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Promising Results With Combination Immunotherapy in Solid Tumors and Leukemia

Surabhi Dangi-Garimella, PhD
As immunotherapy-particularly the checkpoint inhibitors-continues to show promise in solid as well as liquid tumors, clinicians have been evaluating these agents in combination to improve efficacy and outcomes.
Combining PD-L1 Inhibitors With OX40 Agonists
Jeffrey R. Infante, MD, director of the drug development program at Sarah Cannon Research Institute, presented a phase lb dose escalation study of an OX40 receptor agonist, in combination with a PD-L1 inhibitor, in patients with advanced solid tumors.
 
OX40 agonists, Infante said, have a dual mechanism of action: they inhibit regulatory T cells and costimulate effector T cells. This can definitely be complemented by the PD-L1 inhibition. Being a phase 1 study, the primary objective of their trial was to evaluate the safety and tolerability of combining the PD-L1 inhibitor atezolizumab with the OX40 inhibitor MOXR0916. MOXR0916 is a humanized effector-competent agonist IgG1 monoclonal antibody. The secondary objectives of the study included:
  • Establishing a phase 2 dose 
  • Determining pharmacokinetics and immunogenicity of agents
  • Preliminary efficacy
  • Identifying biomarkers
A total of 51 patients were enrolled in the study, with a median age of 58 years. The most common tumor types were NSCLC, renal cell carcinoma (RCC), ovarian cancer, gastroesophageal (GE) junction cancer, and soft-tissue sarcoma. A log that detailed whether patients had received prior treatment with an anti–PD-1 or anti–PD-L1 agent was maintained. A 3+3 dose-escalation was conducted with a 21-day window to evaluate dose-limiting toxicity (DLT), Infante explained. Escalating doses of MOXR0916, in combination with a fixed 1200-mg dose of atezolizumab, were administered every 3 weeks. An expansion cohort to enable immune profiling of serial tumor biopsies was also enrolled in the trial. Prior immunotherapy with adequate washout was allowed if there was no history of grade 3 or greater immune-mediated AEs. 
 
Infante said that the combination was well tolerated overall, with no DLT, deaths, or grade 4 or higher toxicity. A grade 3 pneumonitis in 1 patient was controlled with antibiotics and steroids. “No truly dose-dependent AE was observed,” he concluded.
 
The current expansion regimen is MOXR0918 at 300 mg in combination with atezolizumab 1200 mg, every 3 weeks. Significantly, the study did observe PD-L1 modulation in patients who had had immediate prior therapy with single-agent anti-OX40 or anti–PD-1. 
 
Efficacy studies, Infante said, are ongoing for the combination in melanoma, RCC, NSCLC, urothelial carcinoma, and triple-negative breast cancer.

Discussant’s Comments
Following the 2 presentations, Jedd D. Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, discussed the findings. Expressing his excitement with the results that were presented, Wolchok said that questions remain. “We need additional numbers on patients along with further information on the nature of the response,” he said, including whether the combination treatment generates a deeper response. Information on the PD-L1 status in each group is also important to understand, Wolchok said. “We also need studies that evaluate other agents for combination studies.”
 
With respect to the OX40 study, Wolchok said that lab-based studies have shown a 100% survival response in mice treated with an OX40 agonist with azetolizumab. He was quite impressed by the biomarker analysis done by the study group, evaluating the upregulation of PD-L1. “OX-40 is a potentially promising agent,” Wolchok concluded. EBO
 



References
  1. Antonia SJ, López-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstract 100).
  2. Dangi-Garimella S. Nivolumab approved by EC for melanoma, rejected by NICE for lung cancer. The American Journal of Managed Care website. http://www.ajmc.com/newsroom/nivolumab-approved-by-ec-for-melanoma-rejected-by-nice-for-lung-cancer. Published May 12, 2016. Accessed June 4, 2016.
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