FDA Approves Adagrasib for KRAS G12C-Mutant Locally Advanced/Metastatic NSCLC

Partners | <b>Virginia Cancer Specialists</b>

KRYSTAL-1 results led the FDA to accelerate the approval of adagrasib for KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer.

The FDA has granted accelerated approval to adagrasib (Krazati) for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer, as determined by an FDA-approved test, who have received at least 1 prior systemic therapy.

Approval was granted to adagrsib based on results from the multicenter, single-arm, open-label KRYSTAL-1 trial, (NCT03785249). Data from the study were included in the traditional FDA review. In the study, adagrasib demonstrated promising clinical activity in previously treated patients with advanced or metastatic solid tumors who had a KRAS  G12C mutation and was well tolerated.

“The KRYSTAL-1 study demonstrated that adagrasib is an active drug. It works. It targete the KRAS G12C mutation. The objective response rate in the study was 43%, and the duration of response was 8.5 months. The second thing in KRYSTAL-1 study is that patients with treated brain metastases also had a response to adagrasib,” Alexander Spira, MD, PhD, director of the Virginia Cancer Specialists Research Institute told Targeted OncologyTM, in an interview.

Median follow-up in the study was 12.9 months. Adagrasib showed an objective response rate (ORR) was 43% (95% CI, 33.5%-52.6%) among the 112 patients with measurable disease at baseline. Responses included 1 complete response (CR; 1%) and 47 partial responses (PRs; 42%). Forty-one patients had stable disease (SD; 37%) and 6 with progressive disease (5%) for a disease control rate (DCR) of 80% (n = 89; 95% CI, 70.8%-86.5%).

The median time to response with adagrasib was 1.4 months (range, 0.9-7.2) and median duration of response was 8.5 months (95% CI, 6.2-13.8).

In terms of survival, the median progression-free survival (PFS) was 6.5 months (95% CI, 4.7 to 8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. Similarly, the median OS was 12.6 months (95% CI, 9.2-19.2), with 6- and 12-month OS rates of 71% (95% CI, 61.1-78.3) and 51% (95% CI, 40.9-60.0), respectively.

Any-grade treatment-related adverse events (TRAEs) occurred in 113 patients (97%), of which 50 (43%) were grade 3/4 in severity. The most frequent any-grade TRAEs were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT increase (28%), blood creatinine increase (26%), AST increase (25%), and decreased appetite (24%). Two grade 5 events occurred: cardiac failure and pulmonary hemorrhage.

The occurrence of TRAEs led to dose reductions in 60 patients (52%), interruptions in 71 (61%), and discontinuation in 8 (7%).

“We already had one approved drug from KRAS G12C NSCLC called sotorasib. Approval of adagrasib will give patients another option. Both KRAS G123C inhibitors are active and safe for this patient population,” said Spira.

Along with adagrasib, the FDA granted approval to the QIAGEN therascreen KRAS RGQ PCR kit for tissue and the Agilent Resolution ctDx FIRST Assay for plasma as companion diagnostics for adagrasib.


1. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed December 12, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc?utm_medium=email&utm_source=govdelivery