It’s becoming more and more evident that unlocking the immune system’s full potential to eliminate cancer requires knowing the right combination to that lock. In a series of talks during day two at the annual meeting of the American Society of Clinical Oncology in Chicago, cancer doctors reported making some significant headway in treating patients with combinations of multiple immunotherapy drugs that target different molecular pathways involved in immune system activation and regulation.
Robert Vonderheide, M.D., Ph.D., of the University of Pennsylvania and a member of CRI’s Scientific Advisory Council, opened the Saturday morning session by describing differences in effectiveness in treating “hot” or immunologically active tumors versus “cold” or immunologically inactive tumors. He noted that, although single-agent checkpoint blockade immunotherapy has produced incredible responses in patients with tumors that have already been infiltrated by the immune system’s cancer-fighting T cells, these monotherapies haven’t worked in tumors that lack this T cell infiltration. To promote a strong anti-tumor immune response in “cold” tumors, Vonderheide discussed, we must use combinations of drugs that target non-redundant mechanisms of immune activation. He also spoke of the importance of biomarkers, molecular signals that may help oncologists figure out which patients are likely to respond to these combinations, and which aren’t.
Scott J. Antonia, M.D., Ph.D., of the H. Lee Moffitt Cancer Center and Research Institute, presented the first new data of the morning that showed how the combination of the immune checkpoint inhibitors nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) was more effective in treating patients with small cell lung cancer (SCLC), and led to response rates that were nearly double those achieved with nivolumab alone. Antonia, along with Julie Brahmer, M.D., also used this combination in treating patients with non-small cell lung cancer (NSCLC). These trials will be discussed more in depth in our next post.
Next, Jeffrey Infante, M.D., of the Sarah Cannon Research Institute, discussed results of a trial that tested the combination of Genentech’s MOXR0916—an antibody that activates the OX40 pathway involved in the expansion of cancer-fighting T cells and the suppression of regulatory T cells that limit anti-cancer T cell activity—and Genentech’s anti-PD-L1 checkpoint inhibitor atezolizumab. While this early phase 1 trial focused on dosage and safety rather than the combination’s effectiveness, two patients with bladder cancer and kidney cancer did respond. Additionally, the toxicity profile of this combination was very manageable, and no patients discontinued the trial because of treatment-related side effects.
Later, work involving Mario Sznol, M.D., of the Yale Cancer Center, was presented. This explored the combination of Merck’s anti-PD-1 pembrolizumab and Pfizer’s utomilumab, an antibody that activates the co-stimulatory 4-1BB pathway on activated T cells. Patients tolerated this combination, too, for the most part, and no patients withdrew because of side effects. In patients who responded—including some with head and neck cancer, SCLC, and a type of thyroid cancer, amongst others—doctors noted the presence of increased numbers of activated anti-tumor T cells circulating in the blood. Fortunately, these responses were mostly durable.
With the dramatic increase in the number of combination studies now under way (we estimate a more than 6-fold growth since 2014), we expect in the next two-to-three years ahead to see more evidence of the effectiveness of combination approaches across a broad variety of tumor types.