Therapy shows positive clinical efficacy and favorable tolerability as a monotherapy and in combination with cetuximab in heavily pretreated patients who have a KRASG12C mutation.
Mirati Therapeutics Inc announced results from KRYSTAL-1, a multicohort phase 1/2 study that evaluated adagrasib with or without cetuximab in individuals with advanced colorectal cancer harboring a KRASG12C mutation.
Adagrasib is a highly selective, investigational, and potent oral small-molecule inhibitor of KRASG12C optimized to sustain target inhibition. It is being evaluated as a monotherapy and in combination with other anti-cancer therapies in individuals with advanced KRASG12C-mutated solid tumors.
“These exciting results further our understanding of the well-tolerated profile with robust and sustained responses that adagrasib provides as a monotherapy and in combination with cetuximab to patients with KRASG12C-mutated advanced colorectal cancer,” Charles Baum, MD, PhD, president, founder, and head of research and development at Mirati Therapeutics, said in a statement. “We continue to explore the full potential of adagrasib in combination with cetuximab in late-line [colorectal cancer] in a potentially registration-enabling phase 2 cohort of the KRYSTAL-1 [NCT03785249] study and in second line [colorectal cancer] in the ongoing phase 3 KRYSTAL-10 [NCT04793958] study."
The analysis included 44 individuals who received 600 mg of adagrasib twice a day, and 32 individuals received the combination of 600 mg of adagrasib, twice daily, with full-dose cetuximab. The follow up was 20.1 months and 17.5 months, respectively.
Of the individuals in the monotherapy cohort, the investigators’ assessed confirmed objective response rate (ORR) was 19%, and the disease control rate (DCR) was 86%. In the combination cohort, the ORR was 46% and the DCR was 100%.
The individuals in the monotherapy arm had a median duration of response of 4.3 months compared with 7.6 months in the combination arm. The median progression-free survival was 5.6 months and 6.9 months, respectively.
“These data illustrate the importance of durable KRAS inhibition in colorectal cancer and the added benefit that dual EGFR/KRAS blockade may provide for some patients in their regimen as evidenced by the more sustained responses from the adagrasib and cetuximab combination,” Samuel Klempner, MD, of the Massachusetts General Cancer Center, said in the statement. "Overall, it's encouraging to see the emergence of KRAS inhibitors like adagrasib providing more targeted, efficacious, and safe treatment options for colorectal cancer and other solid tumors with KRAS mutations.”
Investigators found that adagrasib was well-tolerated as a monotherapy and in combination with cetuximab in a subset of individuals with KRASG12C-mutated colorectal cancer. The majority of observed treatment-related adverse events (TRAEs) were grade 1 and 2 at 59%, and there was no grade 5 TRAEs observed.
The data were presented as an oral presentation on September 12, 2022, at 4:15 a.m. EST during the Proffered Paper Session II at the European Society for Medical Oncology (ESMO) Congress 2022.
Also at the ESMO Congress 2022, Mirati Therapeutics had a poster presentation with an additional practice-informing data on AE patterns and management for adagrasib in individuals with KRASG12C-mutated non–small cell lung cancer. The presentation is available online.
Mirati Therapeutics presents late-breaking adagrasib monotherapy and combination results in advanced colorectal cancer. News release. Mirati Therapeutics. September 7, 2022. Accessed September 8, 2022. https://ir.mirati.com/press-releases/press-release-details/2022/Mirati-Therapeutics-Presents-Late-Breaking-Adagrasib-Monotherapy-and-Combination-Results-in-Advanced-Colorectal-Cancer/default.aspx