1. In patients with KRAS p.G12C mutated pancreatic cancer, 21% had a partial response, and 0% had a complete response.

2. Median progression-free survival was 4.0 months and median overall survival was 6.9 months.

Evidence Rating Level: 2 (Good)

Study Rundown: KRAS mutations are found in 90% of pancreatic ductal adenocarcinomas, and 1-2% of patients have a KRAS p.G12C mutation. Recently, sotorasib, a small molecule that irreversibly inhibits KRS G12C was approved by the FDA for the treatment of patients with non-small-cell lung cancer with a KRAS p.G12C mutation. This study reports results from a phase 1 and 2 trial of sotorasib in KRAS p.G12C mutated pancreatic cancer who had at least 1 prior line of systemic therapy. Primary objectives included safety and side-effect profile as well as the recommended dosing and efficacy of sotorasib. The primary endpoint was the objective response, both complete or partial and was assessed according to RECIST version 1.1 by a blinded independent central review. Secondary endpoints included duration of response, time to objective response, disease control, progression-free survival (PFS), and overall survival (OS). The study found no patients had complete responses but 21% of patients had a partial response with a median time to response of 1.5 months and a duration of response was 5.7 months. The median PFS was 4.0 months and the median OS was 6.9 months. The most common patient reported adverse events included abdominal pain, diarrhea, nausea, vomiting, and pyrexia. 63% of patients had adverse events grade 3 or higher, however, only 16% of patients were thought to have treatment-related grade 3 or higher adverse events by investigators. The strengths of this study include its range of endpoints. Limitations to this study include the small sample size and the single-arm methodology. Overall, sotorasib showed some efficacy against KRAS p.G12C mutated pancreatic cancer and further research is needed.

Click to read the study in NEJM

Relevant Reading: KRAS mutation in pancreatic cancer

In-Depth [prospective cohort]: This multicenter, open-label, phase 1-2 trial investigated 38 patients (12 in phase 1 and 26 in phase 2) who were over 18 years old and had pathologically confirmed locally advanced or metastatic pancreatic cancer with the KRAS p.G12C mutation. Patients received oral sotorasib 960mg daily for a median duration of treatment of 18 weeks, with 84% of patients discontinuing treatment due to disease progression. The study found that 21% (95%CI, 10.0 to 37.0) of patients had a partial response, and no patients had a complete response. For those patients who had a response, the median time to respond was 1.5 months and the duration of response was 5.7 months (95%CI, 1.6-NR). In general, 79% of patients were found to have some tumor shrinkage of any magnitude. Median PFS was 4.0 months (95%CI, 2.8 to 5.6), with 31.6% (95%CI, 16.7 to 47.7) of patients reaching PFS at 6 months and 9.9% (95%CI, 2.0 to 25.6) of patients reaching PFS at 9 months. The median OS was 6.9 months (95%CI, 5.0 to 9.1), and OS at 12 months was found to be 19.6% (95% CI, 7.2 to 36.3). The most common patient reported adverse events included abdominal pain (37%), diarrhea and nausea (24% each), vomiting and pyrexia (21% each), with 63% of patients achieving adverse events grade 3 or higher, however only 16% of patients were thought to have treatment-related grade 3 or higher adverse events by investigators. Overall, sotorasib showed some efficacy against KRAS p.G12C mutated pancreatic cancer and further studies will help further the efficacy.

Image: PD

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