Systemic Therapy for KRAS+ Advanced NSCLC

Alexander Drilon, MD: Unfortunately, to date, we have not seen regulatory approval of a specific targeted therapeutic for KRAS-mutant lung cancers. We certainly hope that will change in the future, but for now, the systemic therapy options that are available to these patients include chemotherapy, immunotherapy, or a combination of both in the upfront setting, and the other second- and third-line options that are approved for non–small cell lung cancers in general.

Jonathan Riess, MD, MS: In terms of EGFR TKIs [tyrosine kinase inhibitors] in KRAS-mutant non–small cell lung cancer, that's not really a practice that's used anymore. Afatinib is a second-generation EGFR TKI that's approved after platinum-based chemotherapy in squamous non-small cell lung cancer, based upon a modest benefit that was observed in lung adenocarcinoma. Erlotinib used to be approved in lung adenocarcinoma after progression on platinum-based chemotherapy, even without EGFR mutation. Sometimes that was used, but it's really not used anymore and it doesn't particularly work in KRAS-mutant non–small cell lung cancer.

There are some interesting data, and I think what's more relevant now is ERBB pathway inhibition with EGFR and HER2 on impacting GDP and GTP loading, in terms of shifting KRAS and the GDP downstate that may help synergize in certain settings with direct KRAS G12C inhibitors. That's where I see the future heading, with EGFR TKIs and KRAS-mutant non–small cell lung cancer as part of a combinatorial approach, with direct KRAS inhibition or other combination treatments targeting the RAS/RAF/MAP kinase pathway, rather than as a single agent in KRAS-mutant non–small cell lung cancer. With the changing landscape of much more effective therapies, its role has been substantially diminished.

Paul Bunn, MD: For many molecular drivers, the immunotherapies are less effective. If you look at EGFR and ALK, ROS1, RET, and probably MEK, the immunotherapies don't seem to work so well. For KRAS and BRAF mutations, the immunotherapies tend to work at about the same frequency in the KRAS mutations as in tumors that don't have any actionable driver.

Immunotherapy is a good option for patients who have KRAS and BRAF mutations. If they're those, the selection would primarily be based on the PD-L1 expression. Whereas high PD-L1 patients with KRAS mutations could receive a checkpoint inhibitor alone, and those with lower PD-L1 expression might receive checkpoint inhibitors plus chemotherapy.

There are some co-occurring molecular changes in KRAS such as STK11 or PEAK1, where the chance that immunotherapy might work tends to be lower. The best thing to do in most cases is unknown, but the likelihood that immunotherapy will work in the presence of a KRAS mutation plus a PEAK1 mutation, or an LKB1 mutation, may be lower, but we don't have a specific thing to do for them at the moment.

Transcript Edited for Clarity