In the phase I/II KRYSTAL-1 trial reported in The New England Journal of Medicine, Rona Yaeger, MD, and colleagues found that the KRAS G12C inhibitor adagrasib showed activity alone and in combination with cetuximab in heavily pretreated patients with metastatic colorectal cancer and mutated KRAS G12C.
As stated by the investigators, “Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.”
Rona Yaeger, MD
Study Details
As of data cutoff in June 2022 in the ongoing, U.S.-based, open-label, nonrandomized, multicenter trial, 44 patients (43 response-evaluable) had received adagrasib monotherapy at 600 mg twice daily with a median follow-up of 20.1 months, and 32 (28 response-evaluable) had received adagrasib at the same dose in combination with cetuximab once weekly (initial loading dose of 400 mg/m2 followed by 250 mg/m2) or every 2 weeks (at 500 mg/m2), with a median follow-up of 17.5 months. Treatment in both cohorts was continued until disease progression or unacceptable toxicity.
The median number of prior therapies was three (range = 1–9) in the monotherapy cohort and three (range = 1–8) in the combination cohort. The primary efficacy endpoint was objective response on blinded independent central review.
Responses
In the adagrasib monotherapy group, objective responses (all partial) were observed in 10 (19%, 95% confidence interval [CI] = 8%–33%) of 43 evaluable patients. Median time to response was 1.5 months (range = 1.2–4.4 months). Median response duration was 4.3 months (95% CI = 2.3–8.3 months). An additional 29 patients (67%) had stable disease. Among all 44 patients in the cohort, median progression-free survival was 5.6 months (95% CI = 4.1–8.3 months) and median overall survival was 19.8 months (95% CI = 12.5–23.0 months). At data cutoff, 29 patients (66%) had started subsequent anticancer therapy.
In the combination group, objective responses (all partial) were observed in 13 (46%, 95% CI = 28%–66%) of 28 evaluable patients. Median time to response was 1.4 months (range = 1.2–19.2 months). Median response duration was 7.6 months (95% CI = 5.7 months to not estimable). An additional 15 patients (54%) had stable disease. Among all 32 patients in the cohort, median progression-free survival was 6.9 months (95% CI = 5.4–8.1 months) and median overall survival was 13.4 months (95% CI = 9.5–20.1 months). At data cutoff, 15 patients (47%) had started subsequent anticancer therapy.
In an exploratory analysis of circulating tumor DNA response, ≥ 95% plasma clearance of the KRAS G12C mutant allele occurred by cycle 2 in 16 (55%) of 29 patients in the monotherapy cohort and 14 (88%) of 16 in the combination therapy cohort. No apparent association was observed between objective response and presence or absence of baseline TP53 or PIK3CA mutations in either cohort.
KEY POINTS
- Adagrasib monotherapy produced objective response in 19% of patients, with a median response duration of 4.6 months.
- Adagrasib plus cetuximab produced objective response in 46% of patients, with a median response duration of 7.6 months.
Adverse Events
Among all 44 patients in the adagrasib monotherapy group, the most common treatment-related adverse events of any grade were diarrhea (66%), nausea (57%), vomiting (45%), and fatigue (45%). Treatment-related grade 3 or 4 adverse events occurred in 34% of patients, most commonly anemia (9%), diarrhea (7%), and fatigue, increased QT interval, increased alanine aminotransferase, and increased aspartate aminotransferase (5% each). Treatment-related adverse events led to dose reduction in 39% of patients and to treatment discontinuation in no patients. There were no treatment-related deaths.
Among all 32 patients in the combination cohort, the most common treatment-related adverse events of any grade were nausea (62%), diarrhea (56%), vomiting (53%), and acneiform dermatitis (47%). Grade 3 or 4 treatment-related adverse events occurred in 16% of patients, consisting of diarrhea, acneiform dermatitis, stomatitis, infusion-related reaction, increased QT interval, and dehydration in one patient each. Treatment-related adverse events led to adagrasib dose reduction in 31% of patients and cetuximab dose reduction in 3%, and to discontinuation of adagrasib in no patients and discontinuation of cetuximab in 16%. No treatment-related deaths occurred.
The investigators concluded, “Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination therapy group. Reversible adverse events were common in the two groups.”
Samuel J. Klempner, MD, of Massachusetts General Hospital, and Dr. Yaeger, of Memorial Sloan Kettering Cancer Center, are the corresponding authors for The New England Journal of Medicine article.
Disclosure: The study was funded by Mirati Therapeutics. For full disclosures of the study authors, visit nejm.org.
