Sotorasib (AMG510), a novel KRASG12C inhibitor, provided a manageable safety profile and preliminary antitumour activity that was durable in patients with heavily pre-treated non-small cell lung cancer (NSCLC) harbouring a KRAS p.G12C mutation, according to findings presented by David S. Hong of the University of Texas MD Anderson Cancer Center in Houston, USA at ESMO Virtual Congress 2020.
Dr Hong reported the durability of clinical benefit and biomarker data following sotorasib treatment of patients with NSCLC in this phase I study.
The primary endpoint of the study was safety and key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS). KRAS p.G12C mutant allele frequency (MAF) and PD-L1 level were also evaluated.
Patients eligible for study inclusion had tumours with the KRAS p.G12C mutation and had received prior systemic anticancer treatment. As of the data cut-off of 1 June 2020, 59 patients with NSCLC were enrolled; of these 35 (59.3%) patients were female with a median age of 68.0 years (range, 49 to 83). A total of 44 (74.6%) patients had received ≥2 previous lines of treatment and 30 (50.8%) patients had received ≥3 prior lines.
The safety analysis uncovered no dose-limiting toxicities or fatal treatment-related adverse events; 5 (8.5%) patients discontinued due to adverse events of any cause.
Regarding the secondary efficacy endpoints, with median follow-up of 11.7 (range, 4.8 to 21.2) months, the ORR in the overall population was 32.2% (95% confidence interval [CI] 20.6–45.6). The median DoR was 10.9 (range, 1.1+ to 13.6) months, with 10 of 19 responding patients remaining in response at data cut-off. 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 DCR were 35.3% and 91.2%, respectively.
Median PFS for all 59 patients was 6.3 (range, 0.0+ to 14.9) months. At data cut-off, 14 (23.7%) patients remained on study without disease progression and 26 (44.1%) had died.
Biomarkers predictive of resistance to sotorasib were not identified in the small biomarker analysis
Among 32 (54.2%) patients with KRAS p.G12C MAF data available for biomarker analysis, there were 9 partial response (PR),19 stable disease (SD) and 2 PD.
No significant association between KRAS p.G12C MAF and response was determined (Wilcoxon p = 1 for PR versus SD).
PD-L1 data were available for 18 (30.5%) patients, with 4 patients achieving PR, 12 achieving SD, and 1 PD. The one patient with PD had a TPS of 75%, and there was no significant association between PD-L1 level and response (Wilcoxon p = 0.73 for PR versus SD).
Conclusions
According to the authors, patients with heavily pre-treated NSCLC demonstrated durable responses to sotorasib, with the majority of patients achieving disease control leading to a median PFS of 6.3 months.
The current limited dataset suggests that neither KRAS p.G12C MAF nor PD-L1 expression level from tissue specimen predicts response to sotorasib.
In addition to this presentation, the analysis will also appear in a simultaneous publication in The New England Journal of Medicine (Hong DS, et al. NEJM 2020;ePub ahead of print) and covered in accompanied editorial (Lo Russo PM, et al. NEJM 2020;ePub ahead of print).
This study was funded by Amgen.
Reference
1257O – Hong DS, Bang Y-J, Barlesi F, et al. Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib). ESMO Virtual Congress 2020.