Durable Responders Emerge Even After Stopping Their PD-1/PD-L1 Therapy for Kidney Cancer

Rana R. McKay, MD

Some patients who had to stop their PD-1/PD-L1 immunotherapy because of an immune-related adverse event (irAE) proved to be sustained responders, even after being off the therapy for more than 6 months, according to newly reported findings from a small study of patients receiving checkpoint inhibitors for metastatic renal cell carcinoma (mRCC).

In this retrospective analysis involving 19 patients, 8 (42%) were able to remain off additional systemic therapy for more than 6 months, and of these, 6 patients continue to be free from progression, reported Rana R. McKay, MD, during a presscast in advance of the 2017 Genitourinary Cancer Symposium to be held February 16-18 in Orlando, Florida.

“What we’ve demonstrated is that despite these patients stopping their treatment, there is a subset of them who continue to have disease that is in check and controlled, despite their not being on any therapy,” said McKay, an assistant professor at UC San Diego School of Medicine. “When the durable responders stopped their therapy due to a toxic event, they were able to remain off any therapy with their disease being controlled.”

The analysis is based on patients with mRCC who received treatment at 1 of 5 academic centers but had ceased PD-1/PD-L1 inhibitor therapy due to an irAE. Reasons for stopping therapy included joint pain, eye problems, diarrhea, and organ inflammation. Most of the patients (63%) had received their PD-1/PD-L1 treatment as monotherapy, and the remainder had their immunotherapy in combination with other systemic treatments, McKay noted.

Patients were a median age of 68 years, and the majority (n = 14) were men. Five patients (26%) had aggressive disease according to common diagnostic criteria, and more than half of the overall group (58%) had had prior systemic therapy.

“The patients in this cohort experienced a wide spectrum of adverse events affecting different organ systems,” McKay explained, among them, pneumonitis, myositis, nephritis, hepatitis, pericarditis, and myocarditis. Sixteen patients (84%) needed steroids to manage their irAEs, and 2 required additional immunosuppressive agents to treat their symptoms, McKay said. At the time of the analysis, 10 patients were experiencing ongoing toxicity.

In addition to the 8 durable responders, 3 patients were deemed “immediate progressors,” that is, they required additional treatment less than 4 months after discontinuing their PD-1/PD-L1 therapy; the 8 other patients stopped responding 4 to 6 months after discontinuing treatment.

Among the durable responders, the median time on treatment prior to their therapy discontinuing was 11 months, and the median time off treatment was 20 months, McKay said. For the immediate progressors, however, the median time on treatment was much shorter (4 months), and the median time off treatment was 2 months.

The authors cautioned that although the study findings are novel and compelling, the number of participants is small, and prospective studies are needed to further explore how immunotherapy can be customized:

“Larger studies are warranted to evaluate the need for continuous drug dosing in all patients, identify patients in which continuous dosing is not required, and to evaluate long-term outcomes in this population,” they concluded.

Accordingly, McKay said that the planned phase II OMNIVORE study will examine the optimized management of nivolumab based on response in patients with mRCC, with an eye toward elucidating what clinical characteristics may be linked to a durable immunotherapy response.

“This is really important work,” noted ASCO expert and presscast moderator Sumanta Pal, MD, given the veritable “tidal wave” of new immunotherapies he said that unfortunately also carry a risk of irAEs. “If a patient has immune-related side effects, the impact can be serious, but there is also the possibility that they could have a protracted benefit from the drug in terms of their cancer remaining dormant or shrinking.”

“More broadly,” Pal said, “these findings call into question the current standard of continuous treatment with immunotherapy.” However, he added, “Further research is needed to validate this phenomenon.”

McKay RR, Martini D, Brandao Moreira R, et al. Outcomes of PD-1/PD-L1 responders who discontinue therapy for immune-related adverse events (irAEs): Results of a cohort of patients with metastatic renal cell carcinoma. J Clin Oncol. 2017;35 (suppl 6S; abstract 467).

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