Sotorasib Evidence Builds For KRAS-Mutated Advanced NSCLC

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The latest CodeBreaK 100 trial findings indicate that the first-in-class KRAS G12C mutation-targeted inhibitor sotorasib may be efficacious for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) with the mutation. 

Bob Li, from Memorial Sloan Kettering Cancer Center in New York, USA, told delegates at the IASLC 2020 World Conference on Lung Cancer Singapore Worldwide Virtual Event that the oral highly selective and irreversible inhibitor “demonstrated early, deep, and durable responses” in the phase II portion of this trial, thus “validating the phase 1 results”. 

Overall, 126 patients without brain metastases who had progressed on up to three prior lines of treatment – including platinum-based chemotherapy plus PD-1 or PD-L1 inhibitors in 81% of cases – were given sotorasib 960 mg/day until disease progression. 

After a median of 12.2 months of follow-up, 37.1% of 124 patients with RECIST measurable baseline lesions had achieved a confirmed objective response including three (2.4%) complete and 43 (34.7%) partial responses. A further 43.5% of patients had stable disease, giving a disease control rate of 80.6%, the presenter said. 

The majority (72%) of responses were detected at the first assessment after a median 1.4 months of treatment. Median duration of response was 10.0 months and 43% of the 46 responding patients were continuing treatment without progression at time of data cutoff. 

Median progression-free survival was 6.8 months, Bob Li reported. 

Of note, exploratory analysis of 86 patients indicated that sotorasib response occurred in patients regardless of PD-L1 tissue expression, with rates of 48%, 39% and 22% for patients with a tumour proportion score of less than 1%, 1–49% and 50% or higher, respectively. 

Similarly, responses to sotorasib were found among 104 patients assessed for STK11 or KEAP1 mutations, with response rates of 23% for patients with both mutations, 50% for patients with only a STK11 mutation, 14% for patients with only a KEAP1 mutation and 42% for those wild-type for both genes. 

Treatment-related adverse events (TRAEs) were “generally mild and manageable”, the presenter said, with just 19.8% of the 126 patients experiencing grade 3 TRAEs, most commonly liver enzyme elevations (n=15) and diarrhoea (n=5). One (0.8%) patient experienced grade 4 pneumonitis and dyspnoea and there were no grade 5 TRAEs. 

Overall, TRAEs resulted in dose modification in 22.2% of patients and discontinuation in 7.1%. 

Discussing the results, Bob Li said that sotorasib was “well tolerated”. The US FDA has granted sotorasib breakthrough therapy status and the confirmatory, phase III CodeBreaK 200 trial is now enrolling patients, he added. 

Reference 

PS01.07 - Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational phase 2 trial of sotorasib in KRAS p.G12C mutated non-small-cell lung cancer. IASLC 2020 World Conference on Lung Cancer Singapore Worldwide Virtual Event (January 28-31, 2020).