背景：在注冊階段 2 CodeBreaK 100 試驗中，sotorasib 在經預處理的 KRAS p.G12C 突變非小細胞肺癌（NSCLC）的客觀應答率為 37.1% （95% Cl： 28.6， 46.2）和中位無進展生存（PFS）為 6.8 個月（95%Cl：5.1，8.2）。在攜帶 STK11 共突變的患者中觀察到腫瘤反應，這是臨床結果不佳、護理標準低下的驅動因素。在這裏，我們按關鍵基線特征和生物標記報告一組擴展亞組的療效。

Background: In the registrational phase 2 CodeBreaK 100 trial, sotorasib demonstrated an objective response rate (ORR) of 37.1% (95% Cl: 28.6, 46.2) and a median progression-free survival (PFS) of 6.8 months (95% Cl: 5.1, 8.2) in patients with pretreated KRAS p.G12C mutated non-small cell lung cancer (NSCLC). Tumor response was observed in patients bearing co-mutations in STK11, a driver of poor clinical outcomes with standard of care. Here, we report efficacy across an extended set of patient subgroups by key baseline characteristics and biomarkers.

方法：晚期 NSCLC 攜帶 KRAS p.G12C 並接受先前標準療法的符合標準的患者予以每日口服 Sotorasib 960 mg。主要終點由中心重新審核評估 ORR。關鍵的次要端點包括 PFS、 OS 和安全性。KRAS p.G12C 突變等位基因頻率（MAF）和腫瘤突變負擔（TMB）通過分析組織樣本進行二代測序（NGS）。單個基因的突變狀態由組織和/或血漿樣本的 NGS 確定。在可獲得相應結果的患者亞組中分析了反應與 KRAS p.G12C MAF，TMB 或共突變之間的相關性。MAF 與反應之間的關聯為值比 （95% CI），來自依賴變量的對數回歸，該對數的自變量是比值比，而 MAF 的自變量以 10%為單位。

Methods: Sotorasib was given orally at 960 mg once daily to eligible patients who had advanced NSCLC harboring KRAS p.G12C and received prior standard therapies. Primary endpoint was ORR assessed by central review. Key secondary endpoints included PFS, overall survival, and safety. KRAS p.G12C mutant allele frequency (MAF) and tumor mutational burden (TMB) were analyzed by next-generation sequencing (NGS) using tissue samples. Mutational status of individual genes was determined by NGS using tissue and/or plasma samples. Correlations between response and KRAS p.G12C MAF, TMB, or co-mutations were analyzed in subsets of patients who had available respective results. Association between MAF and response was reported by odds ratio (95% CI), from a logistic regression with dependent variable of log odds of being a responder and an independent variable of MAF in a unit of 10%.

結果：表中介紹了亞組的 ORR。在研究人群中，應答率是不依賴 KRAS p.G12C MAF（比值比 [95% CI]： 1.11 [0.88， 1.39]）。OS 仍然不成熟。

Results: ORR across subgroups is presented in the Table. Response was independent of KRAS p.G12C MAF in the study population (odds ratio [95% CI]: 1.11 [0.88, 1.39]). OS remained immature.

Subgroups (n)	ORR % (95% Cl)
Total patients evaluable (N = 124)	37.1 (28.6, 46.2)
Age < 65 years (65) ≥ 65 years (59)	30.8 (19.9, 43.4) 44.1 (31.2, 57.6)
ECOG PS status 0 (37) 1 (87)	43.2 (27.1, 60.5) 34.5 (24.6, 45.4)
Metastatic disease Yes (120) No (4)	36.7 (28.1, 45.9) 50.0 (6.8, 93.2)
Prior lines of therapy 1 (53) ≥2 (71)	39.6 (26.5, 54.0) 35.2 (24.2, 47.5)
Prior anti-PD-1 or PD-L1 Yes (113) No (11)	36.3 (27.4, 45.9) 45.5 (16.7, 76.6)
TP53 co-mutation Wild-type (20) Mutant (84)	40.0 (19.1, 63.9) 39.3 (28.8, 50.5)
STK11 co-mutation Wild-type (69) Mutant (35)	39.1 (27.6, 51.6) 40.0 (23.9, 57.9)
KEAP1 co-mutation Wild-type (84) Mutant (20)	44.0 (33.2, 55.3) 20.0 (5.7, 43.7)
TMB level Low, < 10 Mut/Mb (69) High, ≥ 10 Mut/Mb (15)	42.0 (30.2, 54.5) 40.0 (16.3, 67.7)

結論：在對 2 期 CodeBreaK 100 臨床試驗的探索性分析中，在患者亞組中觀察到了sotorasib 的臨床獲益。OS 和最新的探索性分析將被呈現。

Conclusions: In the exploratory analyses of the phase 2 CodeBreaK 100 trial, the clinical benefit of sotorasib was observed across patient subgroups. Overall survival and updated exploratory analyses will be presented.