Durable Response Can Remain After Stopping Immunotherapy Treatment for Kidney Cancer

According to findings from a small study of patients with metastatic renal cell carcinoma (mRCC), some patients who stop treatment with PD-1/PD-L1 immunotherapy because of immune-related adverse events (irAE) still were sustained responders after more than six months.

In this retrospective analysis involving 19 patients, eight (42 percent) were able to remain off additional systemic therapy for more than six months, and of these, six patients continue to be free from progression, reported Rana R. McKay, M.D., 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 percent) 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 (14 patients) were men. Five patients (26 percent) had aggressive disease according to common diagnostic criteria, and more than half of the overall group (58 percent) 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 percent) needed steroids to manage their irAEs, and two 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 eight durable responders, three patients were deemed “immediate progressors,” that is, they required additional treatment less than four months after discontinuing their PD-1/PD-L1 therapy; the eight other patients stopped responding four to six 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 (four months), and the median time off treatment was two 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 2 OMNIVORE study will examine the optimized management of Opdivo (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, M.D., 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.”