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New Targeted Therapies for KRAS Mutation in Lung Cancer

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Published on March 31, 2021

Clinical Trials Test New Therapies for KRAS G12C Mutation

Roughly 13% of lung cancer patients test positive for the KRAS G12C mutation, which until recently, was considered largely untreatable. Luckily, clinical trials are paving the way to exciting new targeted therapy treatment options for patients with the KRAS mutation. 

Keep watching as Dr. Pasi Jänne, MD, PhD, world-renowned lung cancer expert and Director of the Lowe Center, Belfer Center, and Chen-Huang Center at Dana-Farber Cancer Institute shares information on the two KRAS G12C inhibitors that are currently being tested in clinical trials. Patient Power Co-Founder Andrew Schorr guides the discussion as they cover how the mutation is identified, the promising outlook of the new targeted therapies, their side effect profiles, and more. 

Support for this series has been provided by Mirati Therapeutics, Inc. Patient Power maintains complete editorial control and is solely responsible for program content.


Transcript | New Targeted Therapies for KRAS Mutation in Lung Cancer

Andrew Schorr: Hello, and welcome to Patient Power. I'm Andrew Schorr in Carlsbad, California, but joining us from Boston is Dr. Pasi Jänne. Dr. Jänne is really a noted, world famous expert in lung cancer. And we're talking about a subtype of lung cancer, KRAS G12C, and we'll get to that in a second. But first of all, welcome to Patient Power, Doctor.

Dr. Jänne: Thank you. My pleasure to be here today.

Andrew Schorr: So, for people diagnosed with lung cancer, you've really devoted your career to helping identify subtypes and can there be drugs to target the subtype you or your loved one has?

What is KRAS G12C Lung Cancer?

Dr. Jänne: So, lung cancer is not one disease anymore. It's really a disease made up of different subtypes. And at the genetic level, today, in 2021, there are, in fact, seven different subtypes of lung cancer, where we have specific, targeted therapies that are approved, and we hope others to come. And, so, it's, of course, important that when one gets diagnosed with lung cancer, to try to understand, is the cancer—or does the cancer have one of these specific genetic alterations? As it will dictate therapy.

Now, that seven does not include KRAS. KRAS, in general, makes up actually quite a significant fraction of lung cancer and of lung adenocarcinoma, which is the most common type of lung cancer, makes up about 20, 25%. And half of that is KRAS G12C. And it is, in fact, quite a substantial proportion of KRAS-mutant lung cancer. And we're, of course, very excited that we can now finally talk about actually targeting G12C.

How Do You Identify the KRAS Mutation in Lung Cancer?

Andrew Schorr: So that would be identified on a genomic test that patients should have now, right? So, is that the right way? It's-

Dr. Jänne: Yeah. Yeah. Either a tumor-based sequencing test, which many institutions are doing it, and there are, of course, many commercial vendors that are doing it. Or, if tumor-based sequencing is not possible, then blood-based genotyping, or sometimes referred to as a liquid biopsy, that's another way to diagnose whether the cancer has a genetic alteration, through this non-invasive method.

Andrew Schorr: So, if the data comes back, the test result, that you, the patient, have KRAS G12C subtype of lung cancer, what have the treatments been traditionally and how effective have they been?

Traditional Treatments and New Targeted Therapies for KRAS Lung Cancer

Dr. Jänne: The traditional treatments have been really chemotherapy and immune therapy. And, although they can be effective, I think the challenge is that we run out of options fairly quickly once those two therapies are exhausted. In the scientific community, it's been a struggle to find effective therapies for all of KRAS-mutant cancers.

In fact, I mentioned that there are all these different genomic subtypes of lung cancer, but, in fact, we've known about KRAS-mutant cancers for 30 years. And it's just until recently that the innovations have come forward in drug development to have specific therapies for the G12C patients.

Andrew Schorr: Right. We saw a quote in the literature that said that KRAS was "undruggable." So now-

Dr. Jänne: Right.

Andrew Schorr: ... you've been working on lots of research, and there are some promising drugs in development. And you've been speaking around the world about it, talking to other scientists and physicians about it. Tell us about the latest studies and the promise of actual medicines now, that may target this and give more hope to patients with this subtype of lung cancer.

Dr. Jänne: Sure. Right. So, there are a number of these in clinical development, of what we call the KRAS G12C-specific inhibitors. The ones that are sort of furthest along, where we have clinical data, is one from Amgen called sotorasib, or also known as AMG 510. And a second one from Mirati Therapeutics known as adagrasib or MRTX849.

Graphic: Dr. Jänne presented at the 2020 ENA Conference. He is the lead investigator for the KRYSTAL-1 trial of adagrasib/MRTX849. Both adagrasib/MRTX849 and sotorasib/AMG 510 target the KRAS G12C mutation. The KRYSTAL-1 trial showed adagrasib to have a 45% overall response rate in previously treated non-small cell lung cancer. Information presented at the WCLC 2021 conference reported that the CodeBreak 100 trial showed sotorasib to have a 37% overall response rate. Adagrasib did have an increase in adverse events including QT prolongation occurring in 14% of adagrasib-treated patients, this was not seen in sotorasib-treated patients.

Dr. Jänne: What we know from these two studies is that, somewhere between 32-45% of patients have frank tumor shrinkage when they take these single agents. What we don't totally know from the Mirati one because it's too early, how long does the therapy last for? We have some understanding from the early Amgen trials about how long the therapies last for. And, in general, both agents are fairly well-tolerated, and I think that, which is also a wonderful thing and, again, wonderful for patients that we have these options.

Clinical Trials Paving the Way to New Therapies

And, so far, from both of these, and, again, these come from fairly early clinical studies, we know that patients with KRAS G12C mutations, who have received the prior therapies, chemotherapy, immune therapy, a subset of those individuals can have significant responses to these agents.

And this has opened multiple, additional clinical trials and single agents and combinations, to move this forward and to try to understand who are the patients who will respond, who are the patients that may not respond, or if they respond and develop resistance, how can we develop combinations? It's opened a whole new area of therapies, which we didn't previously have.

Andrew Schorr: And just to be clear for patients, you mentioned earlier, traditional therapy has been chemo. Chemo is sort of a dirty word for a lot of patients. They want to say, "Is there a targeted therapy or like a pill you could take?" Clearly, not that these are not powerful drugs and can ... you could avoid all side effects, but it's not chemo. Clearly, right?

Dr. Jänne: Correct. Yeah. These are targeted therapies. These are oral agents. These are pills. It's not chemotherapy. It doesn't mean that they have no side effects. They have some side effects, but they are, in general, very different than the side effects we're used to thinking about with chemotherapy.

Andrew Schorr: So, just to sum up, Doctor, how big a deal is this? You've been involved in lung cancer research a long time, how big a deal is this for people with the KRAS G12C type?

Dr. Jänne: This is an incredibly big deal because we didn't have these precision therapies, these targeted therapies, for this population before. We now have them. They're showing clinical activity. This is an incredibly big deal. And I think this is a big population of patients with lung cancer, and I think will have a significant impact for this population and for the entire disease. So, I'm really excited that we have these therapies. They're here. And we're able to administer them, through clinical trials, and, hopefully at some point soon, as approved therapies.

Andrew Schorr: Well, that's really an incredible message of hope to what have been very serious, unfortunately, too often short-term, conditions, allowing people to live longer and hopefully live better. Thank you so much for your devotion to patients and to research, Dr. Jänne, from Harvard. Thank you so much for being with us.

Dr. Jänne: My pleasure. Thank you for the invitation.

Andrew Schorr: Okay. Andrew Schorr, with Dr. Pasi Jänne from Harvard and the Dana-Farber Cancer Institute. Remember, knowledge can be the best medicine of all.

Graphic: An application for FDA approval for sotorasib/AMG 510 for previously treated non-small cell lung cancer was submitted in December 2020. It is expected that an accelerated approval for adagrasib/MRTX849 for previously treated non-small cell lung cancer will be submitted the second half of 2021.

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