In this episode, 2 experts discuss the evolving role of KRAS G12C inhibitors in non-small-cell lung cancer (NSCLC), including the clinical impact of first-generation therapies and challenges related to resistance. They also explore emerging next-generation inhibitors and combination strategies that may expand treatment options and improve patient outcomes.
In this episode, Dr Paz-Ares and Dr Christine Bestvina discuss the evolving role of KRAS G12C inhibitors in non-small-cell lung cancer (NSCLC), including:
Presenters:
Luis Paz-Ares, MD, PhD
Head of Medical Oncology Department
Hospital Universitario 12 de Octubre
Associate Professor, Universidad Complutense de Madrid
Madrid, Spain
Christine Bestvina, MD
Associate Professor
University of Chicago Medicine
Division of Medicine
Section of Hematology/Oncology
University of Chicago Medicine
Chicago, Illinois
Link to full program:
https://bit.ly/4rhoUuN
Get access to all of our new podcasts by subscribing to the Decera Clinical Education Oncology Podcast on Apple Podcasts, YouTube Music, or Spotify.
Introduction
Luis Paz-Ares (12 de Octubre University Hospital): Hello, I am Luis Paz-Ares. I am a Medical Oncologist at the 12 de Octubre University Hospital in Madrid, and I am happy with me today - with you here.
Dr. Christine Bestvina (University of Chicago): Hello. My name is Dr. Christine Bestvina. I am also a thoracic medical oncologist and practicing at the University of Chicago. Dr. Paz-Ares, can you tell us a bit about the current role of KRAS G12C therapies in practice, and also some of the unmet needs in this area?
NSCLC – KRAS mutation
Dr. Paz-Ares: I would start saying that KRAS is actually the more frequent oncogene mutated among solid tumors. That is actually happening in about 30% of the non-small cell lung cancer tumors, being the most frequent G12C mutation, which accounts for about half of the mutations in non-small cell lung cancers. Of course, that allele mutation is more frequent in smokers as compared to non-smokers, where the G12D mutation is the more frequent one.
Immune-strategy in first-line setting NSCLC
We know that this mutation is actually carrying some bad prognosis, and actually even with immunotherapy, is having some issues because G12C mutation are typically linked to smoking. Often these patients benefit from immunotherapy, particularly if they do not coexist with other co-mutations. If other co-mutations such as LKB1 or KEAP1 are present, the benefit from immunotherapy is more doubtful, I would say.
It is then clear that we need some novel therapies to address this population of patients. For more than 4 years, we have been trying to find a drug in this setting. Just recently, the resolution of the crystallographic structure of the KRAS G12C mutation actually shows us the presence of assisting, showing up on the so-called Switch II Pocket which was amenable for covalent binding with some specific compounds.
Targeting KRASp.G12C mutation in advanced NSCLC
The first generation of these covalent inhibitors were adagrasib and sotorasib that actually bind to the cysteine on the G12C mutation guanines on the off state on the GDP bound state, and is actually getting the protein trap, which is not again being activated, and by doing so is actually inhibiting all the dependent signaling, particularly the MAP kinase and the PI3K dependent signaling, which are very important for the oncogenic activity of the KRAS.
Selective KRASG12C inhibitors in advanced NSCLC
Those drugs have actually shown clear activity in this setting, with responses in some 40% of the patients. I would say median PFS in the range of six months and median OS in the range of 11 months. Actually, both drugs have been tested in Phase 3 trials in this setting, showing a mean response rate higher than docetaxel, which was the comparator arm for both drugs. Improving PFS, but so far not showing an increase in survival as yet, I would say.
That means we have shown for the first time an improvement in the treatment in this setting. I have to say, is not overwhelming in terms of results as we are having some better tolerable drugs, but not clear impact in the relevant endpoints such as survival.
I know Christine, looking at that, how do you see this scenario? What are the main unmet needs that are actually coming from this context where this third generation G12C inhibitors are now being used in the clinic? What do we need here?
Dr. Bestvina: Certainly, these trials, I think, have been a good jumping-off point for us to establish some of these unmet needs. We are unfortunately seeing a high degree of primary resistance occur, meaning patients who are not responding in the first place. We heard about response rates on the order of 30% to 35%, but that leaves the balance of patients who are not benefiting from these KRAS G12C (OFF) inhibitors.
We also need to learn more about the mechanisms of acquired resistance, so for these patients who have an initial response and eventually progressed, why is that, and are these mechanisms of resistance that can be otherwise overcome?
Toxicity has also been a barrier in using some of these drugs. We are seeing a good degree of autoimmune hepatotoxicity, particularly when they are used sequentially after immunotherapy, as well as in combination. Then we also have to focus on some of the difficult to treat subsets, including PD-L1 negative patients and patients with STK11 and KEAP1 co-mutations.
Novel selective KRASG12C covalent (OFF) inhibitors
With this, we are starting to see some more promising data come out for more potent KRAS G12C (OFF) inhibitors. Divarasib is a good example. Here we are seeing, in early data, a response rate around 50% with a median progression-free survival of around 13 months. Certainly an improvement over what we have seen with sotorasib and adagrasib, and we will, in fact, have a head-to-head study comparing divarasib to sotorasib or adagrasib in the second or third line setting. So, look for more information to come.
We have also got other KRAS G12C (OFF) inhibitors that have similarly increased potency, such as olomorasib coming. Stay tuned for more advances there.
Combination strategies with G12C inhibitors
With that, I think that also opens the door for combination strategies. Not just, can we have better, more potent drugs, but can we combine these with other things, such as chemotherapy or immunotherapy to augment improved response rates as well as durability? I think some of the exciting combinations that we have seen have been KRAS G12C (OFF) inhibitors with chemotherapy, such as sotorasib plus carboplatin and pemetrexed. That will actually be studied in the front line for patients who are PDL negative. As well as immunotherapy plus KRAS G12C inhibitors. We have seen data from KRYSTAL-7 looking at a combination of adagrasib plus pembrolizumab, with some nice durability of median progression-free survival of 11 months and duration of response of 26 months. Anything to add about the combination strategies, or what are you excited about?
Dr. Paz-Ares: I think that is actually a very important point. The issue that first generation G12C inhibitors are not working particularly well is, of course, due to the emergence of resistance. Typically, resistance is due to the appearance of novel mutation or in other KRAS alleles. In some other circumstances, there are amplification of RAS, and another mechanism is through alternative pathways that are actually signaling through other signal pathways, or even in some cases some novel effusions and so on.
For that reason, a number of strategies of combination had been developed, including horizontal strategies of targeting, shift to EGFR, and so on. Those strategies have shown some efficacy, not particularly overwhelming. Even there are some trials ongoing with some of the new generation inhibitors in combination with cetuximab, for example, fulzerasib with very nice data on the KROCUS Phase 2 trial, also with SHP2 inhibitors and so on.
In terms of the more vertical strategies, mTOR CDK4 inhibitors, the data are not overwhelming. The more important strategies, as you had mentioned, have been in combination with immunotherapy, particularly with the novel generation inhibitors. It looks like they are more able to combine. There is less toxicity as compared with some of the first generation, particularly, sotorasib is getting a very high rates of grade 3, 4 immune-related adverse events. The activity is quite reasonable.
Divarasib plus atezo responses in more than 60% of the patients, the combination of olomorasib plus pembro response rates in the range of 80%, particularly for high expressors. There are a number of Phase 3 trials actually ongoing, such as the SUNRAY-01 trial, which is comparing olomorasib plus pembro as compared to pembro alone in high expressors.
I think those data are actually particularly relevant, I would say, in this very setting. We have said that one of the questions remaining is, are any other type of inhibitors that you think are going to make it in this setting? What are the prospects with the other type of inhibitors that are actually coming to this context?
Classes of KRAS inhibitors
Dr. Bestvina: We have really two other big classes of KRAS G12C [ON] inhibitors. The first is a tri-complex inhibitor. We have seen data from elironrasib, which showed an early response rate of 42%, so an improvement on what we have seen over the KRAS G12C (OFF) inhibitors. Then we are also seeing direct KRAS G12C on inhibitors. These are really dual-state targeting inhibitors that allow for a unique mechanism to bind in both the inactive and active state of KRAS with rapid blockade of KRAS signaling.
Mechanistically, this is very enticing as a way to overcome this pathway overdrive, as well as address some of the common mechanisms of primary resistance that you had brought up earlier. Early data that we are seeing with a compound called BB0 8520 showed a response rate of 65% of just single-agent activity. That is what we are seeing with some of the combination strategies of KRAS G12C (OFF) inhibitors combined with other mechanisms.
If we can see that level of activity, response rate 65% with a single agent, I think it opens up a lot of doors for combination strategies and improving overall response rates as well as durability. Importantly, we are also seeing activity in patients who have STK11 and KEAP1 co-mutated disease, which we all know, those patients have a significantly worse prognosis, tend not to respond well, and not in a durable way to chemotherapy plus immunotherapy, particularly single agent immunotherapy.
I think overall, we have got a lot of exciting stuff coming in the KRAS G12C space. With that, I will ask you, what is the thing that most excites you moving forward for KRAS G12C?
Dr. Paz-Ares: Actually, I have to say that I am particularly excited about the new generation of G12 inhibitors. It looks like they provide higher activity, a higher response rate, and particularly, the duration of response seems to be better. Is having a more clear impact in PFS. Actually, there is a trial that is comparing the novel generation inhibitor divarasib as compared to first-generation adagrasib or sotorasib in the second-line setting. I think that is quite provocative trial.
The second thing is that the combinability with immunotherapy seems to be pretty good. Not always true with the first generation. The third issue to me is that those drugs are already being tested in the early stage setting, and that is great. For example, the SUNRAY-01 trial, which is studying the introduction of olomorasib in the context of chemoimmunotherapy, in the perioperative context, in patients with resectable disease.
I think there is a deep rationale to use that in this type of combination once it is safe in this concept, and looking forward to see those data. I do not know, would you have any other issue that you like to tackle, particularly looking into the future?
Dr. Bestvina: I think what I am most excited about is trying to move some of these agents into the front-line setting. I think right now I find myself in clinic giving patients the news that they have KRAS G12C, and there are targeted therapies available, but wait, we will use those later on. I think as these drugs get better and better, as we are able to combine them with immunotherapy or chemoimmunotherapy, being able to provide targeted therapy in the frontline setting is something that is extremely exciting for me, and I hope that we can really prevent more patients from having primary resistance or developing secondary resistance.