Balar Addresses Advances in Bladder and Kidney Cancer

Arjun V. Balar, MD

Over the last few years, immunotherapy has taken center stage in the landscape of bladder cancer, with the approval of 5 PD-1/PD-L1 agents: atezolizumab (Tecentriq) and pembrolizumab (Keytruda)—both as first- and second-line therapies—and avelumab (Bavencio), durvalumab (Imfinzi), and nivolumab (Opdivo) in the second-line setting. Next steps in this field, experts have noted, are to study these agents in combination with other novel or existing therapies.

Additionally, kidney cancer has also seen an emergence of immunotherapy approaches, especially as combinations. For example, a breakthrough therapy designation was granted by the FDA in January 2018 to the combination of pembrolizumab and the VEGF/FGF inhibitor lenvatinib (Lenvima) for the treatment of patients with advanced and/or metastatic disease. Moreover, in December 2017, the FDA granted avelumab plus the VEGF inhibitor axitinib (Inlyta) a breakthrough therapy designation in treatment-naïve patients with advanced disease.

“There are many advances taking place in the management of genitourinary cancers,” said Arjun V. Balar, MD. “In bladder cancer and kidney cancer in particular, we’re seeing a wave of new therapies, such as how to use novel immunotherapies effectively. There are trials now that are addressing combination approaches that I believe will quickly lead to new standards of care, probably in the next 1 or 2 years. It's critical to follow along with these studies to maintain an updated standard of care.”

OncLive: What is the state of immunotherapy in GU cancers?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Genitourinary (GU) Cancers, Balar, assistant professor, Department of Medicine, director, Genitourinary Medical Oncology Program, NYU Langone’s Perlmutter Cancer Center, and chair of the meeting, discussed the landscape of current and future standards of care for immunotherapy in bladder and kidney cancer.Balar: At the State of the Science Summit^TM on GU Cancers, we spoke about advances in the management of GU cancers and, specifically, my area of focus on the talk was a focus on patients who were treated with metastatic kidney and bladder cancers. In advanced bladder cancer, we have seen a wave of new therapies being approved. These include agents targeting the PD-1 pathway. We have 5 agents approved in the second-line setting, and we have 2 agents approved in the first-line setting. This has been a very active year in terms of drug development. I've covered all of the data that supported the approvals of these agents.

Can you expand on some of these new therapies?

Then, I turned my attention toward the management of kidney cancers, where we have also seen a great deal of activity in terms of new therapies. I reviewed the data with respect to immunotherapy in the second-line setting, as well as emerging agents that include combinations in the first-line setting. Immune checkpoint inhibitors, in particular PD-1 pathway inhibitors in bladder cancer, have led to rapid and durable responses in the second-line setting. What we have seen, as a summary of the phase II and phase III trials, is response rates between 15% and 20%. In the second-line setting, these responses have been durable. The longest-term follow-up shows that some of these responses are going into multiple years—2 and 3 years after starting treatment, which is quite promising.

Will we start looking at more combination regimens of immunotherapy plus targeted therapy in bladder cancer?

Even more [impressive] are the data that we're seeing in the first-line setting for patients with cisplatin-ineligible disease. Two agents are currently approved [in that setting]. The median survival for 1 of the agents has been reported at 15.9 months. This appears to be much better than what we would typically expect for this patient population, which is approximately 9 months when they are treated with carboplatin-based therapy. In bladder cancer, the next step is obviously to combine agents. One of the interesting things to look at is other immune checkpoints, such as CTLA-4. We are seeing ongoing studies that are looking at combining ipilimumab (Yervoy) with nivolumab. Also, another randomized phase III trial is testing durvalumab with tremelimumab, which is a CTLA-4 antibody and PD-L1 combination. It appears that this combination may actually lead to higher response rates, and hopefully these responses are durable.

Are these targeted plus immunotherapy regimens also going to translate to kidney cancer treatment?

What we are also seeing is a combination with IDO1 inhibitors, in particular [the PD-1 inhibitor] pembrolizumab plus epacadostat, which is an oral IDO1 inhibitor. Those drugs are now entering phase III trials, as well. In kidney cancer, combinations are absolutely the future. However, what is unique about kidney cancer is that not only is it an immune-responsive tumor, but this is a tumor where VEGF-targeted agents are already a standard of care. Phase I data of the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, and pembrolizumab plus lenvatinib are demonstrating very promising response rates upwards of 70%.

What does this mean for the role of chemotherapy as time goes on?

This demonstrates that there may be synergy between these agents to generate a more effective antitumor immune response. Ultimately, I do believe that these agents will lead to new standards of care in the first-line setting. Ongoing randomized trials hope to demonstrate that this combinatorial approach will lead to durable responses and better overall survival. In bladder cancer, where we use chemotherapy often, I don't think chemotherapy is going to go away. In the first-line setting, approximately 5% or 10% of patients have cancer that is rapidly growing and highly symptomatic. We know for those patients, immunotherapy is not very effective. They are better treated with chemotherapy. Certainly, because we know that a significant proportion of patients will not respond to the immunotherapy, chemotherapy can still be an effective tool in the second-line setting. There is emerging evidence that certain forms of chemotherapy may combine well with immunotherapy, so we may also see combinatorial approaches. There are certainly phase III trials addressing that question, as well.