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Adagrasib (Krazati) demonstrated antitumor activity in heavily pretreated patients with KRAS G12C-mutated, metastatic colorectal cancer (CRC), according to phase I/II study results.

Monotherapy with the oral KRAS inhibitor led to responses in 19% (95% CI 8-33) of 43 evaluable patients with CRC, with a median duration of response of 4.3 months (95% CI 2.3-8.3) and time to response of 1.5 months, reported Rona Yaeger, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

And in 28 evaluable patients who received adagrasib plus the EGFR inhibitor cetuximab (Erbitux), the response rate was 46% (95% CI 28-66), with a median duration of response of 7.6 months (95% CI 4.1-8.3) and time to response of 1.4 months, they reported in the .

Median progression-free survival was 5.6 months (95% CI 4.1-8.3) and 6.9 months (95% CI 5.4-8.1) in the monotherapy and combination arms, respectively.

Patients in the study had a median of three prior lines of therapy, and while adagrasib monotherapy showed promising activity in this patient population, "the biologic activity of adagrasib appeared to be even greater in combination with cetuximab and supports ongoing clinical investigation," Yaeger and colleagues said.

Median overall survival (OS) was 19.8 months (95% CI 12.5-23.0) in the monotherapy arm and 13.4 months (95% CI 9.5-20.1) in the combination arm (at a follow-up of 20.1 and 17.5 months, respectively), but the researchers noted that the small number of enrolled patients resulted in wide confidence intervals for OS.

Regarding safety in the monotherapy cohort, treatment-related adverse events (TRAE) of any grade occurred in 41 of the 44 patients. The most common TRAEs were diarrhea (66%), nausea (57%), vomiting (45%), and fatigue (45%). No TRAEs led to discontinuation, but TRAEs led to dose reduction in 39%.

In the combination arm, TRAEs of any grade occurred in all 32 patients, the most common of which were nausea (62%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), dry skin (41%), headache (31%), dizziness (25%), maculopapular rash (25%), and stomatitis (22%). Grade 3/4 TRAEs occurred in five patients, and TRAEs leading to cetuximab discontinuation occurred in five patients. However, all of the latter patients continued to receive adagrasib after discontinuing cetuximab.

Compared with other KRAS mutations, KRAS G12C mutations are associated with poor prognosis in patients with CRC, with few later-line options for this patient population.

Adagrasib is an orally available, small molecule covalent KRAS G12C inhibitor with several potentially favorable properties, including dose-dependent pharmacokinetics, a long half-life (23 hours), and central nervous system penetration, the authors explained.

The drug recently landed its first approval in non-small lung cancer for patients harboring KRAS G12C mutations, and has also shown clinical activity in several other tumor types, including pancreatic cancer. Preclinical studies suggested that combining a KRAS G12C inhibitor with an EGFR inhibitor could be a promising clinical strategy, they noted.

The current analysis involved the CRC cohort of , a multi-cohort study evaluating adagrasib alone and in combinations across KRAS G12C solid tumors. It included 76 adults (median age 59; evenly split between men and women; predominantly white) with a histologically confirmed diagnosis of advanced, unresectable, or metastatic CRC. Patients had no available treatment options with curative intent and no available standard-of-care treatment, and were required to have an Eastern Cooperative Oncology Group performance status score of 0 or 1 for eligibility.

In the monotherapy group, patients received oral adagrasib at a dose of 600 mg twice daily, administered in a capsule formulation without food. In the combination therapy group, patients received the same dose of oral adagrasib along with IV cetuximab. The latter was administered either once a week with an initial loading dose of 400 mg/m², followed by a dose of 250 mg/m², or every 2 weeks at a dose of 500 mg/m².

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