番茄社区

In this exclusive 番茄社区 video, , vice chairman of the Department of Hematology and Medical Oncology at Cleveland Clinic's Taussig Cancer Institute, analyzes a recent review by Jia Luo, MD, et al. in the ASCO Educational Book, which highlights the challenges in treating patients with KRAS-mutated lung cancer.

Following is a transcript of his remarks:

I'm Dr. James Stevenson. I am a medical oncologist at Taussig Cancer Center in Cleveland Clinic. Today I'd like to review and discuss an article from this year's ASCO Educational Book by Dr. Luo and colleagues regarding overcoming KRAS-mutant lung cancers. So this is a very hot topic in non-small cell lung cancer right now, especially on the heels of the regarding some news with some agents targeting KRAS.

And in this review, the authors do a great job of presenting background on KRAS-oncogenes, which we know is the most common oncogenic driver in non-small cell lung cancer. It's mutated in approximately 25% of lung cancers. Other aspects of this oncogene are that the mutations are generally seen in patients that are smokers as opposed to other driver mutations.

We also tend to see higher tumor mutation burden in PD-L1 expression in KRAS-mutated tumors, which can be seen in an immune-inflamed tumor microenvironment. So that definitely connects to their responsiveness to immunotherapies and chemoimmunotherapy, which we're still sorting out some of the details of how responsive patients with KRAS-mutated lung cancer are to different immunotherapies, especially when associated with other co-mutations such as STK11, TP53 and KEAP1.

The other thing we know about the KRAS oncogenes are the different alleles with alterations producing different KRAS-mutated subtypes, with a therapeutic focus most recently on the KRAS^G12C mutation, which is the most common KRAS mutation, seen in about 42% of non-small cell lung cancers that have K mutations. And we're talking about KRAS as an oncogenic driver, and we know that there are many targeted therapies that have been developed and approved in non-small cell cancer with other oncogenic drivers -- most notably EGFR and ALK.

Those are historically the ones that have received the most attention. Yet KRAS has been sort of a target that has been elusive in terms of developing agents, even though the authors mentioned that the first agent developed in a laboratory shown to directly inhibit KRAS was reported in 2013, but it really took more than a few years after that to have agents developed that entered the clinic.

The other discussion in this article regards the downstream pathways of KRAS and the attempts to target those in clinical trials and those have been unsuccessful such as targeting pathways such as RAS and MEK, PI3 kinase, and ACT. So that's not proven an effective way to target KRAS lung cancer.

So going back to the direct inhibitors of KRAS, this article was a lead-up to some of the more recent positive news regarding two specific KRAS^G12C inhibitors. The first one is sotorasib, which has been approved for use in non-small cell lung cancers with KRAS^G12C mutations -- patients with advanced disease. And this drug was approved based on the CodeBreaK 100 trial, which was a phase I/II trial that looked at using sotorasib in patients with non-small cell lung cancer with T12C mutations that had received prior therapies -- typically platinum-based chemotherapy.

And when looking at the 960 milligram dose, they found a response rate of 37% in this pretreated population. Duration of response was just over 11 months and the progression-free survival [PFS] was over 6 months. So those data led to the approval of sotorasib, which is now used in the clinic for patients with G12 cancers -- again, that have received prior therapy. So that was the first entry into the clinic that was big news. You know, KRAS was no longer "undruggable."

Since then, most recently we've heard news about adagrasib, another KRAS^G12C inhibitor that was studied in a very similar population, pretreated. This was in the KRYSTAL-1 trial, and the majority of patients on this trial, again, over 100 patients, had received prior chemo and immunotherapy. And relatively similarly, the response rate was 42% in the KRYSTAL-1 trial with a duration of response of over 8 months. And again, progression-free survival of about 6 and a half months. So kind of in line with that 6 to 7 months PFS that we're seeing with sotorasib as well.

So certainly another active drug in this population and in this setting with data that seems pretty similar to sotorasib. These drugs are associated with toxicity, especially GI toxicities, which of course we're learning more about in terms of optimal dosing. Adagrasib is not approved for use yet. It seems like it should be not too far behind after the news at ASCO and KRYSTAL-1. So we may have two different drugs to use in the KRAS^G12C-mutated non-small cell lung cancer.

So that's big news and very clinically relevant news for right now.

The next steps will be understanding resistance to G12C inhibitors. And there are efforts underway. We have some data looking at things like ctDNA [circulating tumor DNA] in patients treated with G12C inhibitors -- very early data, but of course we're going to be learning more about inherent acquired resistance to these drugs. And that will certainly lead to combination therapies being tested in clinical trials.

That'll be a next step, as well as looking at these drug potentially in the frontline setting. And that's being done in at least one trial, the CodeBreaK201 trial that is looking at two different doses of sotorasib -- 960 versus 240 milligrams in the frontline setting. So we'll have some data there as well, because I think the optimal dosing of these patients is also being sorted out.

So this was a great walk through the KRAS story of where we are right now and kind of where we're heading. Lots of recent exciting news and certainly much more to come given that we've really just certainly started the journey with KRAS inhibitors, like sotorasib and adagrasib.

So exciting times for this previously undruggable target. So, another alteration that we need to routinely test for in these patients and that will help a significant number of patients with advanced disease.

Read the review here, an interview about it here, and additional expert commentary about it here.