As reported in The New England Journal of Medicine by David S. Hong, MD, and colleagues, the phase I CodeBreaK100 trial showed activity of the oral KRAS G12C inhibitor sotorasib in heavily pretreated patients with KRAS p.G12C–mutant advanced non–small cell lung cancer (NSCLC), colorectal cancer, and other solid tumors.

As stated by the investigators, “No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of NSCLCs and in 1% to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C.”

David S. Hong, MD

Study Details

In the trial, a total of 129 patients—including 59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors—were enrolled in dose-escalation and dose-expansion cohorts. Patients received daily sotorasib in 3-week cycles at 180 mg (n = 6), 360 mg (n = 27), 720 mg (n =11), and at 960 mg (n = 85), the dose selected for phase II evaluation. Patients had received a median of three lines of treatment (range = 0–11) for metastatic disease.

Toxicity

No dose-limiting toxicities were observed during the dose-escalation phase. Treatment-related adverse events of any grade occurred in 56.6% of patients. Serious adverse events occurred in 45.0% of patients and were considered related to treatment in two patients (1.6%). Treatment-related grade 3 or 4 adverse events occurred in 15 patients (11.6%).

Grade 3 events consisted of increased alanine aminotransferase (ALT; in 4.7% of patients), diarrhea (3.9%), anemia (3.1%), increased aspartate aminotransferase (2.3%), increased alkaline phosphatase (1.6%), hepatitis (0.8%), decreased lymphocyte count (0.8%), increased gamma-glutamyltransferase level (0.8%), and hyponatremia (0.8%). One patient (0.8%) had grade 4 ALT elevation. Adverse events irrespective of causality led to discontinuation of treatment in nine patients (7.0%).

Responses

Among the 59 patients with NSCLC, the median follow-up was 11.7 months. Confirmed objective responses (all partial responses) were observed in 19 patients (32.2%). An additional 33 patients (55.9%) had stable disease, yielding a disease control rate of 88.1%. Among the 34 patients receiving 960 mg of sotorasib, 12 (35.3%) had a confirmed response and the disease control rate was 91.2%. Responses were observed across all dose levels. The median duration of response was 10.9 months (range = 1.1+ to 13.6 months). Median progression-free survival was 6.3 months (range = 0.0+ to 14.9 months).

Among the 42 patients with colorectal cancer, median follow-up was 12.8 months. Confirmed objective responses (all partial) were observed in three patients (7.1%). An additional 28 patients (66.7%) had stable disease, yielding a disease control rate of 73.8%. The three responses lasted for 4.9, 6.9, and 9.9+ months. Among the 25 patients who received 960 mg of sotorasib, responses were observed in three (12.0%) and the disease control rate was 80.0%. Median progression-free survival was 4.0 months (range = 0.0+ to 11.1+ months).

Among 28 patients with other tumor types, 4 (14.3%) had a confirmed partial response, including 1 patient each with pancreatic cancer, endometrial cancer, appendiceal cancer, and melanoma. The four responses lasted for 4.4, 6.9+, 2.7, and 5.6 months, respectively. An additional 17 patients (60.7%) had stable disease, yielding a disease control rate of 75.0%.

The investigators concluded, “Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients.”

Disclosure: The study was funded by Amgen and others. For full disclosures of the study authors, visit nejm.org.