美国德克萨斯大学安德森癌症中心David S. Hong团队研究了索托拉西布治疗KRAS p.G12C突变晚期胰腺癌的疗效与安全性。该项研究成果发表在2022年12月21日出版的《新英格兰医学杂志》上。

KRAS p.G12C突变发生在大约1-2%的胰腺癌中。KRAS G12C抑制剂索托拉西布在先前治疗的KRAS p.G12C突变胰腺癌患者中的安全性和有效性尚不清楚。

研究组进行了一项单组、1-2期临床试验，以评估索托拉西布治疗KRAS p.G12C突变胰腺癌患者的安全性和有效性，这些患者此前接受过至少一次全身治疗。1期主要目标是评估安全性并确定2期的推荐剂量。在2期，患者每天口服一次剂量为960 mg的索托拉西布。

2期的主要终点是集中确认的客观缓解（定义为完全或部分缓解）。在两个阶段的合并人群中评估疗效终点，包括客观缓解、反应持续时间、达到客观缓解的时间、疾病控制（定义为客观缓解或疾病稳定）、无进展生存期和总生存期。还评估了安全性。

第1期和第2期的合并人群由38名患者组成，所有患者在入组时都患有转移性疾病，并且之前接受过化疗。在基线时，患者之前接受过2线（范围为1至8）治疗。在试验中，所有38名患者均接受了索托拉西布。

共有8名患者有集中确认的客观缓解（21%）。中位无进展生存期为4.0个月，中位总生存期为6.9个月；6名患者（16%）出现3级不良事件。没有与治疗相关的不良事件是致命的或导致治疗中断。

研究结果表明，索托拉西布治疗KRAS p.G12C突变晚期胰腺癌患者中显示出抗癌活性，并具有可接受的安全性。

附：英文原文

Title: Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer

Author: John H. Strickler, M.D.,, Hironaga Satake, M.D., Ph.D.,, Thomas J. George, M.D.,, Rona Yaeger, M.D.,, Antoine Hollebecque, M.D.,, Ignacio Garrido-Laguna, M.D., Ph.D.,, Martin Schuler, M.D.,, Timothy F. Burns, M.D., Ph.D.,, Andrew L. Coveler, M.D.,, Gerald S. Falchook, M.D.,, Mark Vincent, M.D.,, Yu Sunakawa, M.D., Ph.D.,, Laetitia Dahan, M.D.,, David Bajor, M.D.,, Sun-Young Rha, M.D., Ph.D.,, Charlotte Lemech, M.D.,, Dejan Juric, M.D.,, Marko Rehn, Ph.D.,, Gataree Ngarmchamnanrith, M.D.,, Pegah Jafarinasabian, M.D., Ph.D.,, Qui Tran, Ph.D.,, and David S. Hong, M.D.

Issue&Volume: 2022-12-21

Abstract:

Background

KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C–mutated pancreatic cancer are unknown.

Methods

We conducted a single-group, phase 1–2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C–mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed.

Results

The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.

Conclusions

Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C–mutated advanced pancreatic cancer who had received previous treatment.

DOI: 10.1056/NEJMoa2208470

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2208470