response rate that was confirmed was 36%, with a median PFS of 5.4 months.

We did get to see some later CNS data from the study, and really it illustrated that patients with and without brain metastases did respond to datopotamab deruxtecan with a lower response rate in patients with brain metastases. And that possibly is representative of more aggressive biology for patients that had brain metastases. But importantly, there was intracranial response. The overall intracranial response rate with datopotamab was 22%. And really important to understand CNS efficacy in this patient group, because as we know, in particular with EGFR, or say ALK-positive lung cancer, the cumulative incidence of brain metastases exceeds 50%. And so we really need to understand CNS efficacy when considering or choosing between these different ADCs.

We also saw combined data from both TROPION-Lung01 and 05. So this is combining really all patients with EGFR-mutant lung cancer that received datopotamab deruxtecan. And so when pooled together, that total was 117 patients. They really had the standard kind of clinical phenotype of patients with EGFR-mutant lung cancer, never smokers, Asian and white background, and somewhat younger age. The breakdown of the different types of EGFR alterations in that pool dataset is visible in the top right. And then the outcome data or efficacy data is right on the bottom of the slide, where you can see the confirmed response rate around 42%, 43%, median PFS of 5.8 months, median OS of 15.6 months.

So, so far what we've seen in my opinion is pretty comparable kind of efficacy data with both datopotamab and patritumab deruxtecan within EGFR-mutant lung cancer. I think the side effect profile is a little bit different and I think it's important to note. So all of these ADCs have the typical sort of cytotoxic chemotherapy toxicities including fatigue, nausea, vomiting, alopecia. One difference with datopotamab is we're actually seeing a higher incidence of stomatitis or mucositis, which was present in 69% of patients. And then there are some also ocular surface events, so eye toxicities that are grouped together in about a third of patients. One thing to note, both the drug-related ILD independently adjudicated for both datopotamab deruxtecan and patritumab deruxtecan sits right at about 5%. So certainly present, but not as high as what we see with trastuzumab deruxtecan.

And so where are we with datopotamab deruxtecan? So we just saw in November, so 2 months ago, that datopotamab deruxtecan submitted a new drug application, a BLA, for accelerated approval for patients with previously treated EGFR-mutant non-small cell lung cancer, so the similar indication as patritumab deruxtecan. And then in terms of ongoing studies, there are 2 important ongoing studies in EGFR-mutant lung cancer with datopotamab. The first 1 is a first-line study where they're looking at osimertinib monotherapy versus osimertinib plus datopotamab deruxtecan in the first-line setting. And so this is escalation of therapy that, if efficacious, would compete with osimertinib chemotherapy and amivantamab lazertinib as kind of escalated combination therapy. And then there's a confirmatory Phase III study that is looking at datopotamab monotherapy or datopotamab with osimertinib versus platinum-based chemotherapy, and so looking at does osimertinib add anything to the datopotamab, and then comparing to standard of care second-line therapy, which would be platinum-based chemotherapy. And both of these studies are ongoing but early in the stage.

So what conclusions can we make from these different ADCs? I think 1 thing that seems to be an overarching theme is that perhaps the biomarker for some of these ADCs are the AGA population, where you can see that there is enrichment of efficacy of both datopotamab and patritumab deruxtecan in EGFR-mutant lung cancer. And then I think another important conclusion is, initially when ADCs were being developed, they were thought to be bulky compounds that were large and sort of — there was a hypothesis that there would be limited CNS penetration. But I think the data that we've seen from both patritumab and datopotamab really suggests that there is CNS efficacy that's actually pretty similar to the systemic efficacy where we're seeing kind of CNS responses that are very similar to the systemic response rate. And then with both datopotamab and patritumab, there are efforts to combine the ADC with the targeted therapy, so in this case osimertinib. And so the idea is, is there any additive benefit with continuing the osimertinib in these EGFR-mutant lung cancers that are still dependent on EGFR signaling? And so we would like to see the data of those combinations compared to single agent ADCs.

And following that same theme, there's sacituzumab tirumotecan, which is another TROP2 ADC. And 2 studies that are currently ongoing are Tro-Fuse-004 and Tro-Fuse-009. So Tro-Fuse-004 is again looking at patients with different AGAs, focusing on EGFR-mutant lung cancer, but also allowing the different, other AGAs, including ALK, ROS1, BRAF, NTRK, MET and RET. And it is randomizing patients 1 to 1 to receiving sacituzumab tirumotecan versus standard of care chemotherapy, so either docetaxel or pemetrexed. And the primary endpoint is a shared primary endpoint of PFS and OS.

And Tro-Fuse-009 is more specifically looking at EGFR-mutant lung cancer and allowing both the typical exon 19 deletion and L858R, as well as some of the atypical EGFR mutations, and then randomizing patients after they've received EGFR TKI therapy to either sacituzumab tirumotecan or the standard second-line therapy of platinum-based chemotherapy. And again, the primary endpoint of PFS and OS. And so you see a trend here of all of these studies being looked at as later line therapy but also kind of assessing themselves against platinum-based chemotherapy, moving up to potentially the second line.

And so in terms of where we are with sacituzumab, the FDA granted breakthrough designation to sacituzumab tirumotecan, again, for patients with metastatic EGFR-mutant lung cancer. The initial data that we've seen showed a response rate as high as 60%. It's a small number in 22 patients treated with EGFR-mutant lung cancer and a PFS of 11 months. And so we'll see if that data stands, but again, showing an enrichment of activity of these ADCs in EGFR-mutant lung cancer.

And so in conclusion there, to add, I think you can see a trend here where all of these ADCs are looking at maybe a lower bar or a higher efficacy point in the AGA space as an entry point. A lot of these agents, in particular datopotamab deruxtecan, first they were aiming for a very broad population. If you remember the initial studies, we're looking at datopotamab in all non-small cell lung cancer, adenocarcinoma and squamous cell. And then as we see kind of waning efficacy, there is this thought to look at what subpopulations might be enriched for efficacy. And I think that there is a concentration of ADC development here. And then of course there are also studies combining these different ADCs with immunotherapy for the non-AGA non-small cell lung cancer population. But I think another kind of summary point when looking at these ADCs is that we're going to need a biomarker to select, you know, which ADC would be better. Because in some point in the future, we might have patritumab, datopotamab, sacituzumab for EGFR-mutant lung cancer, but understanding which patient might benefit from which ADC first and whether there is the ability to sequence among the different ADCs is going to be a question that we need to answer in the future.

And so switching gears here and thinking about EGFR exon 20 positive lung cancers, one of the drugs that we've seen some data for is zipalertinib. So zipalertinib is an oral EGFR exon 20 drug. When looked at in exon 20, the response rate looked to be about 40% with a good median progression-free survival. But since that drug began development, of course amivantamab, the EGFR MET antibody has been approved in EGFR exon 20 positive lung cancers. And so a real question is whether you can sequence the different TKIs, the oral TKIs with the antibodies. And so is there going to be cross resistance or is there the ability to sequence?

And so one of the later zipalertinib studies is helping answer that question. And so it's taking patients with EGFR exon 20 positive lung cancer that have already progressed on amivantamab and looking to see if zipalertinib is effective. Primary endpoint was overall response rate and duration of response. The initial interim report, reported on 30 patients who had gotten amivantamab. And you can see, I would focus on the amivantamab only arm. So 18 patients got amivantamab followed by zipalertinib. And the response rate was 50%. If you remember the monotherapy zipalertinib response rate without prior ami was 40%, so really showing pretty comparable efficacy after amivantamab versus not. And the other thing to note is that there were 12 patients that had received another prior oral EGFR exon 20 drug that might've been poziotinib, mobocertinib or investigational agents like BLU-451. And you can see that the response rate was lower, 25% in those cases. And I think that that intuitively makes sense, where if you've gotten another oral EGFR exon 20 TKI and responded and progressed, you're going to see less efficacy with repeating another EGFR TKI.

But I think very promising to know that there is the ability to sequence. And now we have to go both ways, right, where is zipalertinib better before amivantamab or is the better sequence amivantamab after zipalertinib? But I think really encouraging data in an area where we have really limited options.

And so in terms of ongoing zipalertinib studies, there are 2 to note. There's REZILIENT2, which is looking at zipalertinib in the first-line setting, but also in patients with active CNS metastases after other EGFR exon 20 drugs. And so that initial data of zipalertinib post amivantamab did come from REZILIENT2. And then also looking at other uncommon EGFR mutations like exon 18 alterations like G709X or G719 or S768I, which is another subset which we don't know what the best treatment is.

And then REZILIENT3 is the registrational confirmatory study to look at zipalertinib and chemotherapy versus chemotherapy alone as first-line treatment for EGFR exon 20 positive lung cancer. And so this is similar to the study that looked at amivantamab with chemotherapy that led to the amivantamab chemotherapy first-line approval. But I think seeing whether we can utilize an oral drug in that first-line space, there's a lot of interest in that.

DR LOVE: Just a couple of follow-up questions, just getting back to the last thing you were talking about, zipalertinib.

DR YU: Yeah.

DR LOVE: I never exactly understood why mobocertinib got pulled off the market; I guess because it didn't work first-line. But any reason pharmacologically or clinically to think that zipalertinib is going to be different than the prior TKIs that have been looked at, like mobo?

DR YU: Yeah. I mean, I think that it was honestly solely a drug-development issue where mobocertinib kind of made the bet that they would be better as monotherapy compared to chemotherapy, which was kind of a large step to begin with, because if you looked at the single-agent data, the response rate was only 25%. So you're really cutting it close as to whether you'd be better than chemotherapy.

I think zipa is doing a different strategy where they're obviously combining with chemo, right? If you can't beat them, join them, right, that kind of a strategy. But I do think that there's going to be real interest. I mean, we need an oral TKI for exon 20. There's just plenty of people that either can't tolerate amivantamab or don't want it. And so whether it's sunvozertinib, zipalertinib, we need to get some of these approved, soon hopefully.

DR LOVE: So one final question, getting back to Dato in patients with actionable mutations. Did Dato cause objective responses in people with mutations other than EGFR? I know there was RET and all this other stuff in the trial. Were there mutations — were there responses seen there? And is there interest in looking at that more?

DR YU: Yeah. I think there were responses in all of the different AGAs. The response rates were lower. Like I remember the ALK positive lung cancer responses to Dato being lower. And so it's a strategy, right? Like they're focusing on EGFR because it's the largest subgroup and did seem to have the highest efficacy. But they did report responses in the different AGAs as well.

DR LOVE: The other thing is, in the bigger study, Dato had benefit with adeno versus non-adeno or squamous. Do you think that that's because of the actionable mutations in adeno? Or do you think that the benefit in — it's the other way, that the benefit is in adeno and the actionable mutations are along for the ride?

DR YU: Oh, I think it's definitely the former, Neil. I think that there's clearly, like for whatever reason, an enrichment in efficacy of these. They're all going for EGFR-mutant lung cancer, which I think is funny now. So I think that there is an enrichment there. And then I think a kind of negative enrichment where squamous cell lung cancer seems to be less responsive to these different ADCs. But yeah, no, I think that they tried for the broad indication, didn't hit it, right, and so then now focusing on, okay, what subgroup can we look at where that benchmark is met that we might be able to get approval?

DR LOVE: So do you think that if they get enough patients they would see significant benefit in ALK and these other mutants?

DR YU: I think so. I mean, I guess I would say I suppose so, but I can't be sure. So I think we've looked at EGFR-mutant lung cancer from the patritumab studies and really showed that almost all of those cancers express HER3. I don't think we have that data with some of the, like RET or NTRK or ROS1, where maybe the HER3 expression is lower and the response rate might be a little bit lower, but I would expect there to be activity in all of the AGAs, just maybe a little bit attenuated.

DR LOVE: Just trying to sort of see if there's any themes here. I mean, you have the issue that in general, patients with actionable mutations don't respond to IOs, although people — I don't know that we know exactly why, but at least that seems to differentiate that. And then I guess there's some actionable mutations like BRAF, I don't know about KRAS G12C, that maybe are a little different. They maybe do respond to IOs. Like, do you think that BRAF and KRAS would respond to Dato?

DR YU: Yeah. I think that you’re hitting kind of — within AGAs, there's a separation of what I would call the never-smoking-related AGAs and the other, right?

DR LOVE: Right.

DR YU: I think BRAF and KRAS, there are some BRAF V600E, it's bimodal, right, where we think about half of them are kind of like in the never-smoking category, but then half of the BRAFs do have a heavy smoking history and most of the KRAS do. So I think that it has to do with the biology, right? Is this driven strictly by the oncogene or is there smoking-related kind of mutagenesis that leads to probably better responses to IO and less good responses to these more targeted therapies.

DR LOVE: And just to sort of complete that, does that mean that you think more about using an IO in a patient with BRAF or KRAS?

DR YU: Yeah, absolutely. I just had this case in clinic on Friday where there was a BRAF V600E with a heavy smoking history and a PD-L1 of 90%.

DR LOVE: Wow.

DR YU: And I think, for that person, I think pembrolizumab would be appropriate, right? I think —

DR LOVE: Wow.

DR YU: So I think there's probably not consensus. Like some people might give them dabrafenib trametinib, but a lot of people would, I think, start with IO, because IO has that potential tail of the curve, right, where there are people who have durable, even complete responses. And so, yeah, I think — and then for KRAS for sure, I would not. I think — I wouldn't start with 1 of the KRAS G12C inhibitors. I'd do chemo/IO first.

DR LOVE: That case is really great because I thought you were going to hedge your bet by saying chemo plus IO, but you just, pembro, right?

DR YU: Yeah, I mean, I would say, if I had seen them I would’ve been more conservative and hedged my bets, but they got 1 cycle of pembro on the outside and then saw me on Friday and I was like, let's just continue. So she's not having tox. But yeah, you kind of read it. Yeah, I think I would’ve probably hedged, but yeah, but not TKI.

DR LOVE: So interesting.