Progress in Immunotherapy Continues, But Pseudo-Progression Is a Concern

Daniel Petrylak, MD

Interest is high among urologists and medical oncologists with “the explosion of checkpoint blockade inhibition studies” that initially made inroads in melanoma and non-small cell lung cancer (NSCLC), but is also gaining traction in bladder cancer, said Daniel Petrylak, MD, director of the Genitourinary Oncology Research Program and co-director of the Signal Transduction Program at the Yale Cancer Center during an OncLive Insights Expert Perspectives program about the management of muscle-invasive bladder cancer.

He was joined on the panel by Dean F. Bajorin, MD, an attending physician at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Medical College of Cornell University, and Evan Y. Yu, MD, associate professor in the Department of Medicine, Division of Oncology at the University of Washington, Seattle Cancer Care Alliance.

Considering that there have been no major increases in survival in bladder cancer in more than 30 years, immunotherapeutic approaches are welcome in this setting. The rationale for investigating immunotherapy in bladder cancer gained interest because of the positive results of bacillus Calmette-Guérin (BCG) therapy in superficial disease. The use of BCG has resulted in significantly improved outcomes for patients with non-muscle invasive bladder cancer.

The phase I study by Powles et al¹ demonstrated that the anti-programmed death-ligand 1 (PD-L1) antibody, MPDL3280A, is highly active, especially in bladder cancer. MPDL3280A is a high-affinity, engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 and B7.1. The effect can restore antitumor T-cell activity and enhance T-cell priming.

“If you look at the patients who are high expressers of PD-L1, the collective response rate in that group was 52%. In contrast, in patients who were low expressers, their response rate was 11%,” said Bajorin, MD. “It really looks like the activity of the drug follows the biology of the development of the drug.” He added that the patients in the trial were generally frail and had multiple comorbidities.

Another significant characteristic is the agent’s relatively favorable toxicity profile, including a lack of renal toxicity. “Most of what we’re seeing is fatigue and rash, but no major toxicities. It’s not like what we have seen with chemotherapy in this patient population before, and that’s encouraging,” continued Bajorin.

The Bellmunt et al² study demonstrated the durable response seen in patients. “It’s encouraging because the median progression free survival in some of the older studies was 2½ months. Yet, we are seeing swimmer plots that are going out in quite lengthy responses,” said Bajorin.

This extended durable response has resulted in stable disease, too, added Evan Y. Yu, MD. Treating patients on a long-term basis with MPDL3280A is encouraging, said Petrylak. He said that he has seen three complete responses and one patient is now approaching two years of treatment.

“It’s unlike what we’ve seen with some of the other CTLA-4 antibodies where patients could develop hypophysitis or develop gastrointestinal complaints, colitis, and liver function test abnormalities,” said Petrylak. Because the response rate is rapid, patients can be evaluated earlier in the treatment regimen. “I think the whole issue about trying to figure out who is going to respond and who is not going to respond is really a crucial one.”

Tumors that respond to immune therapy tend to have high mutational rates and they tend to be tumors that have been exposed to external carcinogens like tobacco or other chemicals. As the tumor evolves over time, “PD-L1 expression can be affected based on exposures,” said Yu. This characteristic may be one of the reasons why bladder cancer is unique with its response rates, added Petrylak.

MPDL3280A was granted breakthrough status by the FDA last year based on phase I data, and additional studies of the agent in urothelial bladder cancer (UBC) are planned and ongoing. A phase II, multicenter, single-arm study of MPDL3280A in patients with locally advanced or metastatic UBC (NCT02108652) is evaluating MPDL3280A (1200 mg) every 21 days for up to 16 cycles in 300 cisplatin-refractory patients and 100 treatment-naïve and platinum-ineligible patients.

“It’s going to be interesting to see whether platinum ineligible patients who are chemotherapy naïve will respond or not,” said Petrylak. “We may see a very different pattern based upon prior exposure to chemotherapy or other agents.”

The challenge of immunotherapy in genitourinary cancer, and bladder cancer in particular, concerns pseudo-progression. As the name suggests, the inflammatory response looks like disease progression, but it actually is not. It may precede a good and prolonged response to the immunotherapy. But because it looks just like progression on scans, it is important to know about it and avoid discontinuing a potentially very effective treatment based on a misinterpretation of what the scans suggest.

This concern will be addressed by the current set of clinical trials involving checkpoint inhibitors. “Physicians can treat beyond that initial progression and wait until the next time point to see if pseudo-progression is the cause,” said Yu. “It will require that clinicians rethink our response criteria,” added Petrylak.

That is not always a bad problem to have, said Bajorin. “We have an active class of drugs, and needing to decipher what might contribute to activity is a good problem to have, especially as more research is conducted.”

The future of immunotherapy in bladder cancer looks promising. The drug pipeline in this arena is quite robust, said Petrylak. Understanding the mechanism of response and next- generation sequencing will play a major role for future studies.

“We are involved in a large trial that is looking at targeted therapy with monoclonal antibodies that are linked to cytotoxic agents. Integrating these treatments, looking at particular markers, and understanding how to target tumors better is going to be a trend in the future,” said Petrylak.

“These are exciting times for bladder cancer,” concluded Petrylak. “I think that a lot of things are beginning to converge.”

References

1. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL320A and clinical activity in patients with metastatic urothelial bladder cancer (UBC). Presented at the annual meeting of the American Society of Clinical Oncology, May 31, 2014. J Clin Oncol. 32:52. Abstract 5011.
2. Bellmunt J, Petrylak DP, Powles TB, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in pts with metastatic urothelial bladder cancer (UBC). Presented at the European Society for Medical Oncology 2014, September 29, 2014. d. 2014;25(suppl_4): iv280-iv304.