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Sotorasib demonstrated clinically meaningful activity and acceptable tolerability in heavily pretreated patients with KRAS G12C–mutated advanced pancreatic cancer, according to date from the single-arm, phase 1/2 CodeBreak 100 trial.
Sotorasib (Lumakras) demonstrated clinically meaningful activity and acceptable tolerability in heavily pretreated patients with KRAS G12C–mutated advanced pancreatic cancer, according to date from the single-arm, phase 1/2 CodeBreak 100 trial (NCT03600883) presented during the 2022 ASCO Annual Meeting.1
Combined phase 1/2 date showed that the agent elicited a confirmed objective response rate (ORR) of 21.1% (95% CI, 9.55%-37.32%) in this population, with a median duration of response (DOR) of 5.7 months (95% CI, 1.6–not estimable). The disease control rate was 84.2% (95% CI, 68.75%-93.98%).
Moreover, at a median follow-up of 16.8 months (range, 0.6-16.8), the median progression-free survival (PFS) was 4.0 months (95% CI, 2.8-5.6) with sotorasib, and the median overall survival (OS) was 6.9 months (95% CI, 5.0-9.1).
“This is the largest dataset thus far evaluating the efficacy and safety of a KRAS G12C inhibitor in patients with pretreated KRAS G12C–mutated pancreatic cancer,” John H. Strickler, MD, lead study author and medical oncologist at Duke University, said in a presentation on the data.
In May 2021, the FDA approved sotorasib for the treatment of patients with non–small-cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation who have received at least 1 prior systemic therapy based on data from CodeBreak 100.2 “Approximately 90% of pancreatic adenocarcinoma tumors harbor a KRAS mutation, with G12C accounting for 1 to 2% of these mutations,” Strickler noted. No approved targeted therapies currently exist for this subgroup of patients.
The global, open-label CodeBreak100 trial is examining the safety and efficacy of sotorasib in patients with KRAS G12C-mutated solid tumors. The pancreatic cancer cohort consisted of 38 patients with locally advanced or metastatic disease who received at least 1 prior systemic therapy or who were intolerant or ineligible for available therapies known to provide clinical benefit.
All 38 patients in the combined phase 1/2 population with pancreatic cancer received oral sotorasib at a once-daily dose of 960 mg.
The primary end point in the 12 patients enrolled to the phase 1 dose-escalation and -expansion portion of the research was safety and tolerability. Key secondary end points included pharmacokinetics, ORR, DOR, DCR, PFS, and duration of stable disease.
In the phase 2 portion, an additional 26 patients were assessed for the primary end point of ORR by blinded independent review committee and RECIST v1.1 criteria. Here, secondary end points were DOR, DCR, PFS, OS, time to response, and safety.
The median patient age was 65.5 years (range, 45-81), 76.3% were male, 57.9% had an ECOG performance status of 1, and 97.4% had adenocarcinoma. Notably, all patients had stage IV disease at the time of enrollment, and the majority (79%) had received 2 or more prior lines of therapy.
A waterfall plot of tumor responses showed that 30 of 38 patients experienced a decrease in the sum of diameters of RESIST lesions compared with baseline. Eight (21%) confirmed partial responses were reported. “Two patients had ongoing responses at the time of data cutoff,” Strickler added.
The median duration of sotorasib treatment was 4.1 months, with the longest treatment duration being 11 months.
Any-grade treatment-related adverse effects (TRAEs) were observed in 42.1% of the 38 patients, with most (31.6%) being grade 2 or higher in severity. Overall, 13.2% of AEs led to a reduction in or interruption of sotorasib and 7.9% of patients experienced serious AEs. No TRAEs were fatal or led to treatment discontinuation.
Grade 3 TRAEs included diarrhea (5.3%), fatigue (5.3%), and abdominal pain, alanine aminotransferase increase, aspartate aminotransferase increase, pleural effusion, and pulmonary embolism (2.6% each).
In CodeBreak 100, “the ORR in patients with pancreatic cancer was greater than that observed with colorectal cancer [CRC; 10%]3 but lower than that observed in NSCLC [41%].4 The PFS was similar between pancreatic cancer and CRC, but lower than the 6.3 months observed in NSCLC,” Strickler said. “The DCR was high and similar across all 3 of these leading tumor types.”
Based on these results, several ongoing studies are exploring sotorasib in patients with KRAS G12C–mutated pancreatic cancer.
“CodeBreak 100 has been amended to include a phase 2 expansion cohort that will enroll 25 additional patients with metastatic cancer,” Stricker concluded.
Sotorasib is also under exploration in combination with panitumumab (Vectibix) and in combination with chemotherapy in patients with KRAS G12C–mutated advanced pancreatic cancer.