Treatment of KRAS G12C Mutant NSCLC

Benjamin Levy, MD, explains KRAS G12C mutations in non–small cell lung cancer, and Hatim Husain, MD, provides insight into the mechanism of action of G12C inhibitors.

Benjamin Levy, MD: Let’s move on, for the sake of time, to KRAS. Once thought to be undruggable, KRAS G12C, a subtype of KRAS, makes up 40% or 45% of all KRAS mutations. KRAS G12C is the most common variant for KRAS, and 13% of all lung adenocarcinomas have KRAS G12Cmutations. This is the most common genomic alteration that’s potentially druggable for advanced adenocarcinoma or adenocarcinoma of the lung.

We’ve had some challenges targeting KRAS G12C for a lot of biological and scientific reasons. It’s very difficult to drug. We’ve started to jump that hurdle with the CodeBreaK 100 trial, looking at sotorasib, or AMG 510. This is an oral KRAS G12C-directed therapy. This trial was specifically looking at it in the second line for patients with advanced adenocarcinoma harboring a KRAS G12C mutation who had progressed on prior standard therapies. Importantly, in this trial, stable brain metastases were allowed. At the time of progression, patients were given sotorasib 960 mg until disease progression or it not being tolerated.

Importantly, what we saw in the study was a meaningful response and a response rate of 37%. People say, “This isn’t in the land of EGFR-directed therapies or ALK-directed therapies.” But we need to remember that this was a highly pretreated group of patients where there may be a lot of tumor heterogeneity going on, which may make it more difficult to achieve those response rates. There were 4 complete responses. There was a meaningful duration of response. Duration was close to a year, at 11.1 months.

One of the more important things we learned from this was survival times. Patients had received a median of 2 lines of therapy. This was given at a median of line 3. They had received a median of 2 prior therapies. We saw a median survival time of 12.5 months, which is exceptional, given what we think about KRAS mutations in lung cancer and the potential to be prognostic for worse overall survival.

The drug was reasonably well tolerated. We’ve got some treatment-related adverse events, including diarrhea, nausea, and LFT [liver function test] abnormalities, but most of these were grade 1 or 2. Coming down the pike is adagrasib as well. Hatim, I want to reach to you here. We’ve got a drug that finally can be leveraged for a very difficult genomic alteration. How do you use this drug? Have you used it? Where do you see the field heading with KRAS G12C?

Hatim Husain, MD: This is a critical question. I have used the medicine in a number of patients. My clinical experience with the medicine parallels published reports, both in terms of response rate and tolerability. One of the things I’ve been astounded by is how well tolerated the medicine is. That has been quite important for this refractory patient population that has received many lines of prior therapy.

I feel that combinatorial approaches are likely to be important with both sotorasib and adagrasib. One of the trials that we’re currently awaiting is the combination of PD-1 plus KRAS G12C–directed approach inhibitor. Importantly, there are press releases about such strategies, particularly noting some of the dosing considerations, where some of the doses that are being tested in trial with PD-1, namely adagrasib, are different from what the monotherapy doses are in trials. For that reason, there may be some nuance about how we’re going to combine these KRAS medicines. Is it going to be 1 uniform dosing strategy? Are there going to be considerations around dose? What’s the best combinatorial approach to think about?

Some of the ones that are actively being studied are SHP2 inhibitors plus G12C inhibitors. There are strategies looking at MEK inhibition plus G12C. There are strategies looking at EGFR inhibition with G12C as well, largely because of the parallel space of colon cancer in which some of the data with monoclonal antibodies for EGFR plus G12C have shown some important advances in colorectal cancer for that population of G12C-mutated colorectal cancer.

The field is moving forward. I’ve had patients deriving clinical benefit from sotorasib. I’m eagerly awaiting some of these new data, particularly in combinatorial approaches, and with other agents that are being evaluated, such as adagrasib. Importantly, there are other ways to target KRAS. There are some other approaches looking at locking KRAS in the on state. The G12C inhibitor sotorasib locks the KRAS and the GDP-bound states of the off state. The future is bright here.

Benjamin Levy, MD: Yes. That’s a very nice overview and nice biological explanation of how these drugs work and where we’re heading. I look forward to the combination approaches. We’re doing some of them with SHP2 and IO [immuno-oncology]. I’m looking forward to seeing the toxicity signals we see with some of these KRAS G12C drugs with IO. Because KRAS mutations have immunogenicity, this makes a lot of biological sense to combine immunotherapy with a targeted therapy. We’ll have to see what we can get away with from a toxicity standpoint.

Transcript edited for clarity.

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