Sotorasib Demonstrates Anticancer Activity in KRAS p.G12C+ Pancreatic Cancer

Sotorasib (Lumakras) yielded positive anticancer activity and an acceptable safety profile among patients with KRAS p.G12C–mutated pancreatic cancer based on results from the phase 1/2 CodeBreaK 100 trial (NCT03600883).

"The clinical activity of sotorasib shown in this trial provides evidence that targeting KRAS is a viable strategy for the treatment of advanced pancreatic cancer,” according to the study authors of the phase 1/2 CodeBreaK 100 trial.

Among all evaluable patients (n = 38) across phases 1 and 2, the objective response rate (ORR) was 21% (95% CI, 10%-37%), all of which confirmed partial responses. Moreover, 63% of patients had stable disease and 13% had progressive disease.

Additionally, the disease control rate (DCR) was 84% (95% CI, 69%-94%), the median time to objective response was 1.5 months (range, 1.3-5.6), and the median duration of response (DOR) was 5.7 months (range, 1.6-not estimable [NE]).

“The clinical activity of sotorasib shown in this trial provides evidence that targeting KRAS is a viable strategy for the treatment of advanced pancreatic cancer,” the study authors stated.

Investigators of the single-group phase 1/2 CodeBreaK trial evaluated the efficacy and safety of sotorasib monotherapy among patients with KRAS p.G12C–mutated pancreatic cancer previously treated with at least 1 line of systemic therapy. After identifying an optimal dosing schedule in phase 1, investigators administered sotorasib at a dose of 960 mg orally once a day to patients in the second phase.

The primary end point of the trial was ORR. Other efficacy end points included DOR, time to objective response, DCR, progression-free survival (PFS), and overall survival (OS), with responses assessed based on RECIST v1.1 criteria.

Patients 18 years and older with pathologically documented, locally advanced or metastatic pancreatic cancer harboring KRAS p.G12C mutations were eligible to enroll on the trial. Additional inclusion criteria included receiving treatment with at least 1 line of prior systemic therapy and having an ECOG performance status of 2 or less.

The pooled population across both trial phases included 38 patients who all had metastatic disease at time of enrollment and were previously treated with chemotherapy. Patients had received a median of 2 lines (range, 1-8) of prior therapy, and all 38 were treated with sotorasib in the trial.

Investigators reported that the baseline characteristics of patients enrolled in phases 1 and 2 were comparable. In the pooled overall population, the median patient age was 65.5 years (range, 45-81). Additionally, most patients were male (76%) and had an ECOG performance score of 1 (58%). All patients had metastatic disease at enrollment.

As of the data cutoff time, 25% (n = 2/8) of patients were continuing to receive sotorasib with an ongoing treatment duration of abour 10 months. Additionally, investigators observed tumor shrinkage of any magnitude in 79% (n = 30/38) of patients.

Sotorasib produced a median PFS of 4.0 months (95% CI, 2.8-5.6). Additionally, the 6-month estimated PFS rate was 31.6% (95% CI, 16.7%-47.7%), and the 9-month rate was 9.9% (95% CI, 2.0-25.6).

With a median follow-up of 16.8 months (95% CI, 9.5-NE), the median OS was 6.9 months (95% CI, 5.0-9.1). The Kaplan-Meier OS estimate at 12 months was 19.6% (95% CI, 7.2%-36.3%).

The most common adverse effects (AEs) observed in the trial included abdominal pain (37%), diarrhea (24%), nausea (24%), vomiting (21%), and pyrexia (21%). Overall, 63% of patients had grade 3 or higher AEs.

There were no grade 4 or 5 treatment-related AEs (TRAEs) reported in the trial. Additionally, 37% of patients had fatal events that the investigators reported were not related to treatment with sotorasib. There were no TRAEs that led to treatment discontinuation.

Reference

Strickler JH, Satake H, George TJ, et al. Sotorasib in KRAS p.G12C–mutated advanced pancreatic cancer. N Engl J Med. 2023;388:1. doi:10.1056/NEJMoa2208470