Sotorasib confers durable clinical benefit in KRAS G12C-mutated NSCLC
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Sotorasib conferred durable clinical benefit for patients with pretreated advanced non-small cell lung cancer who harbor KRAS G12C mutations.
Sotorasib (AMG 510, Amgen) — a highly selective, first-in-class KRAS G12C inhibitor — also had a favorable safety profile, according to findings from the international, single-arm, phase 2 CodeBreak 100 trial presented during the presidential symposium of the virtual International Association for the Study of Lung Cancer World Conference on Lung Cancer.
“Sotorasib demonstrated rapid, deep and durable responses in the advanced [NSCLC] cohort, validating phase 1 results,” Bob T. Li, MD, MPH, medical oncologist at Memorial Sloan Kettering Cancer Center, said during his presentation.
KRAS is the most frequently mutated oncogene in human cancers, and the KRAS G12C mutation, which accounts for about 13% of lung adenocarcinomas, is associated with poor outcomes, according to Li.
Previously reported data from the phase 1 CodeBreak 100 trial showed sotorasib demonstrated encouraging anticancer activity among patients with heavily pretreated advanced NSCLC who harbor KRAS G12C mutations, and researchers recommended 960 mg as the phase 2 dose.
For the registrational phase 2 portion of the trial, Li and colleagues assigned 126 patients (median age, 63.5 years; range, 37-80; 92.9% former smokers) with locally advanced or metastatic KRAS G12C-mutated NSCLC across 11 countries to 960 mg oral once-daily sotorasib until disease progression. More than half of patients (57.1%) had received two or three prior lines of treatment, 91.3% had received anti-PD-1/PD-L1 immunotherapy and 81% had received platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy.
Confirmed objective response rate by blinded independent central review per RECIST version 1.1 served as the study’s primary endpoint. Secondary endpoints included disease control rate, PFS, duration of response and safety. Data cutoff occurred Dec. 1, 2020.
At median follow-up of 12.2 months, 124 patients had at least one measurable lesion at baseline and were evaluable for efficacy.
Researchers observed a confirmed response among 46 patients, three of whom achieved a complete response and 43 of whom achieved a partial response, for a confirmed ORR of 37.1% (95% CI, 28.6-46.2).
“Eighty-one percent had tumor shrinkage of some magnitude, and the median percent of tumor shrinkage among all responders was 60%,” Li said.
Moreover, researchers reported median duration of response of 10 months (95% CI, 6.9-11.1) and median time to objective response of 1.4 months. Forty-three percent of responders remained on treatment without disease progression at data cutoff.
“Responses to sotorasib were durable, with 72% observed at first assessment,” Li added.
The overall disease control rate was 80.6% (95% CI, 72.6-87.2) and median PFS was 6.8 months (95% CI, 5.1-8.2).
Any-grade treatment-related adverse events occurred among 69.8% of patients, which led to dose modification for 22.2% of patients and treatment discontinuation by 7.1%. Grade 3 or higher treatment-related adverse events occurred among 20.6% of patients. No patient deaths were reported.
Results of exploratory biomarker analyses showed sotorasib responses among several subgroups of patients, including those with negative or low levels of PD-L1 expression and STK11 co-occurring mutations.
“Sotorasib received breakthrough therapy designation by the FDA, and I am pleased to report that regulatory filings based on current data are underway. There is also ongoing dialogue with other regulatory agencies in the U.K., China, Australia, Canada and Brazil,” Li said. “The confirmatory phase 3 CodeBreak 200 trial is currently enrolling.”
Perspective
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Melina Marmarelis, MD, MSCE
CodeBreak 100 confirms the single-agent activity of sotorasib in patients with NSCLC harboring a KRAS G12C mutation and heralds the beginning of an era of KRAS-targeted therapy in NSCLC.
Similar to other targeted agents, the response to treatment appears to be quick, with the majority of responses occurring at the first 6-week time point. The response rate is lower than we have seen for therapies targeting EGFR and ALK, but we may see better outcomes as KRAS-targeted therapy moves closer to the front line.
The exploratory analyses looking at PD-L1 and co-mutation status did not find these factors predictive of overall response to sotorasib; however, the subgroups were small and there was a trend toward lower response rates among patients with KEAP co-mutations regardless of STK11 status. The role of these and other co-mutations will need to be further analyzed in the larger phase 3 clinical trial and will be an important factor in developing this class of drug and interpreting future clinical trial results.
CodeBreak 100 is an exciting step forward in bringing KRAS-targeted therapy to our patients, and I look forward to the phase 3 results and future combination studies.
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Li BT, et al. Abstract PS01.07. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer (virtual meeting); Jan. 28-31, 2021.
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