Adagrasib Meets Primary Endpoint Among Individuals with KRAS G12C-Mutated Locally Advanced or Metastatic NSCLC

Bristol Myers Squibb recently announced that the Phase 3 KRYSTAL-12 study that assessed adagrasib (Krazati) met its primary endpoint of progression-free survival (PFS) and the secondary endpoint of overall response rate (ORR). Adagrasib was used in the phase 3 study as a monotherapy among individuals with pretreated locally advanced or metastatic non-small cell lung cancer (NSCLC) concealing KRASG12C mutation.

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“Today’s news is an important reinforcement of the power of a targeted therapy for patients with locally advanced or metastatic KRASG12C-mutated lung cancer. FDA approval of Krazati in the US 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,” said Abderrahim Oukessou, MD, vice president, global program lead of Krazati, Bristol Myers Squibb, in a press release. “We are encouraged by the results from KRYSTAL-12 and look forward to helping more patients with KRASG12C-mutated lung cancer.”

The study authors noted that adagrasib is a “highly selective and potent oral small-molecule inhibitor of KRASG12C.” Adagrasib can sustain target inhibition that impacts treatment for KRASG12C-mutated cancers— occurring in 14% of NSCLC.

Adagrasib was previously granted FDA accelerated approval in 2022 to treat individuals with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least 1 systemic therapy prior to treatment. In the same year, the FDA also granted breakthrough therapy designation for adagrasib in combination with cetuximab among individuals with KRASG12C-mutated advanced colorectal cancer that continued after chemotherapy and anti-VEGF therapy, according to study authors. Additionally, in February the FDA accepted priority review for a supplemental new drug application for adagrasib with cetuximab to treat individuals with KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC). The study authors noted that the FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

The current open-label, multicenter, randomized Phase 3 KRYSTAL-12 study assessed treatment with adagrasib compared to a standard-of-care chemotherapy alone among individuals with KRASG12C-mutated NSCLC, according to study authors. The primary endpoint of PFS and key secondary endpoint of ORR were both met and assessed by Blinded Independent Central Review (BICR), according to study authors. However, other secondary endpoints in the study included overall survival (OS), and duration of response (DOR) and safety. The study authors noted that the phase 3 study remains ongoing to evaluate the further secondary endpoints.

The positive results of meeting both PFS and ORR endpoints were endorsed in a confirmatory study that displayed that adagrasib provided significant and clinically meaningful benefit, compared to a second line of treatment of standard-of-care chemotherapy, according to study authors.

The most common adverse reactions with adagrasib included nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite— occurring in 25% of patients. However, no new safety signals were reported in the current phase 3 trial.

Reference

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. Bristol Myers Squibb. News release. March 38, 2024. Accessed April 2, 2024. https://news.bms.com/news/corporate-financial/2024/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-/default.aspx