Oncologists Should Think 'Immunotherapy First' in Kidney Cancer, Expert Says

The field of immunotherapy has been revitalized thanks to the approval of checkpoint inhibitors, and according to Mario Sznol, this could prove beneficial to patients with RCC.

Patients with metastatic renal cell carcinoma (RCC) should talk with their health care team about considering immunotherapy alongside VEGF and mTOR tyrosine kinase inhibitor (TKIs). This is a highly effective treatment for this group of patients, according to Mario Sznol, at the New York GU: 9th Annual Interdisciplinary Prostate Cancer Congress and other Genitourinary Malignancies.

“I think physicians ought to be first thinking about immunotherapies, try and give patients durable remissions and then come back with targeted agents when those fail,” said Sznol, professor of Medicine (Medical Oncology) at Yale Cancer Center. “Obviously, every patient is different. Some of them must get VEGF inhibitors or mTOR inhibitors first.”

Immunotherapy has been a sleeping giant, since the approval of high-dose interleukin-2 (IL-2) in 1992 for RCC. Now, the field has been revitalized by the success of the checkpoint inhibitors. This was demonstrated by the FDA approval of the PD-1 inhibitor Opdivo (nivolumab) for patients with RCC following prior anti-angiogenic therapy, in November 2015, based on an extension in overall survival (OS) in the CheckMate-025 trial.

In the open-labl CheckMate-025 trial, 821 pretreated patients with advanced or metastatic clear-cell RCC were randomized in a one-to-one ratio to Opdivo or Afinitor (everolimus) . Of randomized patients, 803 received treatment. Opdivo was administered intravenously at three mg/kg every two weeks for 406 patients and Afinitor was given orally at 10 mg daily for 397 patients.

According to data published in The New England Journal of Medicine after a minimum follow-up of 14 months, the median OS was 25 months with Opdivo versus 19.6 months with Afinitor. Median PFS was 4.6 and 4.4 months in the Opdivo and Afinitor arms, respectively.

Among patients with PD-L1 expression at least 1 percent, median OS was 21.8 versus 18.8 months for Opdivo and Afinitor, respectively. In patients with PD-L1 expression less than 1 percent, median OS was 27.4 and 21.2 months in the two arms, respectively. Similar outcomes were observed when using a five percent threshold for PD-L1 expression status, although only a small number of patients were evaluable by this criterion.

“As it turns out, in kidney cancer, PD-L1 is not a very good biomarker for Opdivo because the improved survival is seen, whether you were PD-L1—positive or negative,” said Sznol. “The PD-L1–positive patients seem to have an overall worse prognosis, even though they benefitted from Opdivo.”

The rate of grade 3/4 toxicities was lower with Opdivo (19 percent) versus Afinitor (37 percent). The most common grade 3/4 adverse events were fatigue (2 percent) in the Opdivo arm and anemia (8 percent) in the Afinitor arm. Two treatment-related deaths were reported for the Afinitor group and none for the nivolumab cohort.

“It does improve survival. There are few patients who have long durable remissions, but we are not curing the majority of patients,” said Sznol. “It sets a new standard. However, maybe Yervoy/Opdivo may be the next step. VEGF-targeted agents with anti—PD-1/PD-L1 might be the next step."

A phase 3 study is currently comparing Opdivo plus the CTLA-4 inhibitor Yervoy (ipilimumab) as a frontline therapy for patients with metastatic RCC. In this study, the combination will be compared with Sutent (sunitinib), the current frontline standard of care (NCT02231749).

“One of the most exciting studies completed accrual: Yervoy and Opdivo versus Sutent . We are just waiting for the results to come out,” said Sznol.

There are a number of other novel combination studies currently under way for patients with RCC, including the phase 3 exploration of Avastin (bevacizumab) plus the PD-L1 inhibitor atezolizumab versus Sutent (NCT02420821). Additionally, there are other trials looking at anti—PD-1 agents with VEGF or mTOR inhibitors, said Sznol. As it stands now, the future looks bright.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.