PP01.10 A Randomized, Open-Label Phase 2 Study of the TORC 1/2 Inhibitor Sapanisertib in Relapsed/Refractory (R/R) NFE2L2 (NRF2)-Mutated and Wild-Type (WT) Squamous Non-Small Cell Lung Cancer (sqNSCLC)

Document Type

Conference Proceeding

Publication Date


Publication Title

J Thorac Oncol


Background: Activation of the transcription factor NRF2 increases the expression of genes that regulate defense against reactive oxygen species and cellular stress, which is implicated in tumorigenesis of several cancer types. NRF2 activation in tumor cells has also been found to accelerate metabolic inactivation of certain antitumor agents and decrease intracellular drug concentrations, promoting drug resistance and tumor growth. Aberrant activation of NRF2 results from gain-of-function mutations in NFE2L2 (the gene that encodes NRF2) or loss-of-function mutations in KEAP1 (a negative regulator of NRF2) leading to upregulated signaling through the mTOR pathway. This event occurs early in NSCLC tumorigenesis and is associated with poor prognosis in patients with metastatic sqNSCLC. sqNSCLC cell lines harboring NFE2L2 or KEAP1 mutations have demonstrated selective sensitivity to the dual TORC1/2 inhibitor sapanisertib, compared to TORC1-only inhibitors (Paik et al. ASCO 2020). In a phase 2 trial, single agent sapanisertib was well tolerated and led to an overall response rate (ORR) of 25%, disease control rate (DCR) of >90%, and median progression-free survival (PFS) of 8.9 months in 12 patients with NFE2L2-mutated sqNSCLC (Paik et al. ASCO 2020). Preclinical data and encouraging early clinical activity formed the rationale for conducting this phase 2 study to evaluate the efficacy and further refine the dose of sapanisertib monotherapy in patients with R/R NFE2L2-mutant and wild-type (WT) sqNSCLC (NCT05275673).

Methods: This multicenter, randomized, open-label study will enroll approximately 50 patients with histologically or cytologically documented stage IV sqNSCLC in 2 arms: NFE2L2-mutant cohort (Group A) or NFE2L2-WT cohort (Group B). Patients must have disease that progressed during or after prior systemic therapy for metastatic disease, including a platinum doublet and immune checkpoint inhibitor. Additional eligibility criteria include measurable disease per RECIST v1.1, and ECOG performance status 0-1. Study-eligible mutation in NFE2L2 or NFE2L2-WT status will be determined via next generation sequencing. Both Group A and Group B patients (NFE2L2-mutated) will be randomized to sapanisertib 3 mg once daily or 2 mg twice daily in 21-day cycles. The primary endpoints are investigator-assessed ORR per RECIST v1.1 and safety. Secondary endpoints are duration of response, PFS, and overall survival. Exploratory endpoints include PK/PD and biomarker analyses. Findings from this study will inform on the optimal dose/schedule and further confirm previously shown efficacy and safety of sapanisertib in patients with metastatic R/R NFE2L2-mutated sqNSCLC and evaluate its activity in NFE2L2-WT sqNSCLC.





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