Introduction

DR YU: Good evening, everyone and welcome to “Consensus or Controversy? Clinical Investigators Provide Perspectives on the Current and Future Clinical Care of Patients with EGFR-Mutant Non-Small Cell Lung Cancer.” I'm Dr Helena Yu and I will be moderating the meeting this evening.

And we have a great panel of faculty today. We have Dr Pasi Jänne from Boston, Massachusetts, Dr Nicolas Girard from Paris, France, Dr Jonathan Goldman from LA, Santa Monica, California, Dr Ramalingam from Atlanta, Georgia, and then Dr Josh Sabari from New York, New York.

And we also have 2 not in-person faculty, nonpanelists, Dr Gadgeel and Dr Spira, who did take a survey. And results from this survey will be shown throughout the meeting.

Here are the relevant faculty conflicts of interest.

Here are Dr Love’s disclosures.

And here’s the commercial support for today. Research To Practice CME Planning Committee, Staff, and Reviewers have no COIs to disclose.

This educational activity contains discussion of non-FDA approved uses of agents and regimens. Please refer to official prescribing information for each product for approved indications.

Alright. This is where we’re headed today. I will begin by discussing first-line treatment. Dr Sabari will discuss EGFR-targeted approaches for relapsed disease. Then, Dr Ramalingam will cover TROP2-targeted therapy. Dr Goldman will talk about nonmetastatic disease. Professor Girard will cover EGFR exon 20-mutant lung cancer. And then, Dr Jänne will finish us out with HER3-targeted therapy.

Evolving First-Line Treatment for Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) — Dr Yu

DR YU: Alright. Here’s my portion, the first talk. Evolving first-line treatment for metastatic EGFR-mutant lung cancers.

So right now, over the last 2 years, we’ve had several approvals. And so we now have 3 options available to us for first-line treatment. We have osimertinib monotherapy. We have osimertinib in combination with platinum-based chemotherapy. And then amivantamab, which is an EGFR bispecific antibody, as well as lazertinib, which is a different third-generation EGFR TKI. We’ll be going through all of these and discussing the different options.

So what do we consider for first-line treatment? The things that, as a clinician, come to my mind are quality-of-life issues. What are the side effects of the different treatment? What is the time and effort that’s required from our patients? What’s the financial cost to our patients? What do they prefer in terms of treatment since there are some that are intravenous and some that are oral? Efficacy, of course, is topmost importance. Progression free survival, overall survival. We know that these patients develop CNS metastases. So what are the CNS efficacy endpoints? And then, how do we sequence treatment knowing that these patients live for a long time, and provide the most options for our patients? And then, we think about risk factors, so patient and disease-related risk factors. Does the patient have brain metastases? Do they have liver metastases? What co-mutations do they have? And then, what are, you know, the ctDNA status?

So first, we’ll start with the standard of care, the historical standard of care, which is osimertinib monotherapy. This is a well-tolerated oral standard of care. It had a clear improvement in PFS and OS over the earlier-generation EGFR TKIs. It’s an oral therapy. When patients are on this, typical MD visit schedule is every 3 months with scans every 3 months. Toxicity profile is manageable. Low rate of treatment discontinuation. And real-world studies have really shown similar efficacy and safety in the larger real-world population.

Data came out at World Lung as well as recently in press looking at long-term safety now that we’ve had osimertinib available for more than a decade. On the AURA and FLAURA studies, people have been on 3, 5, 10+ years. On the FLAURA study, there were 28% of patients that actually were on osi for 3 years or greater. And looking at toxicities, there really were no late emerging toxicities. And the toxicity profile seen upfront is really what was present throughout treatment.

So moving on to FLAURA2. So FLAURA2 was the combination of osimertinib with pemetrexed and carboplatin versus osimertinib monotherapy. And clear PFS benefit, 9 months. The hazard ratio on the study was 0.62.

And then, in terms of safety. We’re adding treatment, so there’s additive toxicities. There didn’t really seem to be any synergistic toxicities. But certainly, more toxicity than osimertinib monotherapy. Of course, you’re getting both treatments for a longer duration. Particularly, upfront in the first 3 months when you’re getting induction therapy with carboplatin and pemetrexed, you’re seeing more cytopenias. And then, over time with the pemetrexed, you can see renal insufficiency, edema. Of course, there’s quality-of-life and financial cost implications of these frequent visits and frequent infusions. And then, you are using treatments that we previously were giving sequentially, in 1 line of therapy.

One thing to remember in terms of recent data that came out. Of course, the exposure of platinum was about 3 months, that first 4 cycles, and the kind of median exposure with pemetrexed was about 8 months on the study. So the majority of patients after 8 months did discontinue pemetrexed and continue osimertinib monotherapy. A key issue, of course, is CNS efficacy. So you can see this was interesting. In terms of the combination, a little bit unexpected. The hazard ratio for patients that had baseline brain metastases was actually the lowest on the study. Hazard ratio of 0.47. And so this is interesting because I think there’s biomarkers that are predictive but then, there are — biomarkers that are prognostic but then biomarkers that are predictive. And I think here, this clearly shows that there’s something about the combination, there’s synergy for patients with brain metastases, which was somewhat unexpecting knowing that osimertinib monotherapy has such good CNS penetration. And then, you can see from the figure on the right that the time to CNS progression was longer on the combination.

And then, overall survival. We’ve seen immature data where there’s a trend towards a benefit with the combination. Hazard ratio at last check was 0.75, but this is not mature data.

In terms of subsequent treatments, I think this is important when we compare the different regimens. Of course, there is about 20 to 25% that did not receive subsequent therapy, which is important to note about always using your best therapy first. But of the patients that discontinued therapy and went on to new therapy, 81% of the patients on osimertinib monotherapy did cross over and receive platinum-based chemotherapy. And I think that comes to be important when we think about survival in subsequent lines of therapy.

And then finally, amivantamab and lazertinib. This is from the MARIPOSA study. Again, a clear marked PFS benefit of about 7 months. Hazard ratio was 0.70. One thing to point out comparing this study to FLAURA2 is this study did require CNS imaging assessments for all patients on study with or without brain metastases. So that did potentially also show us the rate of asymptomatic CNS metastases.

Safety, I think there are unique toxicities with amivantamab and lazertinib. You’re seeing EGFR-directed toxicities, particularly paronychia, rash and stomatitis. The MET-directed toxicities, hypoalbuminemia and peripheral edema can be treatment-limiting for some patients. And then, unexpectedly, there was an increased risk of VTE that seems to be unique to amivantamab and lazertinib. So 37% of patients developed some sort of VTE. And so prophylactic anticoagulation is recommended with this regimen. And again, this is front line, so we need to be thinking about quality-of-life and financial cost of frequent infusions. We saw really good data that I think some of my colleagues will talk about in terms of preventing or mitigating toxicities with the COCOON trial and SKIPPirr, which definitely can help address some of the toxicities with the regimen.

And this was the big data from ELCC earlier this year. We saw the overall survival data. So a clear hazard ratio of 0.75. And the difference or benefit in survival of the combination was anticipated to be greater than 12 months. So this is the first combination study — combination regimen in the first-line setting that has demonstrated a survival benefit.

CNS efficacy, also good with the combination. I think 1 question is crossover when we think about survival. So amivantamab was not available commercially during the duration of this study. So it was only 3 patients out of 173 that were in the osimertinib arm that were able to get amivantamab in the later arm. And so I think thinking about access. We know amivantamab is active but perhaps, there is a role for it in the second-line setting.

And that really is the MARIPOSA-2 study, which looked at amivantamab with chemotherapy, and really did show an impressive hazard ratio of 0.48 with the combination in second line. And then, did show a clear trend towards overall survival benefit as well. So I think the question is, is the survival benefit amivantamab at any time versus no amivantamab? And I think there’s a real rationale to think about reserving efficacious but more toxic therapies for the later-line setting when other options may be limited. We can hear what our colleagues have to say.

And then most importantly, what do our patients want? So Ivy Elkins, the late Ivy Elkins was a patient advocate, and she wrote a really important editorial talking about how, of course, she wants to extend her life as long as possible, but she had concerns about what that life would be like. And for her, the 9-month benefit in progression free survival was not worth the added toxicity. There was also a Chinese survey of a large number of patients, family members and medical doctors. And the vast majority, 70 — over 70% said that despite the 9-month benefit with combination therapy, they wouldn’t recommend it. And so I think that’s important when we think about exactly what our patients want. And then finally, financial cost. I think there is data that the out-of-pocket cost for patients is significant. And thinking about more visits, more frequent supportive care medications. There’s a cost for that, for sure.

And then, I think thinking about risk-adaptive treatment, to wrap up. I think there are different EGFR-mutant lung cancer patients. It’s a very heterogeneous disease. And when looking at these 2 patients I put up here, you don’t feel like you should treat them the same. And so how do we escalate or de-escalate treatment? And at what timepoint should we escalate?

And then, thinking about what we could use for risk stratification. I think that CNS metastases might be a good potential risk stratification as well as maybe ctDNA clearance or baseline ctDNA.

And then finally, this is my last slide. No size fits all, right? I think this is shared decision making as well as risk stratification. We need to see what our patients want, patient-related factors, disease-related factors, molecular factors. And we want to risk stratify patients who need it the most. But think about for lower-risk patients, if we can identify them, optimizing quality-of-life and sequencing for them. But I think with this OS benefit, in my opinion, it’s opting out of combination therapy for treatment for de-escalation. And then, the default is combination therapy.

Okay. So racing through that. So these are some of the questions that we asked patients — or asked our colleagues. So regulatory and reimbursement issues aside, which first-line therapy would you give someone, 65-year-old patient, metastatic disease, minimal disease burden, EGFR exon 19 deletion, PD-L1 0? So let’s hear from Professor Girard who said amivantamab and lazertinib. Why?

PROF GIRARD: Well because we need to do better in these patients than osi mono. And then, how to choose between FLAURA2 or MARIPOSA? Well this is a matter of sequencing. This patient is likely to get second line, to get access to second line, which is not the case for all the patients. So I would keep chemo for later lines. You told us that it’s good to reserve the most toxic drugs for later lines. Well, I believe chemo is the most toxic one, so I would give ami/lazer first and then have a second line based on chemo or a chemo combination regimen.

DR YU: And maybe, Dr Goldman, you also said combination therapy. But how come you’re choosing osimertinib/chemotherapy versus amivantamab/lazertinib for this patient?

DR GOLDMAN: So I think this is maybe one of the most complicated questions we get now. If they were 55, I would have gone for ami/lazer. If they were 75, I would have gone for osi alone. But 65, I thought it was a challenge. And really, in the end, it really would be a patient discussion. I find that osi/chemo, for me, has been better tolerated than ami/laz. And looking at this patient, hopefully, to have many years ahead of them, the idea of coming in every 2 weeks, et cetera, you know, rash, et cetera, seemed challenging. So I chose for this patient without symptoms to get the simpler, easier regimen.

DR YU: And then finally, Dr Ramalingam. So osimertinib alone for this patient. What made you choose that?

DR RAMALINGAM: Yeah. My go-to for patients who have low-risk, low-burden disease, low symptoms is to do monotherapy. Quality of life is important. You already mentioned the toxicities associated with combination approaches. And this is a conversation we have with the patient. I think the difference between coming every 3 months, getting a scan and being able to live their life on versus coming every 3 weeks, dealing with adverse events, are markedly different. And that’s why I still find osimertinib to be a very good go-to option in these patients.

DR YU: Okay. Let’s change the scenario a little bit. So this is, again, a 65-year-old, symptomatic, has significant tumor bulk and burden of disease, no brain metastases, again, exon 19 deletion, PD-L1 0. Now, you can see the answers are different. So none of our panelists agreed, you know, recommended osimertinib monotherapy. Dr Jänne, in this situation, how come you chose osimertinib/chemotherapy over amivantamab/lazertinib?

DR JӒNNE: Well here, you have someone who is symptomatic with disease, bulky disease and, fortunately, with the good EGFR mutation, the exon 19 deletion. So my thinking here was combination therapy. And I do think of the 2, osimertinib/chemotherapy, in my mind, is better tolerated than amivantamab/lazertinib. And hence, the reason I chose that.

DR YU: I’m going to push you there. So is there a patient scenario where you would give amivantamab and lazertinib? Or is your combination go-to regimen chemotherapy with osimertinib?

DR JӒNNE: For me, it’s chemotherapy and osimertinib. I don’t have a clear scenario where I would give amivantamab/lazertinib. I think that, although it’s a discussion with the patient, of course, given the survival benefit. But I think if I choose a combination upfront, I typically use osi/chemo.

DR YU: Okay. This seems we had consensus here even with our remote faculty, 85-year-old, symptomatic, significant tumor bulk and burden, again, exon 19 deletion, PD-L1 0. Nobody is giving this 85-year-old osimertinib. I guess, does anyone want to comment on the discussion that they have with patients? And what percentage of patients, if you have a rough estimate, are, despite the discussion of survival benefit, PFS benefit, choosing to have osimertinib alone? Anyone?

DR SABARI: Yes, I’ll take this.

DR YU: Josh.

DR SABARI: So if this is a patient who is playing pickleball, who is active, who wants to be more aggressive, I would clearly talk about combination strategies. But I think the whole group here agrees that in a frail patient, a patient who is older, I think we do focus more on quality over quantity. And it’s important to think about sort of how that discussion happens in our clinic. These are sort of broad questions. But an 85-year-old playing pickleball who is active, I would offer them a combination if they were willing to take on the additional toxicity.

DR YU: Okay.

PROF GIRARD: Chemotherapy is hard, actually, to deliver in an octogenarian. So yeah, I believe that osi plus chemo would not be an option for this patient.

DR YU: And this is a little bit different, this case scenario. Again, 65 but several symptomatic brain metastases. Otherwise, the same. We see some people choosing amivantamab/lazertinib, some osimertinib/chemotherapy. Maybe someone that chose osimertinib/chemotherapy, Dr Jänne, why that over amivantamab/lazertinib? What do you make of the CNS data with the osi combination?

DR JӒNNE: Well as you mentioned, it was a little bit surprising to see that there was such an added benefit of chemotherapy with osimertinib. But clearly, the response rate was higher in patients with CNS metastases with the addition of chemotherapy. The intracranial PFS was longer with osi/chemo compared to osi. And the occurrence of new CNS disease was further delayed. So that was my reasoning here for the combination.

DR YU: And then, Dr Sabari, with the CNS data for both options, why ami/lazer for you?

DR SABARI: Yeah, that’s a great question. I think it’s great to hear that we’re looking at reasons to de-escalate as opposed to escalate. Everyone here is doing combination strategies except Dr Spira, so I’ll have to have a discussion with him. But amivantamab/lazertinib, we had interval surveillance imaging in the brain. We know intracranial PFS. So if you look at 3-year landmark data, significant improvement in PFS there. So I don’t have that sort of long-term data, particularly intracranial data, in the osi/chemotherapy study.

DR YU: Okay. Next, we have, again, a 65-year-old, EGFR exon 19 but now, we’re talking about risk factors in terms of co-mutations, so p53 and RB alterations, which we know are the co-mutations that put someone potentially at risk for small cell histologic transformation. And then, again, probably down the line where it’s nearly 50/50 in terms of amivantamab/lazertinib and osi/chemotherapy. What do we know about mechanisms of resistance? And do we know whether histologic transformation is different in frequency between the 2? Anyone have a comment? Josh, you’re looking at me.

DR SABARI: Yeah. So here, we don’t have the data, right? Small cell transformation is one of those things that really bothers us and we don’t have great treatment options. Patients transform and we’re no longer able to give potential targeted therapies. We move to chemo alone or chemo in combination with osimertinib. So for a patient like this, this is a data-free zone. And again, I’m glad to see that all the advisors here are thinking about combination strategies. Again, high-risk patient here. I don’t have any data to support one versus the other.

DR YU: Yeah, I don’t think any exists yet. But I think would be important because that is one of the more, obviously, serious mechanisms of resistance that make the treatment for these cancers much more challenging. I think we have 1 more. What treatment would we recommend for a patient with locally advanced unresectable disease with an EGFR exon 19 deletion, PD-L1, so this is received chemoradiation followed by 2 years of osimertinib, so following the LAURA study, was on osimertinib and then experienced disease progression as described? And what would happen if it happened 9 months into osimertinib versus 2 and a half years? Looking at the — a lot of different answers here. Professor Girard, why — you suggested chemotherapy or maybe with ivonescimab. Tell us why.

PROF GIRARD: Yeah. Actually, it depends on the delay since chemotherapy. If the recurrence is occurring while on the osimertinib as consolidation or adjuvant, I would switch to a second-line regimen. If it’s after the discontinuation of osi, obviously, we start again probably with ami/lazer or rechallenge with osi plus chemo. But we miss data, actually, in such a situation.

DR YU: And, Dr Jänne, so I think that with, you know, you chose osimertinib for both scenarios. But what if the progression was, again, if the osimertinib was discontinued and they progressed, 1, what is the interval that you would feel comfortable with a retrial of osimertinib? And then what would you do if the progression was immediately while on osimertinib?

DR JӒNNE: So my interpretation of this was that this recurrence happened after these intervals off osimertinib. In which case, I would rechallenge with osimertinib. And this is likely due to the fact that once you took — once the person stopped osimertinib treatment, there was some residual disease that was able to survive and appeared at 9 or 2 and a half years later. It’s not really resistant, but was able to survive despite osimertinib, and likely would re-respond. I think in contrast, when somebody progresses while on active therapy in the adjuvant setting or following chemotherapy/radiation, it's kind of like progress — it’s analogous to progression with metastatic disease that you’re now dealing with osimertinib actual true resistance mechanisms like in the metastatic setting. And there, I would use a combination approach.

DR YU: And then, I guess, lastly because we have a minute, I think. What are you guys, you know, with our patients now, we have these 3 options. Are you discussing all 3 options with your patients, Dr Ramalingam? Or do you have sort of ideas of what you think are best that you’re discussing maybe 1 or 2 options?

DR RAMALINGAM: Yeah. I talk about the fact that there are 3 different options. But I tell them how I feel, given their risk factors, what would be the most appropriate for their situation. And once you get down to that, if it’s combination approach, then I talk about the pros and cons of chemo/osi versus ami/lazer.

DR YU: And is it toxicity that sort of helps you guide patients or are there specific risk factors that would prompt you to do one versus the other?

DR RAMALINGAM: These are both very effective regimens, so I’m not concerned about there being a bigger difference in efficacy advantage from one to the other. It boils down to tolerability, side effects management and which one I think would be optimal for the patient.

DR YU: Great. A complex, ever-evolving first-line space. And, of course, what we do first line then dictates what we have available later.

EGFR-Targeted Approaches for Relapsed EGFR-Mutant NSCLC; Strategies to Facilitate Delivery of Recently Approved Agents — Dr Sabari

DR YU: So the next talk will be relevant. Dr Sabari is going to talk to us about the EGFR-targeted approaches for relapsed disease; strategies to facilitate delivery of recently approved agents.

DR SABARI: Thank you, Dr Yu. So when we think about resistance, it’s a complex sort of genetic alteration, acquired resistance. But what is resistance? We all see it in the clinic every single day. A patient is responding to therapy and then, no longer responding over time. Patients are often symptomatic. And here’s a patient I had treated on osimertinib. And you can see dramatic regression in that left upper lobe mass. But over time, recurrence and sort of increased burden of disease.

And Dr Jänne and others here on the stage have studied this. What drives this resistance? Well you can identify resistance mechanisms. And it depends on whether you received a third-generation EGFR first or whether you received a first gen followed by a third gen. And what you can see is that in third-generation EGFR TKI treated patients, the resistance mutations are quite complex and heterogeneous. So it’s not an easy story to solve here. Maybe 10, 12% have C797S, a point mutation in EGFR exon 20. And then, others have other bypass track mechanisms like MET amplification. But there is no 1 dominant resistance mechanism in this patient population.

So when we think about resistance mechanisms, we try to group these into different categories. So you can have mutations in the drug target that affects binding of the drug. Generally, point mutations in EGFR. You can have bypass track signaling. And then, you can also have mutations sort of downstream. And what Dr Yu had mentioned earlier, you can have histologic state transformation, so adenocarcinoma transforming to small cell or squamous cell histology. And then, really, no longer responsive, in my opinion, to targeted therapy alone.

So how do we target this resistance? Well if you biopsy a patient and you identify a resistance mechanism, can we use a targeted therapy in combination with a third-generation EGFR TKI? So here’s just 2 datapoints or 2 sort of cases looking at if a patient develops an acquired RET fusion, can you add a RET inhibitor? And yes, we do see response with the addition of the RET inhibitor, although it’s very short-lived. If a patient develops an acquired ALK fusion as a resistance, you can see radiographic regression. Patients benefit, but these are very short-lived responses.

So there is an ongoing study, the ORCHARD trial, and we’ll hear a little bit about it from Dr Ramalingam, but looking at adding specific targeted therapeutic options to osimertinib, a third-generation EGFR TKI. One that we’ll talk briefly about is MET, so adding savolitinib to osimertinib. We’ll hear a little bit about Dato-DXd, an ADC-targeting TROP2, adding it to osimertinib. And these are all incremental strategies, in my opinion.

Here's this study, the INSIGHT 2 study, where we looked at the combination of tepotinib, a MET tyrosine kinase inhibitor, in MET amplified patients post-osimertinib. And there was an impressive response rate, about 50%. But the progression free survival, about 5, 5 and a half months.

So thinking about more agnostic strategies. We heard briefly about the MARIPOSA-2 study, but I want to talk about the front-line for a moment. Because the front-line regimen will affect what you then give in the second line and will affect what your resistance mechanisms are. So we heard from Dr Yu that first-line MARIPOSA, ami/laz versus osimertinib. There was a third arm of lazertinib contribution of components.

And when you look at an early look at those early progressors in both arms, what you note is that the MET amplification resistance mechanism is more common in those patients treated with osimertinib alone at about 13.6% versus amivantamab and lazertinib, much lower, 4.4. And again, this is paired liquid biopsy. There’s a lot of sort of heterogeneity. There’s a lot — take this data with a grain of salt. But it’s interesting to think about what resistance you develop on your first-line setting. If you look at secondary EGFR resistance mutations, there’s about a 7- to 8-fold reduction with ami/laz for C797S and other EGFR-mediated resistance mechanisms. So what you use in the front line will affect your potential resistance in the second line.

So moving more to a biomarker agnostic approach. When we think about bispecific monoclonal antibodies, we heard about amivantamab, an EGFR and MET ADC. This is a randomized Phase III study looking at chemotherapy as the control arm versus ami/chemo. There was an arm of ami/laz/chemo. But due to toxicity, the data was put on hold. And the study is ongoing with some modifications.

So here’s the primary objective response rate, about 64% for amivantamab/chemo, over 36% for chemotherapy alone.

And we already saw this, an impressive hazard ratio for progression free survival. Ami/chemo, 6.3 months versus chemo alone, 4 months. Hazard ratio of 0.48.

But I think most important, and what we all care about with our patients, yes, quality-of-life is really important. But when you ask patients, they want to live longer. And here, what you see is a tremendous improvement, a trend towards overall survival. So for the 18-month landmark for ami/chemotherapy, 50% of patients are alive versus chemotherapy alone at about 40%.

Clearly, there are toxicities. And we’ll talk a lot about toxicities for amivantamab/chemotherapy. We see EGFR mediated toxicities, cutaneous toxicities. We also see infusion-related reactions for the IV formulation. We also see increased risk of VTE, but more common in the ami/laz than ami/chemo arm.

We also looked at this formulation, the subcutaneous formulation. Here’s the Phase III study of the PALOMA trial. This was presented by Natasha Leighl. This is an equivalence study looking at IV formulation amivantamab versus subcutaneous formulation of amivantamab.

And what we saw was that pharmacokinetically, these were very similar. No differences in the pharmacokinetics of subQ versus IV.

But what was quite shocking to all of us was that there was an improvement in overall survival with the subcutaneous form over the intravenous form.

And this led to an ongoing clinical trial now in the front-line of subcutaneous amivantamab and lazertinib. What was also really impressive is you saw a tremendous reduction in the rate of infusion-related reaction, 13% of subcutaneous versus in the IV arm, about 66%.

So can we prevent these infusion-related reactions? So we saw data for the SKIPPirr. Yes, prophylactic dexamethasone, 8 mg BID 2 days before, a day before will reduce the rate by about 3-fold.

And we also saw that we can reduce the rates of cutaneous toxicities. This is the COCOON trial we saw presented at ELCC and we have the presenter here, I think, on stage. And when you think of this data, using a prophylactic regimen of, you know, chlorhexidine rinses, topical ceramides, as well as oral antibiotics, we can significantly reduce this.

And this is what patients complain about in clinical practice, right? The cutaneous EGFR mediated rash, the paronychia, the breaks in the skin and the nailbeds, as well as some of the scalp reactions that we can see.

So if we use the COCOON regimen, at this study, we saw a dramatic reduction in cutaneous Grade 2 or greater adverse events when we use prophylaxis. And this is now standard of care in my clinical practice. So what are we doing? Prophylactic doxycycline, 100 mg twice a day. We talked about nail cleansing agents with chlorhexidine, as well as ceramide-containing emollients, so moisturizers and other products in this setting.

So we know that acquired resistance is inevitable in the front-line setting. We still have not cured patients with EGFR-mutant lung cancer. And we said that the resistance mechanisms to first- and second- and third-generation EGFR TKI are quite heterogeneous. And we need to think about broader sort of approaches, potentially combination approaches. And MARIPOSA 2, I believe is one of the sort of standards now in the second-line setting. We saw a response rate we talked about of 64%. I didn’t mention, but phenomenal intracranial response here. PFS 12.5 months. And the OS, we saw 50% of patients alive at 18 months.

We just saw this press release this morning. So if anyone is following the news of ivonescimab, a very interesting bispecific antibody. It’s a PD1 VEGF antibody. And this is a study that had positive data in China in the EGFR-mutant patient population in the second-line setting. So patients who’ve been treated with a third-generation EGFR TKI, in the second line got ivonescimab plus chemotherapy. And we saw dramatic responses, dramatic progression free survival, I think, in this patient population. Here, we’re seeing the press release for the HARMONI study. Here, it has a US presence. I think close to 40% of the patients enrolled are in the US. And positive for progression free survival. But just missed narrowly on overall survival. Hazard ratio here of 0.79. And you can see the confidence interval clearly crosses 1. So we look forward to seeing some of the updated data. Again, a very exciting space for our patients. And I thank you for your attention.

DR YU: Thank you, Josh. I think immunotherapy in this EGFR-mutant space is a huge unmet need. And so we’re excited to see the ivonescimab data and some of the other therapies that are coming in the pipeline.

So our first discussion question on this section. In general, for a patient with metastatic nonsquamous non-small cell lung cancer, EGFR exon 19 deletion, PD-L1 0 who receives first-line targeted treatment followed by response, then progression, would you recommend repeat mutation testing? And if so, liquid or tumor tissue? Dr Girard, what are you doing?

PROF GIRARD: Well, it’s recommended to repeat mutation testing because if you have another alteration, bypass or a resistance mutation in the EGFR kinase that drives you to additional options and chemotherapy or chemotherapy plus amivantamab, transformation into small cell. If we do not do the biopsy, it will be very difficult to identify those patients.

DR YU: So what are you finding on these biopsies that are actionable that you’re actually changing treatment?

PROF GIRARD: So small cell, for sure. Probably secondary EGFR mutation. We have seen some data with combination of osi plus third-generation TKI. Obviously, BRAF V600, you will treat the patient with targeted agents. So yeah. If we do not look at those alterations, we will not find the alteration.

DR YU: Yeah. And then maybe a comment from Dr Ramalingam for using the liquid biopsy first and then if negative, moving on to tissue. Tell us the rationale.

DR RAMALINGAM: Yeah. So one caveat to what I answered is if the patient had a baseline p53 mutation or RB1 loss, before I started first-line therapy, I would directly go to the solid tumor biopsy because liquid biopsy may not give me the whole answer. Otherwise, it’s easy to do. In a week or so, I have results available. It helps me find out if there’s secondary mutation. If there’s a fusion, I’ll find out. And MET also, liquid biopsy makes good calls. So you can choose MET for targeted therapies. And, therefore, it’s my go-to.

DR YU: Are you finding that there are some things missed on the liquid biopsy that you find in the tumor tissue besides the transformation? The sensitivity, is it different?

DR RAMALINGAM: Actually, the sensitivity is pretty good between liquid and solid tumors. There’s hardly any situation where you would find something new. I go to solid biopsy — if the liquid biopsy comes back completely negative, then I resort to it. But if I have a slew of findings on liquid biopsy that are not targetable, I’m not going to go and do a tumor biopsy.

DR YU: Yeah, I think the good thing here is we know they have the driver EGFR mutation. So if we find that and the absence of other things, that’s more likely to be a negative than if we find nothing. Then, clearly, we need to look at the tumor tissue.

DR RAMALINGAM: Yeah.

DR YU: Josh?

DR SABARI: I think just for a point on the liquid biopsy here. Liquid biopsy alone is insufficient. But I think that you do understand the heterogeneity of the tumor better with a liquid biopsy than you do of a single biopsy of a growing lesion. So I think it’s important to use these sort of in compendium, together. If you have 1 lesion growing, biopsying it and treating that lesion makes sense. But we do rely on both of these in our clinical practice.

DR YU: And I would say that the liquid biopsies are getting more complicated where you do see multiple mechanisms of resistance. And then, it becomes a little challenging to figure out what’s driving resistance. Sometimes, I use the variant allele frequency to sort of get a sense of maybe there is 1 dominant driver amongst those. But it can be challenging.

Our next question is we have a 65-year-old again, exon 19 deletion, PD-L1 0, first-line osimertinib, experiences asymptomatic disease progression. With regulatory and reimbursement issues aside, after first-line osimertinib, what would you recommend if a patient had acquired no further mutations? Maybe Dr Goldman. So you said MARIPOSA 2, amivantamab and chemotherapy. Is that your go-to post-osimertinib?

DR GOLDMAN: That is. I think you’ve got — they’re already coming in for treatment. You’ve got a proven regimen that’s deliverable. The patient has, unfortunately, progressed. And so often, is willing to undergo more toxicity to get some benefit.

DR YU: And, Dr Jänne, I think you are of the desire to continue the osimertinib and add chemotherapy. Is there a certain patient you would do that for? Explain the rationale.

DR JӒNNE: So certainly, if someone had, initially had CNS disease and that became well-controlled or even disappeared on osimertinib, my preference is to add something to osimertinib as opposed to discontinue it altogether, as I worry about reappearance of the CNS disease when there’s been systemic progression like in this case.

DR YU: I think we’re expected to see the results of the COMPEL trial, hopefully, soon. That is the study looking at after progression on osimertinib when we add chemotherapy, continuation of osimertinib versus just the platinum doublet. And I do think that that’s going to help inform in what situations is continuing the osimertinib helpful.

PROF GIRARD: The IMPRESS trial was a negative trial with third-generation TKI.

DR YU: Correct. So what do you think? Do you think that there — thoughts about positivity on this with the osimertinib and the CNS control?

PROF GIRARD: I don’t know. But in MARIPOSA-2, we have a fair CNS component that is probably driving the world PFS benefit. So CNS efficacy is what’s seen, and maybe coverage of the MET activation is probably another question.

DR YU: Yeah, very interesting. We’ll see those results. So in this situation, we have, again, a 65-year-old, exon 19 deletion, PD-L1 0, first-line FLAURA2, so osimertinib with chemotherapy, experiences asymptomatic disease progression after 18 months. Say we had all the options available to us, reimbursement and regulatory-wise, what would be our second-line treatment recommendation if there were no new acquired mutations? Maybe, Dr Goldman, it sounds like — well this might change. Patritumab deruxtecan.

DR GOLDMAN: You and me together, yeah.

DR YU: If we had it available, explain why.

DR GOLDMAN: So this has become a really complicated question. But I do find, I’ve found patritumab to be particularly well-tolerated among the ADCs. And this patient is asymptomatic, has already had chemotherapy. So this is where we really do need new agents. And I thought that the tolerability of patritumab, I would recommend it over Dato, for example.

DR YU: Yeah, I agree. And just for those that don’t know, the patritumab deruxtecan is a HER3-directed antibody drug conjugate that Dr Jänne will discuss later. So, Dr Ramalingam, you said chemotherapy and amivantamab. So this patient got chemotherapy previously. What’s your thought process about repeating platinum doublet therapy? Is there an interval where you feel comfortable retrying?

DR RAMALINGAM: Yeah. So the answer to this goes back to how I use chemotherapy in the front-line setting with osi. I use 4 cycles of chemo, and I stop the chemo. I do not use maintenance pemetrexed. So in this patient, I looked at 18 months later, let’s say, the patient has progression. I feel comfortable rechallenging with a combination doublet. If somebody was already getting maintenance pemetrexed leading up to this point, my option would not be amivantamab plus chemotherapy.

DR YU: And so that’s with everyone? You don’t continue maintenance?

DR RAMALINGAM: I don’t continue maintenance pemetrexed.

DR YU: And we know that the median exposure was about 8 months, so we know that there are quite a few people who do similar or at the first sign of toxicity, discontinue the pemetrexed. Dr Sabari?

DR SABARI: Yeah. I think if you look at the trial, the FLAURA2 trial, the recommendation is continue pemetrexed maintenance. And that’s where we see the PFS benefit. So if I was going to use the FLAURA2 trial as a regimen for my patient, I wouldn’t want to prevent that. Now, you do give patients better quality-of-life off chemotherapy. But I think for the second-line setting, sure, if a patient is off chemo for a long time, I would start ami/chemotherapy. But if I was going to use FLAURA2 in the front line, I’d like to continue pemetrexed maintenance.

DR YU: I’m going to put you on the spot. Dr Spira said amivantamab/lazertinib. Is there a situation where you would use that if we had that reimbursement, you know, regulatory approved?

DR SABARI: I would not. I think, again, remember the label is for the front-line setting based on the MARIPOSA data. There are patients who don’t want chemotherapy in the second line, and this is a “chemotherapy-free regimen.” But there is increased toxicity with amivantamab and lazertinib. And I think the data that we have to support utilization is with ami/chemo in the second-line setting. So I’m sticking with that.

DR YU: Okay. Here’s our next situation. So this is a person who received, same clinical situation, but received first-line MARIPOSA with amivantamab and lazertinib, had asymptomatic disease progression after 18 months. So after ami/lazer, what would you use second line? And maybe, Dr Goldman, so you would use chemo +/- bevacizumab. Explain that to me.

DR GOLDMAN: So I think this is a nice spot for chemotherapy. Bevacizumab is not a drug I’m using that much anymore, but I do think it does improve response rates usually with minimal toxicity. It’s actually been a little while since I’ve done it, but putting in atezolizumab also is something that I don’t think is totally unreasonable, and sort of following along with the potential ivonescimab story. So I think it’s — but I probably would do chemotherapy.

DR YU: And would you continue osimertinib in that setting? Or actually, not continue. Would you switch to osimertinib in the setting, or no?

DR GOLDMAN: Usually not. In general, I would not. There are — I’m sorry, I’m trying to remember if this is particularly a CNS disease. I don’t think it mentioned that there was CNS disease upfront. If I feel like we’ve barely been keeping CNS disease under control, that’s a different scenario where I would continue it.

DR YU: And then, Dr Girard, you put a couple answers. If you had to choose 1 of those, put your nickel down, what would it be?

PROF GIRARD: Probably the chemo plus ivonescimab. I’ve not seen the data, but the PFS hazard ratio seems pretty high. So I want to do chemo probably, optimize chemo if possible, that would probably be a good option. And then, I answer the patritumab, but we will discuss that later probably. There are also some data with Dato.

DR YU: Okay. And then, we’re going to end with — so using COCOON. So Dr Sabari mentioned this. When you give amivantamab/lazertinib or chemotherapy with amivantamab, he mentioned the COCOON study with the dermatologic prophylaxis. Are you doing this? And do you find it to be effective? I guess I’ll start first in saying that I do think it helps. I think it mitigates or attenuates, but I don’t think it completely takes away the toxicity. And I’ve had patients tell me it takes a very invested patient with, like, the willingness to buy all these things. And one person told me it took an hour every day to sort of do the nail and skin care that’s required. Dr Jänne, you said it was effective. What are your thoughts?

DR JӒNNE: Yes. I definitely use the enhanced dermatologic management. And I do find it to be effective. I agree with you. I don’t think it completely eliminates the dermatologic side effects, but it certainly reduces them.

DR YU: Okay. We’re going to move on.

Potential Utility of TROP2-Targeted Therapy in the Management of EGFR-Mutant NSCLC — Dr Ramalingam

DR YU: So next module, Dr Ramalingam will talk us through the potential utility of TROP2-targeted therapy in the management of EGFR-mutant lung cancer.

DR RAMALINGAM: Thank you, Helena. So we had a nice discussion about first-line therapy. And Dr Sabari led us into mechanism-based second-line therapies that are emerging. I’ll talk specifically about TROP2 as a potential target in patients who have developed acquired resistance, and perhaps has implications of first line down the road.

I’ll focus on these 2 drugs, datopotamab deruxtecan and sacituzumab tirumotecan. If you say that without slurring, you get extra points. These are 2 distinctly different drugs that target TROP2. Dato, which I’ll use that word for the rest of my presentation, has a deruxtecan payload. Saci targets TROP2 with the SN-38, which is an irinotecan metabolite, which you’re familiar with in chemotherapy terms. So these 2 have the same target, different payloads, and different linker mechanisms that have implications for toxicity.

Now why TROP2? TROP2 is expressed in lung cancer. These are TCGA data. When you look at those 2 boxes, lung cancer tends to be among the tumors that have higher expression of TROP2, both squamous and adenocarcinoma are called out. And there is clear expression of the target.

Now specifically, drilling down these data. Close to 1,000 patients in the dataset. You see comparable levels of TROP2 expression, maybe slightly higher in squamous cell. When you look at EGFR versus EGFR nonmutated patients, you don’t see a big difference between TROP2 expression. But what you take home from this is in EGFR mutated tumors, TROP2 is expressed. And for an ADC to work, all you need is the target to be there. If the majority of the patients have this target, at least you’re justified in using drugs that target — ADCs that target.

So this is TROPION-Lung05 study. This is now published. This was given — this study administered datopotamab 6 mg/kg every 3 weeks. This was given to patients with actionable genomic alterations, a number of them. And they had all previously received prior therapy with appropriate targeted agents and even cytotoxic agents.

So in this trial, when you look at the overall efficacy, results were favorable for a wide variety of molecular alterations that are seen in lung cancer. Specifically in EGFR mutated patients, there were 78 of them. Response rate was 44%. PFS was about 5.8 months. And the median duration of response, 7 months. So meaningful results in this patient population once you’ve run out of targeted therapy options.

What about correlation with target expression? At least based on analysis of about 60-odd patients, there didn’t seem to be a big difference in TROP2 expression levels between patients who had a great response, no response, and a modest response. So at this point in this study, you can’t use the level of TROP2 expression to decide who gets therapy or not. We have to wait to see the other biomarkers that are being explored in this space.

Toxicity with datopotamab. I’ll call out 2 specific toxicities one needs to be aware of. One is stomatitis. You see about 10 to 11% Grade 3 stomatitis. You see about 25% — or 22% Grade 2 events. So this is something that needs to be managed proactively. I’ll talk about toxicity management in a few minutes. The other toxicity is corneal toxicity. While most of them are Grade 1 or 2, these are something that one needs to be aware of, so you’re checking with the patient regularly to see if they experience it so you can intervene early on before they develop serious events.

Another report that was shared at the ESMO meeting last year was a pooled analysis. TROPION-Lung05 and Lung01, these 2 trials — the Lung01 had other molecular alterations besides EGFR included. So the investigators decided to call out the EGFR mutated patients from these 2 studies. They all received 6 mg/kg. When you add it up, the EGFR mutated patient population was about 117 patients.

And for those 117 patients, if you look at the overall baseline patient characteristics that are summarized, these are patients who’ve received multiple prior systemic therapy regimens. Majority of them had EGFR exon 19 or 21. They also had some EGFR exon 20 T790 mutated patients.

The results were very similar to what we just saw in TROPION-Lung05. The response rates were approximately 42%. The median duration of response was about 7 months. Median PFS was about 5 and a half months. So this analysis shows yet again that this could be an active agent.

This is a press release from about 4 months ago. Dato has been granted priority review in the United States for patients with previously treated advanced-stage EGFR mutated non-small cell lung cancer. So more to come on this.

More recently, at the ELCC Congress 2 months ago, this study was presented. You heard about the ORCHARD trial from Dr Sabari’s presentation where patients received first-line osimertinib and then when they progressed, they had molecular testing to see what alteration led to the acquired resistance. If they could not be matched to a specific targeted agent based on mechanism, they were given either osimertinib plus datopotamab at 4 mg/kg or 6 mg/kg. So it was randomized to 2 different doses of Dato.

And in this study, the PFS results were about 9 to 11 months favoring the 6 mg dose of datopotamab. The median duration of response was about 6 months in the lower group and, interestingly, 20 months in the higher dose of datopotamab. So this study also showed activity for this combination.

Toxicities, we’ve already talked about it. No surprise here. Higher dose is associated with more stomatitis and ocular events.

So there are some ongoing trials in this space. This is TROPION-Lung14. This is in the front-line setting for EGFR exon 19 and 21 mutated patients, comparison to osimertinib alone versus osi plus Dato-DXd at 6 mg/kg. About 600 patients to be enrolled.

The TROPION-15Lung trial is a Phase III trial in the salvage therapy setting where patients had already progressed on prior targeted agents. Here, randomization is to chemo versus Dato-DXd versus osi plus Dato-DXd.

How about managing toxicities? Again, we’re still learning about these. With regards to managing stomatitis, use of dexamethasone oral solution for prophylaxis appears to be helpful. Holding ice chips in mouth during infusion has also been suggested as a potential way to ameliorate it.

With other toxicities like ocular and pneumonitis, again, we’re still learning. Use of preservative-free lubricant eye drops is helpful for managing ophthalmic toxicity, to prevent it. Baseline ophthalmic evaluation and early intervention when patients develop symptoms are all key.

The other drug that’s coming up in this space is saci-T. This is a cohort of patients with EGFR mutated lung cancer who received this drug. And this is also given intravenously every 3 weeks. You see a response rate of about 55% in the cohort of patients who received prior chemo. Response rate is 40%. In the chemo-naïve cohort, it was about 70%. So interesting results.

I would call your attention to these 2 abstracts that are being presented at this meeting with saci-T. Oral session on the 1^st of June and poster session on the 31^st that will shed more light on how this may play out.

So with that, I will stop and turn it back to Dr Yu.

DR YU: Alright. So a lot of exciting TROP2 novel agents. So our first survey question was based on either clinical experience on the clinical trials or published literature, would you like to have access to datopotamab deruxtecan right now for EGFR-mutant lung cancer? And maybe, Dr Sabari, you said I’m not sure. Tell us why.

DR SABARI: Yeah. This was before the 2 negative press releases, right? This is a crowded space. I think now that we don’t have potentially patritumab deruxtecan and we don’t have ivonescimab, I’d love to have Dato-DXd. So I’d like to change my answer for the record. But I think that we need biomarker-directed strategies. And this is not a biomarker-directed strategy, in my opinion. And we’re sort of moving away from targeting EGFR. That being said, the resistance mechanisms are quite robust, and we’ve talked about that. Maybe we need to think more broadly here.

DR YU: And, Dr Goldman, you said yes.

DR GOLDMAN: Well I think it’s always good to have more agents, more options. These patients start out with a lot of optimism with their EGFR therapies. And sometimes, you go through them quickly, unfortunately. So it’s good to have that possibility.

DR YU: A crowded field has gotten definitely less crowded over the last 2 days.

DR GOLDMAN: Yes.

DR YU: Okay. So complicated side but if Dato-DXd were available, when, if at all, would you integrate it into the treatment algorithm for patients who receive first-line targeted therapy as described? So we know our first-line choice is our osimertinib, osimertinib with chemotherapy, amivantamab with lazertinib. Dr Girard, walk us through what you would do in the different situations.

PROF GIRARD: What is impressive is the efficacy of Dato across all the resistance mechanisms. And we know that there is more — that patients receive different lines of treatment, higher are the numbers of such alterations. So I feel that it would be third line after osi or after amivantamab plus lazertinib to have the opportunity to deliver first line and second line, and then move to the ADC. After FLAURA2, yeah, second line. For sure, because we miss options for those patients. Even if some patients may be rechallenged with chemo and amivantamab after FLAURA2.

DR YU: Dr Jänne, you said for if someone was getting osimertinib, would you do this second line before platinum-based chemotherapy?

DR JӒNNE: Well, it is a space where we don’t have data to know which one is better. But I think I was thinking about the ORCHARD data where there was such a high response rate with the combo in the second line. And similarly, I think even after the FLAURA2 regimen, I think this remains reasonable. And certainly, after ami/laz second- or third line if the patient gets intervening platinum-based chemotherapy there.

DR YU: Okay. And Dr Ramalingam told us the clinical data. But in your experience, what is the primary toxicity that patients experience with Dato-DXd that leads to withholding this regimen? And you can see really across the board, mucositis or stomatitis was the answer. Dr Ramalingam, you discussed the prophylaxis. In your experience, how helpful has it been? How compliant are patients with that regimen?

DR RAMALINGAM: It’s hard to know because it’s personal anecdotal experience. But certainly, you want to do everything you can if it’s not lifting the mountain to reduce the side effects. So mouth rinses are something relatively simple to do. And that’s the reason. I would say stomatitis is a painful toxicity. Even Grade 2 can be substantially disabling for patients to eat and drink. So it’s nothing to be taken lightly.

DR YU: And can you — you mentioned ocular toxicity. What has been reported or what are you seeing personally?

DR RAMALINGAM: It could be as simple as dry eyes. In a more serious form, you have keratitis where patients have pain, redness of the eye, tearing and potentially interference with their vision. So that’s the extreme that one does not want to see. This is why you start with an ophthalmologic evaluation at baseline to make sure they don’t have any underlying corneal problems. And then, if they do have symptoms, make sure you have a friendly ophthalmologist who will get them into the clinic the same week so they can evaluate them and provide appropriate supportive therapy.

DR YU: And for anyone that’s used Dato-DXd, do you find that dose reductions or dose holds are helpful? Dr Goldman?

DR GOLDMAN: Yes. I think both the ocular and the mucositis toxicities are responsive to dose hold and dose reduction quite so. Dexamethasone and also the steroid eye drops do help some. But a lot of times, those are problems that patients continue to face and lose weight, for example.

DR YU: Yeah. I think the mucositis in particular in terms of maintaining po intake. It’s challenging. Okay. So again, kind of talking about mucositis and focusing in on it. What preemptive strategies, if any, do you employ? And what have you found, you know, how helpful has it been? I think you can see that the chance of developing mucositis, up to 80%. I think in the study, it was around 60% in terms of Grade 1 all considered. What about ice chips? It looks like, Dr Sabari, you had mentioned ice pops. Is that something that you find helpful? It’s just like vasoconstriction?

DR SABARI: Yeah. Grape ice pops. I think any ice is sort of helpful. The same way that you think about vasoconstriction for hair, for example. With stomatitis, there is emerging data there. It’s very hard for patients to keep ice in their mouth for an infusion, right? It unfortunately melts. So I think it’s something that you can give the patient to do and they feel good about and active in their care. But I also agree with oral dexamethasone as being very helpful, and oral rinses. But really, managing appropriately and dose reducing and dose holding when needed. Remember, our hematology colleagues, they see this all the time in their practice, and they’re able to manage it with their therapies. So I think we’re a little bit chicken up here.

DR YU: It’s new to us. Okay, last question for this section. So we know that ILD pneumonitis is a class effect for all of these antibody drug conjugates. We certainly do see it with Dato-DXd. We know that deruxtecan backbone agents all have this risk. We asked our faculty, what is the chance of developing ILD? And what do you do for your screening approach? Dr Girard, do you want to comment?

PROF GIRARD: Yes. The point is that we’ve learned ourselves that this is in the lungs. So when you do the follow-up imaging to assess response to treatment, you see the lung on chemo and you need to spend some time on looking at the lung while on chemo. Or so discussing with the patients about this now at each visit is something important to detect indeed when it’s Grade 1 and avoid evolution to Grade 2 and Grade 3, which as you would imagine, may require discontinuation of the drug.

DR YU: And now, we have — I think it’s, especially with lung cancer, it’s challenging, right? Our patients present with, already have cough and dyspnea and hypoxia. So understanding what’s lymphangitic spread of disease and what’s infectious, what’s inflammatory can be really challenging. But I do agree, I think being vigilant and stopping treatment —

PROF GIRARD: Still though, those patients are less fragile than the other ones. As you know, EGFR-mutant usually do not have COPD and so on and never-smokers. So it’s probably a different profile of baseline characteristics as compared to the Dato data that have been generated in smokers and wild-type patients.

DR YU: We have a minute or 2, so I think — Oh, Pasi?

DR JӒNNE: I was going to say 1 challenge that does come up, and I’m interested to see what my colleagues think, is someone who has, let’s say, Grade 2, so more than just CT findings, some symptoms of ILD, and gets better with withholding the drug or treatment with steroids. Is it safe to ever re-treat them?

DR YU: Has anyone re-treated?

DR SABARI: I have not re-treated. Look, a lot of the toxes we’ve talked about are reversible. ILD is one of those that is not. And we lose patients to ILD. Again, it’s rare. But I would not re-treat with a Grade 2 toxicity. Grade 1, I have done.

DR YU: So I think thinking about this ADC space, we heard about — well we will hear about patritumab deruxtecan. We heard about datopotamab. And now, we also have approvals for trastuzumab deruxtecan for HER2 expressing, and Teliso-V with the MET. Dr Ramalingam, now that we have all of these options, what are you doing for your EGFR-mutant patients? And do you have a preference? What’s your biomarker strategy in this setting?

DR RAMALINGAM: Well, Teliso-V is new. We’re beginning to incorporate it into the clinic. But as we talked about for patients on progression, to get some sense of what is their mechanism of resistance is helpful. And for MET, we have targeted approaches. For fusions, there are approaches that you could potentially tap into existing therapeutic agents in the clinic. And for histological conversion, obviously, you have to switch therapies for small cell completely in a different direction. But we’re still in the early days of using that intelligence to develop precision approaches for these patients. And I think the current group of agents are a step towards that direction. I don’t think it’s answered all our questions.

DR YU: Do you foresee that at some point, we’ll have some sort of multiplexed biomarker for these ADCs, and help us guide which ones should go to MET or HER2 or HER3?

DR RAMALINGAM: One hopes that, but at this point, for all of these ADCs, the target expression, at least at the protein expression level, we’ve not seen a connection.

DR YU: Right.

DR RAMALINGAM: Now for Dato, there are some other biomarkers that are being tested prospectively in trials using artificial intelligence. So we’ll see.

Contemporary Care for Patients with Nonmetastatic EGFR-Mutant NSCLC — Dr Goldman

DR YU: Okay. Moving on to Module 4. Dr Goldman will discuss contemporary care for patients with nonmetastatic EGFR-mutant lung cancer.

DR GOLDMAN: Thank you. I switched it to optimal care, even beyond contemporary. Thanks very much. It’s been a really exciting time in the resectable disease trying to really change the long-term curve for these patients.

Just to remind you of our goals and our options for adjuvant systemic therapy for non-small cell lung cancer. Chemotherapy has been our standard for a few decades now. High toxicity, high number to treat. But we do know that there are cures because of adjuvant chemotherapy, particularly in Stage II and III. Immunotherapy has a very different risk/benefit profile. Generally, much more tolerable. And in the high PD-L1, you’ve got a really significant benefit. Used neoadjuvantly, also really meaningful benefits in the nonmutated population. Mutation-based TKI therapy, these drugs in the metastatic setting have high response rates but typically benefits ranging 1.5 to 3 years. Is that going to translate to a cure in the adjuvant setting? So we’ll try to address that.

So early first-gen EGFR TKI trials often showed some DFS benefit, but no overall survival benefit.

And that led to really the current standard, 2 practice-changing trials. We’ll talk about ADAURA using adjuvant osimertinib versus placebo for 3 years for Stage IB to IIIA. And LAURA, adjuvant osi after chemoradiation for Stage III. We’ll also talk about some practice-informing trials with neoadjuvant osimertinib, and trials that are underway, and some with data at this meeting.

So ADAURA, we’ll spend some significant time on. This was IB to IIIA, randomized osimertinib versus placebo for 3 years. Patients could get chemotherapy, but did not need to. The primary readout was disease free survival and then followed up with overall survival.

This was EGFR exon 19 and L858R only. So disease free survival was the initial report. Really, quite significant meaningfully different than the first-gen reports. And then, follow-up soon after with overall survival benefit. So a hazard ratio of 0.49 for overall survival. And those curves do not seem to be getting closer. But that is one of the important questions yet to be answered. When we look at the forest plot, really all the groups seem to be benefiting. There’s the suggestion, like many of the trials, that exon 19 is doing a little bit more benefit than L858R. Whether you got chemo or not, there was benefit. This was not a trial of whether or not to give chemo though, so don’t misunderstand that part. And we’ll get to that in some of the questions, I think. But the 5-year overall survival with osimertinib, really a meaningful improvement from 73% with placebo, up to 85%. Follow-up was good at 5+ years.

And then, as I said, the follow-up initially was looking at Stage II to IIIA but here’s IB to IIIA. Still with a significant improvement and really confirmed what was, at that point, the standard of care, adjuvant osimertinib. CNS control is certainly part of this meaningful benefit. There’s very few patients that are progressing in the CNS while on therapy. But really, it’s very small down there. But at the end of 3 years, CNS event starts to creep up in the group of patients that got osimertinib and then stopped it at 3 years. Is this a sign of some developing challenges for patients as we follow them later?

What are the important take home points? Biomarker testing is, of course, crucial, as we’ve been saying here at this meeting for a decade. You have to know about EGFR. You have to know about ALK. PD-L1 I think is also useful in the nononcogene-driven patients. So I think these 3 should be tested in all of our perioperative adjuvant patients. And is there a role for NGS or some combination of all of these 3? A quick, you know, sufficient tissue, early turnaround time are really important, especially when we’re talking about neoadjuvant therapy, which we’ll get into. We do an EGFR by PCR, a rapid turnaround PCR, and ALK by IHC, PD-L1 by IHC. And a couple weeks later, get the NGS back. That’s been our policy, but it’s going to get more complicated as, perhaps, we have newer biomarkers, especially in the metastatic setting. So I’ll just go through these. I think this is the question that we ask for many of our patients. What lessons do we take from ADAURA to our other targeted therapy patients? Do we use a targeted therapy for RET fusion? For KRAS? For BRAF? So that was just sort of my quick take, that I think RET seems very appropriate whereas I would not use a KRAS G12C inhibitor in the adjuvant setting. And I have used many of those in the maybe category for a high-risk Stage III patient.

And I’m going to have to speed up. Here are the take home points. I’d like to think about this necessary triad of potentially adjuvant, potentially useful adjuvant TKIs. High response rate, very tolerable for long-term use and good CNS penetration. And this question that is not fully answered, are we curing patients or just dramatically improving their DFS? Both are good, but we also do want to know how we can improve the true cure rate. And where can we go from here? And we’ll be talking about that in these slides.

So we’ll talk quickly about ADAURA-2 and the TARGET trial. ADAURA-2 is looking at the Stage IA group, IA2 and IA3, so between 1 and 3 cm. And that is accrued and we’re waiting on results. Because this is a low-risk group, we’re going to have to wait longer for results.

TARGET trial is a nonrandomized trial. Everyone is getting 5 years of osimertinib. It will be interesting to see to what degree this is practice-changing. But it might be practice-informing, particularly for a high stage patient. You might say let’s go beyond 3 years if they’re tolerating it well. They also allowed patients with uncommon EGFR mutations. So that will be useful to support what many of us are probably doing already.

Two trials looking at neoadjuvant osimertinib, the NEOS trial and Collin Blakely’s trial. So NEOS trial, 40 patients. The primary endpoint was objective response rate. And Collin’s trial was path CR rate. So high responses, as we would expect. But very few — no complete path responses and 16% major path responses. So interestingly, there’s some interesting biomarker data. RBM10 seemed to correlate to not getting a major response. But these very similar trials, one was considered promising, one was considered insufficient. Probably insufficient is the right answer.

NeoADAURA trial is what we’ll be hearing more about at this meeting. A 3-arm trial of chemotherapy, osimertinib, or the combination of chemo and osi for 9 weeks prior to surgery. And the oral abstract session I think will be very exciting. Major path response in the 2 osi-containing arms. It’s really quite dramatically improved compared to the chemo-alone arm.

LAURA trial is the other practice-changing trial. And this is a Kaplan-Meier curve to remember and be very excited about. We probably should not have been surprised. The higher-risk patients in ADAURA got the most benefit. These are very high-risk patients. Again, to remind you of an important point. This was indefinite osimertinib until progression. I think for the sake of time, I’ll move a little bit faster. I liked this in New England Journal. You see how many patients are still alive having gotten the osimertinib in the darker color. It really is dramatic.

These 2 trials, PACIFIC-4, probably will not be practice-changing. But this was using osimertinib after SBRT in a single arm.

So are we curing these patients? These 2 curves, you could drive a truck through them. Certainly, if you delay progression or disease recurrence enough, you will get a survival benefit. I do think that the slope of the curves suggests that the resistance to osimertinib develops much more slowly in the micro-metastatic disease setting than it does in metastatic disease. So that is part of why we’re getting this benefit.

Where do we go from here? The minimal residual disease analysis from Nature Medicine earlier this year. This is the money slide. But it’s hard to really take in.

So a couple points, 8% of patients were ctDNA positive after surgery before starting therapy. Those patients, if we identify them, we are probably going to be moving toward that they need to go on a targeted therapy. You can see if they didn’t, they all recurred. If they took a targeted therapy, some of them recurred but most of them after the osimertinib. So if you knew one of those patients, I think you’d go on long-term lifelong osimertinib. The other question is those that are not MRD-positive during — sorry, at the start of treatment but become positive later. Most of them become positive after the osimertinib period.

So I think one of our questions is, should we be continuing longer? One option would be, perhaps, to take a break at 3 years, test for MRD. And then if they turn positive, then restart. But those will require prospective trials.

And I think I’ve covered these main points. ADAURA and LAURA, please always keep them in mind. But we’re expanding our understanding with these combinations. Thanks very much.

DR YU: Definitely the perioperative space, both for EGFR and non-AGA positive lung cancers really has changed dramatically in a very exciting way over the last few years.

Okay. So our first survey question is, which adjuvant treatment would you recommend for a 65-year-old with localized nonsquamous non-small cell lung cancer, exon 19 deletion, PD-L1 0? We seem to have kind of a consensus. But I think for, Dr Ramalingam, so IB, you’re not convinced. You don’t offer adjuvant osimertinib?

DR RAMALINGAM: So if you had a patient who just had a small tumor with visceral pleural invasion, I wouldn’t consider using adjuvant therapy for that patient. That’s why IB is not just 1 disease. And you have to remember the current staging system is different from the one that’s used in ADAURA. So things are changing fast, and you have to know exactly for which patient population you would use it. For me, I just use a 3 or 4 cm tumor or if there is node-positive or both, I would venture into the adjuvant therapy space.

DR YU: I know the rest of us all said chemotherapy for Stage II and Stage III. But Dr Spira said osimertinib only, omitting the chemotherapy. Josh, can you conjecture? Is that what people are doing? What’s your comments on not giving the chemotherapy that has a small but real survival benefit?

DR SABARI: Yeah. I can’t speak for Alex personally. I don’t know if he was reading the question correctly. But there are folks in the community that are getting osimertinib alone. And, again, I think it’s this fear of chemotherapy. In my opinion, chemotherapy has been shown to cure patients in the adjuvant setting. And we don’t have enough data to remove that. Osimertinib does not cure. And I think it’s important to remember that, especially in our higher-risk patients, Stage IIA to IIIA. So when I see Alex, I’ll ask him.

DR YU: Okay. So how long, I think a question is. If somebody is tolerating adjuvant osimertinib well, has a high-risk localized disease, maybe node-positive, exon 19 deletion. You can see that some of us are by the book and said 36 months like the ADAURA study, and then some of us do continue until progression or indefinitely. Professor Girard, you were extrapolating a little bit. Explain the indefinite osimertinib.

PROF GIRARD: Well, that’s a very good question. And we see after 3 years, especially in the higher-risk patients, the Stage IIIA, that we have a kind of more rapid risk or increased risk of recurrence. So 5 years is maybe what needs to be done. But if we look at the LAURA data with this continuation of osimertinib in patients with still higher risk because they were not operated on, to me, it raises really the question of continuation beyond 3 years and maybe beyond 5 years, especially for the patients with high-risk, so the Stage IIIA, maybe patients with positive ctDNA after surgery and so on.

DR YU: Dr Goldman, I think — oh, Dr Jänne?

DR JӒNNE: I was going to say sometimes, it’s a hard conversation with the patient when you get to the 3-year mark and everything has gone well. There’s no evidence of recurrence. And you bring up the fact that the data shows that — or the trials were done for 3 years, and it’s time to stop. And there are patients that don’t want to stop.

DR YU: And if they don’t want to, you continue?

DR JӒNNE: I do. Sometimes, I’ve run into reimbursement issues on that end. But I do.

DR YU: I was going to ask the question about atypical mutations. So we know that exon 18 or S768I, you do less well with all therapies, have a worse prognosis. Anyone on the panel has treated any of those patients and given adjuvant osimertinib? Dr Goldman, have you?

DR GOLDMAN: So I have for L861. I think there’s some that are less common but behave very similar to L858R. So there, I feel comfortable. But in an exon 18 mutation, I have not. Actually, maybe for a Stage III, I have. A Stage III patient can often push me to do something.

DR YU: Yeah.

DR JӒNNE: Just maybe to make 1 more comment about the 36 months versus indefinite. Sometimes, it’s nice, as you’re talking about the treatment for surgically resected EGFR-mutant lung cancer or maybe chemotherapy, it’s nice for patients to look forward to actually being done with a therapy. Yes, there are those who don’t want to discontinue it. But on the other hand, I think it’s in the LAURA trial, it’s harder because it’s an indefinite duration of treatment if you go by the book on the trial.

PROF GIRARD: In my eyes, the key question is what is the contribution of CT, or chemotherapy and radiation therapy at the end in the global efficacy of the treatment in patients with high-risk. Not metastatic, but nearly metastatic, I would say.

DR YU: Absolutely. So this one, we had absolute consensus on. So this is the LAURA setting. Chemoradiation for locally advanced nonresectable disease. We all would give osimertinib. I guess I’ll press the panel. High TMB, high PD-L1, heavy smoker. Is there any instance where someone would give durvalumab in this case? Dr Girard?

PROF GIRARD: The benefit that has been seen in lower is quite impressive at the end to give osimertinib. I feel there is a consensus here.

DR YU: Yeah, I think so too. And then, I think a good question is when patients are early-stage and we’re treating them for curative intent, I think the bar in terms of tolerance of toxicities is lower because this is potentially unnecessary treatment. So we asked, what degree do we believe adherence or toxicity is an issue for patients receiving osimertinib for localized therapy? Dr Sabari, you said moderate.

DR SABARI: I think here, it’s how well are patients tolerating therapy. In my patients that are tolerating therapy well, they’re usually going to take their medication. If a patient starts developing rash or some cutaneous toxicity, could be fissuring of the skin or paronychia, and they’re 2 years out, I start to hear from them that maybe they missed it or maybe they’re stopping to take it. So I think a lot of this depends on how well they tolerate it. You then always have the patients that want to take it every day no matter what. And that’s the complicated part here with the data.

DR YU: Yeah, absolutely. And then, I think, you know, we will hopefully see some definitive data on Sunday with NeoADAURA. But outside of a clinical setting, what do we do? So we know that we give chemoimmunotherapy for a non-AGA patient. But has anyone used neoadjuvant osimertinib prior to surgical resection? Dr Goldman, you said I have. In what instance?

DR GOLDMAN: So we have, in tumor board, we call it the NeoADAURA regimen, and that’s what we do. We give chemo and osi, and we figure we want to really do everything we can to get the patient safely to surgery, shrink the tumor, improve margins and R0 rates. And I think it’s well-tolerated. That’s not the challenge. When I said that adherence was good, it's not that tolerability is always good. But I do think patients are taking their drugs, I think.

DR YU: And, Dr Jänne, we just saw the abstract results. What did you think of the kind of topline NeoADAURA results in terms of do you think osimertinib makes a big difference perioperatively — or preoperatively?

DR JӒNNE: Certainly, based on the abstract results, and I’m looking forward to the actual presentation, MPR rates or pathologic response rates or major pathologic response rates were a lot higher in patients who received osimertinib alone or with chemo compared to chemo. And I have used it outside of a trial. This was in a situation where somebody was known to have an EGFR mutation, was kind of borderline resectable, and we wanted to have a neoadjuvant regimen that would make the individual resectable. And we were able to accomplish that with osimertinib alone.

PROF GIRARD: Maybe osimertinib is facilitating surgery in patients who are marginally resectable, but I’m not sure about the value of PCR or MPR with a targeted agent. It’s very different than what —

DR JӒNNE: It’s a different ballgame than immunotherapy, for sure.

DR YU: Yeah. We’re not seeing those same rates of MPR.

PROF GIRARD: I’m not sure it’s predictive of the long-term survival.

Current and Future Management of EGFR Exon 20 Mutation-Positive NSCLC — Prof Girard

DR YU: Alright. So moving on. Professor Girard will talk to us about a subset of EGFR-mutant lung cancers, exon 20 mutations.

PROF GIRARD: Thank you. So moving to a different subset of patients, ones with EGFR exon 20 insertion mutated non-small cell lung cancer. We discussed in the beginning about the common mutations, L858R and exon 19. And now, moving to EGFR exon 20.

There are some key facts on this group of patients. Testing requires NGS. Otherwise, there is a higher risk to miss those mutations. We know that EGFR TKIs have limited activity in this group of patients as compared to patients with common EGFR mutations. And this is aggressive disease with frequent CNS metastases.

We have a standard of care in the first-line setting, which is amivantamab plus chemotherapy. And this is based on the PAPILLON Phase III trial that enrolled patients with EGFR exon 20 insertion-mutated non-small cell lung cancer, treatment-naïve, 308 patients randomized to receive platinum-based chemotherapy as the regular treatment for those patients or a combination of chemo plus amivantamab. And there was an option to cross over to second-line amivantamab in patients randomized to the control arm. Primary endpoint was PFS.

We see a higher response rate with the combination versus chemotherapy alone, moving from 47% with chemo to 73% with the combination of chemotherapy plus amivantamab.

And PAPILLON is a positive trial. We have a significant benefit in terms of PFS with the combination versus chemotherapy alone, almost a doubling of median, moving from 6.7 months to 11.4 months. And this is with a hazard ratio of 0.40. You see how the curves are separating. With the combination, benefit observed across all the different subsets of patients.

Clearly, this is aggressive disease. And we see that combining amivantamab plus chemotherapy is protecting the patients from CNS disease. Obviously, from all sites of progression but especially in the brain. Probably, this is a major contributor of the benefit in those patients.

What are the subsequent therapies after chemotherapy plus amivantamab? Well second-line chemo, chemo plus IO or plus a unique agent. Some patients received a TKI. So there is a lot to learn from this first-line new standard of care regarding the mechanisms of resistance. We are far beyond what we discussed previously for common EGFR mutations.

We have a tendency to want a benefit in terms of overall survival in PAPILLON. So it suggests that it’s better to combine amivantamab with chemotherapy rather than sequentially deliver chemo and then amivantamab. There was a high crossover rate in this study. Two-thirds of the patients in the control arm crossed to second-line amivantamab.

In terms of safety, pretty similar to what we discussed in MARIPOSA-2 related to chemo side effects related to amivantamab in this trial. So chemotherapy plus amivantamab is a recommended treatment in the NCCN guidelines for those patients, and the same for patients — in the ESMO clinical practice guidelines.

So the question is what to do in the second-line setting. And maybe I want to show you some of the key figures with amivantamab in pretreated patients. Because before moving to first line, amivantamab was evaluated in the late-line setting for those patients after prior exposure to platinum-based chemotherapy. This is the CHRYSALIS trial. It was 114 patients. And you can see that after platinum-based chemo, amivantamab response rate was around 40%, 43% in this subset of patients.

Median PFS, 7 months. And median overall survival, 23 months in those patients. So there is a kind of prolonged efficacy of amivantamab in this setting. Similar safety as previously described.

So there are new agents coming for those patients with EGFR exon 20 insertion mutated non-small cell lung cancer. Mostly, TKIs. And I will discuss some of these TKIs that we have some Phase III trials ongoing.

Furmonertinib, we have this data from the Phase II FAVOUR study. Quite interesting in terms of response rate, around, again, 40%. So quite similar to what we had with amivantamab in this late-line setting.

Safety. Those TKIs designed to target EGFR exon 20 mostly have toxicity, digestive tract toxicity, so diarrhea. Mostly Grade I/II, but it may impact the quality-of-life of patients. Some transaminitis as well.

Sunvozertinib, another TKI with efficacy on EGFR exon 20 insertion mutated non-small cell lung cancer. And interestingly, here we have a profile of patients, limited numbers, who had prior treatment with amivantamab, which is relevant now that we have chemo plus ami in the first-line setting. And reporting a 50% response rate. Limited number of patients here.

And we also have data with zipalertinib, another TKI that is designed to cover not only resistance mutations that may be on the kinase of EGFR but also EGFR exon 20. Here, again, this is the second-line setting post-platinum, 38% response rate. Median PFS, 10 months. So maybe slightly better than the other ones.

And we have also here a similar profile, maybe better safety than sunvozertinib or furmonertinib with a limited number of patients presenting with diarrhea.

We have data with zipalertinib post-amivantamab. So, again, quite relevant given the new standard of care in the first-line setting. Some data, additional data will be presented during this meeting from what we had last year at ESMO. The response rate was 40% and median PFS, 9.7 months with zipalertinib post-amivantamab, which is probably clinically meaningful.

Zipalertinib is also evaluated in the first-line setting in combination with chemotherapy. So this is chemotherapy plus zipalertinib versus chemotherapy, possibly followed by zipalertinib in the case of disease progression. And this trial is ongoing. Thank you.

DR YU: Great. Thank you so much, Dr Girard. So one question we have from the audience is if you have — so exon 20, there’s a locally advanced, say, Stage II or Stage III lung cancer that had a lobectomy and adjuvant chemotherapy. Are there any EGFR-directed therapies that you’re offering this patient adjuvantly, Dr Girard?

PROF GIRARD: Sorry, can you repeat it?

DR YU: So exon 20.

PROF GIRARD: Yeah.

DR YU: Locally advanced post-resection.

PROF GIRARD: Yeah.

DR YU: You could also extrapolate that to ALK, other things. Are you giving anything to these exon 20s?

PROF GIRARD: Not yet. Not yet, actually. But this is a question that we also have for BRAF and others. I’m not sure there will be a trial in this situation, but that’s an open question. It is an aggressive disease, so it’s probably a very rare situation.

DR YU: I think it’s a balance because we have — the effectiveness of the treatments that we have, the toxicity and that kind of pro and con in the adjuvant setting.

PROF GIRARD: Yeah. Because here, it’s probably very different than common EGFR mutation where osimertinib has a very good safety profile or even alectinib, which is also associated with very rare —

DR YU: Right. But amivantamab or dabrafenib and trametinib for 3 years.

PROF GIRARD: Yeah, another story.

DR YU: We’re talking about a different level of toxicity. Okay. So this first survey question here for this section. So first-line systemic therapy for a 65-year-old healthy patient, EGFR exon 20 insertion, PD-L1 0. I think everyone said amivantamab and chemotherapy. I guess I’ll explain my zipalertinib. I’m actually very excited about some of these oral EGFR TKIs that are coming. I think you could replace zipalertinib, furmonertinib, sunvozertinib. They all seem quite similar. They do seem equivalent to amivantamab and much less toxicity. So I really would like to give that option for patients first line. Dr Sabari?

DR SABARI: So we just heard from Nicolas the front-line study of zipalertinib plus chemo versus chemo. Why not zipalertinib alone? And you selected zipalertinib alone here, which to me, also sounds very exciting. We had the Phase I study. Well-tolerated medicine, great response rates. And we’re going to see some data post-amivantamab here. But why the combination with chemo in the front line?

DR YU: I think that the tale of mobocertinib has scared a lot of these drug companies, right? I think there’s — we now have a standard of amivantamab with chemotherapy. Mobocertinib, if you remember, was an originally approved EGFR exon 20 oral agent. Their confirmatory study was versus chemotherapy. And they weren’t superior. So I think there is a caution and kind of if you can’t beat them, join them philosophy. But as you can see, I think in a dream world, that we would have these oral therapies.

DR SABARI: And to your earlier question of adjuvant or neoadjuvant in the future. I think well-tolerated EGFR exon 20-specific inhibitors have an opportunity there.

DR YU: Absolutely, I think. Looking forward to that. And then, I guess, Dr Sabari, you did say symptomatic — would you change it, anything, if there was a symptomatic tumor burden?

DR SABARI: I answered this about 2 or 3 days ago. I think that’s a copy and paste job or something on my end.

DR YU: Okay.

DR SABARI: So I apologize. I’d give ami and chemotherapy in this setting as well.

DR YU: Yeah. I think it’s pretty clear that that’s an active regimen that we all would use in this setting. And so what about if we had a person that received amivantamab and chemotherapy, had asymptomatic disease progression after 12 months? What would be your second-line recommendation if there were no acquired alterations? And say, we had all of these options at our fingertips. Dr Ramalingam, you said chemotherapy over one of the oral TKIs. Comments?

DR RAMALINGAM: Yeah. I think these TKIs have good response rates, 40, 50%. They would be eminently appropriate in this setting. So I was thinking of — I didn’t look at the part that these were available.

DR YU: What would you do today?

DR RAMALINGAM: So I was thinking of my clinical situation where I don’t have anything today.

DR YU: Dr Jänne, sunvozertinib, the recent data. What makes you excited about it?

DR JӒNNE: I think in this situation, an oral TKI, sunvozertinib or zipalertinib. I just picked one. They have a similar degree of activity. And since this is an individual who had been previously treated with ami/chemo, I wanted to go for a chemotherapy-free regimen.

DR YU: Absolutely. I think we’re all waiting for these to be approved, clearly. So based on the published literature and our clinical experience, how would you indirectly compare global efficacy and tolerability of zipalertinib and amivantamab? Professor Girard, you had said, I mean, I think all of us, you can see, clearly agree that the oral TKIs are more tolerable. So we don’t have any difference of opinion there. But your comments on amivantamab being more efficacious.

PROF GIRARD: Yes, because we have the PAPILLON data and we miss the data from HORIZON III. That’s true that in the second-line or late-line setting, the response rates are quite similar.

DR JӒNNE: As single agent.

PROF GIRARD: Yeah, as single agent. Yeah. And at the end, we probably need to see the data. But yeah, we need to see combination with chemo. What is the contribution of chemo into that? And then, the duration of efficacy. Amivantamab, we see the sustained effect in the CHRYSALIS; however, we need to see the data with the TKIs.

DR YU: We’re seeing, so zipalertinib on Sunday and some other data of sequencing these antibodies and the TKIs. What are your thoughts about our ability to do that? Is there a certain sequence we have to do? Antibody to TKI? Or do you think TKI to antibody? It’s reassuring that we’re seeing responses post-one modality versus the other.

PROF GIRARD: We want to give the best treatment first. This is the first thing. We don’t know what are the resistance mechanisms to the TKIs, and it would be very interesting to look at this. We know that amivantamab has also broad efficacy on the resistance mechanisms because it’s binding the extracellular domain. So yeah, at some point, it will be a debate to start with amivantamab first or to reserve amivantamab, which is also more toxic, to cover the resistance mechanisms to the TKI.

DR YU: And then in terms of side effects with zipalertinib or sunvozertinib. We’ve had some earlier EGFR exon 20 oral agents like poziotinib. When you hit the IC50s that are required for EGFR exon 20 are right around, oftentimes hitting EGFR wild type. Dr Jänne, do you want to comment on the toxicities we’ve seen with some of these exon 20 drugs?

DR JӒNNE: I still think with the newer ones like sunvozertinib and zipalertinib, we still do see some on-target EGFR toxicities, GI toxicities and rash. They’re less so than with poziotinib. And certainly, the GI toxicity which was a major issue with mobocertinib is less with the newer-generation TKIs. But they’re not completely free of side effects either.

DR YU: Agree. We have a little time before the next session. So I’m going to answer some of the audience questions. So one question was going back to the first module. So what about co-mutations? So we know that 60% of patients with EGFR-mutant lung cancer have a co-mutation in TP53. Does TP53 ask — have you choose between osimertinib and chemotherapy versus amivantamab and lazertinib? What data do we have about that? Dr Sabari?

DR SABARI: I think co-mutation is a higher-risk patient population. Again, a significant proportion of our patients have TP53 alteration. More commonly in those patients who’ve smoked than never smoked. And I do think about escalating therapy in that patient population. Remember, I’m looking for reasons to de-escalate, right? I escalate in most patients now. I think for ami/laz, we have data in the p53 co-mutant population, that those patients tend to do better with ami/laz over osimertinib alone. There’s similar data for TP53. Obviously, in the FLAURA2 trial. So very hard to cross-trial compare these nonprespecified subset analyses.

DR YU: And then another great question that we had is use of MRD or ctDNA assays real-time presently. So if you had a Stage IIA EGFR-mutant lung cancer after resection that had a positive ctDNA, would you still use adjuvant chemotherapy and osimertinib or would you spare the chemotherapy and use osi alone, just suggesting that there might be metastatic disease? Dr Goldman, what are your thoughts?

DR GOLDMAN: It’s a fascinating question. I hadn’t thought of that before. I think I would choose to give chemotherapy and osimertinib, hoping to convert to a cure, and without much data to support it. And I would give, at least at this point, I would think towards lifelong or indefinite osimertinib.

DR YU: Is anyone currently using any of the MRD assays to help inform care? I’m seeing shaking. Josh, no?

DR SABARI: I’ve used it a couple of times when patients asked for it or in patients that I’m personally worried about. But again, I think more times, it’s confusing than not. We’re hoping for negative, and then we feel better about ourself. We don’t know what to do with the positives.

DR YU: Absolutely. There’s a lot of studies that are ongoing that I think are hoping to use that information to guide clinical trial management.

DR JӒNNE: And many of the assays are still in evolution, which is good to have new assays. But I think, as Dr Sabari mentioned, it’s hard to know exactly what to do with the positives.

DR YU: Right, absolutely. And then, there are those tumor informed assays versus kind of general assays too. So it’s a confusing evolving space.

Emerging Role of HER3-Targeted Therapy in the Management of EGFR-Mutant NSCLC — Dr Jänne

DR YU: Okay, we’re moving on to Module 6 where Dr Jänne will talk to us about HER3-targeted therapy in the management of EGFR-mutant lung cancer.

DR JӒNNE: Thank you. So I’ll talk about HER3.

So most EGFR-mutant cancers don’t just express EGFR. They, in fact, express many of the other EGFR family members shown here, HER2, HER3 or ERBB3 and HER4. And HER3 is — biologically, EGFR-mutant cancers use HER3 in some of their signaling processes. It’s expressed in the majority of EGFR-mutant non-small cell lung cancers. But it’s not a known resistance mechanism to EGFR TKIs. In contrast, to example, HER2 where HER2 amplification is a resistance mechanism to EGFR TKIs.

And HER3 is a little bit unique amongst the EGFR family members. It doesn’t have an active kinase domain. It has to pair up with either EGFR or HER2. And the ligand NRGs, our neuregulins here force the dimerization with HER2 or EGFR and then lead to activation of cellular signaling.

And there are many ways that one can try to inhibit HER3. Most of these have been antibody-based approaches. It makes sense. Most of the antibodies block the interaction of the HER3 ligand, neuregulin with HER3. So you can’t then force that dimerization and force the signaling. And, of course, there’s antibody drug conjugates as well.

Now before we had patritumab deruxtecan, we had patritumab or also known as U3-1287. This is the parenteral antibody. And this was actually tested in a Phase I trial. In this Phase I trial of 57 patients, there were 20 non-small cell lung cancer patients. Most of them had a prior EGFR TKI therapy. And the antibody by itself didn’t have a lot of activity. It was well-tolerated. And has been looked at in combination with early-generation EGFR inhibitors like erlotinib in combination, which was shown to have a longer PFS, specifically in the EGFR-mutant patients and specifically in a prior study of patients where they had high levels of the ligand. So you’re blocking the ligand and activation of HER3. It sort of makes sense that you see better clinical activity there.

So that’s the naked antibody. This is HER3-DXd or patritumab deruxtecan, an ADC that has a linker and then linked to deruxtecan which is a topoisomerase type of payload which we’re used to seeing from any of our ADCs.

In some preclinical studies, you can see on the righthand side, these are patient-derived xenografts that have resistance to either erlotinib or osimertinib, and have varying degrees of expression of HER3. And you can see efficacy in the ones that express HER3, but very little in the one that does not.

And this is just the design of a Phase I clinical trial, the first-in-human trial that specifically evaluated HER3-DXd in patients with EGFR-mutant cancer who had received prior EGFR inhibitors and platinum-based chemotherapy. So in sort of the third-plus lines of therapy. And in the initial analysis, there were 57 patients who were treated with the recommended Phase II dose in these studies.

And there was activity with a 39% response rate in patients who had received prior EGFR TKIs +/- platinum-based chemotherapy, and in patients who had received prior osimertinib and platinum-based chemotherapy. So no significant difference there. Duration of response was about 7 months. PFS, about 8 months.

And responses were seen in patients independent of their specific EGFR resistance mechanism. Remember, HER3 is not a known resistance mechanism to EGFR TKIs. And it’s expressed in the majority of cancers. And hence, you can see activity across majority of EGFR inhibitor resistant cancers, as shown here. And the specific resistance mechanisms are shown below.

However, the expression of HER3 itself did not correlate with efficacy. And this is shown in a couple different ways here in different plots. Color coded on the bottom. Patients who had responses had HER3 — you can see, could have had high or low HER3 expression. So there wasn’t a clear cutoff or a clear correlation there.

A subsequent trial known as the HERTHENA-Lung01 trial looked at that dose, that established Phase I dose or the Phase II dose of 5.6 mg/kg. And it had a second arm initially that had kind of an up-titration where it started with a lower dose and went to a higher dose. This was initially intended to mitigate some of the toxicities but ultimately, was found not to be really that different from just using a fixed dose. And the trial was subsequently converted to have everyone start out, everyone be treated with the 5.6 mg/kg dose. Primary objective here was ORR.

And here in this bigger trial, the response rate was a little bit lower, about 30%. Most of them were partial responses. Duration of response, 6.4 months. Median PFS, about 6 months. And OS, about a year in this, again, broken down whether patients had any prior EGFR TKI and platinum-based chemotherapy or had a third-gen EGFR TKI and platinum-based chemotherapy.

Now similarly, responses were seen in a wide — independent of the specific resistance mechanisms to EGFR TKIs. They’re sort of divided in the bottom into EGFR dependent and independent. And similarly, sorry, activity was seen independent of HER3 expression. So, again, didn’t correlate with the degree of HER3 expression.

One of the things we learned in this trial, and this has been seen for other ADCs, is that they did have intracranial activity. And so in a subset of patients, 30 patients in this trial that had baseline brain metastases and had no prior radiotherapy, confirmed response rate was 33%. Not something I think any of us expected for an ADC, a big molecule, to have this degree of activity. But it’s nice to see this, and has been seen for other ADCs including trastuzumab deruxtecan.

Now in terms of side effects, there are treatment-related AEs that happen in the majority of patients. Minority of them are, or about 40% are Grade 3 or higher. And some are associated with reduction, discontinuation or dose interruption.

And the specific side effects are mostly — come from the payload. So chemotherapy-type side effects, nausea, hematologic toxicities are common. You do see ILD as a side effect as well.

And this has now gone on to a Phase III clinical trial called the HERTHENA-Lung02 trial. This compared the Phase II dose in patients that had received only EGFR TKIs, no prior systemic chemotherapy.

And randomized patients in a 1:1 fashion to patritumab deruxtecan or to the combination of platinum — or combination chemotherapy, so platinum-based combination chemotherapy. The primary endpoint being PFS with other secondary endpoints shown below.

There was a press release last year that this met its primary endpoint leading in improvement in PFS. This trial will be presented at ASCO, again, at a lung oral session on Sunday morning by Dr Mok. And you’ll see the full results of that trial at that presentation.

Now as alluded to earlier, we’re full of press releases tonight. And this came out yesterday basically saying that although the PFS was positive, the OS was not positive. And as a result of that, the company decided to withdrawal its biologics license application for patritumab deruxtecan, which was for previously treated patients with EGFR-mutant lung cancer. So I think we’re all disappointed by this finding. It was nice to have this — or we were hoping to have this as an option in addition to datopotamab deruxtecan for patients that progress on EGFR TKIs and chemotherapy.

There are other HER3 ADCs in clinical development, one from Duality Biotherapeutics, called DB-1310. This was presented at the molecular targeted agents session today. About a similar response rate and PFS as patritumab deruxtecan in previously treated EGFR-mutant non-small cell lung cancer.

There’s also a bispecific EGFR HER3 ADC that has been studied extensively in a prior study in China.

And this dose escalation expansion trial had a high degree of activity with a 63% response rate in the EGFR-mutant patient population. And, again, responses were seen independent of the specific resistance mechanism to EGFR inhibitors. There’s no biomarker data available to correlate HER3 expression or EGFR expression with this ADC.

It too has hematologic toxicities because it’s a topoisomerase payload. You can see here on the righthand side, especially highlighted in yellow, including Grade 3 or higher ones in a substantial number of individuals.

And there are ongoing trials of this drug in the US at the current time. I’ll stop there.

DR YU: And there is one in combination with osimertinib, right?

DR JӒNNE: Yes. In combination with osimertinib as well and as a single agent.

DR YU: I think for all of these ADCs, we’d like to see is there added benefit with continuing the driver mutation-directed TKI with a more nonspecific ADC.

So this question, I think a general question. Would you like to have access to HER3-DXd? I think all of us largely said yes. I think in the end, we want active, safe drugs for our patients, and we’d like the option to choose. And so our hope is that hopefully, we’ll have datopotamab deruxtecan. We’ll see about ivonescimab. But we do want to later-line setting, second line and beyond, we don’t — after amivantamab, chemo and osimertinib, we really don’t have targeted therapies available.

And then I think our last question is, what have we observed in terms of tolerability of HER3-DXd in patients? Dr Sabari?

DR SABARI: Yeah. So I think this is a drug that’s a bit more better tolerated than Dato-DXd, but you still see risks of hematologic tox. You still see fatigue. Stomatitis has been reported, but lower, and ILD. So again, this is a drug I was hoping to have for patients. I was hoping to have it since last June with that CRO. And I think, again, depressing press release yesterday. So it’s unfortunate that we don’t have a growing body of therapies available in the second line for our patients.

DR YU: Yeah, absolutely. And, of course, the survey was obviously done by all of us prior to the press release. And so you can, you know, tell that we were hopeful for this drug. I think, as we mentioned, a lot of these ADCs have deruxtecan backbones, so similar chemotherapy payload toxicities. And I think a real question, hopefully, when we have a few of these ADCs, many of them have that topo-1 backbone. So can we sequence between them? And again, trying to find a biomarker to help us select are going to be key.

Well, thank you so much for attending with us, both here and online. We really enjoyed being with you. And it’s a really exciting space and we look forward to some of those abstracts that we will see later at ASCO.

Thank you so much.