AACR: Colon Cancer Patients Respond to Antibody/KRAS Inhibitor Combo

A combination of adagrasib, a small-molecule KRAS inhibitor, and cetuximab, an anti-EGFR antibody, demonstrated promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer (CRC). These findings, which are supported by pooled results from the Phase I/II KRYSTAL-1 trial, highlight the significance of testing and identifying KRASG12C mutations in CRC patients. The findings may also support a new standard of care.

The findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 by Scott Kopetz, MD, PhD, professor of gastrointestinal medical oncology and associate vice president of translational integration at the MD Anderson Cancer Center. Also, the findings were published in the AACR journal Cancer Discovery, in a paper titled, “Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG^12C-Mutated Metastatic Colorectal Cancer.”

“[Patients] with previously treated KRAS^G12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab,” Kopetz and colleagues reported in the paper. “The primary endpoint was objective response rate (ORR) by blinded independent central review.”

The targeted therapy combination achieved a disease control rate of 85.1%, an overall response rate of 34%, and a median duration of tumor response of 5.8 months. Median progression-free survival (PFS) was 6.9 months and median overall survival (OS) was 15.9 months.

“No treatment-related adverse events led to adagrasib discontinuation,” the paper’s authors continued. “Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance.”

Based on preliminary results from the Phase I trial, the FDA granted Breakthrough Therapy designation to this combination.

“This population of patients with KRAS^G12C-mutated colorectal cancer faces a poor prognosis, and there currently are no effective targeted therapies,” Kopetz said. “Therefore, it’s promising to see that this combination shows clinically meaningful benefit both in response rates and duration of disease control along with a very encouraging safety profile.”

KRYSTAL-1 is a multicenter Phase I/II trial testing the safety and efficacy of adagrasib alone or in combination with other anticancer therapies in patients with KRAS^G12C-mutated metastatic solid tumors. In these two cohorts presented at AACR, the combination of adagrasib plus cetuximab showed antitumor activity and was well tolerated in previously treated patients with KRAS^G12C-mutated metastatic CRC, meeting its primary endpoints of safety and objective response rate.

KRAS^G12C mutations occur in approximately 3–4% of patients with CRC and are associated with shorter PFS and OS when treated with standard of care chemotherapy, highlighting a critical unmet need.

Adagrasib is a selective and irreversible KRAS^G12C inhibitor which can penetrate through the central nervous system, and it previously was shown to be effective for patients with KRAS^G12C-mutated non-small cell lung cancer (NSCLC) and untreated brain metastasis as part of the same trial. The FDA granted accelerated approval to adagrasib for the treatment of certain patients with advanced KRAS^G12C-mutant NSCLC, with continued approval contingent on verifying clinical benefit in a confirmatory trial.

Adagrasib monotherapy has shown limited activity in patients with KRAS^G12C-mutated CRC, and some CRC patients develop resistance to KRAS^G12C inhibitor treatment via epidermal growth factor receptor (EGFR)-mediated reactivation of the MAPK signaling pathway. Preclinical data suggested that dual blockade of KRAS^G12C with an EGFR inhibitor could help overcome that resistance, leading to evaluation of adagrasib and cetuximab.

The study included 94 heavily pretreated patients with unresectable or metastatic KRAS^G12C-mutated CRC with limited treatment options. Participants had a median age of 57 years and 53% were female.

All patients experienced side effects consistent with previous reports on the safety profile of both drugs, with 72.3% of patients experiencing low-grade and 27.7% of patients experiencing more moderate adverse events. Dose reductions of adagrasib and cetuximab occurred in 28 (29.8%) and 6 (6.4%) of patients, respectively. Eight patients (8.5%) discontinued the use of cetuximab due to side effects, but none led to adagrasib discontinuation.

Further exploratory analysis showed that baseline KRAS G12C mutations were detected in the circulating tumor DNA of 69 out of 83 patients, with 83% concordance between paired tumor samples. This highlights the potential future use of liquid biopsies as a means of stratifying patients most likely to respond well to the combination regimen.

“These results suggest this combination treatment should be considered as a late-line treatment for patients with unresectable or metastatic KRAS^G12C-mutated CRC,” Kopetz said.

Kopetz noted that the combination now is recommended by the National Comprehensive Cancer Network guidelines, and that Phase III trials are currently ongoing.