Immunotherapy should be considered along with VEGF and mTOR TKIs as a highly effective treatment modality for patients with metastatic renal cell carcinoma (RCC).
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“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 nivolumab (Opdivo) 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-label CheckMate-025 trial, 821 pretreated patients with advanced or metastatic clear-cell RCC were randomized in a 1:1 ratio to nivolumab or everolimus. Of randomized patients, 803 received treatment. Nivolumab was administered intravenously at 3 mg/kg every 2 weeks (n = 406) and everolimus (Afinitor) was given orally at 10 mg daily (n = 397).
According to data published inThe New England Journal of Medicineafter a minimum follow-up of 14 months, the median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93;P= .002). Median PFS was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03; P= .11).
Among patients with PD-L1 expression ≥1%, median OS was 21.8 versus 18.8 months for nivolumab and everolimus, respectively. In patients with PD-L1 expression ≤1%, median OS was 27.4 and 21.2 months in the two arms, respectively. Similar outcomes were observed when using a 5% 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 nivolumab because the improved survival is seen, whether you were PD-L1positive or negative,” said Sznol. “The PD-L1–positive patients seem to have an overall worse prognosis, even though they benefitted from nivolumab.”
The rate of grade 3/4 toxicities was lower with nivolumab (19%) versus everolimus (37%). The most common grade 3/4 adverse events were fatigue (2%) in the nivolumab arm and anemia (8%) in the everolimus arm. Two treatment-related deaths were reported for the everolimus 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 ipilimumab/nivolumab may be the next step. VEGF-targeted agents with antiPD-1/PD-L1 might be the next step."
A phase III study is currently comparing nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy) as a frontline therapy for patients with metastatic RCC. In this study, the combination will be compared with sunitinib (Sutent), the current frontline standard of care (NCT02231749).
“One of the most exciting studies completed accrual: ipilimumab and nivolumab versus sunitinib. 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 III exploration of bevacizumab (Avastin) plus the PD-L1 inhibitor atezolizumab versus sunitinib (NCT02420821). Additionally, there are other trials looking at antiPD-1 agents with VEGF or mTOR inhibitors, said Sznol. As it stands now, the future looks bright.