Immunotherapy Overtakes Targeted Therapy as First-Line Standard of Care for mRCC

Thomas Powles, MD

An extension in overall survival (OS) seen with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has completely changed the standard of care for patients with metastatic renal cell carcinoma (mRCC), Thomas Powles MBBS, MRCP, MD, told audience members during the 9th European Multidisciplinary Meeting on Urological Cancers.

“We have witnessed the replacement of VEGF-targeted therapy with combination immune therapy,” said Powles, clinical professor of genitourinary oncology, Barts Cancer Institute, London, United Kingdom. “First-line renal cancer has changed and will never be the same. I expect immune therapy will be frontline for many patients.”

The frontline evolution was brought about by findings from the CheckMate-214 study in which nivolumab combined with ipilimumab was compared with sunitinib (Sutent) in previously untreated patients with advanced or mRCC. Patients were randomized 1:1 to receive oral sunitinib at 50 mg a day for 4 weeks in 6-week cycles or nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab alone at 3 mg/kg every 2 weeks.

Patients were stratified based on the International Metastatic Renal Cell Carcinoma Database Consortium prognostic score into 3 categories: favorable, intermediate, and poor risk. The coprimary endpoints in intermediate and poor-risk patients were objective response rate (ORR), progression-free survival (PFS), and OS. Key secondary endpoints were ORR, PFS, OS in the intention-to-treat patients and adverse incidence rate in all treated patients.

Median PFS for patients in the nivolumab and ipilimumab arm was 11.6 months (95% CI, 8.7-15.5) compared with 8.4 months for sunitinib (95% CI, 7.0-10.8), representing an 18% reduction in the risk of progression or death (HR, 0.82; 99.1% CI, 0.64-1.05; P = 0.0331); however, this benefit was not found to be statistically significant, as a P value of .009 was required for the trial. In response to this, Powles suggested that PFS “is not a great endpoint for immune therapy trials.”

In those specifically with intermediate- and poor-risk RCC, there was a 37% reduction in the risk of death with the combination versus sunitinib (HR, 0.63; 99.8% CI, 0.44-0.89; P < .0001). There was not a benefit for the combination versus sunitinib in those with favorable risk. In the intention-to-treat patients, including the good-risk patients, the immune therapy arm still demonstrated an advantage over sunitinib. The median OS was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003).

Across the full study, the ORR was 39% for nivolumab/ipilimumab versus 32% with sunitinib (P =.0191). The ORR in the intermediate/poor risk patients was 42% in patients assigned to nivolumab plus ipilimumab compared with 27% in those assigned to sunitinib (P <.0001). Favorable risk patients had a significantly higher ORR with sunitinib versus the combination arm (52% vs 29%; P =.0002), as well as a significantly longer PFS (25.1 vs 15.3 months; P <.0001). Results from the favorable arm have caused controversy, given the complexity of explaining the findings, Powles noted.

Adverse events (AEs) leading to discontinuation occurred in 22% of patients in the combination immunotherapy group compared with 12% in the sunitinib group. The most common grade 3/4 AEs in the combination group were fatigue (4%) and diarrhea (4%). In the sunitinib group, the most common grade 3/4 AEs were hypertension (16%), fatigue (9%), and Palmar-plantar erythrodysesthesia syndrome (9%). According to the patient-reported kidney cancer symptom index, quality of life was better among patients in the immunotherapy combination arm than sunitinib. Powles described this “live longer, feel better.”

Other immunotherapy combinations are currently being explored for patients with mRCC. One of these combinations looked at the PD-L1 inhibitor atezolizumab (Tecentriq) with bevacizumab (Avastin), atezolizumab alone, or sunitinib alone. This approach was tested in a randomized phase II trial (IMmotion150) involving 300 patients. Powles noted that the phase III study is expected out soon.

In the IMmotion150 study, the atezolizumab and bevacizumab combination showed a median PFS of 14.7 months compared with 7.8 months with sunitinib and 5.5 months for atezolizumab alone. In patients with PD-L1 expression on immune cells (IC), the combination further outpaced the other 2 arms. “This suggests that biomarkers may be important for this subgroup of patients,” said Powles. “It may be that the biomarker is different for different drugs and different combinations. I think we’ll be routinely using biomarkers in kidney cancer within the next 5 years.”

Studies involving axitinib (Inlyta) with pembrolizumab also demonstrated high response rates, in the region of 70%, said Powles. Looking ahead, Powles said that this initial round of practice-changing trials has paved the way for the second generation of trials.

The incidence of adverse events was surprising “because everyone talks about how toxic these drugs are,” said Powles. “Yet, only 7 deaths were reported in the nivolumab and ipilimumab arm, about 1.2% [of patients].”