Adagrasib, an inhibitor of the KRAS G12C mutation, showed encouraging activity as monotherapy and in combination with cetuximab in patients with metastatic colorectal cancer (CRC) in the phase 1/2 KRYSTAL-1 clinical trial. All patients had metastatic CRC with KRAS G12C mutations and had received previous treatment.
The response rate to adagrasib monotherapy was 22% and the response to the combination of adagrasib plus cetuximab was 43% (confirmed later as 39%). The disease control rate was 100%.
KRAS, a target formerly considered undruggable, now has 1 KRAS G12C inhibitor approved for the treatment of lung cancer by the US Food and Drug Administration—sotorasib. Several other KRAS G12C inhibitors are in development.
“Adagrasib is tolerable and has a manageable safety profile, both as monotherapy and in combination with cetuximab,” said lead author Jared Weiss, MD, Associate Professor of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, speaking at a Presidential Symposium of the 2021 European Society for Medical Oncology Congress.
KRAS G12C mutations are present in 3% to 4% of all cases of CRC. These mutations act as oncogenic drivers and are a negative predictor of cetuximab efficacy. Adagrasib irreversibly and selectively binds KRAS G12C. The drug was designed to have a long half-life, dose-dependent pharmacokinetics, and brain penetration.
Dr Weiss explained that the combination of adagrasib plus the EGFR inhibitor cetuximab “may enhance the inhibition of KRAS-dependent signaling or overcome adaptive feedback to improve outcomes.”
The multicohort KRYSTAL-1 study evaluated adagrasib in 78 patients with solid tumors harboring KRAS G12C mutations who had no other treatment options. These included 46 patients with previously treated CRC who received adagrasib 600 kg twice daily as monotherapy and 32 patients who received adagrasib in combination with cetuximab. More than 50% of the patients had received ≥3 previous lines of therapy; 69% had TP53 mutations, and 15% to 20% of the patients had other mutations. The median follow-up was 8.9 months for the monotherapy cohort and 7 months for the combination cohort.
In the adagrasib monotherapy cohort, the objective response rate (ORR) was 22% and the disease control rate was 87% (including complete response, partial response, or stable disease). The response rates were much higher in the combination cohort; 32 patients who received the combination of adagrasib plus cetuximab had an ORR of 43% and a disease control rate of 100%.
In the monotherapy cohort, the median duration of response was 4.2 months, and at the time of analysis, 40% were still receiving treatment. The median progression-free survival was 5.6 months, and at 6 months, 42% had no disease progression.
In the combination cohort, after data cutoff, 1 or 2 patients with unconfirmed response achieved a confirmed response, for a total confirmed response rate of 39%. All the other patients in this cohort had stable disease.
“In the combination cohort, 71% of patients remained on treatment. The data are too immature for a meaningful analysis of duration of response or progression-free survival in this cohort,” Dr Weiss said.
No association was found between co-mutational status and response.
Adagrasib as monotherapy and in combination with cetuximab was well-tolerated. Grade 3 or 4 treatment-related adverse events were reported in 30% of the monotherapy cohort and 16% in the combination cohort. Combination treatment led to dermatitis and rash of any grade in 44% and 22% of the patients, respectively.
Adagrasib plus cetuximab is being evaluated in the second-line setting in a phase 3 clinical trial of patients with CRC and KRAS G12C mutation.
Invited discussant Federica Di Nicolantonio, MD, PhD, Associate Professor, Oncology Department, University of Turin, Italy, noted that adagrasib and sotorasib (another KRAS G12C inhibitor) achieve higher response rates in non–small-cell lung cancer than in metastatic CRC. “This is reminiscent of what has been observed with BRAF inhibitors—about 50% of patients with metastatic melanoma respond compared to about 5% of metastatic CRC.”
“KRAS G12C inhibitors as monotherapy yield a relatively low ORR, but when you combine them with an EGFR inhibitor, the response rate is nearly double,” Dr Di Nicolantonio said. “There is a striking synergy in mouse models.”
“We eagerly await the results of the phase 3 KRYSTAL-10 trial of second-line adagrasib plus cetuximab versus conventional chemotherapy [in metastatic CRC]. We are also eager to see other combinations of KRAS G12C inhibitors for which we have solid preclinical data,” she said.