WCLC 2021 | CodeBreak 100: sotorasib in KRAS-mutated NSCLC

CodeBreak 100 is a Phase II registrational international trial looking at sotorasib, the first-in-class KRAS G12C inhibitor, in patients with advanced non-small cell lung cancers harboring the KRAS G12C mutation. This is a study where we enrolled 126 patients across 11 countries and three continents, North America, Europe and Asia Pacific. Most patients has progressed on a platinum chemotherapy doublet as well as PD-1/PD-L1 immunotherapy. More than 80% of patients, 81% of patients have progressed on both. This is in a treatment-refractory setting. Most patients were former or current smokers, that’s 92.9%, and the median age was 63.5 years.

In the primary analysis we saw a confirmed overall response rate of 37.1%. That included three complete responses as well as 43 partial responses. We saw a median percent tumor shrinkage of 60% and 81% of patients had any magnitude of tumor shrinkage, suggesting that the responses were fairly deep. We also saw rapid responses in these patients where 72% of responders had a response, a partial response, by the week six scan. The median time to objective response was 1.4 months, a very short time to an objective response. We also saw durability of response with the median duration of response being 10 months, and 43% of responders still continue to respond at the data cutoff last month, December 2020. This is a more longitudinal follow-up and encouraging data suggesting durability of response with a median progression-free survival of 6.8 months, which is consistent with what was published in the Phase I trial in the New England Journal, September last year.

The safety data also were encouraging. There were no treatment-related deaths. Most toxicities were low grade, grade 1 or 2. Primarily gastrointestinal, diarrhea, nausea, elevated liver enzymes, things that we knew about from the Phase I trial. The grade 3 toxicity occurred at about 19.8%, but most of them were treatable, reversible with supportive measures and 22.2% of patients needed a dose modification due to toxicity, and 7.1% had a treatment discontinuation with toxicity but, again, mostly were manageable.

We also did an exploratory biomarker analysis that showed sotorasib responses across a wide range of PD-L1 expression subgroups, ranging from PD-L1-negative to PD-L1-positive, and PD-L1-high more than 50%. We saw responses in all of those groups, as well as subgroups of mutational profiling, including STK11 and KEAP1 mutants and wild-type. We also looked at P53 and we saw responses across all of those subgroups. Interestingly, there were some numerical differences suggesting a higher response rate in those STK11 mutants and KEAP1 wild-type, but those numerical differences were not statistically significant with overlapping confidence interval so this observation requires further study. But I can say now that it’s encouraging to see that responses were observed across all molecular subgroups.

In conclusion, this was a Phase II registration study which had more than double the number of patients compared to the Phase I. It confirmed and validated the findings in Phase I, that this is an active drug and the results are clinically meaningful in a population of patients that are treatment-refractory with unmet medical need. The safety data was also acceptable and we saw some tumor responses across molecular subgroups.

The breakthrough therapy designation was granted by the United States FDA and regulatory filings have been submitted to the FDA as well as the EMA. There’s discussion with other regulatory agencies in other countries in Asia, in Australia, Canada, Latin America and we hope that we can move forward to bring this new medicine to patients as quick as possible.

The confirmatory Phase III study, CodeBreak 200, is still ongoing. That’s looking at a sotorasib versus second line docetaxel to see a significant difference against the standard of care. All in all, I’m very encouraged by the results. I think this is a collaborative effort, getting the world together to fight cancer and crack KRAS. I think a lot of credit goes to patients and their families for putting up the fight, as well as all the investigators and clinical staff, Amgen, the sponsor. Really, really happy about the results overall.