1. Gutierrez, Martin MD

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As part of our ongoing efforts to advance understanding of novel immuno-oncologic agents, our team recently published Phase I/IIa data showing that BMS-986178, an investigational OX40 agonist, appears to be safe to use as monotherapy or in combination with immune checkpoint inhibitors in the treatment of advanced solid tumors.

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Our findings, published in the online edition of Clinical Cancer Research on November 4, 2020, suggest that BMS-986178 has an acceptable safety profile in patients with advanced solid tumors, whether used as monotherapy or in combination with the checkpoint inhibitors nivolumab and/or ipilimumab (2021; doi: 10.1158/1078-0432.CCR-20-1830). The rationale for using an OX40 agonist in this setting is based on its binding to the OX40 protein receptor found on memory T cells, which can trigger a signal associated with production of additional T cells. The results appear to clear the way for the continued development of BMS-986178, starting with a Phase II breast cancer study.


Study Design & Safety Results

Our multinational, open-label, Phase I/IIa study evaluated the safety and activity of BMS-986178 (at doses ranging from 20 mg to 320 mg), both as monotherapy and in combination with nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg of body weight), in patients with non-small cell lung cancer, renal cell carcinoma, bladder cancer, and other advanced solid tumors. Twenty patients were treated with BMS-986178 monotherapy, and 145 received various combination regimens.


After follow-up for as long as 103 weeks, the most common treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, serious (grade 3-4) TRAEs occurred in 1 of 20 patients (5%) receiving BMS-986178 monotherapy, 6 of 79 (8%) receiving BMS-986178 plus nivolumab, 0 of 2 receiving nivolumab monotherapy, 6 of 41 (15%) receiving BMS-986178 plus ipilimumab, and 3 of 23 (13%) receiving BMS-986178 in combination with both checkpoint inhibitors.


No deaths occurred in the study. There were no dose-limiting toxicities observed with monotherapy. The maximum tolerated dose was not reached with escalating doses of either BMS-986178 monotherapy or any of the combination regimens.


Elucidating the Benefits of OX40 Agonism

We were pleasantly surprised to find that T-cell stimulation with an OX40 agonist did not exacerbate the inflammatory response and other off-target effects of checkpoint inhibitors. Indeed, the adverse events we observed in the monotherapy and combination cohorts were manageable, suggesting that BMS-986178 is safe to use in combination with checkpoint inhibitor therapy, and possibly also with a cancer vaccine.


BMS-986178 binds with a high affinity to the OX40 receptor, a member of the tumor necrosis factor receptor super family (TNFRSF), which includes several proteins with key roles in T-cell development and survival, immune activation, and anti-tumor immune responses.


While nivolumab and ipilimumab have established a niche as viable treatments for several solid tumor types, many patients develop resistance to these checkpoint inhibitors, underscoring the need for novel immuno-oncology strategies. In theory, adding an OX40 agonist to checkpoint inhibitor therapy would modulate the immunosuppression that occurs in the tumor microenvironment while enhancing the T-cell response. Our results suggest it is safe to combine these two immunomodulatory approaches.


Potentiating T-cell Response Via OX40 Activation

We did not observe objective tumor responses with BMS-986178 monotherapy. Objective response rates ranged from 0 percent to 13 percent among patients receiving combination therapy. We were somewhat surprised that the efficacy signals observed in preclinical trials did not translate to more robust efficacy in this first-in-human trial. Nevertheless, our findings underscore the complexity of the immune system, and the importance of maintaining a delicate balance between the T-cell compartment and antigen-presenting cells in the tumor microenvironment.


Moreover, our findings suggest we may be able to use OX40 activation as part of a priming intervention early in the course of certain cancers. For example, we could use a cancer vaccine to prime T-cell stimulation, and then use an OX40 agonist to enhance T-cell activity. As a next step, we plan to pursue such an approach in a Phase II study involving patients with triple-negative breast cancer.


Reaping the Benefits of Partnership

The Phase I/IIa study of BMS-986178 is the latest in a string of successful research collaborations between John Theurer Cancer Center (JTCC) and various industry partners. Our Experimental Drugs program aims to keep JTCC at the forefront of immunotherapy research, particularly in the use of checkpoint inhibitors that unleash the immune system and are now approved across many cancer subtypes.


We initiated the collaboration with BMS after reviewing preclinical data showing that BMX-986178 was biologically sound, was efficacious in animal models, and had a favorable toxicity profile. Those data suggested that the novel OX40 agonist might address some of the limitations of checkpoint inhibitor therapy, making it stand out as a particularly attractive candidate to study at JTCC and other participating centers.


A key factor in the success of our collaboration has been the bi-directional, one-to-one relationship, which has grown to the point that we are exploring future research collaborations for nearly a dozen investigational therapies. As part of those discussions, our lab is providing input to the Phase I protocols for those therapies, and working closely to coordinate trial logistics while ensuring regulatory compliance.


At JTCC, we continually seek mutually beneficial partnerships with industry, particularly those that facilitate exploration of novel combinations that re-engage the immune system in the fight against cancer. These collaborations help us advance our goal of increasing the number of patients who can benefit from such potentially game-changing therapies, which are typically very durable, even after patients fail to respond to multiple lines of therapies.


MARTIN GUTIERREZ, MD, is Chief Medical Oncologist of the Thoracic Division at the John Theurer Cancer Center at Hackensack University Medical Center.

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