PS01.07 Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutant NSCLC: First Disclosure of the Codebreak 100 Primary Analysis


      Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial.


      This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety.


      Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported.


      In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.


      KRAS p.G12C, NSCLC, sotorasib (AMG 510)