KRAS Inhibitors in Frontline and Combination Therapy

Drs Sabari and Spira comment on the use KRAS inhibitors in both frontline and combination therapies.

Joshua Sabari, MD: The KRAS inhibitors are approved in the second-line settings. Sotorasib is FDA approved in the second-line setting post immunotherapy or chemoimmunotherapy. Adagrasib is under review pending a PDUFA [Prescription Drug User Fee Act] date in December 2022. These are going to become potential standard of care in the second-line setting. How do we then move these agents to the frontline setting? With the current response rates of 40% and the current progression-free survival at 6 months, if you compared these drugs head-to-head with standard of care in the frontline—pembrolizumab single agent in a patient who is PDL-1 high or pembrolizumab plus chemotherapy in a patient who's PDL-1 low or negative—it would be a tough study to do. I'm not sure that these [KRAS] G12C inhibitors would improve upon what our currently available strategies are.

One option is to think about a combination strategy. Both agents are being looked at in combination with pembrolizumab. [We have not seen data to date] using sotorasib plus pembrolizumab, as well as potentially adagrasib plus pembrolizumab in the frontline setting, but this is an interesting strategy for potentially moving these agents to the frontline setting. The concern here is the rate of immune-related adverse events. We've seen [high rates of transaminitis and potentially pneumonitis] with other TKI or small molecule combinations. Another strategy is to think about combination strategies in the second-line setting. There are many that are ongoing with SHP2, SOS1, or downstream with ERK and MEK inhibitors, for example, or potentially cytotoxic chemotherapy. If those [combination] regimens are successful in the later lines, we can potentially move those combinations into the frontline setting. As it is right now, it's going to be very difficult for single agent, either sotorasib or adagrasib, to be better or beat out chemotherapy immuno-oncology in the frontline setting.

Alexander Spira, MD, PhD, FACP: It's been an amazing turnaround over 2 years’ time. KRAS has been thought as the most undruggable target for many years, but now with the clear activity with sotorasib, adagrasib, as well as third generation drugs, we expect there to be new ways of approaching [treatment]. There are combination studies and changing lines of therapy already ongoing. There's a frontline study combining immuno-oncology pembrolizumab with immuno-oncology adagrasib in the frontline setting. I expect there to be chemotherapy combinations as well. We're trying to do 2 things. One is to improve the efficacy, so how do you combine it with another drug? How do you move it up the line of therapy? Treat patients with it earlier based upon the paradigm a patient has an actual mutation; by targeting that early on, we hope that they do better. Those studies are ongoing as we speak. Then there are new mechanisms of action. There are SHIP2 inhibitors and other drugs as well that are being combined right now to see if we can improve the activity of these drugs with a single agent, possibly in the second or third line. Unfortunately, as is apparent with all these drugs, the duration of response is good but not great. In other words, these are not cures. What do you do after sotorasib or adagrasib failure? In those patients, we'd like to combine it with something else.

This transcript has been edited for clarity.

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