Targeting KRAS Mutations: A Novel Approach in Advanced NSCLC - Episode 7

KRAS G12C Inhibition in Advanced NSCLC: AMG 510

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Alexander Drilon, MD: Thankfully, we now have a variety of different selective direct inhibitors of KRAS G12C. As a reminder, it's a specific mutation that you're looking for. One of these drugs is AMG 510, which right now is named sotorasib, and it is in clinical trials for patients who have these G12C mutations, such as lung cancer, and other cancers that might harbor G12C, such as colorectal cancers. We've seen very good activity in KRAS G12C-mutated lung cancers, and we’re seeing response rates that approach 50%. That’s a dramatic difference from the older strategies that target KRAS. This drug has been very exciting for the field in general. The design of these drugs is unique and has been made possible because of the particular configuration of the KRAS G12C mutant protein that’s unique relative to other proteins such as G12D or G12V. In a particular, there is an IL [interleukin] group on the cysteine of KRAS G12C that can be targeted with these covalent inhibitors. In general, one thing we haven't mentioned is that these direct inhibitors target the protein and lock it in the inactive state, noting thatthe KRAS mutant protein, shuttles between these active and inactive states for it to trigger continuous downstream signaling.

Paul Bunn, MD: Obviously, in an early phase 1/2 study, the goal is to determine the dose, safety, and early signs of efficacy. Those early signs of efficacy are generally, first, objective response rate. And then later, duration of response, progression-free survival, and overall survival.

Most molecular therapies have objective response rates as single agents of 50% or more and median progression-free survival of 9 to 10 months or more. The FDA has determined from other molecular drivers that chemotherapy and other standard treatments in the past have had response rates lower than 50%. The median progression-free survival is in the 4- or 5-month range. They have given accelerated approval to agents that have response rates over 50% and a median progression-free survival of 9 months or more.

These 2 agents do seem to have response rates that are appearing to be in the 50% or higher range. The median progression-free survival is too early to determine, but certainly, could be in the 9 month or more range. The safety profiles have been really good for these agents so far. The rates of grade 3 and 4 serious adverse events is quite low. So far, these agents seem to be as safe or safer than some of the other molecular therapies that we have. That's because normal cells don’t have KRAS G12C mutations. These therapies seem to be highly specific and therefore, not causing serious adverse effects. For the grade 2 anemias and so on that have been reported, it's not clear whether those are due to the disease or due to the treatment at this point.

Alexander Drilon, MD: The CodeBreak 100 study is a phase 1/2 trial of the selective KRAS G12C inhibitor AMG 510, or sotorasib, for patients with KRAS-mutated lung cancers and other cancers. In particular, we're looking for that G12C mutation. The goals of the study were to show the safety and activity of this molecule in this molecularly enriched population, and we certainly saw that the drug was not only active, but also safe. I think that's critical to know because KRAS G12C doesn't exist in the normal human body, and so there is not a KRAS G12C molecule that is harbored by normal tissues. Conceptually, in the design of these drugs you would have a good therapeutic window where you're able to hit the target hard, but not actually hit normal tissues to a substantial extent. You would see a high frequency of drug-related toxicities.

Jonathan Riess, MD, MS: In terms of the development of AMG 510 in KRAS G12C inhibition, I do think it has the potential to be practice changing. In non–small cell lung cancer, overall response rates are about half, about 50%. I think we need to know more about duration of response and progression-free survival among a larger group of patients to see if it stacks up to osimertinib in EGFR-mutated lung cancer or alectinib in ALK-positive non–small cell lung cancer. We need those data to mature and get the result of larger trials. I'm hopeful it will be practice changing, even if it seems too early to say. I would note that there appears to be some differential activity based on histology. For example, activity in non–small cell lung cancer seems to be better than colorectal cancer where response rates are lower. That's where I think we need to look at the effects of histology and other comutations and how they may impact the activity of KRAS G12C inhibitors.

In terms of the practical implications of AMG 510 as your direct KRAS inhibitor, I do think it has the potential to be practice changing. I also think it's too early to say without further data, without the progression-free survival, duration of response, and having more data with that among a larger group of patients, to say how practice changing it will be and what those practical implications are.

Paul Bunn, MD: For these agents, toxicity has been pretty minimal. These have been well tolerated. There have been a couple of cases of diarrhea and anemia, and these have been well controlled and have not been dose-limiting. In fact, when it comes to anemia, it's not totally clear whether it's due to the drug or the disease, but diarrhea and anemia have been quite infrequent and easily managed and have not required discontinuation of the drug.

Transcript Edited for Clarity