Alexander Drilon, MD: When we find a KRAS mutation on a patient’s molecular report after testing for lung cancer, it’s important to underscore that KRAS mutations are really a heterogeneous group of different mutation types, meaning there are different amino acid changes that involve different residues along the KRAS protein. For example, in smokers, the KRAS G12C mutation is the most common mutation. But in nonsmokers you see other mutations, such as the KRAS G12D mutation, that are much more common. Beyond that, it can involve other amino acids, such as the amino acid 13 of the KRAS protein. The difference is that we now have drugs for particular mutations or substitutions, such as KRAS G12C, versus the other mutation types where we might employ different strategies altogether. The specific mutation that’s identified in a patient’s cancer may dictate the likelihood of us having a more exciting clinical trial for a patient, versus just more standard options for these patients on a targeted-therapy front.
Jonathan Riess, MD, MS: How do I counsel patients when KRAS is found? The discussion we typically have is that previously, it was thought to be a poor prognostic feature, but with the evolution of immunotherapy and also these direct KRAS inhibitors, it’s really unclear if that’s true anymore. In terms of up-front treatment outside a clinical trial, the KRAS mutation, I explain to patients that it’s the most common mutation we encounter in their type of lung cancer, and that immunotherapy can still be effective. For example, unlike the EGFR or ALK non–small cell lung cancer, KRAS lung cancer patients—especially the ones associated with smoking, such as G12C—can still derive good benefit from immunotherapy. But for EGFR and ALK, there’s really limited demonstration of effectiveness of immunotherapy, such as pembrolizumab and atezolizumab, especially as single agents.
I counsel them that they could still respond to immunotherapy or chemoimmunotherapy, stratified by what their PD-L1 status is. For example, PD-L1 high, they get pembrolizumab or chemotherapy with pembrolizumab. I also counsel them that we may have clinical trials for them. If they have KRAS G12C, the direct inhibitor trials are very exciting and are in development. We also have trials targeting certain computations of KRAS. I emphasize that we have potentially excellent treatments for them, whether they are immunotherapy, chemoimmunotherapy, direct RAS inhibitors, or clinical trials with combination therapies.
Transcript Edited for Clarity