Primary Endpoint Results from SHERLOCK: a Phase 2 trial of Sotorasib, Bevacizumab and Chemotherapy in Advanced KRAS G12C NSCLC.

Abstract

Introduction: The combination of sotorasib, bevacizumab, and platinum- based chemotherapy may exert synergistic anti-tumor effects enhancing clinical outcomes in patients with NSCLCs harboring KRAS G12C mutations. We conducted a phase 2 trial evaluating the efficacy and safety of this novel first-line regimen in treatment-naive, newly diagnosed advanced or recurrent NSCLC with KRAS G12C mutations. Method(s): SHERLOCK was an investigator-initiated, multicentre openlabel trial across 13 sites in Australia. Study treatment consisted of sotorasib 960mg once daily with 4 cycles of induction carboplatin (AUC5), pemetrexed (500mg/m2 ) and bevacizumab (15mg/kg) every 3 weeks, followed by maintenance sotorasib, pemetrexed and bevacizumab every 3 weeks until disease progression. CT imaging was performed at baseline and every 8 weeks until disease progression. Plasma samples for ctDNA were obtained at baseline, week 8, week 16 and at progression. The primary endpoint was to determine the objective response rate (ORR) according to RECIST 1.1. Key secondary outcomes included progression-free survival (PFS) and adverse events. Result(s): Between August 2022 and June 2025, a total of 52 participants were enrolled. Baseline characteristics were: median age 67 years; 62% female; 40% ECOG 0; 96% were former or current smokers; and 38% had brain metastases. Baseline tumor characteristics showed PD-L1 expression >50% in 23% (12/52). In ctDNA evaluable participants, baseline TP53 co-mutation occurred in 51% (19/37), STK11 in 30% (11/37), and KEAP1 in 16% (6/37). With a median follow-up of 20 months, 47 participants were evaluable for the primary endpoint. Unconfirmed ORR was 72% (34/47). Confirmed ORR was 62% (29/47). The median duration of unconfirmed and confirmed response was 9.0 and 7.5 months respectively. In PD-L1 evaluable participants, confirmed ORR according to PD-L1 >50%, 1 49%, and < 1% was 80% (8/10), 58% (7/12) and 57% (13/23), respectively. Confirmed ORR for participants harboring plasma comutations in TP53, STK11, or KEAP1 was 79% (15/19), 64% (7/11) and 50% (3/6), respectively. Intracranial CNS response was docu mented in non-target lesions in 30% (3/10, none with prior radio therapy). There were 63% PFS events (33/52) and median PFS was 9.0 months (95% CI 7.9-15). Median PFS according to PD-L1 >50%, 1 49%, and < 1% was 15.0, 7.9 and 9.0 months respectively. In ctDNA evaluable population (n=37), median PFS according to TP53, STK11 or KEAP1 co-mutation was 11.0, 9.6 and 5.8 months respectively. Plasma KRAS G12C clearance was observed in 84% (27/32) of participants with paired baseline and week 8 samples, and in 85% (23/27) of those with paired baseline and week 16 samples. Among participants with confirmed ORR, 79% (23/29) had detectable plasma KRAS G12C mutations at baseline, and 95% (20/21) achieved clearance by week 8. Adverse events were consistent with the known safety profiles of each individual study drug with no new safety signals identified. Conclu sion: Sotorasib, in combination with bevacizumab and chemotherapy, demonstrated promising anti-tumor activity as a first-line treatment for advanced NSCLC with KRAS G12C mutation. High ORR were observed across all PD-L1 expression levels and molecular subgroups, including those with TP53, STK11, or KEAP1 co-mutations. These findings warrant further evaluation in a randomized phase 3 trial.