In a phase I/II CodeBreaK 100 study, sotorasib monotherapy showed promising anticancer activity in patients with heavily pretreated KRAS p.G12C–mutated advanced pancreatic cancer. Treatment with sotorasib resulted in a response in 21% of the patients and a median progression-free survival (PFS) of 4 months. Overall, sotorasib was associated with mainly low-grade side effects in the heavily pretreated population in this study, and the safety findings were consistent with those previously reported in other CodeBreaK 100 trials. The authors commented that the clinical activity of sotorasib shown in this study provides evidence that targeting KRAS is a viable strategy, and the results are promising in the context of the outcomes observed with approved regimens of second-line treatment for advanced pancreatic cancer. The findings are published by Dr. David S. Hong of the Investigational Cancer Therapeutics, University of Texas M.D. Anderson Cancer Center in Houston, TX, US and colleagues on 21 December 2022 in The New England Journal of Medicine.
The authors wrote in the background that FOLFIRINOX, albumin-conjugated paclitaxel plus gemcitabine, and nanoliposomal irinotecan plus leucovorin and fluorouracil chemotherapy regimens offer modest survival and quality-of-life benefits in pancreatic cancer and cause side effects, so they are unsuitable for many patients because of age, performance status, or disease-related frailty. Several other therapies have been approved for the treatment of pancreatic cancer. A PARP inhibitor, olaparib has been approved as maintenance treatment for pretreated metastatic pancreatic ductal adenocarcinoma harbouring a germline BRCA mutation, which occurs in 4-7% of patients. Pembrolizumab has been approved to treat unresectable or metastatic, MSI–high or dMMR solid tumours which occur in 1-2% of pancreatic ductal adenocarcinomas. Larotrectinib and entrectinib are TRK inhibitors approved to treat solid tumours with an NTRK gene fusion.
KRAS mutations are found in approximately 90% of pancreatic ductal adenocarcinomas, which is the most prevalent histologic type of pancreatic cancer, with KRAS p.G12C mutation occurring in approximately 1-2% of patients. Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C. The US Food and Drug Administration recently granted accelerated approval to sotorasib for the treatment of patients with KRAS p.G12C–mutated non–small cell lung cancer (NSCLC) who had received at least one previous systemic treatment. In the latest article published in the NEJM, the authors report the results in heavily pretreated patients with KRAS p.G12C–mutated pancreatic cancer from the phase I and phase II portions of the CodeBreaK 100 study.
The study team conducted this single-group, phase I/II trial to assess the safety and efficacy of sotorasib in patients with KRAS p.G12C–mutated pancreatic cancer who had received at least one previous systemic treatment. The primary objective of phase I was to assess safety and to identify the recommended dose for phase II. In phase II, patients received sotorasib at a dose of 960 mg orally once daily. The primary endpoint for phase II was a centrally confirmed objective response, defined as a complete or partial response. Efficacy endpoints 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, PFS, and overall survival (OS). Safety was also assessed.
In this international, multicentre, open-label study, in both phases, patients received sotorasib until the occurrence of disease progression, development of unacceptable side effects, or withdrawal of consent. Tumour response was assessed in both phases by blinded independent central review according to the RECIST v1.1.
The pooled population from phases I and II consisted of 38 patients, all of whom had metastatic disease at enrolment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of previous treatment. All 38 patients received sotorasib. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI] 10 to 37). The median time to response was 1.5 months; disease control was observed in 84% of the patients. The median PFS was 4.0 months (95% CI 2.8 to 5.6), and the median OS 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. The safety findings were consistent with those previously reported in other CodeBreaK 100 trials. Diarrhoea and fatigue were the most frequently occurring treatment-related adverse events (in 5% of patients).
The authors commented that the response observed with sotorasib in this analysis (21%) was numerically lower than that among patients with KRAS p.G12C–mutated NSCLC (37.1%) and greater than that among patients with KRAS p.G12C–mutated colorectal cancer (9.7%). Although the response observed in this study is promising, the mechanisms in various tumour types with a sensitivity to KRAS pathway inhibition are unknown, and further cancer cell biology studies are warranted.
An analysis of the data from patients with colorectal cancer who were treated with KRAS G12C inhibitors suggests that higher receptor tyrosine kinase signalling in these tumours and reactivation of receptors, particularly EGFR with RAS inhibition attenuates response to KRAS G12C inhibitors, and combination treatment with KRAS G12C and EGFR inhibitors improves efficacy. It is unclear whether a similar receptor reactivation limits sotorasib activity in pancreatic cancer. Studies examining new sotorasib combinations, such as CodeBreaK 101, are actively under way.
The authors underlined that safety profile compares favourably with current standard regimens used for the treatment of pancreatic cancer. However, a higher number of patients were enroled in the pivotal studies evaluating the safety and efficacy of these regimens than were enroled in the current study. Therefore, studies with larger cohorts are needed to clarify the prognostic effect of KRAS p.G12C mutation in patients with pancreatic cancer.
The authors commented that clinical activity of sotorasib shown in this study provides evidence that targeting KRAS is a viable strategy for the treatment of advanced pancreatic cancer. In addition, the clinical activity of sotorasib against the KRAS p.G12C mutation should invigorate efforts aimed at the design and development of inhibitors relevant to the forms of KRAS mutations that are more common in pancreatic ductal adenocarcinomas. Studies assessing the safety and efficacy of sotorasib in combination with other anticancer therapies are ongoing.
This work was supported by Amgen, a Cancer Center Core Grant to Memorial Sloan Kettering Cancer Center, an M.D. Anderson Cancer Center Support Grant, a Clinical Translational Science Award, and a grant from the Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core. The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy provided molecular and other services.
Strickler JH, Satake H, George TJ, et al. Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer. N Engl J Med 2023; 388:33-43.