Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design

Abstract

Introduction: There are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor MLN0128 (sapanisertib) in combination with the glutaminase inhibitor CB-839 HCl. Methods: Phase 1 dose finding will use the queue-based variation of the 3 þ 3 dose escalation scheme with the primary endpoint of identifying the recommended expansion dose. To confirm the acceptable tolerability of the recommended expansion dose, patients will subsequently enroll onto 1 of 4 expansion cohorts (n ¼ 14 per cohort): (1) LSCC harboring NFE2L2 or (2) KEAP1 mutations, or (3) LUAD harboring KRAS/(KEAP1 or NFE2L2) coalterations, or (4) LSCC wild type for NFE2L2 and KEAP1. The primary endpoint of the dose expansion is to determine the preliminary efficacy of MLN0128/CB-839 combination therapy. Conclusion: This phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced nonesmall-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations.

Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy

“…The phenomenon is the basis of an interesting therapeutic strategy [ 169 ]. Currently, phase 1 clinical trials have started to check the effect of the glutamine inhibitor telaglenastat (CB-839) in advanced NSCLC [ 170 ]. However, the preliminary results of the studies in an animal model showed that the use of CB-839 as monotherapy in lung tumors with the K-Ras mutation did not give satisfactory results; for this reason, it is suggested to include selective inhibitors of glycolysis as well [ 171 ].…”

Role of NRF2 in Lung Cancer

“…At the same time, for pathways that crosstalk with NRF2, preexisting compounds for these pathways can be used in combination with NRF2-directed compounds [13]. In fact, a phase I trial combining MLN0128 (sapanisertib), an mTOR inhibitor, and CB-839, a glutaminolysis inhibitor, is ongoing in patients with advanced NSCLC (KRAS-mutant LUAD and LUSC) having NFE2L2/KEAP1 mutations [234].…”

Methylation Landscape: Targeting Writer or Eraser to Discover Anti-Cancer Drug

“…The combination of drugs has achieved the effect of improving the efficacy and reducing the side effects of alkylating agents, which can be considered as a new strategy. In addition, the glutaminase inhibitor CB-839 has entered clinical trials for determining its safety and activity ( Riess et al, 2021 ).…”