Activity Transcript

Heather Wakelee, MD, FASCO: Hello and welcome to this MedscapeLIVE program on biomarkers in non-small cell lung cancer, from detection to novel therapeutics and decision-making, with a focus on new data from ASCO® 2023. I'm Heather Wakelee, professor of medicine and chief of the Division of Oncology at Stanford University, and I'm joined today by Dr Josh Sabari, assistant professor at the NYU Langone Health Cancer Center in New York.

So welcome to our program. We're going to kick it off with Josh talking about heterogeneity in non-small cell lung cancer and the importance of biomarkers.

Joshua Sabari, MD: Thank you, Heather. There's really been a revolution of targeted therapy drug development in non-small cell lung cancer, and we really have to think about every patient in unique fashion. Over 50% of our patients will have a driver alteration identified, clearly with EGFR being the most common.

Here you see the National Comprehensive Cancer Network (NCCN) recommendations as well as the College of American Pathologists (CAP) guidelines recommending doing broad-panel, next-generation sequencing in all patients with non-small cell lung cancer, really irrespective of any clinical features, such as smoking status or age. I'll turn it back to you, Heather, to talk about EGFR-mutated non-small cell lung cancer.

Dr Wakelee: Thanks. All right, so this is just a quick reminder. I think most of our audience is aware that when you do identify a driver mutation in EGFR with the common activating mutation, such as deletion 19 and L858R, the preferred option in the US and where it's available globally is osimertinib. But we've got a lot of opportunities for improvement because, even with osimertinib, we do see relapse, we do see progression.

And there's been some interesting recent data and actually going back a couple of decades looking at what we can add to our first-line EGFR tyrosine kinase inhibitors (TKIs) to help them work better. There's a lot of work with VEGFR TKIs, novel compounds, but also with chemo. And we've seen data in the recent era looking at combining chemo plus EGFR TKIs up front where a couple of trials have actually shown survival benefit, though we haven't adopted that.

And, if you go back in time, the FAST-Act II trials and others had this sort of an approach where patients received chemo and then the EGFR TKI, sort of back and forth or intercalating. So this was a study that was done in Japan. This was late-breaking abstract 9009, with that idea of patients starting on the EGFR TKI, and the study opened using gefitinib and then switched to osimertinib once that became widely available. After 2 months on the EGFR TKI, patients then switched to chemo with a little 2-week gap in between, and then went back to the EGFR TKI indefinitely.

So this is that schema, and we can think about it sort of as a sandwiching approach. And this is the progression-free survival (PFS); it was not statistically significant. If you look at some of the subsets, if you look overall, it was close, 0.76, not necessarily a practice-changing result; the gefitinib data was actually more robust than the osimertinib data. So, with osimertinib, this intercalation wasn't that helpful.

And when we look at the overall survival, which was the main endpoint, the primary endpoint, really no difference. We're not seeing a benefit from this sandwiching--with getting your EGFR TKI, going to chemo, going back to EGFR TKI. So we're kind of back to the drawing board on this strategy.

And this switch from EGFR to chemo to EGFR didn't improve overall survival (OS). This is not a standard approach, but we continued to grapple with what are other things we might do. And we do have upcoming data, such as from FLAURA2, where we at least have a press release showing that that maybe hit the PFS, seems to have done that, but we don't know yet about what's the nature of that result, how significant was it.

And with that, I'm going to switch it back to you, Josh, and talking about what do we do after progression.

Dr Sabari: Thank you, Heather. So as you described, third-generation EGFR TKI is the standard of care in activating EGFR mutations, but what about on progression? And there's been a lot of excitement with immunotherapy in the non-driver population. What about in the EGFR-mutant driver mutation-positive population?

So we saw some data from ORIENT-31, that's sintilimab, a programmed cell death protein 1 (PD-1) inhibitor plus an EGFR TKI, showing improvement in progression-free survival. We also saw the CheckMate-722, which was nivolumab plus an EGFR inhibitor, and unfortunately that study did not look as positive.

So here we see KEYNOTE-789. This was late-breaking abstract 9000 looking at pemetrexed and platinum therapy plus pembrolizumab for TKI-resistant EGFR-mutant disease. And, unfortunately, this is an essentially negative trial. Hazard ratio here of 0.80. So really not practice changing with a P value of .012. So the addition of pembrolizumab did not seem to improve PFS to this patient population.

And lastly, when we look at overall survival, also not a positive trial, these curves are relatively superimposable on each other, maybe slight differences between the 2 groups here. Even when we looked at programmed death-ligand 1 (PD-L1) expression, tumor proportion score (TPS) greater than 1% vs less than 1%, no significant difference in my opinion.

So is there a role for a PD-1 inhibitor, particularly pembrolizumab, in this patient population? We saw that the addition of pembro to chemo did prolong PFS and OS vs placebo plus chemotherapy in this resistant TKI population. However, it did not reach a statistical endpoint, and it's not something that I'll be using in my clinical practice.

It's important to note, though, that the adverse events (AEs) were manageable. There was really no new safety signals that were identified, and I really think that we need more data in this space to better understand what our next options are.

I'll turn it back to you, Heather, to talk about afatinib in combination with pemetrexed-carboplatin (pem-carbo) in this resistant population.

Dr Wakelee: Thanks, Josh. I think we've all got osimertinib thinking about that a lot, especially with the early-stage data we had at ASCO® this year with the phenomenal ADAURA overall survival.

Here though, it's important not to forget that there are other options; afatinib is a very good second-generation agent, and there is earlier data looking at what might the second generations do after a third generation. So this is from that perspective. So, this took patients who had already been on an EGFR TKI and had developed resistance--specifically, had developed resistance to osimertinib--and they received afatinib in combination with chemotherapy, and that was with carboplatin and pemetrexed.

So you see this design, again, this was not a randomized trial, this was open label; so it's really just a signal-finding study. And we see here some pretty encouraging results. They had a reasonably high response rate. You can see that really nice waterfall plot, and progression-free survival was quite good. So this is a strategy one might consider when we do combinations of our EGFR TKI and chemotherapy.

With osimertinib we worry a bit more about some of the thrombocytopenia and neutropenia. Not as much of an issue with this combination, but of course with afatinib you do have to grapple with rash and some of the gastrointestinal (GI) toxicity.

So, this is not a practice-changing study, but it's an intriguing one. There were 36 patients enrolled. That 57% getting to 6 months without progression, it was better than they had in anticipated. PFS median of 8 months. Again, half the patients are responding. So this is something to look at, I think worthy maybe of some further exploration. There were some patients developing some interstitial pneumonitis, so we still need to be mindful of that risk.

So, let's turn it back to you to talk about this novel drug.

Dr Sabari: So abstract 9103 is an exciting agent, sunvozertinib. It's interestingly an EGFR and HER2 exon 20-specific inhibitor. And we heard a lot about this drug specifically in the EGFR exon 20 population. But here we're looking at a pooled analysis in patients with the activating EGFR mutations, commonly exon 19 del and L858R.

So really this is a high-risk population. This is the population where we need further therapies, and these are patients who've had prior third-generation EGFR TKI--I believe the median line of therapy on this study was about 5. And when you look at the anti-tumor activity of sunvozertinib in patients with activating EGFR mutations post-progression on third-generation EGFR TKI, the response rate across all dose levels was 27%.

Now 27% may seem low for a targeted therapy, but you have to remember that these patients are heavily pretreated. And with single-agent chemotherapy, like gemcitabine or docetaxel, we wouldn't expect to see response rates above 10% here. The median duration of response was 6.5 months and the median progression-free survival was 5.8 months.

You've got to look at the different dose levels. These were a pooled analysis. So it'll be interesting to see what the response rate was specifically at the recommended phase 2 dose moving forward.

So really in this heavily pretreated patient group, sunvozertinib--the EGFR HER2 exon 20 inhibitor that clearly has some activating response rates or activating activity--monotherapy demonstrated a promising and durable anti-tumor activity, with a PFS reaching up to 6 months. So really, sunvozertinib demonstrated a similar safety profile that we've seen with the EGFR exon 20 space, and I do believe that further study of this agent, specifically in this population, is really warranted.

The next abstract we saw was abstract 9013, which looked at biomarkers to amivantamab. And you have to remember that amivantamab is an EGFR and a cMet bispecific antibody.

We've been studying this agent post-progression third-generation EGFR TKI. It's now also been combined with lazertinib, an EGFR inhibitor, a third-generation EGFR inhibitor, relatively similar to osimertinib.

So we're looking at multiple different cohorts. But this is the CHRYSALIS-2 study design, which looked at the combination of amivantamab plus lazertinib in patients who had progression on EGFR TKI.

If you remember, the efficacy in this population, very similar to what we just saw, was about a 30% response rate across all comers, with a median progression-free survival of 5.7 months. So the question is, are there any specific subsets of patients that did better? Can we select a biomarker to specifically utilize this therapy? So, for this study, we looked at the mesenchymal-epithelial transition factor (MET)-high subgroup. So we know that this is a MET by EGFR immunohistochemistry (IHC), so it does have some activity in MET-mediated disease. But clearly looking at a biomarker when we measured MET-high, this is 3+ by IHC, it subdivides into 28 patients who are MET-high and 49 patients who were MET-low.

And what's really exciting to see, Heather, is that the response rate clearly enriched 61% in the MET-high population, whereas in the MET-low it's only about 14%. When you look at median progression-free survival, 12.2 months in the MET-high group vs only 4.2 months in the MET-low group, suggesting that maybe MET-high patients are benefiting more from this MET by EGFR ADC, excuse me, bispecific than those who are MET-low.

What's important to note, though, is that the MET-high group is a relatively infrequent population; it only makes up about 10% or 15% of our patient population. So key takeaways for the biomarker analysis of CHRYSALIS-2, which is amivantamab plus lazertinib in MET 3+, MET-high, sustaining of greater than 25% of tumor cells, the objective response rate in that population was 61% vs only 14% in the MET-low. Longer PFS in that population as well, and, potentially, MET as an IHC could be a predictive biomarker regardless of the resistance mechanism or mutation. And safety profile was similar to what we've seen on the other reports.

So I'm going to turn it back to you, Heather, to talk about EGFR exon 20 insertions, which are less common but have become a very exciting space.

Dr Wakelee: Great, thanks. So to remind the audience, when we get EGFR testing, we're looking for any of the activating mutations, and the common ones, exon 20 is not, but it is definitely one that's seen maybe 10% of the time. These are insertion mutations, and it's important to recognize that we have different drugs approved.

There is some activity of osimertinib, but it's relatively low. And so approvals that we've seen are with the amivantamab, you were just talking about, with mobocertinib. And the data that was focusing on it at ASCO® was with sunvozertinib, which you have already mentioned. So this was the WU-KONG6 study--sunvozertinib for patients with EGFR exon 20 insertions. And what we saw were some pretty encouraging results.

So the response rates here were 61%. I will emphasize all of these patients had previously been treated, so that's quite a high response rate. And when we look at this waterfall plot, it's beautiful. Almost all patients responding. And something I don't have in this slide, but they looked at the different types of insertions. So when we're dealing with EGFR exon 20 mutations, it's an insertion -- and where that insertion happens can change the behavior. At least with this compound, it didn't matter. We saw nice robust responses with all of those different insertion sites.

And the duration was also encouraging. It's still a little early. We don't have enough patients who have been on long enough to have a clear... what is that median response duration? But there are definitely some encouraging hints that are seen with the duration of treatment looking quite long. And I think with follow-up we're going to end up seeing these median durations of response being very encouraging. So, very high response rate in this patient population that's already been treated, and with a pretty good duration of response. So, the sunvozertinib is looking very promising.

We already have some other promising agents, but with the amivantamab, and especially with the mobocertinib, there's been toxicity concerns. Some of the early reports with sunvozertinib, but it was looking maybe to be better tolerated. And it might be, but there are also hints of toxicity we do need to be mindful of. So we are seeing about two-thirds of patients with some level of diarrhea; lower than the mobocertinib and some of the other drugs in this class, but still something to take note of.

The rates of grade 3 [AEs] were relatively lower, and there's also the creatine phosphokinase (CPK) increase, which could just be a lab thing or could be reflective of potentially some discomfort for patients. And so these are things we'll need to watch as this drug continues in its development, but it looks really, really encouraging at this time.

And so the take-homes: very significant anti-tumor efficacy; probable reasonable duration of response, it's still hard to put a number on that; and a safety profile that looks reasonable, but still one that remains a challenge in the setting of the EGFR exon 20.

All right, so I'm going to turn it back to you to talk about KRAS. You gave a masterful discussion at ASCO® 2023, by the way, on KRAS. So I'm looking forward to hearing you go through this here.

Dr Sabari: Thank you, Heather. So KRAS is a very common alteration in non-small cell lung cancer. KRAS as a whole makes up about 30% of the driver alterations in non-small cell. And there are many different KRAS alleles. KRAS-G12C is the most common KRAS alteration. And when you look at all of lung cancer, probably about 13% to 14% of patients will specifically have a KRAS-G12C.

It's important to note, moving forward, every time we talk about a therapy, we're really specifically talking only about KRAS-G12C. If you have a KRAS-G12V or D mutation, the KRAS-G12C medications will not work in those settings.

So what is the current standard of care in KRAS-G12C? Well, standard of care in the frontline setting remains chemotherapy and immunotherapy in patients who are PD-L1 expression less than 50% and potentially immunotherapy alone in patients who have a PD-L1 greater than 50%. At progression or in the second-line setting, we now have 2 FDA-approved agents, sotorasib as well as adagrasib. These are both KRAS-G12C-specific small molecules.

And it's important to note that the response rates for these agents are in the high 30% to low 40% range. And the median progression-free survival is about 6 months or so. So nowhere near where we're at in the EGFR space; obviously a lot more to come.

We saw an update of the late-breaking abstract 9016 was the CodeBreak 200. This was a randomized phase 3 study comparing docetaxel vs sotorasib. So this was a confirmatory study that led to the FDA approval of sotorasib in the second-line setting.

So this study looked particularly at the intracranial response rate, and it's important to note that we have seen responses with adagrasib in active untreated brain metastasis. Here, in this retrospective analysis, we're looking at patients with stable, treated brain metastases. And when you compare sotorasib to docetaxel, there was a higher response in the sotorasib group of 33.3% vs 15.4% in the docetaxel arm. And there was really nice concordance between durability and response in the brain as well as extracranially in the chest.

Again, important to note that these are not patients with active untreated brain metastases, and I would still consider radiating patients up-front if you were using a medication like sotorasib in this setting.

So again, this is a post hoc analysis of patients with stable, treated central nervous system (CNS) lesions, and it's nice to see that you do see a response higher in the sotorasib arm than the docetaxel arm. Good concordance between systemic and intracranial disease control in this setting.

Moving on to abstract 9006, this was a phase 2 study of sotorasib plus chemotherapy. Interestingly, we commonly use immunotherapy in the frontline setting. So this study excludes immunotherapy and is specifically looking at using the combination in the frontline setting. So these again are patients with KRAS-G12C-altered non-small cell lung cancer. They had not had prior therapy. They received sotorasib plus chemotherapy followed by sotorasib and pemetrexed maintenance.

Primary endpoint here was the objective response rate--and I nearly fell off my seat here, Heather--88.9% response rate, the highest we've seen. Again, a very small study; only 30 patients in this patient population. Despite this high response rate, when we look at the progression-free survival, it's only 5.7 months, which is aligned to what we see in the second-line setting with the G12C inhibitors that are currently FDA-approved.

So, despite great response, we're not really seeing durability to the point that targeted therapies and chemotherapy in the metastatic setting are oftentimes not curing patients. The median overall survival here was not reached, but the 6-month OS rate was 87.3%.

So really, key takeaway here is that there was no additional toxicity seen with combining chemo and sotorasib, a G12C inhibitor, and that we could safely combine the 2. And you saw a very high or favorable response rate. But, in my opinion, we didn't really achieve durability here. And could there be a patient population where this is a successful strategy? Potentially those who are ineligible for immunotherapy or for patients who may not derive durable responses to immunotherapy, like the patients who have STK11 and Keap1 co-alterations. Thought-provoking, but we really need prospective data in those specific subsets of patients.

Moving on to abstract 9007, I think this is one of the more interesting presentations in the KRAS section. This is the KontRASt-01. JDQ443 is a novel KRAS-G12C inhibitor. The space is getting saturated or busy, but I think this is great for our patients. You see the multiple different studies that are ongoing.

This was specifically looking at the efficacy and safety profile. The safety profile was in 96 patients across multiple different arms. The efficacy was only in 27 patients, so take it with a grain of salt, in the phase 1 dose escalation followed by the food-effect trial.

So what did we see at the recommended phase 2 dose, 200 mg twice a day? The efficacy of JDQ443 was a 57.1% response rate, so quite impressive. But again, very small numbers. When you looked at the whole pool dose label--when you looked at 200 mg daily, 400 mg daily, as well as 200 mg twice daily (BID)--the response rate went down to about 44.4%, more in -ine with what we've seen with other G12C inhibitors.

The data is still early, but it was nice to see that patients did have durability here. So median duration of treatment as of now is 4.9 months. But the data is really immature at this time.

The one thing that was really important for me is the toxicity profile. We know that adagrasib and sotorasib have GI toxicities--some nausea, diarrhea--and the adagrasib might have higher rates dose discontinuation of both of those agents, about 7%. When you look at the tox profile for JDQ443, you see a very impressive toxicity profile, very little if any, grade 3 GI toxicity in this setting.

When you looked at the liver tox rate, again very low rates of grade 3 transaminitis, about 3%. So JDQ443 is a novel G12C inhibitor. Preliminary data for the objective response rate, 57.1% at that recommended phase 2 dose. It's well tolerated. We didn't really see any grade 4 or 5 treatment-related adverse events, and clearly we're excited to see the data in the phase 2 dose expansion.

I'm also excited to potentially see data in the future in combination with immunotherapy, potentially leading us to a frontline opportunity with patients who have KRAS-G12C-mutant non-small cell lung cancer.

Heather, I'll turn it back to you to close out with ROS1 rearrangements.

Dr Wakelee: Great, thanks. All right. So reminder to our audience, we do have a couple of targeted agents approved, entrectinib and crizotinib. Ceritinib is also an active drug and, of course, chemotherapy is quite active in ROS1 as well.

This was an abstract looking at this drug, repotrectinib. We've seen data in ROS1 before, which has looked quite encouraging. This was focusing on patients who had CNS metastases as part of this trial, the TRIDENT trial.

And we see here a very robust response. We see that within the intracranial disease as well as with the primary disease. So very encouraging from my perspective here. We see that in patients who had never been treated before, the line for progression is completely flat, meaning nobody progressed, looking amazing at this time point out to that 18-month mark. Again, we're not looking at huge numbers of patients, so we have to be cautious as we interpret, but it's very encouraging. For those who had been previously treated, we do see progression starting to be seen; however, still very encouraging, especially comparing to others.

So the repotrectinib had durable clinical activity in ROS1 TKI-naive, as well as pretreated patients with ROS1-positive lung cancer with or without baseline CNS metastases. The systemic activity of this drug has been very encouraging, and the response in the brain was also quite durable. And that's very important when we're thinking about ROS1, which does have a high tendency towards developing brain metastases. And then no surprises on the toxicity profile.

And so with that, I want to try to wrap all of this up. It was an exciting ASCO® in many ways, and this focus on some of our newer targeted agents was fantastic. When we think about the patients with EGFR mutations, we didn't make a lot of progress in our options for patients with the standard mutations, such as deletion 19 and L858R, but continuing to explore these questions of what can we add -- chemo, immune therapy -- we're still working on that best strategy, but some really encouraging data for the EGFR exon 20, especially with the sunvozertinib.

We also, as you went through, Josh, lots of things happening in the world of KRAS. Exciting new agents, some ideas about combinations that look good, and more in expanding data about activity and brain metastases with a lot of these agents. So it's really quite an exciting time.

Well, thanks for joining me on this MedscapeLIVE, and thanks to our audience. I think it's been a fantastic conversation. So much data coming out about all these different targeted approaches and a lot to learn, and it's great to be able to talk through it with you today, Josh.

So a big thanks to everybody and hope to see you on an upcoming program sometime.

This transcript has not been copyedited.