On October 3, 2022 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision oncology biopharmaceutical company, reported that the U.S. Food & Drug Administration (FDA) has granted Fast Track designation for the company’s investigational mTORC 1/2 inhibitor sapanisertib (CB-228) for the treatment of adult patients with unresectable or metastatic squamous non-small cell lung cancer (sqNSCLC) whose tumors have a mutation in nuclear factor erythroid 2-related factor (NFE2L2, also called NRF2) and who have received prior platinum-based chemotherapy and immune checkpoint inhibitor therapy (Press release, Calithera Biosciences, OCT 3, 2022, View Source [SID1234621631]).

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"While there have been significant advances in targeted treatments for lung cancer, little progress has been made specifically for patients with squamous lung cancer. In addition, we know that patients with lung cancers that harbor mutations in the NRF2/KEAP1 pathway typically have poorer outcomes than those whose tumors do not have these mutations," said Susan Molineaux, chief executive officer of Calithera. "This Fast Track designation allows for a variety of benefits, including the possibility of priority review of sapanisertib as we seek to provide a first-in-class treatment option that may help address the major unmet need in this patient population."

NRF2 mutations are found across multiple solid tumor types, with these mutations occurring in approximately 15% of sqNSCLC patients. Sapanisertib targets a key survival mechanism in NRF2-mutated tumor cells. In a recent investigator-initiated Phase 2 trial, the compound was well-tolerated and demonstrated durable single-agent activity with a 27% (or 3/11) confirmed overall response rate (ORR) and median progression free survival (PFS) of 8.9 months (95% CI: 7 months, not reached) in heavily pretreated patients with NRF2-mutated sqNSCLC.1

Calithera’s ongoing Phase 2 trial (NCT05275673) is a multi-center, open-label study of sapanisertib monotherapy in patients with NRF2-mutated sqNSCLC whose disease has progressed on or after platinum-doublet chemotherapy and immune checkpoint inhibitor therapy (anti-PD/L1) with or without anti-CTLA-4. The study is evaluating sapanisertib 2 mg twice a day or 3 mg once a day in patients with sqNSCLC harboring either wild-type (WT) or mutated NRF2, as detected by next-generation sequencing. The study is designed to confirm the selective activity of sapanisertib in NRF2-mutated tumors compared to WT tumors, and to refine dose in this biomarker-defined population. The primary endpoints of the study are investigator-assessed overall response rate (ORR) per RECIST v1.1, and safety. Secondary endpoints include duration of response, progression-free survival and overall survival. Calithera plans to share data from this study by the first quarter of 2023. Data generated from this open-label study could position the company to initiate a study with registrational intent in biomarker specific sqNSCLC populations.

The FDA grants Fast Track designation to facilitate development and expedite the review of therapies with the potential to treat a serious condition where there is an unmet medical need. A therapeutic that receives Fast Track designation can benefit from early and frequent communication with the agency, in addition to a rolling submission of the marketing application, with potential pathways for expedited approval that have the objective of getting important new therapies to patients more quickly.