“In the past decade, major improvements in treating lung cancer have come from identification of mutations and development of drugs to target those mutations: EGFR, ALK, RET, HER2, and others. Finally, we can add KRAS as a druggable target,” stated invited discussant Mark Awad, MD, PhD, Clinical Director of the Thoracic Oncology Treatment Center at the Dana-Farber Cancer Institute and Associate Professor at Harvard Medical School.

Mark Awad, MD, PhD

“We are making significant headway in treating non–small cell lung cancer (NSCLC) with these targeted agents, in some cases doubling or tripling progression-free survival compared with earlier--generation drugs. These advances have been made through biomarker selection, choosing drugs that improve potency, selectivity, tolerability, and better central nervous system penetration,” he pointed out.

“However, the magnitude of benefit with sotorasib, although encouraging, is not quite as high in terms of response rate or progression-free survival as we have seen with other targeted agents.” A second KRAS G12C inhibitor under development, adagrasib, has comparable response rates, he said.

Therapeutic Ceiling?

Dr. Awad discussed that it is currently unknown if “we have hit a therapeutic ceiling with KRAS monotherapy.” He noted that additional KRAS agents are being tested in trials to see if they will improve upon efficacy, or if combinations with other therapies may yield better results.

“The more modest activity in KRAS G12C–mutated NSCLC may be due to drug properties, patient factors, baseline factors that confer intrinsic primary resistance, or perhaps we are seeing rapid emergence of acquired resistance in this type of cancer,” Dr. Awad said.

KRAS-mutated NSCLC is associated with heavy tobacco exposure and is more highly mutated than other subtypes of NSCLC. “It is not clear if these co-mutations have a significant effect on outcome. It doesn’t seem so in preliminary findings. We need larger studies with more numbers of patients,” he said. “It may be that KRAS-mutated tumors are ‘wired differently’ to develop resistance.”

An important issue is how to sequence KRAS G12C inhibitors with checkpoint inhibitors. Perhaps prioritizing sotorasib for patients with KRAS mutation–positive disease who don’t respond to immunotherapy would be a reasonable approach. “Sequencing gets more complicated as we integrate various biomarkers,” he said. “We also need to study whether we can safely combine sotorasib with our conventional therapies.” 

DISCLOSURE: Dr. Awad reported no conflicts of interest.