Targeting KRAS Mutations in Advanced NSCLC - Episode 9
David R. Gandara, MD: We’ve talked a lot about the fact that KRAS G12C is a distinct mutation, highly associated with tobacco carcinogenesis, and it used to be undruggable. Tell us about the drugs. What are these small-molecule inhibitors? How did they come about, and what do we know so far? As you said in the introduction, none is actually FDA approved at this point.
Benjamin P. Levy, MD: It’s been quite a year for these small-molecule inhibitors, and these drugs were developed to covalently and irreversibly bind to a pocket adjacent to the GTP site, which essentially renders the altered protein in a GDP state, locking GDP in and inactivating the downstream signaling. The first drug that has made a splash and a name for itself is AMG 510. This drug has been presented several times, most recently at the ASCO [American Society of Clinical Oncology Annual] Meeting last year, although there may have been an additional presentation. This was an open-label, phase 1 study, first for adult patients with locally advanced or metastatic KRAS G12C tumors. Some of the key eligibility criteria were that you had to have measurable disease, you had to have received prior standard therapy, and most, if not all, of these patients had received at least 2 lines of therapy. This wasn’t just lung cancer: There were colorectal patients as well. They did not include patients with brain metastases, and it will be interesting to see what the activity of this drug is in the CNS [central nervous system].
As in any phase 1 study, the primary end point was safety and tolerability. What we’ve learned about it, just cutting to the chase, is that this drug and the other that we’ll talk about are extremely well tolerated. The key secondary end points, of course—and the things that we look at—included objective response rate and duration of response and PFS [progression-free survival]. There was a dose escalation study where cohort 1 was 180 mg, cohort 2 was 360 mg, cohort 3 was 720 mg, and cohort 4 was 960 mg. I say that only because we saw activity with the drug across all these cohorts.
The first thing to talk about with this drug is the tolerability, because that is the primary end point of any phase 1 study. There were no dose-limiting toxicities reported from this trial. There were no treatment-related serious or fatal adverse events [AEs] reported. There were no AEs that led to treatment discontinuation. That’s important to note. The 960-mg daily dose was what was identified for the expansion dose, and that was the recommended phase 2 dose. The efficacy is probably as important or more. As of the ASCO 2019 meeting, there were a total of 34 patients evaluated, of which 23 had non–small cell lung cancer. These were patients where the majority had seen at least 2 lines of therapy, and they had a response rate of close to 50%, 48%, and a disease control rate of 96%. I don’t think we’ve ever seen data like these for KRAS-mutated lung cancer. Certainly, this drug has landed on the map and moved on and will hopefully go through vetting through the FDA in rapid fashion. But, importantly, there were not that many adverse events: maybe some GI [gastrointestinal] toxicity, but clearly this is a well-tolerated drug with very meaningful activity.
Transcript edited for clarity.