Synapse - Clinical and genomic features of response and toxicity to sotorasib in a real-world cohort of patients with advanced KRAS G12C-mutant non-small cell lung cancer

Clinical and genomic features of response and toxicity to sotorasib in a real-world cohort of patients with advanced KRAS G12C-mutant non-small cell lung cancer Journal Article

Authors:	Thummalapalli, R.; Bernstein, E.; Herzberg, B.; Li, B. T.; Iqbal, A.; Preeshagul, I.; Santini, F. C.; Eng, J.; Ladanyi, M.; Yang, S. R.; Shen, R.; Lito, P.; Riely, G. J.; Sabari, J. K.; Arbour, K. C.
Article Title:	Clinical and genomic features of response and toxicity to sotorasib in a real-world cohort of patients with advanced KRAS G12C-mutant non-small cell lung cancer
Abstract:	PURPOSE With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice. MATERIALS AND METHODS We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity. RESULTS Among 105 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; P = .004; OS HR, 4.10; P = .003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR, 1.10; P = .731; OS HR, 1.19; P = .631) or STK11 (rwPFS HR, 1.66; P = .098; OS HR, 1.73; P = .168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti-PD-(L)1 therapy. Among these patients, anti-PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs (P < .001) and TRAE-related sotorasib discontinuation (P = .014). Twenty-eight percent of patients with recent anti-PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity. CONCLUSION Among patients treated with sotorasib in routine practice, KEAP1 comutations were associated with resistance and recent anti-PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.
Keywords:	inhibitor; outcomes; g12c
Journal Title:	JCO Precision Oncology
Volume:	7
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2023-09-01
Start Page:	e2300030
Language:	English
ACCESSION:	WOS:001197689200050
DOI:	10.1200/po.23.00030
PROVIDER:	wos
PMCID:	PMC10581626
PUBMED:	37384866
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Kathryn C. Arbour -- Source: Wos