Expert Calls for More Research in Checkpoint Blockade for Upper Tract Urothelial Cancers

Elizabeth Plimack, MD, MS

The excitement among urologic oncologists about the potential for checkpoint blockade treatments, especially in bladder cancer, is almost palpable. Results from ongoing trials involving atezolizumab, pembrolizumab, nivolumab, and avelumab in bladder cancer are eagerly awaited. But there is one subset of patients who require special attention: patients with upper tract urothelial cancer (UTUC). The “upper tract” sessions created quite a buzz among the attendees of the Society of Urologic Oncology annual meeting in Washington, DC, December 2-4.

“For my presentation, I was charged with talking about checkpoint blockade in UTUC, a topic for which there are no data,” said Elizabeth Plimack, MD, MS, an associate professor of hematology/oncology and director of genitourinary clinical research at Fox Chase Cancer Center. “Looking at these patients as a subset has not been explored.” The subset has not been carved out relative to the larger group made up of the urothelial cohort of the checkpoint inhibitor trials. In addition, preclinical work has been conducted in the pan epithelial space, but it is not specific to upper tract.

Over the past year during medical meetings, compelling evidence has been presented about the various checkpoint inhibitors in bladder cancer,1-5 but, additionally there have been some provocative papers looking at genomic sequencing of upper tract compared with bladder that shows certain differences, according to Plimack.

“One of the challenges associated with upper tract is collecting enough tissue samples to conduct analysis,” said Plimack. “We can only use tissue that has been resected and those samples represent the more aggressive forms of upper tract cancers.”

Plimack offered some initial steps to further elucidate UTUC. “The first step is to look at the subsets in these larger trials and to see if there’s anything that stands out in the group. It may be that they perform just as well in these metastatic trials. I think therapy directed toward upper tract will come after it is better defined in the wider group.”

Mutations and mutational burden may play a role in treatment for both chemotherapy and immunotherapy. In some upper tract tumors, especially those associated with Lynch syndrome or certain carcinogens, there may be a hypermutation phenotype that may render those tumors more susceptible to immunotherapy.

This may be significant because mismatch-repair status has been suggested as a potential predictor of clinical benefit with pembrolizumab in a phase II study by Le, et al. 6 The researchers conducted a phase II study to evaluate the clinical activity of pembrolizumab in 41 patients with progressive metastatic colorectal carcinoma with or without mismatch-repair deficiency. The co-primary endpoints were the immune-related objective response rate (ORR) and the 20-week immune-related progression-free survival (PFS) rate.

Le and colleagues reported that the immune-related ORR and immune-related PFS rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair—deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median PFS and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P < .001], and hazard ratio for death, 0.22 [P = .05]). Patients with mismatch repair—deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related ORR, 71% [5 of 7 patients]; immune-related PFS rate, 67% [4 of 6 patients]).

Although some of the findings reported with checkpoint inhibitors have been dramatic, Plimack emphasized that there are adverse effects. “It’s important not to under-emphasize them,” she said. “Defining treatment related toxicity for some of these immunotherapy trials has been a challenge.”

The intended effect of these agents is to get the immune system to attack the tumor, but sometimes that results in healthy tissue damage. “The effects can manifest in a wide spectrum of symptoms, which is different from targeted therapy or chemotherapy. With these agents it’s always a surprise and it can happen at any time, sometimes months into therapy. They deserve a special focus on how to manage them.”

Plimack concluded her presentation with a plea for additional research. “Given the biological differences suggested between upper tract and urinary bladder cancer, it’s time to form some hypotheses and to test them with dedicated trials and analysis.”

References

1. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-562.
2. Kim JW, Bellmunt J, Powles T, et al. Clinical activity, safety, and biomarkers of MPDL3280A in metastatic urothelial bladder cancer: additional analysis from phase IA study. Presented at: 2015 Genitourinary Cancers Symposium. February 26-28; Abstract 297.
3. Rosenberg J, Petrylak D, Abidoye O, et al. Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 21LBA.
4. Plimack ER, Bellmunt J, Gupta S. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. 2015 ASCO Annual Meeting; May 29-June 2 Abstract 4502
5. Apolo AB, Infante JR, Hamid O, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic urothelial carcinoma: a phase Ib trial. Poster: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2630.
6. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372:2509-2520.