OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors

Abstract

This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, AE nivolumab and/or ipilimumab in patients with advanced solid tumors. Patients and Methods: Patients (with non-small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20-320 mg) AE nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1. Results: Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a followup of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3-4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts. Conclusions: In this study, BMS-986178 AE nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.

Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis

“…These results indicate that sequential, rather than simultaneous administration of OX40 agonists and anti-PD-1 can revert PD-1 resistance and improve responses to combination therapy. Consequently, one of the approaches in a Bristol-Myers Squibb (BMS) clinical study (39) involves exploring the effectiveness of sequentially administering an OX40 agonist, BMS-986178, anti-PD1 (Nivolumab), an allogeneic autophagosome-enriched vaccine, DPV-001 and cyclophosphamide in TNBC patients (ClinicalTrials.gov Identifier: NCT02737475). Another co-stimulatory molecule, the inducible co-stimulator (ICOS), is mainly expressed by activated CD4+ and CD8+ T cells and constitutively by Tregs.…”

Stay on Target: Reengaging Cancer Vaccines in Combination Immunotherapy

“…Preliminary data from this trial demonstrate that BMS-986178 as a monotherapy or combined with nivolumab and/or ipilimumab is well tolerated with no dose-limiting toxicities (DLTs) or discontinuation due to study treatment [ 79 ]. Although earlier data showed that BMS-986178 monotherapy resulted in increased proinflammatory cytokines and higher proliferation and activity of CD4 and CD8 T cells when combined with either anti-PD-1 or anti-CTLA-4 [ 96 ], this was not recapitulated in this trial upon interrogation of intratumoral or peripheral CD8 T cells [ 90 ]. Results obtained here suggest that the responses observed were not greater than what would have been projected for nivolumab or ipilimumab treatment alone.…”

“…The tumor necrosis factor receptor superfamily (TNFRSF) contains many receptors responsible for the development, survival and function of immune cells, including OX40, CD40, FasR, 4-1BB, among others [ 84 ]. Studies interrogating the efficacy of monoclonal antibodies specific for costimulatory receptors, such as CD40 (dacetuzumab, CP-870,893 and lucatumumab [ 85 , 86 , 87 , 88 ]), OX40 (9B12 [ 89 ], BMS-986,178 [ 90 ]) and LAG3 (IMP321 [ 91 ]), are currently underway. Targeting these receptors with agonistic monoclonal antibodies could be beneficial in generating more robust antitumor immune responses.…”

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

“…BMS-986178 is another fully human IgG mAb against OX40 assessed as monotherapy or in combination with nivolumab in advanced solid tumors. No anti-tumor activity was observed with monotherapy and overall response rate (ORR) was 6–12% in the combination cohort [ 39 ]. Overall, OX40 targeting monotherapy appears to be tolerable however, it does not induce durable anti-tumor responses.…”