ESMO 2026: KRASCENDO-1 and SAFFRON Advance Targeted Therapy in NSCLC

Drs. Joshua Sabari, Alfredo Addeo, Julia Rotow, and Helena Yu review practice-changing data from ESMO 2026, highlighting advances in targeted therapy for KRAS G12C-mutated and EGFR-mutated non-small cell lung cancer (NSCLC). They discuss findings from KRASCENDO-1, where divarasib demonstrated progression-free and overall survival benefits compared with sotorasib or adagrasib, alongside opportunities to move newer KRAS inhibitors into frontline treatment. The panel also examines results from SAFFRON, which demonstrated improved survival outcomes with savolitinib plus osimertinib in patients with MET-positive disease following progression on osimertinib. They emphasize the importance of comprehensive molecular testing, including tissue-based MET amplification and overexpression assessments, to identify patients who may benefit from emerging targeted therapies.

Transcript:

Dr. Sabari:  Hello, and welcome from ESMO 2026. We’re joined by OncoNexus. My name is Dr. Joshua Sabari. I’m a thoracic medical oncologist at NYU. We’re really excited to talk about updates from ESMO, as well as the HER2-mutant non-small cell lung cancer space. I’m joined by my colleagues. Helena, please introduce yourself.

Dr. Yu: Of course. Hi, everyone. I’m Helena Yu. I am a thoracic medical oncologist at Memorial Sloan Kettering in New York.

Dr. Addeo: Hello, everyone. My name is Alfredo Addeo. I’m a medical oncologist at the University Hospital of Geneva.

Dr. Rotow: I’m Julia Rotow. I’m a thoracic medical oncologist at Dana-Farber Cancer Institute. Great to be here speaking with you all today.

Dr. Sabari: Yeah, so welcome, everyone. We saw a lot of exciting data. Dr. Addeo, I’ll start with you. In the KRAS space, we saw the update from KRASCENDO-1, divarasib clearly beating out adagrasib and sotorasib. How does that change your practice?

Dr. Addeo: Yeah. Thank you very much for the question. I think it was one of the main events at the second plenary at ESMO, where the KRASCENDO-1 study was presented by Dr. Skoulidis, where divarasib in the second line for patients with metastatic non-small cell lung cancer carrying a KRAS G12C mutation was compared to sotorasib or adagrasib, which are the common standard of care at the moment.

The primary endpoint was progression-free survival. As you mentioned, it was met, so a clear advantage in progression-free survival. But not only that, there was also an improvement in overall survival, which was a secondary endpoint.

It is practice-changing. Dr. Besse discussed the study and showed that it is relevant, clinically and statistically significant.

So I think from tomorrow onwards, we’re going to try to get a hold of the drug and start using it straight away. The safety profile, I think, was in line with what we’d expect with the drug. There’s no doubt that it’s one of the practice-changing trials we have seen at ESMO. Not the only one, but at least a relevant one.

Dr. Sabari: Yeah. So KRAS G12C is quite an exciting space, and we know that a lot of these agents are moving into the frontline setting. Divarasib is one of the first second-generation KRAS inhibitors, a KRAS G12C off-state inhibitor. Julia, does this have any implications for the frontline setting for you?

Dr. Rotow: Yeah, it’s a great question. KRAS, of course, we’re seeing evolution in the second-line or previously treated setting with novel G12C inhibitors, novel KRAS and RAS inhibitor mechanisms of action showing interesting activity within clinical trials.

But you’re right, in the frontline, there’s also a lot of curiosity about to what extent KRAS inhibitors can move into that line of treatment.

And here, of course, KRAS is an immunologically sensitive tumor on average. So there’s a lot of interest in understanding how, or should we combine KRAS inhibitors with immunotherapy or with chemotherapy to try to improve outcomes for frontline patients, and can this even replace chemotherapy for this patient population?

So there’s a large number of clinical trials ongoing right now and some Phase 1 and Phase 2 trials beginning to read out, looking at KRAS plus checkpoint inhibitor combinations here upfront or in the perioperative setting. I think there’s a lot of possibilities for what we’ll be able to do for these patients.

Dr. Sabari: Yeah. So Julia, you bring up a great point of combining these KRAS G12C inhibitors with immunotherapy. Alfredo, any concern about toxicity in the frontline setting? And can you extrapolate any of the data we’ve seen in the later-line setting with AST and ALT elevations, liver test abnormalities? How do you think that’s going to pan out in the frontline?

Dr. Addeo: That is a very fair point. I think sotorasib and adagrasib have taught us that they were just proof-of-concept drugs, so they were difficult to combine. We had a lot of toxicity, particularly, as you said, increased transaminases, but not only that.

And now it seems that with the new drugs, the new compounds, it’s easier to combine. Divarasib has already been tested in the first line. The results are quite good, very good in terms of response rate, but also in terms of safety.

So I think, yes, there might be some possible toxicity, particularly liver toxicity. We need to be very careful and test for it because patients very often are asymptomatic.

But overall, I think I’m quite optimistic about the fact that we might be able to combine the new-generation drugs with immunotherapy, particularly, and chemotherapy. I think that’s something being explored, and there’s already a study ongoing.

Dr. Sabari: Yeah, not only are there off-state inhibitors, there are also these pan-RAS inhibitors and RAS-on inhibitors. So really an exciting time.

But really doubling down on the importance of doing genetic testing in all patients with non-small cell lung cancer, not only those patients who’ve never smoked, really all patients.

And bringing that to EGFR, Helena, you are the queen of EGFR-mutant non-small cell lung cancer. We saw an update on the SAFFRON study, a very impressive study. Walk us through it, and how does that change your practice?

Dr. Yu: Yeah, absolutely. So this was a long-awaited study. I think we know that MET amplification or MET positivity is a mechanism of resistance to EGFR-directed targeted therapy, but understanding what the right cutoff to use and who to treat really was the challenge.

And so the SAFFRON study took patients with progression on osimertinib in the first or second line that had evidence of either high expression of MET protein, so it was 3+ in greater than 90% of cells, or a gene amplification by FISH, so copy number gain greater than 10.

And then took those patients and randomized them one-to-one to either savolitinib with osimertinib or platinum-based chemotherapy.

I think one thing to note is that it was platinum-based chemotherapy as the control, not with osimertinib, not with amivantamab, which clinically, at least in the US, is how we usually move forward with platinum-based therapy.

But in that population, there was a significant progression-free survival benefit with the savolitinib-osimertinib combination, as well as a statistically significant overall survival benefit. I think it was about nine months.

So I think this is immediately practice-changing. Some of us off-label have been using MET inhibitors in this setting, but I think to have a true combination approval, and this is the first biomarker-directed second-line therapy, is important.

So I think another implication, my hope, is that we will increase tissue biopsy at progression. I think we now have a real indication. It’s about one-third of patients that we think will have this MET positivity. And so this would be something to biopsy, test, and then hopefully act upon in the next line.

Dr. Sabari: Yeah, I agree. Practice-changing data.

Dr. Addeo: I just want to say that the point that was made was that they also analyzed two different subgroups, the amplified and the overexpressed, and they saw that there was consistent and similar benefit.

But the message must be that we should not overinterpret the results. The message is we should still do both FISH and the overexpression testing.

At some point, somebody might think, “Oh, I’ll just do the immunohistochemistry, and it would be as good as the FISH.”

But the message is, as you said, Helena, you’ve got to test it. The NGS is essential, but also immunohistochemistry. You don’t want to miss any of those patients given the benefit that they can achieve with just oral treatment.

Dr. Sabari: Yeah, it’s a great point. And Julia, a lot of confusion with overexpression and amplification. How do you define those? Are you testing for both of those? How are you testing for those? I think that’s important as we think about the biologic relevance of these alterations.

Dr. Rotow: Yeah, MET’s an interesting biomarker because there are many ways to identify potentially MET-driven tumors or MET-driven resistance. And I think there’s a gap from how we’re currently doing a lot of our testing. For example, plasma-based profiling is really not very sensitive or accurate in identifying MET overexpression or quantifying MET overexpression.

With tissue-based profiling, we’re often doing NGS, where you can look for MET gene amplification, so that copy number gain you might see on NGS. But that potentially under-identifies patients who have MET-driven resistance. So if you look more broadly, not just on NGS-based profiling, but also by things like IHC for protein overexpression or by FISH, which is another way to measure gene copy number gain, you’ll find more patients.

And when you think about the Venn diagram of who has MET overexpression at the protein IHC level versus, say, MET amplification at a FISH or NGS level, these are not fully overlapping populations. You’re going to miss patients if you’re not testing in these orthogonal ways on tissue profiling at this point. So I agree. We like to rebiopsy at progression. This is another reason to rebiopsy at progression, along with seeking things like histologic transformation.

And now across, I think, three different studies looking at their prescreening rates, we’ve seen about one-third of patients will have MET-driven resistance at progression on EGFR TKIs if you’re truly testing more comprehensively. So we’re under-identifying it by plasma. We’re potentially under-identifying it even just by NGS, so we need to test more broadly.

Dr. Yu: It is more complicated, though. Yeah, because I think in the US we have the Teliso-V indication too, and that’s MET 3+ in 50% of cells. And so now we have different therapies with different thresholds for MET positivity.