Adagrasib Shows Impressive Activity in KRAS G12C–Mutant CRC

Jared Weiss, MD

Adagrasib (MRTX849) alone or in combination with cetuximab (Erbitux) elicited encouraging antitumor activity and safety in heavily pretreated patients with KRAS G12C–mutant colorectal cancer (CRC), according to findings from the phase 1/2 KRYSTAL-1 (NCT03785249) trial that were presented at the 2021 ESMO Congress.¹

KRSTYAL-1 is a multicohort phase 1/2 study that evaluated the KRAS G12C inhibitor adagrasib, an investigational agent that irreversibly and selectively binds KRASG12C locking it in its inactive state. KRAS G12C is a negative predicator for the efficacy of cetuximab chemotherapy, and these tumor mutations occur in 3% to 4% of patients with CRC. Therefore, researchers hypothesized that by combining adagrasib with cetuximab would enhance the inhibition of KRAS G12C and overcome adapted feedback to improve clinical outcomes, according to Jared Weiss, MD, who presented the preliminary data of KRSTYAL-1 at ESMO.

“Maintaining continuous adagrasib exposure above the target threshold enables inhibition of KRAS-dependent signaling for the complete dosing interval and maximizes antitumor activity,” Weiss explained in his ESMO presentation.

As of the follow up on May 25, 2021, 46 patients with a median of 3 prior lines of therapy had received adagrasib monotherapy and researchers saw a response rate of 22% and a disease control rate (DCR) of 87%. At a further follow up on July 9, 2021, 32 patients were still being treated with the combination of adagrasib and cetuximab with a response rate of 43%, but with a DCR of 100%.

According to Weiss, the overall response data from the study was still too immature to determine a meaningful analysis for duration of response (DOR) and progression-free survival (PFS). However, the DOR observed in the monotherapy arm of the study was 4.2 months and PFS was 5.6 months. Data for the combination arm was not reached.

“We looked for and did not see any association between commutational status and response,” said Weiss, an associate professor of medicine at the University of North Carolina School of Medicine. “Swimmers plots showed that the median time to response was 1.4 months, otherwise known as first assessment, and median [DOR] was 4.2 months, and at the time of analysis 40% of all patients remained on treatment.”

The multicohort study looked at the use of adagrasib in both patients with non–small cell lung cancer and CRC. For patients with CRC, adagrasib monotherapy was given at 600 mg twice a day in phase 1/2 of the study. In comparison, patients on the combination arm in the phase 1b portion of the trial were given 600 mg of adagrasib twice a day plus 400 mg/m² of cetuximab followed by 250 mg/m² once a week or 500 mg/m2 twice a week. End points of the trial include safety, pharmacokinetics, and clinical activity.

Safety data showed that treatment-related adverse events (TRAEs) of any grade occurred in 91% of patients in the monotherapy arm but that grade 3 and 4 TRAEs occurred in 30% of patients with no grade 5 events observed. In the combination arm, 100% of patients experienced a TRAE of any kind and 16% experienced grade 3/4 events. The most common TRAEs in the monotherapy arm was diarrhea and nausea at 63% and 57%, respectively. These were both the most common TRAEs in the combination arm, and 50% of patients experienced vomiting with the combination as well. With the addition of chemotherapy, 44% of patients experienced rash and 38% dry skin.

“Adagrasib is tolerable and has a manageable safety profile as a monotherapy and in combination treatment,” Weiss said when discussing future study of the treatment. “Adagrasib plus cetuximab is being evaluated in the second line setting, in a phase 3 trial in patients with [KRAS G12C-mutated] colorectal cancer.”

Reference

1. Weiss J, Yaegar R.D, Johnson M.L, et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Presented at: 2021 European Society for Medical Oncology Congress; September 16-21, 2021; virtual. Abstract LBA6.