Targeted Agents Show Efficacy in KRAS-Mutated NSCLC

Lyudmila Bazhenova, MD, medical oncologist and professor of medicine at UC San Diego, discusses targeted therapies for patients with KRAS-mutated non–small cell lung cancer (NSCLC).

KRAS mutations are present in about 30% of patients with NSCLC, according to Bazhenova. Sotorasib (Lumakras) has been approved by the FDA as second-line therapy for targeting the KRAS G12C mutation that is present in 13% of patients with NSCLC. The single-arm phase 2 CodeBreaK 100 trial (NCT03600883) of sotarasib showed an objective response rate (ORR) of 37% and a median progression-free survival (PFS) of 6.8 months.

In the phase 2 KRYSTAL-01 trial (NCT03785249), investigators found an ORR of 43% in patients treated with adagrasib (MRTX 849), another KRAS G12C-targeted agent, but other data are not yet available, and this agent is not yet approved. Bazhenova says both drugs had an adverse event (AE) profile of gastrointestinal (GI) toxicities including diarrhea, nausea, and vomiting.

In both studies, a small number of patients with both the KRAS G12C mutation and a STK11 mutation showed a higher ORR than the overall patient population: 50% with sotorasib and 64% with adagrasib. Bazhenova says that co-mutations could help determine the best possible choice of treatment if this association is substantiated by more clinical data.

TRANSCRIPTION

0:08 | KRAS mutations are seen in approximately 30% of patients with non–small cell lung cancer. The specific mutation that we can target today is a KRAS G12C mutation, which happens in approximately 13% of patients with lung cancer. And we have sotarasib approved, which is currently approved in second-line therapy in patients who have failed platinum doublet and that has shown a response rate of 37% and median PFS of [6.8] months. Right behind sotarasib, not yet approved, but looks promising as well, is adagrasib, which showed the ORR of [43%]. And we do not yet know any data on median PFS or median duration of response because the medication is a little bit earlier in development. What we have learned from both of those compounds is that the majority of the [AEs] are GI toxicities, such as diarrhea, nausea and vomiting.

1:09 | We're also learning very interesting information about significance of co-mutations in patients with KRAS G12C, and in both of the studies with sotarasib as well as adagrasib. Although on a very small number of patients, we have seen that patients who have a co-mutation in STK11 tend to have a higher response rate compared to all patients in general. Again, this is very early, additional trials are needed to confirm that, but I find it's actually quite interesting that maybe co-mutations will make a difference on how we decide where to use sotarasib in patients with KRAS mutations.