First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety

360490 Background: KRAS mutation is present in 90% of pancreatic ductal adenocarcinomas with p.G12C accounting for 1% to 2% of these mutations. Sotorasib, a small molecule that specifically and irreversibly inhibits KRAS G12C , has been investigated in the CodeBreaK100 trial in patients with KRAS G12C -mutated advanced solid tumors. Herein, we report on the largest dataset evaluating efficacy and safety of a KRAS G12C inhibitor in patients with pretreated KRAS G12C -mutated pancreatic cancer. Methods: CodeBreaK100 (NCT03600883) is an international, single arm, phase I/II study evaluating the efficacy and safety of sotorasib in patients with KRAS G12C -mutated advanced solid tumors with ≥ 1 prior systemic therapy unless intolerant or ineligible for available therapies. The primary efficacy endpoint is confirmed objective response rate (ORR), assessed by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoints include duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: As of November 1, 2021, 38 patients with pancreatic cancer (mean age: 65 years, 76.3% male) from the combined phase I/II study received sotorasib 960 mg once daily. Stage IV disease was present in 55.3% of patients at diagnosis, and in all patients at enrollment. Baseline ECOG scores were 0, 1, or 2 in 31.6%, 57.9%, and 10.5% of patients, respectively. Most patients (79%) had ≥ 2 prior lines of therapy (median: 2 [range: 1-8]). Median treatment duration was 4.1 months with a median follow-up of 16.8 months. Eight patients had confirmed partial response by BICR with a resulting ORR of 21.1% (95% CI: 9.55%-37.32%). DCR was 84.2% (Table 1). Treatment-related adverse events (TRAEs) of any grade occurred in 16 (42.1%) patients. Grade ≥ 3 TRAEs occurred in 6 patients: diarrhea (2); fatigue (2); abdominal pain, ALT increase, AST increase, pleural effusion, and pulmonary embolism (1 each). No TRAEs were fatal or resulted in sotorasib discontinuation. Conclusions: Sotorasib demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRAS G12C -mutated advanced pancreatic cancer, who have limited treatment options and poor prognosis. Clinical trial information: NCT03600883. [Table: see text]