In a phase I/II trial (KRYSTAL-1) reported in The New England Journal of Medicine, Rona Yaeger, MD, of Memorial Sloan Kettering Cancer Center, New York, 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.¹

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 [EGFR] 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 primary endpoint for the monotherapy cohort was investigator-assessed confirmed objective response rate, and the primary endpoint for the combination cohort was safety. Tumor response was a secondary endpoint for the combination cohort.

The median number of prior therapies was three (range = 1–9) in the monotherapy cohort and three (range = 1–8) in the combination cohort. All patients had received fluoropyrimidine-based chemotherapy, and the majority had also received oxaliplatin, irinotecan, or both; 82% and 88% had received anti-VEGF, 2% and 0% had received anti-EGFR, and 11% and 12% had received anti–PD-1/PD-L1 therapy. Among patients in the monotherapy and combination cohorts with available data: 0 of 42 and 0 of 36 had BRAF V600E mutation; 1 of 35 and 0 of 19 had microsatellite instability–high/mismatch repair–deficient status; 1 of 35 and 1 of 38 had EGFR amplification; 23 of 34 and 18 of 26 had TP53 mutation; and 5 of 36 and 3 of 26 had PIK3CA mutation.

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, at least 95% plasma clearance of the KRAS G12C mutant allele occurred by cycle 2 in 16 of 29 patients (55%) in the monotherapy cohort and 14 of 16 patients (88%) 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.

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.” 

DISCLOSURE: The study was funded by Mirati Therapeutics. Dr. Yaeger has received institutional research support from Array BioPharma, Boehringer Ingelheim, Daiichi Sankyo, Mirati Therapeutics, and Pfizer; has served as a consultant to Array BioPharma, Mirati Therapeutics, and Natera; and has had a speaking engagement for ZaiLab.

REFERENCE

1. Yaeger R, Weiss J, Pelster MS, et al: Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 388:44-54, 2023.