FDA Gives Priority Review Status to Bristol Myers Squibb’s sNDA for Krazati Combo in Colorectal Cancer

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The FDA has granted Priority Review status to Bristol Myers Squibb’s supplemental new drug application (sNDA) for Krazati (adagrasib) plus cetuximab for patients who received prior treatment for KRAS^G12C-mutated locally advanced or metastatic colorectal cancer (CRC).¹ Krazati, an oral small molecule inhibitor of the RAS GTPase family, has been found to inhibit tumor growth and the viability in cells that carry KRAS^G12C mutations, which subsequently causes tumor regression.²

“Pretreated KRAS^G12C-mutated CRC is associated with poor outcomes and the current standard of care offers limited clinical benefit for patients,” Anne Kerber, senior vice president, head of late clinical development, Hematology, Oncology, Cell Therapy at Bristol Myers Squibb, said in a press release. “The acceptance of this filing for Krazati in combination with cetuximab is a positive step toward providing a potential new option for patients and their physicians. It reinforces our commitment to developing potentially transformative targeted cancer therapies for patients for whom few treatment options exist.”¹

The sNDA submission was based on data from the open-label, multicenter, multiple expansion cohort Phase I/II KRYSTAL-1 trial. Investigators analyzed both Krazati monotherapy or in combination with other anticancer treatments in patients with advanced solid tumors carrying a KRAS^G12C mutation.1

The trial’s primary endpoint among the registrational cohort was objective response rate (ORR), with secondary endpoints among the pooled cohorts that included duration of response (DOR), progression-free survival, overall survival, and safety. Results from the trial indicate that Krazati was well tolerated with promising clinical activity among pretreated patients with locally advanced or metastatic CRC that harbor a KRAS^G12C mutation. In terms of safety, Krazati in combination with cetuximab was found to be manageable with a profile that is consistent with what has previously been reported with the individual therapies.

The FDA granted Krazati with accelerated approval for adults with KRAS^G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in 2022 based on ORR and DOR data.

The approval was based on the expansion cohort of KRYSTAL-1 (NCT03785249), which enrolled 112 patients with locally advanced or metastatic KRAS^G12C–mutated NSCLC who received prior treatment with an immune checkpoint inhibitor and a platinum-based regimen, had an ECOG performance status of 0 or 1, and had at least one measurable lesion as defined by RECIST v1.1. Patients were administered Krazati 600 mg orally twice daily until disease progression or unacceptable toxicity observed during tumor assessments conducted every six weeks. The trial’s primary efficacy endpoints were confirmed DOR and ORR as evaluated by blinded independent central review according to RECIST v1.1. The trial showed a median DOR of 8.5 months and an ORR of 43% among patients treated with Krazati.^2,3

The most common adverse events reported with Krazati are reduced appetite, diarrhea, dyspnea, edema, fatigue, hepatotoxicity, musculoskeletal pain, nausea, renal impairment, and vomiting. The most common grade three or four laboratory abnormalities reported with Krazati were reduced hemoglobin, reduced leukocytes, reduced lymphocytes, reduced neutrophils, hypokalemia, hyponatremia, elevated alanine aminotransferase, elevated alkaline phosphatase, elevated aspartate aminotransferase, and elevated lipase.²

The FDA assigned the sNDA for the Krazati combination in CRC with a Prescription Drug User Fee Act goal date of June 21, 2024.

References

1. U.S. Food and Drug Administration (FDA) Accepts Supplemental New Drug Application for KRAZATI® (adagrasib) in Combination with Cetuximab as a Targeted Treatment Option for Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or... Bristol Myers Squibb. News release. February 20, 2024. Accessed February 20, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-KRAZATI-adagrasib-in-Combination-with-Cetuximab-as-a-Targeted-Treatment-Option-for-Patients-with-Previously-Treated-KRAS-G12C-Mutated-Locally-Advanced-or/default.aspx

2. Krazati. Prescribing information. Mirati Therapeutics Inc; 2022. Accessed February 20, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf

3. Mirati Therapeutics announces U.S. FDA accelerated approval of Krazati (adagrasib) as a targeted treatment option for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a KRASG12C Mutation. News release. Mirati Therapeutics. December 12, 2022. Accessed February 20, 2024. https://ir.mirati.com/press-releases/press-release-details/2022/Mirati-Therapeutics-Announces-U.S.-FDA-Accelerated-Approval-of-KRAZATI-adagrasib-as-a-Targeted-Treatment-Option-for-Patients-with-Locally-Advanced-or-Metastatic-Non-Small-Cell-Lung-Cancer-NSCLC-with-a-KRASG12C-Mutation/default.aspx