Management of Non-Small Cell Lung Cancer (NSCLC) with an EGFR Mutation — Karen Reckamp, MD, MS

DR RECKAMP: Hello, I’m Karen Reckamp, Professor of Medicine and Division Director for Medical Oncology at Cedars-Sinai in Los Angeles. I’ll be talking about management of non-small cell lung cancer with EGFR mutations with the latest updates.

So as we know, lung cancer is not 1 disease but many diseases. And though we used to think of lung cancer as non-small cell versus small cell, moving on to our histologic breakdowns and then to molecular breakdowns and PD-L1 expression. We know that each of the molecular changes that occur changes the biology and changes the treatment for lung cancer.

The oncogenic drivers are shown here. EGFR is by far the most common. And in a mixed Western population, we see about 15% to 20% EGFR mutations. In an Asian population, this can be up to 50% of patients with EGFR mutations.

The best data we have for first-line treatment for EGFR-mutated non-small cell lung cancer is with osimertinib. And in the FLAURA study, we learned that osimertinib improved progression-free survival over erlotinib or gefitinib, and had a benefit in overall survival though modest and not statistically significant. But the progression-free survival may be different based on the mutation. As we see here, a longer progression-free survival with exon 19 deletions and a shorter progression-free survival with EGFR L858R. So this may change how we think about treating these patients.

So moving forward, one of the biggest studies this year was FLAURA2. And this was a Phase III randomized study looking at patients with exon 19 and L858R mutations. And they received osimertinib with chemotherapy versus osimertinib alone. And the primary endpoint was progression-free survival. Secondary endpoints looked at overall survival, response rates, and quality of life and safety.

As we see here below, we had improvement in progression-free survival for patients who received osimertinib and platinum/pemetrexed chemotherapy, about 25 months versus 16 months on osimertinib alone. For those who, in the blinded independent cohort, there was also an improvement in progression-free survival with the chemotherapy, about 29 months versus about 19 months with osimertinib alone. So significant improvement with the addition of chemotherapy.

We’re always concerned about our patients with brain metastases. So we see here too from the FLAURA2 study, the PFS with CNS metastases on the left-hand side. We see those who had CNS metastases at baseline, and an improvement with the osimertinib and chemotherapy. Those who did not have CNS metastases at baseline on the right-hand side, we see an improvement though not as striking as we see with the patients with brain metastases at baseline.

DR LOVE: Any explanations that you’ve heard about why there might be a difference with CNS? Could it just be like a statistical thing or is there some biology behind it?

DR RECKAMP: Well, we do know that pemetrexed-based chemotherapy does enter the brain and can cause tumor responses in the brain in EGFR patients. So this may be a synergistic property where we’re getting more benefit within the brain. But I think it is biology driven.

DR LOVE: Interesting. Please continue.

DR RECKAMP: So as we might expect, when we add chemotherapy to osimertinib, we had more toxicity. And so here, we see increased cytopenias, some increase in Grade 3 and Grade 4 toxicities, especially with the cytopenias. And then when they looked at interstitial lung disease, they did not see a difference between the groups in interstitial lung disease.

Additional data looking at the risk of CNS progression was also presented. And what we see here is, again, in the light blue, we see the chemo plus osimertinib, and those lines all show longer time to CNS progression. Also, non-CNS progression, and very few deaths in both arms but also longer time to death. So the red arms are those with osimertinib monotherapy, and the CNS progression and non-CNS progression were both higher. We see on the right-hand side some evidence of CNS responses in those patients.

So moving on to other potential options. We had the MARIPOSA study that was presented at ESMO this year. And this is a Phase III study, again, in the front-line setting for patients with EGFR exon 19 deletions of L858R. And patients received a 3-way randomization to amivantamab and lazertinib, osimertinib, or lazertinib to look at the contribution of components. The primary endpoint again being progression-free survival and then also looking at overall survival, response rates and safety.

And we also see here an improvement in progression-free survival with the combination of amivantamab and lazertinib over osimertinib. And we see about 24 months versus about 16 months with a hazard ratio of 0.7.

Again, when we want to look at brain metastases. Here on the left-hand side, history of brain metastases. Still an improvement with amivantamab and lazertinib, about 18 months versus 13 months. And those without brain metastases also had significant benefit.

Again, when we’re adding medications to EGFR-TKIs, so lazertinib is a third-generation EGFR-TKI very similar to osimertinib. When we add amivantamab, the EGFR-MET monoclonal antibody, we do see an increase in EGFR-type toxicities with rash, paronychia, diarrhea all increasing and somewhat increased in the higher-grade toxicities. So on the left-hand side, you see the combination, and the right-hand side is osimertinib alone. The ILD in this group was low and similar in both arms.

So thinking about front-line therapy, we now have multiple options. It’s going to be important to understand how to select patients for these options. But you can see over on the left-hand side, we have FLAURA monotherapy osimertinib that is very well-tolerated, the combination with chemotherapy from FLAURA2 increasing the progression-free survival to 25.5 months, and then MARIPOSA adding amivantamab to a third-generation EGFR-TKI, lazertinib, increasing progression-free survival to about 24 months.

We know that the combinations are causing increased toxicity, so selecting patients will be important. The patients with brain metastases may benefit from additional therapy upfront, potentially those with higher disease burden, potentially those with L858R mutations, as we know they don’t do as well on osimertinib alone. And then also looking into options of following ctDNA and tumors that continue to shed.

DR LOVE: Any sort of clinical observations in terms of side effects and quality-of-life osimertinib plus chemo versus ami/lazer?

DR RECKAMP: I think the timing is a little too early. We’re starting to potentially use these combinations. But they all have different toxicities. I think the other challenge is that you’re putting a patient on infusions. And with osimertinib and chemotherapy, it’s every 3 weeks. With amivantamab, it’s every 2 weeks after they get their loading doses. So obviously, the rash and diarrhea become significant when you’re combining 2 EGFR agents with amivantamab. And then the cytopenias and fatigue will be an issue with chemotherapy. So I think these are big considerations for our patients. And still, the majority of patients at this time I think benefit from osimertinib and do very well on osimertinib.

DR LOVE: Okay. Please continue.

DR RECKAMP: So moving on to the setting of resistance. So this year, we had the MARIPOSA-2 trial, again, looking at patients with documented EGFR exon 19 or exon 21 L858R mutations. These patients had progressed on osimertinib as monotherapy or as the most recent line of therapy. They had to have stable brain metastases to enter into the trial. And they were randomized to amivantamab, lazertinib and chemotherapy or chemotherapy alone versus amivantamab and chemotherapy. And, again, the primary outcome was progression-free survival. And they looked at the 2 arms versus chemotherapy separately.

Here, we see the results. And we see here in the purple, the amivantamab/lazertinib/chemotherapy, in the blue/green color, we see amivantamab/chemotherapy, and in the gray, chemotherapy alone. So we saw improvements in progression-free survival with both the amivantamab/lazertinib/chemotherapy and the amivantamab/chemotherapy. And very similar median progression-free survival, 6.3 months versus 4.2, and 8.3 with the 3-agent combination with amivantamab and lazertinib. Overall, the hazard ratios, 0.48, 0.44. And significant benefit for these patients.

Again, looking at intracranial progression-free survival. Here, we see benefit for patients who received the amivantamab with lazertinib and chemotherapy, and those who received the amivantamab and chemotherapy, and very similar for both. And I think this was a surprising result for us, as we assumed that the third-generation TKI would add some benefit in the CNS. But here, for patients who’d had progression on osimertinib, we see similar benefits. And, again, this may be a component of chemotherapy synergizing with the amivantamab to have improved intracranial benefit.

And again, the toxicity profile. Here, we see in the gray on the left-hand side, chemotherapy alone. Amivantamab and chemotherapy in the middle. And in the green on the right-hand side, the combination of amivantamab and lazertinib and chemotherapy. We see some increase in cytopenias. For the patients who received amivantamab, lazertinib and chemotherapy, there were higher rates of all toxicities and potentially Grade 3 toxicities. Looking at the bottom row, we saw AEs that were of special interest. And again, rash, slightly higher, Grade 3 with the lazertinib and amivantamab combined with chemotherapy. But the interesting toxicity we also see is venous thromboembolism. And that was higher in the combination group. ILD, similar in the 2 groups, but higher than chemotherapy. And based on this toxicity, what is really moving forward is the amivantamab/chemotherapy combination with similar clinical benefit and activity, but less toxicity. So in the second-line setting, I think we’re really going to be looking at the amivantamab and chemotherapy, not adding the lazertinib in this setting.

DR LOVE: I’m just kind of curious. Roughly, how many times have you used amivantamab?

DR RECKAMP: So I have been a part of the clinical trials using amivantamab, so I’ve had some experience over the past several years using the drug. And we have started to use it for some of our patients as it’s become a little more available with this data. So we’ve used it with the amivantamab, you do get the infusion-related reactions in a large proportion of patients, in most patients. We do a lot of education of our patients and our staff to help them understand that these infusion-related reactions are expected. And they have a very good protocol for the way that the dosing is given. Usually, by the day 2 infusion, the infusion-related reactions do not recur. So that’s very manageable. The toxicity of rash can be challenging, and patients need a lot of prophylaxis, education and a lot of care of their skin and the rashes that develop.

DR LOVE: Interesting. Please continue.

DR RECKAMP: So moving on to other interesting agents. In the resistant setting for EGFR-mutant non-small cell lung cancer, we have patritumab deruxtecan. And the HERTHENA-Lung01 study was presented and published this year. And what we saw with this, this is an antibody drug conjugate with a HER3 antibody and deruxtecan linker. And in this study, we see progression-free survival in the 5.5-month range with duration of responses about 6 months. And we see over on the right-hand side, response rate in about the 30% range. So this is showing activity. What is very small at the bottom is that this is across multiple types of resistance mechanisms and mutations, and the responses occur across all of these. This was not dependent on HER3 expression, and so no expression is required for the patritumab deruxtecan.

Again, where we are very interested in these patients, where we see a lot of the progression occurs in the brain. And in the CNS within the HERTHENA-Lung01 study, there was a second report that showed, again, improved time to CNS progression. And you see this here in those patients with a history of brain metastases, the green line is those with CNS disease. And so some prolongation of time without CNS progression. And even with those without a history of brain metastases, as you see, those who develop brain metastases, a very, very low number with that green line at the bottom.

Here's just another image of patients with response in the brain. And again, this is an antibody drug conjugate. We don’t always expect these drugs to go to the brain. But yet, there are these reports of responses and even complete responses in a subset of these patients.

So moving down to more nontargeted therapies for patients with EGFR mutation upon resistance. Again, the line of ADCs, this is looking at the TROPION-Lung01 study. And this is datopotamab deruxtecan, a TROP2 antibody linked again to deruxtecan. And this is showing all-comers for patients who had, on the left-hand side, with and without genomic alterations. And we saw an improvement in the progression-free survival over docetaxel. This was more pronounced in those patients with non-squamous non-small cell lung cancer. So based on this, there has been some interest in looking at patients with actionable genomic alterations or AGAs.

So moving forward, there’s a trial, the TROPION-Lung05, so the datopotamab deruxtecan in patients with actionable genomic alterations. And so this is an ongoing study. Again, presented at ESMO by Dr Paz-Ares. And they’re looking at the treatment in those patients with alterations. As you see on the bottom there, more than 50% of these patients have EGFR mutations. So it will be highly relevant to patients with EGFR mutations.

Early data, again, showing response rates in about 35% of all treated and over 40% in those with EGFR mutations. Duration of response, 7 months. And median progression-free survival, 5.8 months. On the right-hand side, you see the waterfall plot and the percent change on the bottom. So we see these responses and treatments that have activity in patients with EGFR mutation following a significant number of prior therapies.

The safety profile is shown here. Again, nausea, the stomatitis with the TROP2 inhibitors can be an issue, GI constipation, decreased appetite, nausea/vomiting. Rash and cough very minimal. So overall, tolerated. And the mucositis and stomatitis is a known toxicity of this agent that is manageable and does require some, again, patient education and potentially some prophylaxis.

So thinking about subsequent therapies for patients who have received front-line osimertinib or combinations with third-generation EGFR-TKIs who then development resistance, which are most of our patients. We really are excited to see some emerging options with response rates and some options that are not your typical targeted therapies that cover multiple mutations and mechanisms of resistance.

So chemotherapy with amivantamab improved overall survival over chemotherapy alone, and had less toxicity than the chemotherapy with amivantamab and lazertinib. We saw CNS benefit in this group. And this may be an option for our patients in the future. Patritumab deruxtecan also improved responses and had a 5.5-month progression-free survival in heavily pretreated patients, and had about 30% complete responses in the brain. Datopotamab deruxtecan, early efficacy in patients with actionable genomic alterations and response rates in EGFR mutant non-small cell lung cancer in the 40% range. All of these combinations and treatments have very differing toxicities and mechanisms of action, so we need to consider that as we’re thinking about what the subsequent lines of therapy that we’re introducing to our patients. And we need to consider the potential for sequencing-based therapies. And so patients may be able to receive more than 1 because we’re not, we do not have overlapping mechanisms of action and resistance mechanisms may be very different across these agents. So I think it’s an exciting time in this area of resistance in non-small cell lung cancer.

DR LOVE: Before you go on, I was going to ask you about another paper that we found that you did specifically focused on the management of infusion reactions related to amivantamab in the journal Lung Cancer. Was there anything in that study that you might want to comment on? There’s some pretty cool graphics there about timing and all. Anything about that paper particularly that you think would be worth bringing up? It’s such a practical, important point.

DR RECKAMP: I agree. The infusion reactions, as we discussed, with amivantamab are relatively common. And the majority of patients will have an infusion-related reaction. So early intervention with steroids and emergency medications when it occurs. We can often slow down the rate and resume on that day 1. And again, even when they can’t resume on day 1, the second day, they often do get the infusion. And by the week 2 infusion of the loading doses, I haven’t seen any further infusion-related reactions. So it is very common and it is very treatable. And I think that that’s the biggest message. And with education of both the patients and the staff, it’s a relatively manageable side effect.

DR LOVE: Alright. Please continue.

DR RECKAMP: Moving on to exon 20 EGFR mutations. We now have new data and new therapy for the front-line for patients with exon 20 EGFR mutations. And the PAPILLON trial was presented this year, again, at ESMO and published in the New England Journal of Medicine. These were treatment naïve patients with documented exon 20 insertion mutations. And these patients received amivantamab with chemotherapy versus chemotherapy alone. And, again, progression-free survival was the primary endpoint, also looking at response rates, duration of response, overall survival and safety.

So here, we see the bottom line. Patients who received amivantamab and chemotherapy had improved progression-free survival over chemotherapy alone. And we’re looking at 11 months versus 6.7 months with a highly significant hazard ratio below 0.4, and so significant benefit in this population.

There’s an interim overall survival as we see here. They’re too early to determine, but we do see a slight benefit toward overall survival improvement with the combination up front.

And thinking about the safety profile. So we’ve seen the combination of chemotherapy and amivantamab. And with the amivantamab with the EGFR and MET combination, we do see EGFR type toxicities, paronychia, rash, dermatitis, stomatitis, diarrhea. We also see the MET type of toxicities with hypoalbuminemia and peripheral edema, but the Grade 3 were quite low for these patients. And then the cytopenias, as expected, potentially slightly higher. Slightly higher Grade greater than 3 neutropenia in these patients. But overall, reasonably tolerated and manageable. And pneumonitis, again, was reported, but a low percentage, about 3% in patients.

So again, amivantamab remains the targeted option for exon 20 non-small cell lung cancer. And front-line amivantamab with chemotherapy can improve progression-free survival over chemotherapy with a trend toward improved overall survival. We are still looking for novel drugs for these patients with improved therapeutic window. And we need drugs with improved CNS activity. And the work in this area is still in its infancy. And we look forward to seeing what comes next.

DR LOVE: Generally speaking, right now, outside of clinical trial, what is first-line therapy likely to be in the hands of a clinical investigator like yourself?

DR RECKAMP: So we’re moving toward amivantamab and chemotherapy for these patients. And again, it takes a little bit of working with the toxicities. And cytopenias are a little bit higher with the combination, but patients are tolerating it. And, again, it’s early days, but we’re seeing good responses. So I think it’s easy to move this to the front line. We still would like to see more targeted TKIs and things like that that have good efficacy and safety profile mixed together. We don’t have that yet.

DR LOVE: But in general, do you think most investigators, NCCN, et cetera, are they blessing chemo plus ami?

DR RECKAMP: I think this is moving forward. Yes, I do think this is moving forward. Because these patients have limited options and don’t necessarily do very well with therapies. So seeing this improvement in progression-free survival I think makes it an easy choice.

DR LOVE: Great. Please continue.

DR RECKAMP: So now that we’ve covered advanced-stage disease, we’re always excited to move these targeted agents into the earlier course of disease. And so we had the approval of osimertinib in the adjuvant setting back in December of 2020. And we’ll be talking about osimertinib, and potentially in the locally advanced stages also.

So ADAURA was the Phase III study that, again, looked at patients who had surgically resected non-small cell lung cancer, Stage IB through IIIA. And these were tumors greater than 4 cm or with lymph node involvement. And patients went on to receive chemotherapy as required by or necessary by the treating investigator followed by randomization to osimertinib versus placebo. And this was a unique treatment duration of 3 years in these patients. And the primary outcome was disease-free survival. And secondary outcome of overall survival.

So at ASCO this year, we learned that osimertinib can improve overall survival in our patients with resected EGFR mutant non-small cell lung cancer, which is an exciting time. So here, looking at Stage II and Stage IIIA where we generally see a more significant benefit, it’s about 5 years, the 5-year benefit is about 12%, but a hazard ratio of 0.49. And when you add the Stage IB to this on the right-hand side, we still have a hazard ratio of 0.49 and about a 10% benefit at 5 years. And this is still pretty early. There were very few deaths that have occurred. We wait for the maturity, but we still see a benefit in this overall survival.

And, again, looking across stages. IB alone, here we see 94% versus 88%. Stage II alone, 85 versus 78. And then Stage III where we often see the highest benefit, we have 85% versus 67%. And, again, event levels are still very low for death. And you see the forest plot here on the right-hand side.

Toxicity. So we do see, obviously, toxicities with osimertinib over placebo. And generally, the Grade 3 and higher, less than 25%. Less than 1% leading to death. About 13% had discontinuation. Another 12% with dose reduction. And about 30% with interruptions. But overall, reasonably well-tolerated. And 11% greater than Grade 3 toxicities with the osimertinib. And very few serious AEs, 3%.

And here, we see another paper that was published this past year by Dr John looking at tolerability and health-related quality-of-life. So we see here, adverse events. Osimertinib in the blue versus placebo in the yellow. And we do see more adverse events, but tend to be not a significant percentage of patients. And looking here, those with the quality of life did not change significantly. Quality of life was maintained with the osimertinib, and really close to the baseline. And here, we see on the right-hand side, those with dose discontinuation, interruption and reductions. And overall, well tolerated and patients able to continue on therapy for the most part.

So based on this, we still have a lot of questions in the adjuvant setting. We’re looking at perioperative targeted therapy. As we see benefits in the immunotherapy arena, will perioperative neoadjuvant therapy be better? What’s the optimal duration of therapy? Is it 3 years? Is it longer? Is chemotherapy necessary? And we’ll hear that from Dr Gainor with the ALINA trial where they omitted chemotherapy in the ALK population. What’s the best timing for this TKI therapy? Do they need it prior to surgery? Do they need it just adjuvant or do they need both? There is a study ongoing for Stage IA disease. And so those early, early stage, we may have some data to support the use in earlier-stage disease. And, again, this was a study for deletion 19 and L858R, but would this be also beneficial for patients with other EGFR mutations? And then can we detect minimal residual disease? Can we de-intensify therapy for patients who don’t need it and intensify for patients who may need it? Adding chemotherapy and such like we may do in the metastatic setting. And then what are the mechanisms of resistance? Are they going to be different? And what are the best therapies following resistance?

DR LOVE: I wanted to ask you a little bit about dose reduction of osimertinib. Again, I saw a paper you did. I think it was in the advanced disease setting. But just sort of globally, what do we know about the relationship between dose reduction and activity? It sounded like maybe there could be a correlation. But what’s the bottom line?

DR RECKAMP: I think that overall, there may be a little higher activity with the higher dose. But for patients who can’t tolerate the higher dose, obviously, being on the drug is better than being off or having to take multiple breaks of the drug. And so I think overall, being on the lower dose is beneficial. But we have seen those step-up in patients, especially with brain metastases and things like that, that we do see potential even overcoming progression in patients who go up on the dose. And so I do think dosing is important. But obviously, staying on the drug is also important and some of our patients really cannot tolerate the highest dose of drug.

DR LOVE: Alright. Please continue.

DR RECKAMP: So I’ll end with the LAURA study as a preview to ASCO this year. So this is consolidation osimertinib in unresectable Stage III non-small cell lung cancer. And we see, again, these are patients with standard exon 19 and L858R mutations. They received concurrent or sequential chemoradiation. And then, they went on to receive osimertinib versus placebo. And, again, these patients did not receive consolidation immunotherapy. This is not a patient population where we think immunotherapy is necessarily beneficial. And so they went on to just receive the osimertinib or placebo. And we know now in the overall, progression-free survival is the primary endpoint.

We know now from a press release that this did demonstrate an efficacy benefit for patients in this setting. To note, these patients received ongoing osimertinib. There wasn’t a timepoint. There wasn’t an endpoint of 2 years or 3 years with osimertinib. So this was ongoing osimertinib following chemoradiation. But we do see a progression-free survival benefit, and this will be presented at the plenary session at ASCO this year.

So again, we have a very exciting time for EGFR mutant non-small cell lung cancer. The treatment landscape is evolving quickly. We have more options for patients in the front-line therapy that improve efficacy, again, with chemotherapy or the combination of amivantamab and chemotherapy. The paradigm for subsequent therapy after resistance is also shifting. And have, again, multiple options that show responses and potential benefit with amivantamab and chemotherapy, patritumab deruxtecan and potentially datopotamab deruxtecan, again, all with differing mechanisms of action and potential for sequencing in our patients. In the adjuvant setting, osimertinib makes a lot of sense. We now have overall survival benefit for these patients. And really should be used in most patients who fit those criteria. Consolidation osimertinib improving progression-free survival is also an exciting outcome to await to see the full results at ASCO this year. And we’ll be discussing that presentation and the implications for our patients. Biomarker testing, again, highly important. And now, we see it should be done in the perioperative setting. We need to know these, at least EGFR mutation and likely ALK alterations, very early on in the setting so that we can send them down the right pathway because immunotherapy will not be the right pathway for our EGFR patients. And looking at these biomarkers and finding biomarkers for selection for resistance is also going to be important, and for early detection.

Therapeutic Approaches for Patients with NSCLC and Other Actionable Genomic Alterations — Justin F Gainor, MD

DR GAINOR: Hello, my name is Dr Justin Gainor. I’m a thoracic medical oncologist and the Program Director for the Center for Thoracic Cancers at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. Today, I’ll be sharing updates on targeted therapy in non-small cell lung cancer.

And we’ll kick things off with ALK fusion-positive lung cancer. Obviously, this has been an area with immense drug development over the last decade with multiple new next-generation inhibitors approved, and we continue to see drug development in this space. And really, basically extending off of the benefits of the ADAURA study, we now have the ALINA study, really investigating the role of adjuvant ALK inhibitor in patients with resectable ALK-positive disease. Quick reminder that whenever we think about adjuvant lung cancer studies, we always have to look at the staging criteria because this has evolved over time. We’re currently using the 8th edition, soon to be 9th edition. This study was done under the 7th edition, so basically tumors 4 cm and above. These were tumors that you would typically think about adjuvant chemotherapy. And patients were randomized 1:1 to either alectinib 600 mg twice daily for 2 years or platinum doublet chemotherapy. And this is a critical distinction between ADAURA where all patients in ADAURA, you could have received chemotherapy and then the randomization was to targeted therapy or not. Here, the randomization is ALK inhibitor versus chemotherapy. So distinction in terms of study design.

No surprise here when we look at the primary endpoints. Disease-free survival, you can see in the Stage II to IIIA population, marked benefit with alectinib here. We’re seeing hazard ratio, 0.24. Really impressive 3-year landmark disease-free survival at 88% in these patients. If you look at the intention to treat population in the lower right, this is where you’re now starting to include those IB patients. Hazard ratio is identical. It continues to be incredibly impressive data. And we don’t have OS data yet. That’s immature right now. You can see only 2.3% of patients having events.

But nonetheless, based on this data, the FDA recently granted FDA approval just within the last 2 weeks. So I would say based on ALINA, my take is adjuvant alectinib is now a new standard of care for patients with resected ALK-positive lung cancer. I think this underscores that we need to genotype resectable disease too. We can’t just look at EGFR, we need to be doing ALK testing. And I would argue that we should do broad-based genotyping including in resectable disease. In my own practice, how I might approach this a bit differently is I still think there’s a role for adjuvant chemotherapy. So much like I approach EGFR mutant lung cancer, I think there’s still worth conversation about giving chemotherapy for patients. We know chemotherapy offers a survival benefit which is the gold standard when you’re talking about adjuvant therapy. So I’m generally talking to my patients about adjuvant chemotherapy as well. I think the questions this raises for us as a field moving forward is, would this push towards neoadjuvant therapy? What is the role of neoadjuvant ALK inhibitor? There are now Phase II studies like the NAUTIKA study that are exploring that. So I think that will be an interesting approach. That’s coming up increasingly in tumor boards, right? Now that we are doing genotyping, what is the role for induction therapy first? And I think more broadly, this raises the question of now that we have definitive data in EGFR and ALK, do we actually need a randomized Phase III study for each rare genotype when the targeted therapies work so well? And for that, I’m including things like ROS1, RET, you know, the genotypes where we’re seeing very, very high response rates. My personal feeling is no, I don’t think we need a randomized Phase III study for each of these genotypes. But that is something that, there’s debate in the field there.

DR LOVE: So I guess the flip side of your last question is, in what situations, if you could, would you give adjuvant therapy in a targeted situation where we don’t have a Phase III trial? So I’m curious what your answer is, starting with RET.

DR GAINOR: Yeah. So RET, there is a Phase III study that has been launched with selpercatinib. Have I pulled the trigger on that yet? No. I think there are always questions on reimbursement. And I may be a bit too far out here, but I think for ROS1 and RET, I think those are 2 populations where we know the response rates are really high and they’re pretty well-tolerated drugs. And so I would say even on the basis of a feasibility study, I’d be comfortable starting to think about it. Have I done it yet? No. But I think now that we have this brand-new data in ALINA, I think we should be asking that question. And I’d personally be a fan of it.

DR LOVE: So another thought that I had as you were going through the ALINA data is all the things that we’re hearing in other solid tumors about MRD assays, Signatera™, et cetera. And I was just kind of flashing on, what would you do in a targeted situation in lung cancer, for example, with a liquid biopsy? In breast cancer, they’ve got a study where they’re starting out with adjuvant hormonal therapy and then they’re looking in the blood. When they see the resistance mutations, they’re going to randomize between switching and continuing. And you see this kind of thing. Colon, they’re looking at it. What about in lung in these targetable? Can you do a liquid biopsy and see whether there’s still disease there?

DR GAINOR: I think this is going to be a really important point in the field. And right now, your typical tumor uninformed assays I don’t think have sufficient dynamic range to actually do this, particularly for fusions. It’s much harder to find fusions in liquid. And so even in metastatic disease, most patients are going to be able to clear their fusions in your standard off-the-shelf assay. So I think you’re going to need to do a tumor-informed approach to get sufficient dynamic range. But I think that’s where we need to move. And in fact, we have a position paper coming out in the next month in Cancer Discovery, myself, Jessica Lin, Christine Lovly and Vincent Lam, talking about this idea of treatment residual disease. Basically, when you take an ALK-positive lung cancer patient, most patients with metastatic disease don’t have a CR. There’s still something visible on the CT. So MRD, you know, we went back and forth. Is MRD the right term? There’s still macroscopic disease. But starting to think about, can we actually start intervening at that point? Can we intervene when there’s still residual disease on the scan targeting these drug-tolerant persister cells and using things like next-generation liquid biopsies, radiomics to try to guide who needs to be intensified and who doesn’t?

DR LOVE: So I guess I’ve heard the term “bespoke assays,” which I guess are individualized. Do you think that’s what it’s going to take or do you think maybe you could have sort of one kind of assay just for RET or ROS1, et cetera?

DR GAINOR: There are different approaches that people are taking. Some where it’s just 100 genes. I don’t think that’s going to be sufficient. I think it needs to be supplemented. You could supplement it though in different ways. Some people are thinking about adding fragmentomics. Some people are thinking of, can you start looking at the methylation patterns as a way to augment just mutation calling? And then another way to do it is to sequence the original tumor and develop personalized primers and just look for those specific mutations. There are pros and cons of each approach, cost, speed. So no one has done a comparison. So that is something that we’re actually doing a lot of research on right now.

DR LOVE: I’m waiting for you to say that somehow AI is going to enter the picture.

DR GAINOR: Well, I think it is. But how so, right? I think what’s going to end up being the solution is where you have these multimodal models where it’s not just all liquid biopsy, but can you actually use digital pathology plus liquid biopsy plus something with the radiomics.

DR LOVE: Wow.

DR GAINOR: And that’s what we’re trying to build.

DR LOVE: Wow.

DR GAINOR: Working with machine learning, but integrating data sets to really give some sort of risk score moving forward. I think that’s where we need to go.

DR LOVE: Awesome. Alright, let’s talk about HER2.

DR GAINOR: Yeah. So a lot of updates in this space. So of course, over the last several years, we’ve been focused on HER2 insertion mutations. So in the upper left-hand corner, it basically shows a pie chart of the different types of HER2 mutations. We know that these are seen in about 2% of patients with lung cancer. Most of them are in the kinase domain, but there are some HER2 mutations that are in the transmembrane domain or in even the extracellular domain. There have been a variety of attempts to target this therapeutically. I’d say that the main strategies have been monoclonal antibodies, which had modest effects. Targeted therapies with kinase inhibitors historically have had low response rates. Some of the next-generation inhibitors look a bit better. But really, what’s changed the field has been the antibody drug conjugates such as trastuzumab deruxtecan. And so this has also been a lesson in terms of kind of drug development and dose optimization. So the initial data that we saw with trastuzumab deruxtecan from DESTINY-Lung01 was using a 6.4-mg/kg dose, higher than the dose approved in other cancer types, right? And we saw a response rate above 50% with a nice durability of response. Subsequently, we’ve now seen data from this recent publication in JCO from Dr Goto and colleagues where, under Project Optimus, testing 2 different doses, the 6.4 versus 5.4 dose of trastuzumab deruxtecan. And you can see here that the response rate looks somewhat comparable, 49% in the 5.4 dose, 56% in the higher dose. The median PFS was a little bit higher in the 6.4-mg dose.

But I think this needs to be taken into the context of what we saw in terms of toxicity. The main toxicity, particularly as a thoracic oncologist, that I’m worried about with these agents is interstitial lung disease. Two cases shown on the left. And what we are seeing in the updated trastuzumab deruxtecan data is that it does look like dose plays a role, right? If you look at adjudicated drug-related ILD in the table on the right, you see at the higher dose, 28%, versus 14.9% in the lower dose. Those are, of course, patients treated with prior PD-1. If you then take out patients and just focus on those who haven’t received PD-1, we can see that in the high dose, it’s still an issue. It’s still more than one quarter of patients are experiencing ILD. Lower with the 5.4 mg/kg dose. And so this is the FDA-approved dose now. And so I think if we’re trying to balance efficacy and safety, I do think the lower dose is what we should be using.

One additional update is just to show you that we are seeing data in the central nervous system with these drugs. We do know that, you know, these are big molecules. So the question is always, can you actually see CNS activity? And this is a pooled analysis that was presented by David Planchard at ESMO this last year pooling data from DESTINY-Lung01 and 02. And you can see a pretty encouraging waterfall plot for both doses of intracranial responses. So I think this is encouraging data. One caveat though is that the time to intracranial progression was relatively short. And so I think you can get some initial responses but unlike TKIs, I’m not going to bank on the response. I think if you have a large brain metastasis that’s symptomatic, I’d still reach to my radiation oncology colleagues first.

For HER2 mutations, just to summarize, 5.4 mg/kg of trastuzumab deruxtecan is now the standard of care for HER2 mutant non-small cell lung cancer. We’ve seen antitumor activity across various HER2 mutations. So if you actually look at those waterfall plots, it’s not just the kinase domain mutations. We’re also seeing activity in those with extracellular domain mutations. I highlighted the CNS antitumor activity but, again, caution that the time to intracranial progression is shorter than what we typically see with tyrosine kinase inhibitors. So for small brain metastases, subcentimeter, asymptomatic, I think it’s reasonable to proceed, but close CNS surveillance. I think the last point is, when do you actually use these drugs? Do you use it first line or do you use it second line? The FDA label is after patients have already received a prior line of therapy. And in my own practice, that’s generally where I position this drug. Because of the pneumonitis concerns, I generally use this second-line, but I have plenty of colleagues who are using it upfront. In my own practice, I start with platinum doublet plus or minus PD1 and then I use trastuzumab deruxtecan in the second-line setting.

One thing that is hot off the presses though is that we’ve recently seen another FDA approval targeting HER2. This is just within the last couple weeks. This is another example of a tumor agnostic approval from the FDA. So this is really looking at patients with HER2 overexpression as evaluated by IHC. This is, 3+ is the approval. The data that we have in terms of peer-reviewed literature though is from Dr Smit and colleagues recently published in Lancet Oncology. And here, they actually combined data. So this is, if you look at the table in the upper left-hand corner, they had 2 different cohorts. Again, getting at the 2 different doses. But if you just focused on the patient population here, 2+ and 3+ in this cohort, you see that most patients, so 77%, had HER2 2+ by IHC, a smaller proportion of patients with 3+. If you look at the clinical outcomes, which are listed below and then you can see in the waterfall plot on the right, so not as high response rates as what one saw with HER2 mutations. But still, for lung cancer, I think this is promising. We’re seeing partial response rates here in the 26 to 34% range. So, again, this is combining the 2+ and 3+ together.

In the next few slides, I’ll just try to break this down a little bit more. If you focus on, this wasn’t in the publication, but if you look at the FDA label, it listed that for HER2 IHC 3+ tumors, the response rate was close to 53%. And I think this is what led to the approval. So median duration of response, 7 months. So not as good as what we see with mutations. But still, I think a step forward for patients with HER2 overexpression.

And so I think this begs the question now, not even a question, but I do think we need to start testing for HER2 overexpression in lung cancer as well as other tumor types. This had not been part of our workflow. So when we saw this approval, so we’ve now been in touch with our pathologists. This is now part of our standard workflow. So in addition to PD-L1 testing, we do now need to be checking for HER2 overexpression. The word I’ve heard is, depending on the study, it’s 2% to 6% of patients will have this degree of overexpression with lung cancer. We need more data though to guide us. What are the clinical pathologic characteristics of those patients? There can be overlap with canonical drivers like EGFR, and that was highlighted in the publication. So I would consider this now a new standard of care for patients with lung cancer and IHC 3+. But this would be after standard of care chemo/IO for these patients. And so we need more data on HER2 2+. I think that’s a question mark of, is there still a role? It seems like from the Smit publication that there could be. But in order to get an accelerated approval, I think a single arm study isn’t going to be sufficient. I think you’d need to see more of a randomized study given the more modest activity there.

DR LOVE: So I’ve got to say that the way you presented it just now gave me a completely different view of that pan-tumor approval. For some reason, when I saw that, the first thing I thought about were all the very, very unusual cancers where we haven’t even seen Phase II data. But actually, now that I think about it, yeah, this thing’s been standing there. I’ve been wondering when is it going to be approved for overexpression, not just in lung but also colorectal. They have very good data there, but it’s not approved. And we’re like, well when is it going to get approved?

DR GAINOR: Yeah.

DR LOVE: I never really thought about the fact that this pan-tumor approval is just going to bring all of that in, right?

DR GAINOR: Absolutely, absolutely. I think now, it all comes with it.

DR LOVE: I don’t know if you see what I’m saying. It’s like we and everybody else, we’ve been all focused on these individual tumors, so I just figured it was going to go that way. But I see what’s happening here. It’s like all of a sudden, the dam broke sort of. So that’s one thing that’s really interesting about what you were saying.

The other thing, and a little bit disturbing too. We’ve seen data on T-DXd and brain mets in breast cancer. It looks very encouraging. We saw the same kind of waterfall plot. But I never heard anybody comment on duration of response, which also is a very important issue in general with T-DXd. Because, again, in breast cancer, that really is the thing that distinguished it, was the more prolonged responses. So what you’re saying about brain gets me a little nervous. What about outside the brain? Duration of response?

DR GAINOR: So duration of response is good. We’re talking about it, depending on which study you’re looking at, the duration of response is around a year. So that’s good. It’s not as good as what we’ve gotten used to with some of the TKIs, right? So I do think we need to keep working to improve upon that. The mechanism of action for why HER2 mutation is more susceptible to an antibody drug conjugate is an interesting one compared to, say, amplification or overexpression. It turns out that in the presence of a HER2 insertion mutation, you actually get increased cycling of the receptor off the cell surface, so you get increased internalization of the receptor from the cell surface. And so that’s ideal for an ADC, right? You’re just bringing more of the drug inside. And it turns out with some of the TKIs, if you give a TKI plus an ADC, you can actually accelerate that cycling even more. So that actually may be a strategy moving forward, combining TKI plus ADC. And not just in an additive way, but there may be actually true synergy there.

DR LOVE: So interesting. One more thing. I don’t know why, again, I never thought to ask this before. But how do you grade ILD in a patient with baseline pulmonary symptoms? In breast, they have this real hard thing. If they have Grade 2, if they have symptoms, they’re not getting it again. I’m not sure I hear that as much outside of breast, but that’s their thing. But then how do you define Grade 2 in somebody who is on oxygen or baseline pulmonary symptoms from COPD? Like they get worse? Is that how you do it?

DR GAINOR: Yeah. It’s worsening, but you’re right. It’s a challenge. It’s really sitting down with your radiologist too to also try to get a better sense of what’s the extent of disease, how likely is that going to be causing issues. These are the situations where we really challenge, is between that Grade 1 versus Grade 2. Are they really symptomatic from this or not? And do I pull the trigger on steroids or not? And I think the extent of disease also influences you. Based on the radiographic pattern, it may tip you one way or the other.

DR LOVE: A lot of times, there’s not much choice of the matter. But in general, it is kind of an intimidating situation to give somebody who has already got serious compromise, maybe they’re on oxygen, a drug that could potentially make it worse. But on the other hand, if they don’t get any treatment, we know what’s going to happen. So really difficult decisions.

DR GAINOR: It is. And that’s why I think it is helpful to see that with the lower dose that the rates have come down considerably, right? Now, you’re talking about 8%. That just feels better as a clinician rather than 25%. Because the other thing that we need to keep in mind, especially for me as a clinical investigator, is I label someone as having pneumonitis, I can’t ever get them on a clinical trial. That is, it’s not just the acute toxicity. It’s then most trials are prohibiting those patients from ever getting on a study. And so the lower we can keep those rates, the better.

DR LOVE: That’s a really great point. Alright, let’s talk about ROS1.

DR GAINOR: So ROS1 fusion. So this is, while rare, only 1% to 2% of non-small cell lung cancer, this too we’ve seen a lot of development in this space. So as a reminder, ROS1 fusions are very closely related to ALK in terms of the ATP binding pocket. They actually share remarkable similarity in terms of overlapping residues. And so we can use many of the same drugs for ROS1 as we can for ALK, but not all. So the classic example I always like to remind people, you can’t use alectinib here. While it’s a good ALK inhibitor, it’s not a ROS1 inhibitor. But crizotinib is really where we saw the initial data, 72% response rate. Good median PFS of 19.2 months. On the right, we then saw the second agent enter the field, entrectinib. Very similar response rate, 67% in a much larger cohort though. This is combining multiple studies together. Median PFS of 15.7 months. Where entrectinib really had the leg up though is in intracranial control. We know that CNS penetration is a vulnerability with crizotinib. It’s poorly CNS penetrant. Whereas entrectinib, we saw here in the initial reports close to an 80% intracranial response rate.

Recently, Alex Drilon and colleagues presented updated data. This is a pooled analysis of 168 patients across these 3 studies outlined there. And the data has really held up. So response rate, 68%. We have a much more mature PFS now. The median PFS is still around 16 months. And on the right, some of the first signs where we’re seeing overall survival data. Granted, it’s a single-arm study. But giving you some benchmarks, right? And seeing a median OS here of close to 48 months in ROS1 fusion positive lung cancer.

The new kid on the block in terms of recent FDA approvals has been repotrectinib. This was recently published in The New England Journal of Medicine earlier this year. And the waterfall plot on the upper left here shows an impressive response rate close to 80%. You can see it looks very similar whether patients had received prior chemotherapy or no prior chemotherapy here. On the right, I think is what got people’s attention is the progression-free survival for patients who were TKI naïve. And you can see here a median progression-free survival that looks quite different than the other drugs. It’s close to 36 months with this drug. So that’s, I think, certainly got people’s attention with this asset. This drug also has intracranial control. Showing on the bottom left, this is duration of intracranial responses. Granted, it’s only 9 patients though. But high rates of intracranial responses with this drug. Now when it comes to CNS penetration, I think of that as a double-edged sword. It’s a good thing against the tumor, but it can be a double-edged sword when you have a TKI that’s hitting other kinases expressed within the central nervous system. And so repotrectinib, TRK is in the name, it does hit TRK receptors, which are expressed in the CNS. And so that explains some of the toxicities that we’re seeing at high end of the list here, dizziness, dysgeusia being some of the big ones, weight gain.

Those can be challenging toxicities for patients, particularly the dizziness, if you’re on therapy for a long period of time.

Here's just some data looking at repotrectinib in patients who’ve already received a ROS1 TKI. So you can see the different types of agents. Most of these patients have received prior crizotinib although a couple had received prior entrectinib or ceritinib, all with ROS1 activity. You can see that the response rate drops but still quite good, close to 40%. Importantly, we know that there’s 1 particular ROS1 resistance mutation. It’s in the solvent front, this G2032R mutation. It’s analogous to G1202R for ALK. And in preclinical models, repotrectinib was able to overcome that mutation. And indeed, if you look at the clinical data, if you’ve already received a ROS1 TKI and you have that alteration, saw a response rate of close to 60%. So this agent does appear to be able to overcome TKI resistance in a subset of patients. The median PFS though in that setting is lower, it’s more like 9 months.

And this is just to show you that the frequency of that G2032R mutation in our cohort, it was about one-third of patients progressing on crizotinib will have G2032R. And so that’s where I think drugs like repotrectinib in the TKI treated population are going to work best.

So my take on ROS1 fusions. Crizotinib, entrectinib and repotrectinib are now all FDA approved for management of treatment-naïve ROS1 fusion-positive lung cancer. I think both entrectinib and repotrectinib have both demonstrated significant intracranial activity. Repotrectinib has produced the longest median PFS seen to date in treatment-naïve ROS1-positive lung cancer. It’s also shown, I would say, more moderate antitumor activity in previously treated ROS1-positive patients, but particularly those with the G2032R mutations. So I think that repotrectinib is a reasonable now first-line option. I think clinicians need to be aware though of those TRK-related side effects, because those can be quite disruptive to quality of life.

So moving on to RET fusions. So similar frequency, 1 to 2% of lung cancer has RET fusions. On the left, I’m just distinguishing RET can also be activated via point mutation. But in lung cancer, it’s fusions. Both selpercatinib and pralsetinib have received prior approvals for RET fusion positive lung cancer showing high response rates in both the previously treated population as well as in the treatment naïve setting. And so in my view, these have been standard of care drugs for several years.

Recently, though, we’ve seen data from LIBRETTO-431. This was a randomized Phase III study that enrolled newly diagnosed RET fusion positive patients to receive either selpercatinib versus platinum doublet chemotherapy plus or minus pembrolizumab. It was a 2:1 randomization. Crossover was allowed. I would say the no-brainer result here was that selpercatinib was superior to chemotherapy. We saw that not just in terms of progression-free survival but also, we saw high rates of intracranial tumor responses as well. So I view this data as really data reaffirming what we should be doing instead of changing the standard of care.

I’ll editorialize in a second. But my take, both selpercatinib and pralsetinib are FDA approved here. I would say that selpercatinib now has a Phase III study showing a clear benefit over chemotherapy. I would say the greatest, I think, lesson or piece of data that came out of LIBRETTO-431 in my mind was that if you look at the control arm and you look at those who got chemo versus chemo plus pembro, there wasn’t a difference in PFS, and really reinforcing that anti-PD1 doesn’t add much in oncogene-driven lung cancers like RET fusions. So I think that’s helpful. But I really don’t think this is a study that should have been done. We knew that the activity from a large study, the Phase I was over 400 patients, that the response rates were in the 70, 80% range. And so I don’t think we need any more studies comparing highly effective targeted therapies against chemotherapy in oncogene-driven lung cancer.

The study didn’t enroll anybody in the US. Sadly, because access is an issue throughout the world. The study was able to enroll and it was a positive study, but I don’t think we should be doing these studies.

DR LOVE: So just to qualify that just a little bit. You said, I think, a highly effective targeted therapy. So any commonly used targeted therapies that you think are appropriate second-line, but not first line? You just said T-DXd, although I don’t know if that’s a classic type of targeted therapy.

DR GAINOR: Yeah, I don’t think that’s a classic. Where I was qualifying that is I wouldn’t group KRAS here, right?

DR LOVE: Right, right.

DR GAINOR: I think KRAS is an example of where response rates were more in the 30 to 40% range.

DR LOVE: Not yet.

DR GAINOR: Right. Not yet. But once you’re starting to get drugs in the 75%, 80% response rate, really well-tolerated, and chemo is only in the 30% range, I don’t think we can really be randomizing patients with equipoise there.

DR LOVE: Right. One other question. I brought this up to you before just in terms of an update. In terms of the choice between selpercatinib and pralsetinib, assuming they’re both available. You mentioned the issue about the Phase III trial that shows selpercatinib has favor. But beyond that, in terms of tolerability, do you see any difference? Because you had mentioned chylous effusions to me. And I’m curious if you have an update on that, whether or not you see it with other RET inhibitors, and how much of an issue it is, and any difference in the 2 drugs tolerability wise.

DR GAINOR: They’re a lot more similar than they are different. I think the similarities are you see hypertension with both. So even though they’re labeled as selective, they do still hit VEGF a bit. Where they differ is selpercatinib, as you mentioned, there’s this issue with chylous effusions. The rate there is around 7% in our series, 7%, 8%. So in a subset of patients, it can be problematic but it’s not the majority of patients. QTc prolongation and symptoms for patients who have already received PD1, you can see more hypersensitivity reactions with selpercatinib. On the flip side, with pralsetinib, you run into more issues of low counts. So you can certainly see more cytopenias, neutropenia because it does hit JAK. I think there’s more data with selpercatinib, and I think people are creatures of habit. And so I think, you know, I tend to use selpercatinib a bit more. But I think both drugs are perfectly reasonable.

DR LOVE: Just out of curiosity, have you switched patients who got chylous effusions to pralsetinib? And do they still have it?

DR GAINOR: Good question. I have offered patients to switch, but none of them have taken me up on it. So part of that is many of these patients were patients who enrolled in the Phase I study, and so they’ve been on it for 4 or 5 years. And so they’re very hesitant to switch. And I can’t blame that. I have had patients though make the switch where they were running into cytopenias on pralsetinib, and we switched to selpercatinib. And not surprisingly, the cytopenias got better.

DR LOVE: Wow.

DR GAINOR: So I do think there’s advantages to having 2 drugs in the same space because some people will tolerate one better than the other. The other side effect that I think people should be aware of that is one of those constant Grade 1/Grade 2 that can be bothersome and patients may not bring it up is dry mouth. We actually see a lot of dry mouth with selpercatinib. It’s generally Grade 1/Grade 2, but having a Grade 1/Grade 2 side effect for years can be more disruptive.

DR LOVE: Interesting. Alright, let’s talk about MET.

DR GAINOR: So MET. I would say less updates in the MET space, but this slide is really just a reminder that we can have multiple different ways by which MET can be activated. And so when we discuss whether someone is MET positive, we should be discussing what the specific alteration is. Where we have seen the most data really is MET exon 14 skipping. But now with the ADCs, there’s also interest in MET overexpression, et cetera.

So our data with MET exon 14 skipping. We have 2 FDA-approved drugs. So on the left, this is data from capmatinib. We see a higher response rate in patients, in the treatment naïve setting compared to the previously treated setting. In the treatment naïve setting, we’re talking about response rates close to 60% with some durability as well. The latest data on capmatinib, we don’t have updated clinical endpoint data except for some quality-of-life data, which you can see on the right. So this is just showing that, yes, if you use a targeted therapy, this is not comparing 2 arms, this is comparing first line versus second line. And not surprisingly, when you use something that’s got a higher response rate in the first line, you tend to see some more improvement in cancer-related symptoms such as cough and chest pain.

We’ve seen more updated data with tepotinib. And I would say that this is not practice-changing, this is more practice-reaffirming. Similarly, looking at tepotinib in the treatment naïve and previously treated setting, again, higher response rate in the treatment naïve setting. And it’s hard to line up, but the L+ and the T+ underneath the Kaplan-Meier curves, those are showing liquid biopsy detected versus tissue detected. And just showing you that, indeed, regardless of the modality by which you’re finding these alterations, if you find it, these tumor types tend to respond to targeted therapy. So when we look at progression-free survival, 11 to 12 months with tepotinib. And not super surprising, patients with MET alterations tend to be a bit older than other and tend to have some more comorbidities compared to patients with, say, ALK and ROS1 fusions.

And so my take on MET exon 14 skipping right now is we have 2 approved agents, capmatinib and tepotinib. I recommend these agents upfront, so this is my first-line therapy for patients with MET exon 14 skipping. With long-term follow-up, we really haven’t seen major changes in the data. But one thing clinicians should be aware of is that the longer patients are on these therapies, we do see some cumulative toxicities that can be very bothersome for patients. And this most notably peripheral edema. And once it starts, it gets really hard to manage. You can try diuretics. But it’s really challenging as a clinician to deal with. So a lot of counseling upfront before you even start the drug, talking to patients about avoiding salt, compression stockings, things like that because it is quite difficult to manage once it occurs.

DR LOVE: Any way to distinguish these 2 drugs in terms of activity or tolerability? Or is this kind of an anastrozole/letrozole thing?

DR GAINOR: I’d say more of the latter. These drugs are remarkably similar. The efficacy endpoints, response rate very similar, PFS very similar with the updated data with tepotinib and the toxicity profiles. We know that edema is an on-target effect. And so it’s identical with the two of them.

DR LOVE: So harkening back to our earlier discussion of adjuvant targeted therapy. First, I’d like to hear whether you think MET exon 14 fits into the category of high response rate, something to consider doing potentially outside of a trial. And the other thing we didn’t talk about, but I think is also relevant is locally advanced unresectable where now, again, we’re seeing data with osimertinib as opposed to durvalumab. How are you going to apply that paradigm to targeted therapy including MET exon 14 in that setting?

DR GAINOR: Great questions. And these are the questions that keep our tumor boards lively because everyone’s got an opinion here. On the adjuvant question, so I think from an activity standpoint, it passes the bar in my mind. The main concern I would have though is with the edema. So when you’re giving 2, 3 years of MET inhibitor, it’s not just lower extremity edema. People start developing edema in their hands, trouble buttoning things. That would be my main concern, is that this person could be disease-free and I’m giving them 3 years of a therapy that’s really affecting their quality of life. So that would be the conversation in my mind.

And I think where we’re all interested to see the locally advanced osimertinib data. I think what I’d want to see is some — even a small study giving us a sense of what is the pneumonitis risk. It doesn’t need to be a randomized Phase III study, but if you give — for locally advanced, if you have MET exon 14 skipping, and you give chemoradiation, and you’re then following it up with a MET inhibitor, what is the pneumonitis risk with a MET inhibitor after chemoRADS? We know the pneumonitis risk with chemoradiation, definitive chemoradiation in the control arm of the durva study was 30%. If I add a TKI on top of that, am I going to be pushing up the pneumonitis risk? So that’s my main concern there.

DR LOVE: Is there some reason to think that might be more likely with the MET drugs than, for example, EGFR?

DR GAINOR: No, no.

DR LOVE: Do they cause more pneumonitis or something?

DR GAINOR: No. But we don’t know. So that’s where I think even — I don’t think you need a big Phase III, but even a small —

DR LOVE: Right, right.

DR GAINOR: A Phase II just to give some comfort. I’ve certainly given off-label ALK inhibitor before after chemoRADS and had patients develop pneumonitis. So being able to quote what the frequencies are I think would be helpful as a clinician.

DR LOVE: Alright. Well, let’s finish out with KRAS G12C, and I guess try to figure out whether your talk became outdated last night.

DR GAINOR: Exactly, exactly.

DR LOVE: To both of our surprises, right?

DR GAINOR: Right. And this field is moving quickly, right? We’ll start with the approved drugs. So we have sotorasib, the first agent that was approved. And the Phase I expansion cohort showed modest antitumor activity. It’s baseball season, so I consider that a good solid base hit. It’s good, but it’s not great. And not surprising when you compare it against standard of care second-line chemotherapy. It’s better, but it’s not dramatically better. Now anyone who viewed the ODAC meeting around this data, you heard about a lot of the flaws in the conduct of the study. But nonetheless, it was a positive study. But it was disappointing in the degree of clinical benefit. And so I think with this, this data really tells us this is not a first-line drug. How do we move these drugs to the first-line setting?

And I think the strategies that people are pursuing. So one, you could develop a better RAS inhibitor. So there’s efforts to develop RAS on inhibitors instead of the off inhibitors, so interest there. The other would be through combinations. So can we actually start combining RAS inhibitors with chemo? Can we start combining it with PD1? Obviously, PD1 has been where there’s been a lot of interest.

And we’ve seen some data in this space. So this is from CodeBreaK 100/101 kind of looking at sotorasib with both pembro as well as atezolizumab in this presentation. This was Bob Li presented at World Lung now 2022. I think the big issue here has been hepatotoxicity. So if you look at rates of hepatotoxicity, really it’s prohibitive with the combination of sotorasib and pembrolizumab here, even when they tried doing lead-in versus concurrent. I don’t see a path forward with this combination. So the question really was, is this a class effect or was that unique to that particular molecule?

And so KRYSTAL-7, this was looking at adagrasib plus pembrolizumab. You can see here, response rate, encouraging response rate here, 63%. And then focusing our attention on the hepatitis rates, I would say lower rates of hepatitis. So not 0, but lower rates of hepatitis. I think some question marks on why are some of these numbers like hepatitis so much different than ALT versus AST? How is that being judged one versus the other? But nonetheless, I think just purely looking at ALT and AST increase, it looks like more modest elevations compared to the sotorasib data. And so there is now interest in moving to the first-line setting with combinations like this.

And so my take on KRAS G12C right now is, (1), I think sotorasib and adagrasib are now FDA approved in previously treated patients. In my own practice, I tend to use these as second-line agents. If you’re asking me which of the 2 I would use, I would say that all things equal, sotorasib has one advantage in that I’ve found it to be a more tolerable drug when given by itself. On the flip side, there’s more data on adagrasib with CNS penetration compared to sotorasib. And there’s more data combining it with PD1. That’s relevant if you think about these are drugs used in the second-line setting. So most patients are going to be coming off a PD1 inhibitor. And data from Memorial showed that if you start one of these within 3 months of a PD1 inhibitor, if you start sotorasib within 3 months of a PD1 inhibitor, you also see the hepatotoxicity. So patients coming off a PD1 inhibitor, I’m currently using adagrasib because of that concern. So I think we need to see combinations, we need to see better RAS inhibitors. And I think a lot of interest in, can we actually develop on inhibitors or ones faster at mode of onset? And we will see. I think there’s a lot of interest in this space, and not just for KRAS G12C, but KRAS G12D inhibitors are in clinic, pan-RAS inhibitors. This is an exciting space.