The Lynx Group

Sotorasib, First-in-Class KRAS p.G12C Inhibitor, Induces Durable Responses in Patients with Advanced NSCLC

April 2021, Vol 12, No 2

Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutations. In the phase 2 CodeBreaK 100 clinical trial, the responses to sotorasib in patients with advanced non–small-cell lung cancer (NSCLC) and KRAS p.G12C mutation were early, deep, and durable, according to Bob T. Li, MD, PhD, MPH, Medical Oncologist, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. He presented the study results at the 2021 International Association for the Study of Lung Cancer meeting.

Sotorasib is an oral, first-in-class, small-molecule agent that specifically and irreversibly inhibits KRAS p.G12C, Dr Li said at the 2021 International Association for the Study of Lung Cancer meeting. In December 2020, the FDA granted sotorasib breakthrough therapy designation for patients with NSCLC and KRAS p.G12C mutations.

In patients with advanced NSCLC who are receiving current second- or third-line therapies, the outcomes are poor and the response rate is <20%, Dr Li noted. The median progression-free survival (PFS) in these patients is less than 4 months.

A phase 1 analysis of 59 patients in the CodeBreaK 100 study showed that sotorasib is well-tolerated. The confirmed response rate was 32.2%, the duration of response was 10.9 months, and the median PFS was 6.3 months. All the patients were heavily pretreated.

Phase 2 CodeBreaK Study

The phase 2 portion of the study included 126 patients in 11 countries, all of whom had centrally confirmed KRAS p.G12C mutations, and their disease progressed after receiving a PD-1/PD-L1 inhibitor and/or platinum-based combination chemotherapy, or targeted therapy if EGFR, ALK, or ROS1 mutations had been previously identified. All patients had previously received ≤3 lines of therapy.

The patients received 960-mg sotorasib orally once daily until disease progression and were followed for a median of 12.2 months. The study’s primary end point was the objective response rate (ORR) per RECIST 1.1.

The mean patient age was 63.5 years, and 4.8% were never-smokers. Most patients (89.7%) had received platinum-based chemotherapy, PD-1/PD-L1 inhibitor (91.3%), or both (81%).

At the median follow-up of 12.2 months, the ORR was 37.1%, including 2.4% complete responses, 34.7% partial responses, and 43.5% stable disease cases, for a disease control rate of 80.6%. The median percentage of best tumor shrinkage among all responders was 60%. Progressive disease was reported in 16.1% of the patients.

The median time to objective response was 1.4 months, and the median duration of response was 10 months (95% confidence interval, 6.9-11.1). As of the data cutoff on December 1, 2020, 43% of responders continued treatment without disease progression. The median PFS was 6.8 months. The confirmatory phase 3 CodeBreaK 200 study is currently underway.

Safety Profile

The treatment-related adverse events were generally mild and manageable, and no fatalities were reported. The most common adverse event was diarrhea (31%, including 4% grade 3). The most common grade 3 treatment-related adverse events were increases in alanine aminotransferase (6.3%) and aspartate aminotransferase (5.6%). Overall, 69.8% of patients had treatment-related adverse events, and 19.8% had grade 3 events. Adverse events led to dose modification in 22.2% of the patients and to treatment discontinuation in 7.1%.

Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low levels of PD-L1 expression and those with STK11 mutation, Dr Li noted.

Meeting Unmet Need

“I personally would be very comfortable, once approved, to prescribe this drug to my patients in the second-line setting, based on the clinical trial evidence,” Dr Li said. “The first step is to get KRAS mutation testing in all patients with non–small-cell lung cancers. That needs to be done routinely. For 40 years, we thought KRAS was undruggable and there was no point in testing, because you can’t do anything about it. For the first time, that’s changed.”

“It’s a remarkable study,” commented Dean Fennell, FRCP, PhD, Chair, Thoracic Medical Oncology, University of Leicester, England. “The ‘undruggability’ of KRAS has been something of a challenge for decades, and to see results like this is absolutely fabulous,” he added.

“There is an unmet need for KRAS; we screen for it routinely at our center and at many centers in the UK, but without any predictive value until now. Based on these data, in the UK this will be a new option,” Dr Fennell suggested.

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