What the New KRAS Inhibitor Means for Lung Cancer

Last month, the FDA granted accelerated approval of sotorasib (Lumakras) for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), following the results of the phase II CodeBreaK 100 trial, data from which were presented during the recent virtual American Society of Clinical Oncology annual meeting.

In this second of four exclusive episodes, MedPage Today brought together three leaders in the field — moderator Vinay Prasad, MD, of the University of California San Francisco, is joined by Chul Kim, MD, of Georgetown University and MedStar Health in Washington, D.C., and Andrae Vandross, MD, of NEXT Oncology in San Antonio and Austin — for a roundtable discussion on the potential treatment of KRAS mutations in NSCLC.

Episode one: What Did We Learn From IMpower010 in Resectable NSCLC?

Following is a transcript of their remarks:

Prasad: I’m back doing this video for MedPage Today. I am joined by Dr. Chul Kim and Dr. Andrae Vandross. We are going to talk about KRAS G12C.

Dr. Kim, there is a new drug out there. It’s sotorasib. Sotorasib for G12C. Now, I think people who follow the oncology drug space, they will know that trying to drug RAS has been the Holy Grail of oncology for a long time. I like to tell people that drugging RAS is like sleeping on the side of the mountain. It’s a precarious perch.

Dr. Kim, why has it been so hard to drug RAS, and why is RAS so interesting to lung cancer doctors?

Kim: The RAS pathway has been implicated in non-small cell lung cancer in terms of pathophysiology. As you know, many cancers have the pathway alteration in the RAS pathway. We talk about KRAS, EGFR, and others.

It has been difficult to drug RAS because it was hard to find the right molecule to really hit the mutant form of the RAS. For example, KRAS G12C has not been able to be drugged up until now. Now, we have several drugs in development, and one drug, which is sotorasib, has been approved by the FDA, based on the CodeBreaK data showing the response rate around 35% to 40%.

This is an oral pill that patients can take kind of on a daily basis and can induce tumor shrinkage, which is remarkable, because this is the first time that we see that a RAS-driven lung cancer is able to be treated with targeted therapy.

Prasad: Andrae, you’re no stranger to targeted therapies in lung cancer. When you think about targeted therapies, what are the drugs that you’re using often, and what are the response rates you’re expecting to see?

Vandross: First, I’m just pleased that we’re going to be able to open pathway-specific clinics and get subspecialty training in such pathways. I am a phase I investigator. I use a variety of targeted therapies. Most of them I can’t mention now. But in general, I have used the KRAS G12C inhibitors in my clinics. I have seen responses.

Some of those responses that I’m expecting to see — between 20% and 30%, that would be nice. Obviously, the number of complete responses, as I discussed with patients, wouldn’t necessarily be high, but it’s a good place to start to get those partial responses.

Then, obviously, the long-term question is whether that’s actually going to correlate with having a clinical impact on the patients. Those are the discussions that I have to have with my patients.

Prasad: That’s right, I think. Dr. Kim, when I look up KRAS G12C, the first thing that pops up is an ad that says “Have you found the unseen 13%?” It looks like people are on the hunt for KRAS G12C. My question to you is, do you think that number is fair and accurate? Is it about 13% of non-small cell lung cancer? Are there are other RAS mutations that we’re not drugging? How do you think about G12C in the landscape of all druggable alterations?

Kim: Right. There are various subtypes of KRAS mutations in non-small cell lung cancer. There is G12C, which is one of the most common forms of KRAS mutation. There is a G12V/D, and there are trials trying to target those non-G12C mutations nowadays.

In terms of the frequency or prevalence of G12C, I think that’s about right — 13%, depending on what studies you’re looking at. It’s not an uncommon mutation.

Personally, the rate of response that we see with sotorasib is not as high as other drugs that we use in lung cancer. For example, osimertinib [Tagrisso], alectinib [Alecensa], lorlatinib [Lorbrena], or brigatinib [Alunbrig].

However, I think this is a good start, and there are multiple studies looking at combination therapy approaches. I think this is a good option for patients. In my mind, clearly a better option than docetaxel [Taxotere].

Although we don’t have direct randomized data comparing those two, there is an ongoing study actually comparing sotorasib versus docetaxel, I believe, in the second-line setting. That will give us an answer as to whether sotorasib will lead to a better survival, especially the overall survival. That’s an important study to look at when the results are out.

But at this point, based on response rate and some of the side effects profile, I think this is a favorable option in my mind compared with docetaxel second-line therapy.

Prasad: Yeah, that’s the question. I guess one thing you’re pointing out that’s really important to point out is that this is a targeted therapy drug that’s approved for subsequent lines, not for initial treatment. We are still expecting people to get probably chemo-IO [immunotherapy] as the initial treatment.

Then they are going to face the choice. Are they going to go to the G12C inhibitor? Or are they going to do what you do otherwise, which is probably Taxol [paclitaxel]? But maybe Taxol-ramucirumab [Cyramza]. Dr. Kim, where is the ramucirumab?

Kim: Ramucirumab. Oh, yeah. I forgot to mention it — a very important combination. I mean, there was a randomized study comparing docetaxel plus ramucirumab versus docetaxel showing modest sort of benefit based on the REVEL trial. Yeah. I mean, in my practice do I use it? Yes, but selectively, because toxicity increases with the combination.

Prasad: Yes, I think that will be a very important study to look at, which is whether or not this drug can outperform Taxol. I think … I tried to do some cross-trial comparisons, but it’s quite difficult because … and if anyone is aware of this, you can email me because I want to find this. Which is that does anyone know the response rate to Taxol or Taxol-ramucirumab in just the G12C cohort? Has that been reported?

Kim: Not that I’m aware of, yeah. Now people are looking at different segments of the KRAS mutation. Maybe one day we’ll have the data, but I am not aware of any data at this point.

Prasad: Dr. Vandross, in your experience with these G12C drugs, that’s not the only one. There is a lot of enthusiasm here. How do you think about this landscape? What do you think is coming? Are you optimistic about this space, that this will yield and bend to targeted therapy?

Vandross: Sure. I think there is definitely going to be room for it and even the other tumor types. I know we’re talking about lung cancer, but I have seen some responses in colon cancer as well. Frankly, they are being combined with other medications, other targeted therapies, in order to get maximal benefit. I think that, once again, expanding to other tumor types as well as combining with other targeted therapies.

Prasad: I learned in oncology that the best way to have a great study is to not have a control arm. That’s what they taught me.

Prasad: I see that that’s employed here. Dr. Kim, one last thought on this drug, because I think the data — which is that we know the response rate. Let’s talk about the median duration of response, though. The median duration of response [DOR] wasn’t as long as I would have expected. Dr. Kim, what do you think about that median DOR?

Kim: Yeah, it was not as good as some of the other drugs I was mentioning before. For example, alectinib, the median duration of response is very long with those ALK TKIs [tyrosine kinase inhibitors] or osimertinib. It was 11 months, if I’m not mistaken, right?

It wasn’t as bad given the overall response rate of 37%. If you have a response and can stay on the drug for about a year or 11 months, I think it can have some positive impacts on patients’ quality of life.

Prasad: Yeah, I think that’s an interesting median DOR and the PFS [progression-free survival] is about 6 months. It will be interesting to see. I’m very curious what happens when it goes up against Taxol.

Dr. Vandross, any last thoughts on this? You have these new drugs out there. You got an uncontrolled study. You got a responsive rate. You got a median DOR to hang your hat on. You got an ongoing randomized trial. If you were seeing a patient off study, is this entering into your armamentarium? Where are you going to use it? You’re going to use second-line? Maybe third-line? How do you think about this drug?

Vandross: I think I’m just going to go back to what Dr. Kim was saying earlier with it’s going to be a personalized … it’s going to be an individualized discussion with the patient. Present the information, present the data.

Just even this morning, I’m talking with a patient, what is their preference? How much do they want to be on a therapy? What is their current quality-of-life status, their disease status? Some people don’t want to be off of the therapy. I would feel comfortable presenting this as an option and then move ahead, making sure that we’re accounting for side effects and managing those appropriately. Then hopefully the patient will in fact derive benefit.

Prasad: All right. I’ll give you the last word, Dr. Kim.

Kim: Sure. One last thought about the data is that sotorasib showed the response in some of the difficult-to-treat populations with some combination mutations. For example, STK11, they saw a good response. KEAP1-mutant KRAS G12C had a little slightly lower response rate.

I use chemo-IO therapy for those with poor prognostic genetic markers. For example, KRAS plus STK11 or KEAP1. Those patients progress pretty quickly on chemoimmunotherapy based on my personal experience in clinic. If we can use sotorasib, those patients can at least induce some shrinkage. I think it can have good results in some of the patients.

Prasad: You make an excellent point, which is that maybe not all G12C is created equally and maybe there is an important role of concomitant mutations that occur. I think one of the challenges and one of the ways we need to improve on oncology is try to figure that out.

One of the challenges in this space is when registration studies are a small sample size, you just don’t have the power to tease out these differences. But it would be really great if there were some registry after the fact, so we got everyone we’re treating with this drug, we can look at all the mutational profile, and we can see is there some interaction we’re missing.

Dr. Kim and Dr. Vandross, thank you so much for taking us through sotorasib, the new G12C inhibitor.