Sotorasib Produces Promising and Clinically Meaningful Efficacy in KRAS G12C+ Pancreatic Cancer

John H. Strickler, MD

Sotorasib (Lumakras) demonstrated encouraging and clinically meaningful anticancer activity coupled with a positive benefit-risk profile in patients with KRAS G12C-mutated advanced pancreatic cancer, according to results from the phase1/2 CodeBreak 100 study, presented during the February 2022 ASCO Plenary Series.¹

The confirmed objective response rate (ORR) with sotorasib in the phase 1/2 pancreatic cancer cohorts was 21.1% (95% CI, 9.55%-37.32%). In addition, the median duration of response (DOR) was 5.7 month (95% CI, 1.6 to not evaluable), achieving a disease control rate (DCR) of 84.2% (95% CI, 68.75%-93.98%).

Currently, there is a 5-year survival rate of 10% associated with pancreatic cancer, and the FDA-approved therapies in the second-line setting demonstrate just 6-month survival and a response rate of 16%. Once patients progress on frontline and second-line therapy, there are no next-line options.

With knowledge that 90% of all pancreatic ductal adenocarcinoma (PDAC) tumors harbor a KRAS mutation, with p.G12C in 1 to 2% of the mutations, targeted therapy with sotorasib was considered for this patient population. Sotorasib is a selective and irreversible KRAS G12C inhibitor undergoing investigation in the global, open-label CodeBreak100 clinical trial.

The study is evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of sotorasib in patients with solid tumors harboring a KRAS G12C mutation. Previous study finding showed modest activity for the agent in patients with colorectal cancer² and durable clinical benefit in the non–small cell lung cancer population.³ The pancreatic cancer cohort consisted of 38 patients with locally advanced or metastatic disease who received at least 1 prior systemic therapy or who are intolerant or ineligible for available therapies that can provide clinical benefit.

According to the ASCO Plenary data and presenter John H. Strickler, MD, of Duke University Medical Center, the median age in the study was 65.5 years; most patients were male with an ECOG performance status of 1 or 2; and all patients had stage IV disease at enrollment, and more than half (55%) were diagnosed with de novo stage IV metastatic disease at initial diagnosis. In addition, he added, 84% of patients had 1 or 2 sites of metastasis, with liver metastases being the most common, followed by lung, and bone metastases.

Strickler also explained that the majority of patients were heavily pretreated. About 79% of patients had received at least 2 prior lines of therapy before being enrolled to CodeBreak 100, and 76% of patients had received prior FOLFIRINOX (irinotecan, fluorouracil, folinic acid, oxaliplatin) and nearly two-thirds had received prior gemcitabine in combination with nab paclitaxel.

Sotorasib was administered at 960 mg orally once daily. The primary end point assessed in the phase 1 dose-escalation cohort was safety and tolerability with PK, ORR, DOR, DCR, and progression-free survival (PFS) as the secondary end points. In the phase 2 portion, the remaining 26 patients were assessed for the primary end point of ORR by blinded independent review committee and the secondary end points were DOR, DCR, PFS, overall survival (OS), time to response, and safety.

A waterfall plot of tumor responses also showed that 30 of 38 patients experienced a decrease in the sum of diameters of RESIST lesions compared with baseline measurements.

Treatment with sotorasib in the study went on for a median duration of 4.1 months with the longest treatment duration of 11 months. There were 2 patients in the study noted to have ongoing responses at the time of the data cutoff.

Secondary survival outcomes were estimated using a Kaplan-Meier analysis. At a median follow-up up 16.8 months (range, 0.6-16.8), the estimated median PFS was 4.0 months (95% CI, 2.8-5.6), and the estimated median OS was 6.9 months (95% CI, 5.0-9.1).

Any-grade treatment-related adverse events (TRAEs) were observed in 42.1% of patients with the majority being grade ≥ 2 in severity (31.6%). Overall, 13.2% of AEs led to reduction in or interruption of sotorasib, 7.9% of patients experienced serious AEs, and no AEs were fatal or led to treatment discontinuation. Grade 3 TRAEs included diarrhea (5.3%), fatigue (5.3%), as well as abdominal pain, alanine aminotransferase increase, aspartate aminotransferase increase, pleural effusion, and pulmonary embolism in 2.6% of patients each. Overall, the therapy was considered to be well-tolerated.

The CodeBreak 100 study represents the largest dataset evaluating a KRAS G12C inhibitor in heavily pretreated KRAS G12C-mutated pancreatic cancer that resulted in a centrally confirmed ORR of 21.1% and disease control rate of 84%.

“These data support further exploration of sotorasib in this patient population with high unmet medical need,” concluded Strickler.

_Reference:

_{1. Strickler JH, Satake H, Hollebecque A, et al. First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety. Presented at: ASCO Plenary Series: February 2022 Session; February 15, 2022.}

_{2. Fakih M, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022; 23: 115–24. doi.org/10.1016/ S1470-2045(21)00605-7}

_{3. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003}