Medicine Matters oncology

In my ASCO presentation, I will presenting overall survival and exploratory subgroup analysis from the registration enabling phase II CodeBreaK 100 clinical trial in patients with KRAS G12C non-small cell lung cancer that were previously treated. The most important findings from this study are that with a median follow-up of 15.3 months, sotorasib yielded an objective response rate, a confirmed objective response rate, of 37.1% with four patients achieving a complete response to therapy corresponding to a 3.2% of complete response.

The median duration of response was 11.1 months. The median progression-free survival with sotorasib was 6.8 months, and the median overall survival with sotorasib was 12.5 months. This is important because this is the first report of a clinically meaningful overall survival benefit with the KRAS G12C inhibitor in previously treated patients with KRAS G12C non-small cell lung cancer.

The second point from the presentation that I would like to highlight is that sotorasib exhibited broad and consistent clinical activity across a range of patient subgroups as defined on the basis of baseline characteristics, but importantly also on the basis of molecular profiles. Specifically, responses to sotorasib were observed across subgroups of patients defined on the basis of co-occuring mutations in P53, STK11, and KEAP1.

It is particularly notable that the subgroup of patients with co-occuring mutations in STK11 that were wild type for KEAP1 appeared to derive improved benefit from sotorasib with an objective response rate of 50% in this subgroup, a median progression-free survival of 11 months, and the median overall survival of 15.3 months.

This is, in my opinion, very interesting because typically clinical outcomes for patients with STK11 co-mutations are poor. These patients exhibit poor responses to standard of care therapies, being docetaxel, immune checkpoint inhibitors, or even platinum doublet chemotherapy. I think these results clearly demonstrate that we have dealt KRAS G12C-mutant lung adenocarcinoma and a knock-down punch, but the fight is not over.

I think immediate priorities for the future are the identification of genomic and non-genomic determinants of response to sotorasib as well as a full elucidation of mechanisms of both intrinsic and acquired resistance that could then potentially be tackled with rationally designed combination regimen. So it is important to understand how the tumors become resistant to sotorasib, what determines the patterns of resistance, and of course, ultimately, can we develop strategies that will either prevent the emergence of resistance or tackle resistance once it has occurred.