Durability of clinical benefit and biomarkers in patients with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib).
CodeBreaK 100 is an important, multicenter, open, phase I and II study that assesses the efficacy, safety, tolerability, and pharmacokinetics of AMG 510 or sotorasib, a drug designed to treat patients with several mutated solid KRASG12C tumors. In addition to the presentation at ESMO Virtual Congress 2020, the analysis of the phase I trial will also appear in a simultaneous publication in The New England Journal of Medicine (Hong DS, et al. NEJM 2020; ePub ahead of print).
Sotorasibe (AMG510) provided a manageable safety profile and durable preliminary antitumor activity in patients with non-small cell lung cancer heavily pretreated with a KRAS p.G12C mutation. The results were presented by David S. Hong, MD Cancer Center, University of Texas, Houston, USA, who also commented on biomarker data, including the MAF (mutant allele frequency) in KRAS p.G12C and the level of expression of PD-L1.
Some experts claim that for decades the KRAS protein has been considered a molecule impossible to be blocked. Previous analyzes (ESMO 2019 and ASCO 2020) had already shown that sotorasib has a favorable safety profile, low toxicity grades 3 and 4, and anti-tumor activity in lung, colorectal tumors, among others.
The primary endpoint of the CodeBreak 100 phase I was safety and the main secondary endpoints included objective response rate (ORR; assessed every six weeks), disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS). The frequency of the KRAS p.G12C mutant allele (MAF) and the level of PD-L1 were also assessed. Patients eligible for inclusion in the study had tumors with the KRAS p.G12C mutation and had received prior systemic treatment. On the cut-off date of June 1, 2020, 129 patients were enrolled, 59 with non-small cell lung cancer. Of these patients, 35 (59.3%) were women, with a median age of 68.0 years (range, 49 to 83).
A total of 44 (74.6%) patients received ≥2 previous lines of treatment and 30 (50.8%) patients received ≥3 previous lines. The safety analysis did not reveal dose-limiting toxicities or fatal treatment-related adverse events. Five (8.5%) patients were withdrawn due to adverse events of any cause.
Regarding secondary efficacy endpoints, with a mean follow-up of 11.7 months (range, 4.8 to 21.2), the ORR in the general population was 32.2% (95% confidence interval [CI] 20 , 6–45,6). The median DDR was 10.9 months. The DCR was 88.1% (95% Cl, 77.1-95.1). Five (8.5%) patients had progressive disease (PD). Among 34 patients treated with the 960 mg daily dose, the ORR and DoR were 35.3% and 91.2%, respectively. The median of PFS for all 59 patients was 6.3 months (range from 0.0+ to 14.9). In the data cut, 14 (23.7%) patients remained in the trial without disease progression and 26 (44.1%) died.
Predictive biomarkers of sotorasib resistance were not identified in this analysis and no significant association between KRAS p.G12C MAF and response was determined.
In patients with polytrated non-small cell lung cancer, lasting responses to sotorasib are observed, where the majority of individuals obtain 88% disease control on isolated treatment and with a median SLP of 6.9 months. Regarding the response biomarkers, the data set is still quite limited today, suggesting that neither the expression level of the KRAS p.G12C MAF nor the PD-L1 of the tissue sample predicts the response to sotorasib.
D.S. Hong, et al. Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib). Abstract 1257O. ESMO 2020.
Hong, DS et al. KRAS p.G12C Inhibition with Sotorasib in Advanced Solid Tumors September 20, 2020 DOI: 10.1056/NEJMoa1917239