Adagrasib Induces Meaningful Responses in KRAS G12C-Mutated Solid Tumors

Shubham Pant, MD

Adagrasib (Krazati) monotherapy has exhibited clinically meaningful activity across multiple KRAS G12C-mutated solid tumors that have no available standard-of-care options, according to results from the solid tumors cohort of the phase 2 KRYSTAL-1 study (NCT03785249).

The results were presented by Shubham Pant, MD during the ASCO Plenary Series: April 2023 Session. The data come from 64 patients with KRAS G12C-mutated solid tumors, excluding patients with non–small cell lung cancer (NSCLC) and colorectal cancer (CRC).

“This cohort is the largest phase 2 tumor-agnostic dataset to evaluate KRAS G12C-mutated solid tumors, excluding NSCLC and CRC. Adagrasib monotherapy demonstrated clinically meaningful activity in a broad range of KRAS G12C tumors, including pancreatic and biliary tract cancers. I am very hopeful that this is the decade when we finally crack the KRAS code,” Pant, associate professor in the Department of Gastrointestinal Medical Oncology and the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center told Targeted Oncology™.

Patients in KRYSTAL-1 all had histologically confirmed disease, unresectable or metastatic disease, no available curative options, and an ECOG performance status of 0-1. Patients had a median baseline age of 65 years (range, 21-89 years), and 51.6% were female. The population was also 75.0% White, 9.4% Black, and 4.7% Asian, and 10.9% other. At baseline, patients had received a median of 2 (range, 0-7) prior lines of systemic anti-cancer therapy.

With adagrasib administered orally at 600 mg twice daily, the primary end point assessed was overall response rate (ORR), and the secondary end points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

The ORR observed with adagrasib monotherapy in the study was 35.1% among 57 evaluable patients. The best objective response was a partial response, however, 50.0% of patients had stable disease, 8.8% had progressive disease, and 5.3% of the study population was not evaluable. The disease control rate observed was 86.0%.

Patients with the best tumor change form baseline were those with pancreatic ductal adenocarcinoma (PDAC), small bowel cancers, and esophageal and gastroesophageal junction adenocarcinoma, and ovarian cancer.

Investigators also evaluated responses by tumors type and observed an ORR of 81.0% in the PDAC group, 91.7% in the biliary tract cancer (BTC) group, 83.3% among patients with other gastrointestinal cancers, 85.7% among those with gynecologic cancers, and 100.0% in patients with other solid tumors.

The median duration of response to treatment was 5.3 months, and the median time to response was 1.4 months.

In terms of survival, the median in the overall study population PFS was 7.4 months (95% CI, 5.3-8.6 months). The median OS was 14.0 months (95% CI, 8.5-18.6 months).

Among patients with PDAC, the median PFS was 5.4 months (95% CI, 3.9-8.2 months), and the median OS was 8.0 months (95% CI, 5.2-11.8 months). The BTC population had a median PFS of 8.6 months (95% CI, 2.7-11.3 months), and a median OS of 15.1 months (95% CI, 8.6 months to not evaluable).

Treatment-related adverse events (TRAEs) of any grade occurred in 96.8% of patients. Of the any-grade TRAEs observed, the most common were nausea (49.2%), diarrhea (47.6%), fatigue (41.3%), vomiting (39.7%), and blood creatinine increase (15.9%). Grade 3 TRAEs were seen in 25.4% of patients. One case of grade 4 febrile neutropenia occurred during the study, but there were no grade 5 TRAEs.

Dose reductions and interruptions were required in 39.7% and 44.4% of patients, respectively, because of TRAEs. No TRAEs led to discontinuation of treatment. Overall, treatment with adagrasib was well-tolerated by the patients in the study.

Considering the efficacy and manageable safety profile of adagrasib monotherapy in KRYSTAL-1, Pant concluded that KRAS G12C inhibitors could play a key role in KRAS G12C-positive solid tumor treatment.

_REFERENCE:

_{Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023; 41 (suppl 36; abstr 425082). doi. 10.1200/JCO.2023.41.36_suppl.425082}