Merck (NYSE:MRK), known as MSD outside of the United States and Canada, announced that calderasib (MK-1084), an investigational oral specific KRAS G12C inhibitor, in combination with KEYTRUDA® (pembrolizumab), Merck's anti-PD-1 therapy, has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the first-line treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C-mutation and expressing PD-L1 (tumor proportion score [TPS] ≥1%). This is the first Breakthrough Therapy designation for calderasib and was supported by positive data from the Phase 1 KANDLELIT-001 trial.

"As our understanding of cancer biology and precision medicine continues to advance, we're encouraged by the potential of new approaches, like calderasib, to help address the underlying drivers of cancer growth," said Dr. Shweta Jain, vice president, global clinical development, Merck Research Laboratories. "The Breakthrough Therapy designation for calderasib underscores the promising potential of this medicine and unmet need for certain patients with KRAS G12C-mutated NSCLC."

The KRAS G12C mutation is the most frequently observed KRAS mutation in patients, occurring in approximately 14% of patients with NSCLC (adenocarcinoma).

The FDA's Breakthrough Therapy designation is granted to expedite the development and review of medicines that are intended to treat serious or life-threatening conditions. To qualify for this designation, preliminary clinical evidence must indicate that the product may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies. The benefits of this Breakthrough Therapy designation include more intensive guidance from the FDA on an efficient development program, organizational commitment involving senior managers and experienced review staff, rolling review and potential eligibility for Priority Review.

The KANDLELIT clinical development program for calderasib includes five Phase 3 trials across a range of tumor types and stages, including:

  • KANDLELIT-004, evaluating calderasib in combination with KEYTRUDA for patients with newly diagnosed metastatic NSCLC with KRAS G12C-mutation and PD-L1 TPS ≥50%.
  • KANDLELIT-007, evaluating calderasib in combination with KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) in patients with newly diagnosed advanced or metastatic nonsquamous NSCLC with KRAS G12C-mutation, regardless of PD-L1 expression.
  • KANDLELIT-012, evaluating calderasib in combination with cetuximab and mFOLFOX6 for the first-line treatment of certain patients with locally advanced unresectable or metastatic CRC who have KRAS G12C-mutated tumors.
  • KANDLELIT-013,evaluating calderasib in combination with KEYTRUDA QLEX for certain patients with locally advanced KRAS G12C-mutated NSCLC following receipt of either neoadjuvant KEYTRUDA plus chemotherapy or adjuvant chemotherapy.
  • KANDLELIT-015, evaluating calderasib in combination with durvalumab in certain patients with locally advanced, KRAS G12C-mutated NSCLC after chemotherapy and radiation therapy.

Calderasib is being developed through a collaboration with Taiho Pharmaceutical Co. Ltd. and Astex Pharmaceuticals (UK), a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd. This collaboration was announced in January 2020.