As reported inThe New England Journal of Medicine by David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues, a phase I trial (CodeBreak 100) has shown activity of the oral KRAS G12C inhibitor sotorasib in heavily pretreated patients with KRAS G12C–mutant advanced non–small cell lung cancer (NSCLC), colorectal cancer, and other solid tumors.¹

David S. Hong, MD

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.”

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 960 mg (n = 85); 960 mg was 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. The most common adverse events of any grade among all patients were diarrhea (29.5%), fatigue (23.3%), nausea (20.9%), vomiting (17.8%), abdominal pain (17.8%), dyspnea (16.3%), and cough (15.5%). Adverse events were considered related to treatment in 56.6% of patients.

Grade 3 or 4 adverse events occurred in 52.7% of patients, the most common including anemia (4.7%), increased alanine aminotransferase (ALT; 4.7%) levels, diarrhea (3.9%), and vomiting (3.9%). Grade 3 or 4 adverse events were considered related to treatment in 15 patients (11.6%): grade 3 events consisted of increased ALT levels (4.7%), diarrhea (3.9%), anemia (3.1%), increased aspartate aminotransferase levels (2.3%), increased alkaline phosphatase levels (1.6%), hepatitis (0.8%), decreased lymphocyte count (0.8%), increased gamma-glutamyltransferase levels (0.8%), and hyponatremia (0.8%); 1 patient (0.8%) had grade 4 ALT elevation. Serious adverse events occurred in 45% of patients and were considered related to treatment in two. Adverse events irrespective of causality led to discontinuation of treatment in nine patients.

Treatment Responses

Among the 59 patients with NSCLC, median follow up was 11.7 months. Confirmed objective responses (all partial responses) were observed in 19 (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, 12 (35.3%) had a confirmed response, and the disease control rate was 91.2%. Responses were observed across all dose levels.

The median time to response was 1.4 months (range = 1.1–9.5 months). The median duration of response was 10.9 months (range = 1.1+ to 13.6 months), with response ongoing in 10 of 19 responders at data cutoff. The median duration of stable disease was 4 months (range = 1.4 to 10.9+ months). At data cutoff, 14 patients (23.7%) were still on treatment. Median progression-free survival was 6.3 months (range = 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, with one response ongoing at data cutoff. The median duration of stable disease was 5.4 months (range = 2.5+ to 11.1+ months). Among the 25 patients who received 960 mg, an objective response was observed in 3 (12.0%), and the disease control rate was 80.0%. At data cutoff, three patients (7.1%) were still on treatment. Median progression-free survival was 4 months (range = 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 (60.7%) had stable disease, yielding a disease control rate of 75.0%. Treatment was ongoing in five patients at data cutoff.

The investigators noted: “Despite the fact that the cancers in our patient population had been refractory to previous treatments, 32.2% of the patients with NSCLC had a confirmed response and the majority (88.1%) had disease control for a few months or more with sotorasib, leading to a median progression-free survival of 6.3 months. Similarly, most patients in the colorectal cancer subgroup had disease control, with a median duration of stable disease of 5.4 months and median progression-free survival of 4.0 months. With current therapies, approximately 9% to 18% of patients with NSCLC have a response to second- or third-line therapies, with median progression-free survival of 2.5 to 4.0 months…and approximately 1.0% to 1.6% of patients with previously treated colorectal cancer have a response to standard therapies, with median progression-free survival of 1.9 to 2.1 months…. Thus, the treatment outcome in patients with NSCLC or colorectal cancer similar to patients in our study is generally poor. Responses and disease stability associated with sotorasib in these patients are encouraging.”

The investigators concluded: “We found that sotorasib showed promising anticancer activity in patients with heavily pretreated KRAS p.G12C mutant solid tumors. Trials evaluating sotorasib as monotherapy or in combination with various agents in patients with NSCLC or other solid tumors are under way (ClinicalTrials.gov identifiers NCT04303780 and NCT04185883).

DISCLOSURE: The study was funded by Amgen and others. Dr. Hong holds stock or other ownership interests in MolecularMatch, Oncorena, and Presagia; has served as a consulant or advisor to Acuta Capital, Adaptimmune, Alpha Insights, Amgen, Axiom Biotechnologies, Bayer, Boxer Capital, ECOR1, GLG, GroupH, Guidepoint Global, Infinity Pharmaceuticals, Medscape, Merrimack, Numab, Pfizer, PrimE Oncology, Seattle Genetics, Takeda, Tavistock, Trieza Therapeutics, and WebMD; has received institutional research funding from AbbVie, Adaptimmune, Aldai Norte, Amgen, AstraZeneca/MedImmune, Bayer, Daiichi Sankyo, Fate Therapeutics, Genentech, Infinity Pharmaceuticals, Kite Pharma, Kura, MedImmune, Molecular Templates, NCI-CTEP, Novartis, Numab, Pfizer, Seattle Genetics, Shattuck Labs, TCR2 Therapeutics, TP Therapeutics, Turning Point Therapeutics, and Verastem; and has been reimbursed for travel, accommodations, or other expenses by AACR, ASCO, Bayer Schering Pharma, Genmab, and SITC.

REFERENCE

1. Hong DS, Fakih MG, Strickler JH, et al: KRAS^G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.