Abstract CT008: Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100

Abstract

Introduction: Sotorasib, a first-in-class KRASG12C inhibitor, has been FDA-approved for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapies based on the Phase 1/2 global, single-arm CodeBreaK100 trial. We will report the longest follow-up for a KRASG12C inhibitor, including 2-year survival, safety, and genomic profiles associated with durable clinical benefit. Methods: Sotorasib was administered orally at 960 mg once daily to patients who progressed on prior therapies and had KRAS p.G12C-mutated locally advanced, metastatic NSCLC. Primary endpoint was objective response rate (ORR) assessed by central review. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. In an exploratory analysis, baseline tumor tissue and/or plasma samples were collected and analyzed for genomic alterations. Tumor samples were analyzed for PD-L1 levels to evaluate correlates with prolonged tumor response, defined as patients with PFS ≥ 12 months, in comparison with those with PFS ≤ 3 months. Results: In the first analysis of the combined Phase 1 and Phase 2 study (N=174), the median number of prior lines of therapy was 2.0 (range 1-4+). 90.2% received prior anti-PD1 or anti PD-L1 treatment; 82.8% received both prior platinum-based chemotherapy and anti-PD1/PD-L1. Updated ORR by central review was 40.7% (95% CI: 33.2, 48.4) and median DOR was 12.3 months (7.1, 14.6). Median PFS and OS was 6.3 months (95% CI: 5.3, 8.2) and 12.5 months (10.0, 17.8). One and two-year OS was 50.8% and 30.3%. Sotorasib was well-tolerated in the long-term with mild and manageable toxicities, and no new safety signals emerged. Prolonged tumor response was observed across PD-L1 expression, including in tumors with low PDL-1 expression and STK11 co-mutation that may derive less benefit from immunotherapy. Conclusions: In the longest follow-up of any KRASG12C inhibitor, sotorasib continued to demonstrate a favorable safety profile and durable efficacy, including a 2-year OS observed in 30% of patients. Current analyses continue to support long-term clinical benefit across subgroups in patients with KRAS p.G12C-mutated NSCLC, and additional biomarker data will be presented. Citation Format: Grace K. Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S. Falchook, Antoine Italiano, Juergen Wolf, Adrian G. Sacher, Toshiaki Takahashi, Suresh S. Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, Qui Tran, Simon Jones, Agnes Ang, Abraham Anderson, Antreas A. Hindoyan, David S. Hong, Bob T. Li. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT008.

Genomic and epigenomic profiles distinguish pulmonary enteric adenocarcinoma from lung metastatic colorectal cancer

“…Nevertheless, future clinical efficacy in KRAS G12C-mutant PEAC might be achieved by sotorasib, as shown by the latest data of CodeBreaK100 study. 34 Moreover, EGFR sensitive mutations were exclusively found in five PEAC patients, which is similar to a previous Chinese report on PEAC. 35 Less frequent EGFR mutations have been described in other European studies possibly due to different mutation profiles across ethnic groups.…”

The Path to Personalized Treatment in KRAS-Mutant Non-Small Cell Lung Cancer: A Review of Targeted Therapies and Immunotherapy

“…Grade 3 and grade 4 TRAEs were reported in 20% and 1% of patients, respectively, and no fatal TRAEs were reported. 15 …”

“…Grade 3 and grade 4 TRAEs were reported in 20% and 1% of patients, respectively, and no fatal TRAEs were reported. 15 Furthermore, the global Phase III study (CodeBreak 200) of sotorasib versus docetaxel for previously treated NSCLC with KRAS G12C mutation was published by the European Society for Medical Oncology (ESMO) in 2022. 16 The results showed that sotorasib significantly improved the primary endpoint of PFS compared to docetaxel (5.6 vs 4.5 months, HR=0.66, p=0.002).…”

Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg

“… 50 An updated ORR from combining phases I and II NSCLC patients ( n = 174) was 40.7% [95% confidence interval (CI): 33.2–48.4] and median progression-free survival (PFS) and overall survival were 6.3 months (95% CI: 5.3–8.2) and 12.5 months (95% CI: 10.5–17.8), respectively. 51 …”