In 2011, ipilimumab—an anti-CTLA-4 antibody—become the first checkpoint inhibitor immunotherapy approved for any cancer, for the treatment of advanced melanoma. Since then, the combination of ipilimumab and the anti-PD-1 antibody nivolumab have shown increased effectiveness in melanoma patients and the combination also received FDA approval. Unfortunately, even this combination does not help all patients.
Sunday at ASCO, we saw new approaches to help these patients: the combination of ipilimumab and radiation, as well as the combination of the anti-PD-1 pembrolizumab and chemotherapy. The first combination, in work presented by Michael Atkins, M.D., in collaboration with Antoni Ribas, M.D., Ph.D.,—a member of the leadership team of CRI’s clinical program and a co-investigator on the CRI-SU2C Cancer Immunology Translational Research Dream Team—showed promising clinical activity in melanoma patients, leading to responses better than using pembrolizumab alone. The idea behind using radiation is that by killing cancer cells and causing them to release their intracellular contents, it makes it easier for the immune system to identify, target, and destroy remaining tumor cells.
The second combination, presented by Ribas, was shown to be safe in melanoma patients, but it was only a phase 1 trial that didn’t look at its effectiveness. Hopefully, the phase 2 trial currently being conducted will show that this combination—which aims to promote complementary anti-tumor activity by both directly (via chemotherapy) and indirectly (via checkpoint immunotherapy) targeting melanoma cells—works.
Additional cancer types that have benefited from checkpoint immunotherapy are genitourinary diseases of the kidney (renal cell carcinoma, RCC) and bladder (urothelial carcinoma, UC), with nivolumab approved for RCC and the anti-PD-1 atezolizumab approved for UC.
In work presented by David McDermott, M.D., and conducted with Charles Drake, M.D., Ph.D.—a member of CRI’s Scientific Advisory Council—long-term follow up in RCC patients treated with nivolumab revealed that these responses are indeed durable, with about one-third of patients surviving to five years and three years, in the phase 1 and phase 2 trials, respectively.
The aforementioned study by Atkins and Ribas also showed that, like melanoma, RCC responded to the combination of ipilimumab and pembrolizumab.
Another study by Christophe Massard, M.D., Ph.D., revealed that the anti-PD-L1 antibody durvalumab also had clinical activity in bladder cancer patients, and more importantly that almost all of the responses occurred in patients with expression of the PD-L1 biomarker. Also in bladder cancer, further analysis by Robert Dreicer, M.D., of patients treated with the already-approved atezolizumab, confirmed the improvements in overall survival in response to this therapy.
Colorectal cancer (CRC) has proven hard to treat with checkpoint inhibitors, though a small subset of patients with heavily mutated CRC tumors have benefitted from pembrolizumab treatment. New data, presented today by Michael Overman, M.D., showed that the combination of nivolumab and ipilimumab also improved outcomes in these patients, with one out of every three patients benefiting from durable responses and almost nine out of every ten patients experiencing at least disease control.
Previously, CRC patients without heavily mutated tumors didn’t benefit from checkpoint immunotherapy. Fortunately, a new study presented today by Johanna Bendell, M.D., revealed that the combination of the checkpoint inhibitor atezolizumab that targets PD-L1 and cobimetinib, a MEK pathway inhibitor that targets growth pathways, produced responses that were higher than expected from either treatment alone based on results from past trials of the drugs as monotherapies. Importantly, the patients chosen for this had mutations that led to overactivity in the MEK-governed growth pathway. This combination also improved 6-month overall survival, from 1% in patients treated with the standard of care, to 72%. This represents an incredible breakthrough, and will hopefully pave the way for more effective approaches to treating these CRC patients.