A phase 1b/2 study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma

Abstract

Background: Omaveloxolone (Omav) reduces production of reactive oxygen and nitrogen species by myeloid derived suppressor cells (MDSCs) and restores immune surveillance in preclinical cancer models. Administration of Omav with checkpoint inhibitors (CI) may enhance the anti-tumor immune response of immunotherapies. A Phase 1b/2 study was designed to evaluate the safety and efficacy of Omav in combination with ipilimumab (Ipi) or nivolumab (Nivo) for treatment of patients with unresectable or metastatic melanoma. Data from the ongoing Phase 1b study are reported. Methods: Patients with or without prior exposure to CI, and with >5% of tumor cells from a screening biopsy positive for inducible nitric oxide synthase (iNOS) were enrolled. Serial biopsies were also collected at Weeks 2 and 13. Omav monotherapy (5, 10, 20, 100, or 150 mg PO QD) was dosed continuously starting one week prior to CI initiation (Ipi x 4 doses or Nivo q 2 weeks). Primary objectives were safety, MTD, and ORR measured via RECIST v1.1. Results: At data cutoff, 39 patients were enrolled (Omav þ Ipi: n ¼ 12; Omav þ Nivo: n ¼ 27) with median treatment duration of 13 weeks. Of 30 patients with evaluable tumor restaging, 7/30 (23%) of patients were CI-naïve, while 23/30 (77%) of patients were refractory to prior CI therapy. The ORR (confirmed þ unconfirmed) observed in all evaluable patients was 8/30 (27%, 6 partial response (PR) and 2 complete response (CR)) and 4/7 (57%) in CI-naïve patients, including 1 CR. 3/18 (17%) patients treated with Omav þ Nivo who were refractory to prior CI therapies had objective responses including 1 CR. Omav was associated with decreases in tumor iNOS, PD-L1, and IDO-1 expression. The MTD for Omav has not been established since no dose-limiting toxicities were observed. No serious AEs considered related to Omav have been reported to date. Commonly reported treatment-related adverse events included fatigue, nausea, pruritus, transaminase increases and decreased appetite. Conclusions: Omav was well tolerated at doses up to 150 mg in combination with CI and initial efficacy data suggest that Omav may overcome CI resistance. The Phase 2 portion of the trial will study the effects of Omav with Nivo in patients refractory to prior anti-PD-1/PD-L1 therapies.

Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review

“…Recently, a Phase Ib/II study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma was conducted. 108 No dose-limiting toxicities were observed for 33, and it was well tolerated at doses up to 150 mg. Initial efficacy data showed that checkpoint inhibitors resistance may be overcome in the presence of 33.…”

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

“…Other Phase 1 and 2 trials combined the nuclear factor erythroid 2-related factor 2 (NRF2) agonist, Omaveloxolone, with Ipilimumab or Nivolumab in hopes of abrogating MDSC-driven immunosuppression (ClinicalTrials.gov Identifier: NCT02259231). Omaveloxolone was associated with decreases in tumor iNOS, PD-L1, and IDO-1 expression without any dose-limiting toxicities and thus, it may overcome ICI resistance ( 130 ). Furthermore, Ipilimumab was also combined with oncolytic virus (T-VEC) therapy, yielding, a 50% progression-free survival and 67% overall survival at 18 months demonstrating superiority over T-VEC monotherapy.…”

Mechanismen der Immuntherapie-Resistenz bei kutanem Melanom: Erkennen eines Formwandlers

“…Andere Phase-1- und Phase-2-Studien kombinierten den Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)-Agonisten Omaveloxolon mit Ipilimumab oder Nivolumab in der Hoffnung, die MDSC-bedingte Immunsuppression aufzuheben (ClinicalTrials.gov Identifier: NCT02259231). Omaveloxolon war mit einer Abnahme der Tumor-iNOS-, PD-L1- und IDO-1-Expression ohne dosislimitierende Toxizitäten verbunden und kann daher die ICI-Resistenz überwinden [130]. Darüber hinaus wurde Ipilimumab auch mit einer Therapie mit onkolytischen Viren (T-VEC) kombiniert, was zu einem progressionsfreien Überleben von 50% und einem Gesamtüberleben von 67% nach 18 Monaten führte, was die Überlegenheit gegenüber einer T-VEC-Monotherapie belegt.…”