Adagrasib promising in KRASG12C -mutated NSCLC

The KRAS^G12C inhibitor adagrasib shows durable clinical benefit, without new safety signals, in pretreated patients with advanced non–small cell lung cancer (NSCLC) harbouring a KRAS^G12C mutation in the KRYSTAL-1 trial.

After a median follow-up of 12.5 months, the primary endpoint of objective response rate (ORR) was 42.9 percent with adagrasib, with a disease control rate of 79.5 percent.

“Responses were deep, with 75 percent of responders achieving greater than 50 percent tumour reduction,” said study investigator Dr Alexander Spira from the Virginia Cancer Specialists Research Institute in Fairfax, Virginia, US, who presented the findings (as of October 15, 2021) at ASCO 2022. At the data cut-off, treatment is still ongoing in half of the responders (n=24) and 33 percent (n=16) continue to have a response.

“Based on this data, a new drug application for adagrasib has been accepted and is currently under review by the US Food and Drug Administration,” he shared.

KRAS^G12C: A druggable target

“KRAS ^G12C mutations occur in over 10 percent of patients with NSCLC, which remain difficult to target and have poor outcomes,” added co-investigator Dr Joshua Sabari from the Perlmutter Cancer Center at NYU Langone, New York City, US.

Adagrasib irreversibly and selectively binds KRAS^G12C, locking it in its inactive state.

“Our results confirmed that KRAS^G12C is a druggable target,” said Sabari. “Our patients benefited clinically from adagrasib. It appears to have improved overall survival (OS) compared to historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

PFS, OS results

Spira reported results for 112 evaluable patients with KRAS^G12C -mutated NSCLC, who were pretreated with platinum-based chemotherapy and anti-PD-1/L1 therapy, in this registrational phase II cohort A trial. The median age was 64 years; 56 percent were women. They had an ECOG status of 0 or 1 (on a 6-point scale, with higher numbers suggesting greater disability); 86 percent were former smokers. Patients were administered adagrasib 600 mg orally twice daily while in a fasted state. [ASCO 2022, abstract 9002; N Engl J Med 2022;doi:10.1056/NEJMoa2204619]

Among 48 patients with a response, the median time to response was 1.4 months while the median duration of response was 8.5 months. The median progression-free survival (PFS) in the total cohort was 6.5 months. Six- and 12-month PFS rates were 52 percent and 29 percent, respectively.

At a median follow-up of 15.6 months (updated cut-off date, January 15, 2022) median overall survival (OS) was 12.6 months. Six-month OS rate was 71 percent, with about 50.8 percent of patients still alive at 1 year.

“In patients with stable central nervous system metastases at baseline, the intracranial ORR was 33.3 percent and intracranial disease control rate was 85 percent,” reported Spira.

Safety profile

Adagrasib was well tolerated with a manageable safety profile. Treatment-related adverse events (TRAEs) of any grade occurred in 97 percent of patients and grade 3 or 4 in 43 percent. Two patients experienced grade 5 TRAEs. Overall, 7 percent of the cohort had TRAEs leading to study discontinuation.

If approved, adagrasib would be the second KRAS^G12C inhibitor in this line, the first being sotorasib, which was US FDA-approved in May 2021.  

“It is important to see how this drug weighs against sotorasib,” commented ASCO discussant Dr Sukhmani Padda from the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in Los Angeles, California, US.