LUGANO-GENEVA – A novel compound may restore immune response in patients with melanoma, according to a study presented at the ESMO Immuno Oncology Congress 2017. (1)
“Checkpoint inhibitors are a standard of care immunotherapy for metastatic melanoma,” said lead author Dr Sapna Patel, Assistant Professor, Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, US. “However, many patients do not respond because myeloid derived suppressor cells (MDSCs), a type of inhibitory cell, are present in the tumour microenvironment.”
“In animal studies, omaveloxolone inhibited MDSCs and restored immune activity,” she continued. “Myeloid-derived suppressor cells (MDSCs) produce reactive nitrogen radicals that alter the receptors on the surface of the tumour to hide it from cytotoxic lymphocytes that kill tumour cells. Omaveloxolone inhibits MDSC activity, suppresses reactive nitrogen radicals, and restores anti-tumour immune responses. Administering omaveloxolone with checkpoint inhibitors may improve the antitumour response of these immunotherapies.”
This open label, multicentre, phase 1B trial investigated the safety and efficacy of omaveloxolone in combination with the checkpoint inhibitors ipilimumab or nivolumab. The study included 30 patients with unresectable or metastatic melanoma, of whom seven were naïve to checkpoint inhibitors and 23 had prior checkpoint inhibitor treatment.
The overall response rate was 57% in checkpoint inhibitor naïve patients and 17% in those with prior exposure. Median time to response was 19 weeks. There were no serious adverse events related to omaveloxolone and it was well tolerated in combination with ipilimumab or nivolumab.
Dr Patel said: “Our findings suggest that omaveloxolone may overcome resistance to checkpoint inhibitors. Omaveloxolone in combination with checkpoint blockade had activity in both naïve and checkpoint inhibitor refractory melanoma patients.”
She added: “This is one of the first studies to demonstrate a meaningful response rate in the checkpoint inhibitor refractory melanoma population. Further dose escalation and dose expansion studies are underway as well as translational tissue-based experiments to clarify the impact of this treatment combination.”
Commenting on the study for ESMO, Dr Olivier Michielin, head of Personalised Analytical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, said: “Omaveloxolone’s novel mechanism of action is to block MDSCs, cells known to suppress the immune response. This study tested a new combination therapy in immuno oncology and found encouraging response rates with omaveloxolone plus ipilimumab or nivolumab in patients who were checkpoint inhibitor naïve or resistant. The combination was well tolerated and may address some of the immune escape mechanisms that limit the activity of current checkpoint blockade therapies.”
Michielin added: “More data is needed before we can make a final call on whether there is a place, and where would the place be, for this combination in the current treatment portfolio. The next step should be a randomised trial to investigate whether omaveloxolone provides additional benefit when combined with the checkpoint blockade backbone, for example, comparing the efficacy of PD-1 blockade alone versus PD-1 blockade plus omaveloxolone.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO Immuno Oncology Congress 2017
Official hashtag: #ESMOImmuno17
References
- Abstract 5O_PR ‘A phase 1b/2 study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma‘ will be presented by Sapna Patel during a Proffered Paper Session on Friday 8 December, 08:30 to 10:30 CET in Room A. Annals of Oncology, Volume 28, 2017 Supplement 11.
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Abstract 5O_PR
A phase 1b/2 study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma
S.P. Patel1, F.S. Hodi2, D. Gabrilovich3, M. Chin4, G. Gibney5, A. Goldsberry4, R. Gonzalez6, J. Hurt4, J. Markowitz7, E. Whitman8, C. Meyer4, A. Salama9
1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 3Immunology, The Wistar Institute, Philadelphia, PA, USA, 4Product Development, Reata Pharmaceuticals, Irving, TX, USA, 5Georgetown Lombardi Comprehensive Cancer Center, Washington DC, USA, 6School of Medicine, University of Colorado, Denver, CO, USA, 7Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA, 8Atlantic Health System Cancer Care, Morristown, AL, USA, 9School of Medicine, Duke University, Durham, NC, USA
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 + Ipi: n=12; Omav + Nivo: n=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 + 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 + 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.
Clinical trial identification: NCT02259231
Legal entity responsible for the study: Reata Pharmaceuticals
Funding: Reata Pharmaceuticals
Disclosure: S.P. Patel: Research funding (paid to institution): BMS, Deciphera, Novartis, Reata; Advisory board: Amgen, Castle Biosciences, Genentech, Incyte, OncoSec DSMB: Immunocore, Reata; Nonpromotional speaker’s bureau for: BMS, Merck.
F.S. Hodi: Consultant for Merck, Bristol-Myers Squibb, EMD Serono, Novartis, Genentech, Amgen, Celldex.
D. Gabrilovich: Research grant from Reata. M. Chin, A. Goldsberry, J. Hurt: Employee of Reata Pharmaceuticals.
G. Gibney: Consultant for Genentech, Novartis, and Incyte; Speaker’s bureau for Genentech and Merck.
J. Markowitz: Consultant to Idera and Newlink Genetics.
E. Whitman: Speaker’s bureau and Advisory board for BMS. C. Meyer: Employeer of Reata Pharmaceuticals.
A. Salama: Research funding (paid to institution): BMS, Celldex, Genentech, Merck, Immunocore; Advisory board: Merck; Speaker’s bureau: BMS; Spouse: Research funding/national PI- AbbVie.
All other authors have declared no conflicts of interest.
Keywords: Phase 1b/2 trial, Immune checkpoint inhibitors, Omaveloxolone, Unresectable/ Metastatic Melanoma