The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.
“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.
“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.
“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Li is absolutely fabulous and will lead to a new stratification option.”
Rationale and Study Details
Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.
Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.
The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.
Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.
Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.
Phase 2 Results
Sotorasib “demonstrated early, deep, and durable responses,” Li said.
In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.
The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.
“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Li said.
The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.
Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Li said.
TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.
Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).
“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Li said.
A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.
The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Li disclosed relationships with Amgen and many other companies. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.