Advancing KRAS G12C-Targeted Therapies in NSCLC: Current Evidence and Future Directions

0:00Hello, and welcome to the Sarah Clinical Education's Oncology Podcast. In this episode, we are joined by Dr. Louise Pass-Ares from hospital 12th de-October, and Dr. Christine Pasfina from the University of Chicago, who will be discussing the evolving role of next generation Keras, G12C inhibitors, and non-small cell lung cancer. This episode is part of a larger educational program titled, Research Focus, and Advanced Non-Small Cell on Cancer, emerging insights on next generation Keras, G12C inhibitors. For more information on our faculty, along with a link to the larger educational program, please visit the show notes for this episode. Thank you all for being here, and I'll go ahead and hand it over to Dr. Pasfina. Hello, I'm Louise Pass-Ares, and I'm a medical oncologist at the 12th of October University Hospital in Madrid, and happy with me today with you here. Hello, my name is Dr. Christine Pasfina.

1:01I'm also a thoracic medical oncologist and practicing at the University of Chicago. Dr. Pasfina, can you tell us a bit about the current role of Keras G12C therapies in practice, and also some of the in-met needs in this area? Okay, so I would start saying that Keras is actually the more frequent oncology mutated among solid tumors. There is actually happening about 30% of the non-small cell lung cancer tumors being more frequent on the G12C mutation on the, sorry, being the more frequent the G12C mutation, which accounts for about half of the mutation in non-small cell lung cancers, and of course that allele mutation is more frequent in smokers, as compared to non-smokers, where the G12D mutation

2:06is the more frequent one. We know that these mutations are actually carrying some bad prognosis, and actually even with immunotherapy is having some issues, because G12C mutations are typically linked to smoking, often these patients benefit from immunotherapy, particularly if treated, if do not go assist with other commutations, if other commutations such as the LKB1 or KB1 are present, the benefit from immunotherapy is more a doubtful, I would say. So it's then clear that we need some novel therapies to address this population of patients. For more than four years, we have been trying to find a drug in this setting, and just recently

3:07the resolution of the crystallographic structure of the K-RAS G12C mutation actually show us the presence of a system showing up on the so-called switch to a pocket, which it was so amenable for cobalan binding with some specific compounds. The first generation of these cobalan inhibitors were adagressive and soterative that actually bind to the system on the G12C mutation, when it's on the office state, on the GDB band state, and it's actually getting the prodding trap, which is not again being activated and by doing so, it's actually inhibiting all the dependent signaling, particularly the MAP

4:08kinase and the BIFK's dependent signaling, which are very important for the oncogenic activity of the K-RAS. Those drugs have actually shown clear activity in this setting, with responses in some 40% of the patients, I would say, medias revival in the rate of medium BFS in the rate of 6 months and media nowhere in the rate of 11 months. Actually, both drugs had been tested in phase 3 trials in this setting showing a response rate higher than orthotaxel, which was with comparator arm for those drugs, improving BFS, but so far not showing an increase in survival as yet, I would say. So that means we have shown, for the first time, an improvement in the treatment in this setting, I have to say, it's not overwhelming in terms of results, as we're having some

5:11better tolerable drugs, but not clear impact in the relevant employees such as survival. So I know Christian, looking at that, how do you see this in earlier? What are the main and main needs that are actually coming from these contexts where this first generation, G2S inhibitors, are now being used in the clinic? What do we need here? Certainly, these trials, I think, have been a good jumping off point for us to establish some of these unmet needs. And we're unfortunately seeing a high degree of primary resistance occur, meaning patients who aren't 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 aren't benefiting from these K-RASG12C often 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?

6:16And are these mechanisms of resistance that can be otherwise overcome? Toxicity has also been a barrier in using some of these drugs. We're seeing a good degree of autoimmune hepatotoxicity, particularly when they're used sequentially after immunotherapy, as well as in combination. Then we also have to focus on some of the difficult-to-treat subsets, including PDL-1 negative patients and patients with SDK-11 and keep one commutations. And so with this, we are starting to see some more promising data come out for more potent K-RASG12C often inhibitors. If a RASG12C is a good example, and here we're seeing in early data a response rate around 50% with a median progression-free survival of around 13 months. So certainly an improvement over what we've seen with SOTORASIB and ADIGRACIB. And we will, in fact, have a head-to-head study comparing DIVIRASIB to SOTORASIB or ADIGRACIB

7:21in the second or third-line setting. So look for more information to come. We've also got other K-RASG12C often inhibitors that have similarly increased potencies such as OlimorASIB coming. And so stay tuned for more advances there. And with that, I think that also opens the door for combination strategies. So 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've seen have been K-RASG12C often inhibitors with chemotherapy such as SOTORASIB plus carboplatin and hematrexin that will actually be studied in the front line for patients who are PDL negative, as well as immunotherapy plus K-RASG12C

8:21inhibitors. We've seen data from crystal seven, looking at a combination of ADIGRACIB plus PEMBRALISMAD with some nicer ability of medium 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? I think that's actually a very important point. I mean, the issue that a first generation, D-20 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 the, in other K-RASGEL yields. In some other sealed existence, there are amplification of RASG. And another mechanism is through alternative pathways that are actually signaling through other signal pathways,

9:26or even in some cases some novel effusions and so on. So for that reason, a number of strategies of combination had been developed, including horizontal studies of targeting, shift to EFR and so on. Those studies had been shown some efficacy, not particularly overwhelming. Even there are some trials ongoing with some of the new generation inhibitors in combination with RUSIMAPA, for example, FulseraCIB with very nice data on the Crocken's face with trial, also with shift to inhibitors and so on. In terms of the more vertical strategies, M2, CDK4, we inhibitors, the data are not overwhelming. So the more important studies as you had mentioned had been combination with immunotherapy,

10:29particularly 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 SOTORRASIB is getting a very high rates of RASG 3, 4 immune-related adverse events. The activity is quite reasonable. The virus is so responsive more than 60 percent of the patient, the combination of Olimarasi plus PEMBO, response rating, the rate of 80 percent, particularly for the highest pressures, and there are a number of phase 3 trials actually ongoing, such as the Sanri O1 trial, which is comparing Olimarasi plus PEMBO, compared to PEMBO alone in high pressure. So I think those data are actually particularly relevant, I would say, in this very setting.

11:34So one 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? Absolutely. So we have really two other big classes of K-RASG 12C on inhibitors, on inhibitors. The first is a tri-complex inhibitor, and we've seen data from a Laurent RASIB, which showed an early response rate of 42 percent, so an improvement of what we've seen over the K-RASG 12C off inhibitors. And then we're also seeing direct K-RASG 12C on inhibitors. So these are a really dual-state targeting inhibitors that allow for a unique mechanism to bind in both the inactive and active state of K-RAS with rapid blockade of K-RAS signaling. And so mechanistically,

12:41this 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. And early data that we're seeing with a compound called BBO8520 showed a response rate of 65 percent of just single agent activity. That's what we're seeing with some of the combination strategies of K-RASG 12C off inhibitors combined with other mechanisms. So if we can see that activity, response rate 65 percent was single agent, then it opens up a lot of doors for combination strategies and improving overall response rates as well as durability. Importantly, we're also seeing activity in patients who have STK 11 and keep one commutated 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 and immunotherapy.

13:46And so I think overall, we've got a lot of exciting stuff coming in the K-RASG 12C space. And so with that, I'll ask you, what is the thing that most excites you moving forward for K-RASG 12C? So actually, I have to say that I'm particularly excited about the new generation of G-12 inhibitors. It looks like they provide higher activity, higher response rate, and particularly the duration of response seems to be better. It's having a more clear impact in PFS. Actually, there is a trial that is comparing the novel generation inhibitor, the virus compared to first generation, adagressive, or so totally in the second incident. And I think that is quite provocative trial. The second thing is that the compatibility

14:49with immunotherapy seems to be pretty good, not always true with the first generation. And the third issue to me is that those drugs are already being tested in the early stage setting. And that is great. I mean, for example, the San Ray one trial, which is a study in the introduction of Olamarasib in the context of chemo-immunotherapy in the perioperative context in patients with susceptible disease, I think that it is vibrational to use that in this type of combination. Guant is safe in this concept and looking forward to see those data. So I don't know if you have any other issue that you like to tackle, particularly looking into the future. I think what I'm most excited about is trying to move some of these agents into the frontline setting. I think right now I find myself in clinic giving patients the news that they

15:49have K-RESG12C and there are targeted therapies available. But wait, we'll use those later on. And so I think as these drugs get better and better, as we're able to combine them with immunotherapy or chemo-immunotherapy, being able to provide targeted therapy in the frontline setting is something that's extremely exciting for me and I hope that we can really prevent more patients from having primary resistance or developing secondary resistance. Thank you, Dr. Spesvina and Pazaris, for joining us today. As a reminder, to view the full program on emerging insights in next generation K-RESG12C inhibitors, please click the link below in the show notes. And be sure to check back frequently for more episodes on important oncology topics.