FDA Fast Tracks Sapanisertib for NRF2-Mutated Squamous Lung Cancer

After results from a phase 2 trial demonstrated durability with sapanisertib, the FDA granted fast track designation to the agent for patients with unresectable or metastatic squamous non–small cell lung cancer.

The FDA has granted a fast track designation to sapanisertib (CB-228) for adult patients with unresectable or metastatic squamous non–small cell lung cancer (NSCLC) who harbor a mutation in nuclear factor erythroid 2-related factor (NRF2) and have received prior platinum-based chemotherapy and immune checkpoint inhibitor therapy.1

Sapanisertib is a potent and investigational mTOR complex 1/2 inhibitor which targets a key survival mechanism in tumor cells harboring a NRF2 mutation.

A recent investigator-initiated phase 2 trial demonstrated the compound to be well-tolerated and showed durable single-agent activity. Findings revealed a 27% confirmed overall response rate (ORR) and median progression-free survival (PFS) of 8.9 months (95% CI, 7-not reached) in heavily pretreated patients with NRF2-mutated squamous NSCLC.

“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, in the press release. “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."

The ongoing, multi-center, open-label, phase 2 trial (NCT05275673) is evaluating sapanisertib monotherapy in patients with NRF2-mutated squamous NSCLC whose disease has progressed on or after platinum-doublet chemotherapy and immune checkpoint inhibitor therapy (anti-PD/L1) with or without anti-CTLA-4.2

With an estimated enrollment of 50 patients, the study is evaluating sapanisertib at 2 mg twice a day or 3 mg once a day in those with squamous NSCLC harboring either wild-type (WT) or mutated NRF2, as detected by next-generation sequencing (NGS).

The study aims to confirm the activity of sapanisertib in NRF2-mutated tumors vs WT tumors. Additionally, investigators look to refine a dose in this biomarker-defined population.

Patients enrolled must be aged 18 years and older with stage IV squamous NSCLC, disease which progressed during or after prior systemic therapy for metastatic disease, including platinum-doublet chemotherapy and immune checkpoint inhibitor therapy, study-eligible mutation in NRF2 or WT NRF2 using NGS. Additional eligibility requirements include having at least 1 radiographically measurable lesion per RECIST v1.1, an ECOG performance status of 0-1, and adequate organ function.

Within 7 days prior to the first dose of sapanisertib, female patients of childbearing potential must have a negative serum or urine pregnancy test and agree to use acceptable methods of contraception during the time of the study and until at least 14 days following the last dose of the study drug. This does not apply to post-menopausal females or surgically sterilized females.

Male patients are required to use an effective barrier method of contraception if sexually active with a female of childbearing potential. Additionally, these patients must refrain from donating sperm during the duration of the study and for a minimum of 14 days following the last dose of sapanisertib.

The primary end points of the study include investigator-assessed ORR per RECIST v1.1, and safety. Secondary end points are duration of response, PFS, and overall survival.

Further data from this study are expected to be released in the start of 2023. These data have the potential to lead to another study with registrational intent in biomarker specific squamous NSCLC populations.

Calithera receives FDA fast track designation for sapanisertib for the treatment of NRF2-mutated squamous lung cancer. News release. Calithera Biosciences, Inc. October 3, 2022. Accessed October 4, 2022. https://yhoo.it/3RAtXoj
A study of sapanisertib in relapsed/refractory NFE2L2-mutated and wild-type squamous non-small cell lung cancer. ClinicalTrials.gov. Updated August 8, 2022. Accessed October 4, 2022. https://clinicaltrials.gov/ct2/show/NCT05275673?term=sapanisertib&draw=2&rank=3