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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.

Purpose: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer., Materials and Methods: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil., Results: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria., Conclusion: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation., Competing Interests: Maurício Fernando Silva Almeida RibeiroTravel, Accommodations, Expenses: Foundation Medicine Rodrigo Medeiros BovolinStock and Other Ownership Interests : Abbott Laboratories (ABT), Johnson & Johnson (JNJ), Novo Nordisk A/S (NVO), Edwards Lifesciences (EW), Zoetis Inc (ZTS), Gilead Sciences (GILD), Varian Medical Systems Inc. (VAR), Varex Imaging Corporation (VREX) Fernando Costa SantiniHonoraria: Merck Sharp & Dohme, Roche, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Wyeth, AmgenConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Roche, Bayer, Lilly, AmgenSpeakers' Bureau: Roche, Merck Sharp & Dohme, AstraZeneca, BayerTravel, Accommodations, Expenses: Bayer, Merck Sharp & Dohme, Bristol Myers Squibb Rodrigo Ramella MunhozHonoraria: Bristol Myers Squibb, MSD, Roche, Novartis, Sanofi, Merck SeronoConsulting or Advisory Role: Roche, Merck Serono, Sanofi, Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, MSD, Novartis, RocheResearch Funding: Lilly, Roche, Bristol Myers Squibb, Novartis, MSDTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Roche, Sanofi Denis Leonardo Fontes JardimHonoraria: Janssen-Cilag, Roche/Genentech, Astellas Pharma, MSD Oncology, BMS Brazil, Pfizer, Libbs, MerckConsulting or Advisory Role: Janssen-Cilag, Pfizer, MSDTravel, Accommodations, Expenses: MSD, BMS Brazil, Janssen-Cilag Gustavo dos Santos FernandesHonoraria: Roche, MSD Oncology, BayerResearch Funding: Roche, Memorial Sloan-Kettering Cancer Center, BMS BrazilTravel, Accommodations, Expenses: Roche Maria Isabel AchatzConsulting or Advisory Role: RocheSpeakers' Bureau: AstraZeneca, MSD Oncology, Merck Sharpe & DohmeNo other potential conflicts of interest were reported.