Adagrasib Significantly Improves PFS Vs Chemo in KRAS G12C-Mutated NSCLC

The FDA previously granted accelerated approval to adagrasib as a treatment for patients with NSCLC harboring a KRAS G12C mutation in December 2022.

Adagrasib (Krazati) met the primary end point of progression-free survival (PFS) and the key secondary end point of overall response rate (ORR) as a treatment for patients with locally advanced or metastatic KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to a press release on findings from the phase 3 KRYSTAL-12 trial (NCT04685135).¹

Data from this confirmatory trial highlighted a statistically significant and clinically meaningful improvement in PFS as well as ORR via blinded independent central review with adagrasib compared with standard chemotherapy. Investigators will continue to assess overall survival (OS), a key secondary end point, as the trial remains ongoing. The safety of treatment with adagrasib in the KRYSTAL-12 trial was comparable with prior reports of the agent, and investigators observed no new safety signals.

Developers plan to fully assess the trial data and present the results at a future medical meeting. Additionally, they look to discuss their findings with regulatory health authorities.

The FDA previously granted accelerated approval to adagrasib as a treatment for patients with NSCLC harboring a KRAS G12C mutation in December 2022.² Supporting data for this approval came from the multicenter, single-arm, open-label, phase 2 KRYSTAL-1 trial (NCT03785249), in which adagrasib elicited an ORR of 43% (95% CI, 34%-53%) and a median duration of response (DOR) of 8.5 months (95% CI, 6.2-13.8).

“The approval of adagrasib for KRAS G12C–mutated NSCLC will open up another therapeutic option,” Alexander I. Spira, MD, PhD, FACP, a medical oncologist and co-director of the Virginia Cancer Specialists Research Institution, and director of the Thoracic and Phase I Program and clinical assistant professor at Johns Hopkin, stated in an interview with CancerNetwork^® ahead of the approval.

Under accelerated approval status, continued approval for adagrasib in this patient population may be dependent on verified clinical benefit demonstrated in a confirmatory trial. Developers intend for findings from the KRYSTAL-12 trial to support the full approval of adagrasib in the aforementioned indication.

“Today’s news is an important reinforcement of the power of a targeted therapy for patients with locally advanced or metastatic KRAS G12C-mutated lung cancer,” Abderrahim Oukessou, MD, vice president and global program lead of adagrasib at Bristol Myers Squibb, said in the press release.¹ “FDA approval of [adagrasib] in the United States has allowed us to provide a new treatment option for these patients, and topline results of the KRYSTAL-12 confirmatory study will build greater trust in the medical and patient community. We are encouraged by the results from KRYSTAL-12 and look forward to helping more patients with KRAS G12C-mutated lung cancer.”

In the open-label, multicenter, randomized phase 3 KRYSTAL-12 trial, patients were assigned to receive adagrasib or docetaxel as part of 21-day treatment cycles.³ Secondary end points included DOR, safety, pharmacokinetics, patient-reported outcomes, and quality of life.

Patients 18 years and older with histologically or cytologically confirmed NSCLC harboring a KRAS G12C mutation were able to enroll on the trial. Those with evidence of disease progression on docetaxel based on blinded independent central review per RECIST v1.1 criteria and an ECOG performance status of 0 to 2 were eligible for crossover between treatment arms.

Patients who received prior treatment with agents targeting KRAS G12C such as sotorasib (Lumakras) or had active brain metastases were unable to enroll on the trial. Additionally, those who received any other systemic anti-cancer therapy following docetaxel on the study were ineligible for crossover between treatment arms.

References

1. Bristol Myers Squibb announces pivotal KRYSTAL-12 confirmatory trial evaluating KRAZATI (adagrasib) meets primary endpoint of progression-free survival for patients with pretreated KRAS G12C-mutated locally advanced or metastatic non-small cell lung … News release. Bristol Myers Squibb. March 29, 2024. Accessed March 29, 2024. https://tinyurl.com/276b7ntc
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed March 29, 2024. https://bit.ly/3UUVphS
3. Phase 3 study of MRTX849 (Adagrasib) vs docetaxel in patients with advanced non-small cell lung cancer with KRAS G12C mutation (KRYSTAL-12). ClinicalTrials.gov. Accessed March 29, 2024. https://tinyurl.com/47ebzwyc