Expert Discusses Promise of Nivolumab in Advanced Bladder Cancer

Matthew Galsky, MD

Results from the phase II CheckMate-275 trial demonstrated favorable safety and efficacy with the PD-1 inhibitor nivolumab (Opdivo) as a second-line treatment for patients with metastatic urothelial cancer who have progressed on first-line chemotherapy.

CheckMate-275 is the largest study of a PD-1 inhibitor in bladder cancer reported to date. Results showed that treatment with nivolumab was associated with a confirmed objective response rate of 19.6% (95% CI, 15.0-24.9),

“Most importantly, the responses were durable, as has been reported with other immune checkpoint inhibitors in other diseases,” lead study author Matthew Galsky, MD, said when presenting the findings at the 2016 ESMO Congress in October.

Based on the results of this trial, the FDA has granted a priority review designation to nivolumab as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-based regimen. The agency is expected to make a decision on the application by March 2, 2017.

OncLive: Could you provide an overview of CheckMate-275?

In an interview with OncLive, Galsky, a professor of Medicine at the Mount Sinai School of Medicine, provided an overview of the trial and discussed the significance of these novel findings.Galsky: Metastatic bladder cancer is treated in the first-line setting with chemotherapy, and chemotherapy has been the standard treatment for the past several decades. When patients progress on first-line chemotherapy, there really haven’t been any global standards of care in that patient population because no treatment has really been shown to have enough efficacy to become a standard of care for that patient population.

What were some of the major results of the trial?

So it’s with that background that CheckMate-275 was designed, to determine whether or not immune checkpoint blockade in patients with disease progression, despite having chemotherapy, would be an effective strategy.Two hundred seventy patients were treated. The primary objective of the study was to define the objective response rate, which was determined by a blinded independent review committee. This study showed an objective response rate of 19.6%. Most importantly, the responses were durable, as has been reported with other immune checkpoint inhibitors in other diseases. The median duration of response has not been reached yet, with a median follow-up of 7 months.

Are there any plans to test nivolumab in combination with other agents in this setting?

What do you expect the results to look like for that trial?

Were there any noteworthy toxicities associated with nivolumab?

Tumor PD-L1 expression did somewhat enrich for an increased likelihood of response. But even in patients with no tumor PD-L1 expression, the lower bound of the 95% confidence interval for response rate exceeded 10%, which was really the threshold set below which nivolumab would have been considered an improvement upon what’s been achieved historically with chemotherapy.There are plans to explore nivolumab with multiple other agents. The combination furthest along is probably the one with ipilimumab (Yervoy), the CTLA-4 antibody. That’s being explored in a cohort of patients enrolled on the CheckMate-032 study. Many of those patients have already been enrolled, but that data has not been presented yet.I anticipate that the results of the combination will be similar to what’s been seen in other tumor types—that there will be an increase in the response rate with combination therapy. Regarding the side effect profile of the combination regimen in this patient population, I think we’ll need to determine how that looks, to see if this is a viable strategy moving forward.Nivolumab, as an immune checkpoint inhibitor, can have immune-related toxicities associated with treatment. The rates of grade 3/4 treatment-related adverse events on this study were about 16%—so only a minority of patients have severe treatment-related side effects.

What are the next steps following these results?

What would you like the community oncologist to take away from these findings?

Immune-related adverse events in this study most commonly occurred on the skin. For example, most typically, rash, which can be managed by just observation if it’s very mild, and with steroids, if it’s very severe. The rate of pneumonitis—which is also a potential immune-related adverse event—of any grade was 3.7%. That’s also managed with steroids if it is symptomatic, but we saw a low rate of pneumonitis in this study.The next steps are to determine whether or not nivolumab can be moved into earlier treatment lines of the disease. There is an ongoing study comparing nivolumab with placebo in the adjuvant setting for patients with clinically localized bladder cancer that have had their bladders removed. Some of these patients can have received prior chemotherapy, as long as there’s residual cancer in the bladder when the specimen is removed. This study is really determining whether immune checkpoint blockade after surgery can prevent recurrences and really make a potentially bigger impact by preventing the development of metastatic disease in the first place.The ultimate takeaway is that nivolumab has a durable objective response rate of about 20% in this patient population—in the context of second-line chemotherapy, which has really never been approved in the United States, because there have not been any drugs that have shown improved survival, and standard chemotherapy has a response rate of about 10% in this patient population.

What do you hope to see in the next 5 to 10 years in the treatment of bladder cancer?

More importantly, the responses tend to be durable when patients do respond to these drugs. The safety is very similar to what’s been seen in other solid tumor types. Quality of life is maintained for patients remaining on study long-term. I think that speaks to a treatment that is potentially both effective and tolerable once it becomes available for this patient population.I hope to see patients having durable responses to treatment who aren’t in the minority of patients who are responding to single-agent therapy. I think that will occur both with immuno-oncology combinations and with other treatment strategies that we probably can’t even name today.

Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.