Nivolumab/Ipilimumab Established as New Standard in Frontline sRCC

The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated long-term survival and response benefits as treatment of poor- to intermediate-risk patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) compared with sunitinib (Sutent), according to published results from the phase 3 CheckMate 214 clinical trial.

Rationale for the CheckMate 214 trial (NCT02231749) comes from preclinical research in sRCC which showed that PD-1/PD-L1 immune checkpoint inhibition is effective for the treatment of these patients. There was also an unmet medical need for new therapies to improve upon the objective response rates (ORRs) of 16% to 33%, progression-free survival (PFS) on a range of 2 to 5 months, and median overall survival (OS) of 5 to 12 months observed with the available therapies in the sRCC treatment landscape.

The study included 1096 patients who were randomized 1:1 to received nivolumab 3mg/kg in combination with ipilimumab 1 mg/kg every 3 weeks or sunitinib 50 mg/kg orally every 4 weeks for a 6-week cycle. The primary end points of the study were investigator-assessed ORR, OS, and PFS in the poor- to intermediate-risk patient group. The same outcomes were explored as secondary end points in patients of all risk levels.

A total of 550 patients in the study received the immunotherapy combination and 546 received sunitinib. Poor- to intermediate-risk patients made up 425 of the subjects in the combination arm and 422 in the sunitinib arm.

In the nivolumab/ipilimumab arm, the median OS was not reached (95% CI, 25.2 months-not estimable [NE]) compared with 14.2 months (95% CI, 9.3-22.9) in the sunitinib arm (HR, 0.45; 95% CI, 0.3-0.7; P =.0004). Investigators led by Nizar M. Tannir, MD, noted a 42-month probability of survival of 50.1% (95% CI, 37.9%-61.2%) with the combination versus 22.5% (95% CI, 13.3%-33.4%) with sunitinib.

The median PFS observed with nivolumab plus ipilimumab was 26.5 months (95% CI 8.4-NE) compared with 5 months (95% CI, 4.0-6.9) in the sunitinib arm (HR, 0.54; 95% CI, 0.3-0.9; P =.0093).

In terms of responses, higher ORRs were observed in the nivolumab/ipilimumab arm compared with the sunitinib arm at 60.8% (95% CI, 49%-72%) versus only 23.1% (95% CI, 14%-35%; P <.0001). No increase or reduction in target lesion size was observed in the combination arm,

Treatment with nivolumab plus ipilimumab had a median time to response of 2.8 months (range, 0.9-18.1) compared with 2.8 months (range, 2.4-23.5) with sunitinib. The median duration of response observed with the combination was not reached (95% CI, 22.5 months-NE) versus 20.7 months in the sunitinib arm (95% CI, 7.2-38.7). Notably, 69% of the nivolumab plus ipilimumab population had ongoing responses at the time to data cutoff, compared with 53% of the sunitinib population. The percentage of patients who remained on treatment at the time of data cutoff was 24% of the combination group versus 7% of the sunitinib group. Treatment-free interval without subsequent therapy occurred in 44% of the nivolumab/ipilimumab arm compared with 335 of the sunitinib arm.

According to baseline characteristics, 51% of the nivolumab/ipilimumab population had tumor PD-L1 expression ≥1%, as did 53% of the sunitinib population.

In the patients with poor- to intermediate-risk disease and tumor PD-L1 expression ≥1%, the median PFS was not reached (95% CI, 29.9 months-NE) with the combination of nivolumab/ipilimumab versus 20.9 months (95% CI, 9.3-41.2) with sunitinib (HR, 0.42; 95% CI, 0.20-0.91; P =.0260). The median OS was 40.4 months (95% CI, 18.5-NE) with the combination versus 13.8 months (95% CI, 5.5-20.3) with monotherapy (HR, 0.38-0.20-0.71; P =.0020). The ORR observed in this group was 69.4% with nivolumab/ipilimumab versus 24.5% with sunitinib (Odds ratio, 7.1%; 95% CI, 2.2-23.9).

Among patients with PD-L1 expression <1%, the median PFS was 10.9 months (95% CI, 3.3-NE) in the combination arm compared with 5.1 months (95% CI, 2.9-17.0) in the monotherapy arm (HR, 0.65; 95% CI, 0.34-1.24; P =.1852). The ORR was 54.3% for the combination arm versus 20.5% for the sunitinib arm.

The safety analysis of CheckMate 214 revealed treatment-related adverse events (TRAEs) in 97% of patients who received nivolumab plus ipilimumab as well as 97% of the patients who received sunitinib. The TRAEs were grade 3 and grade 4 in 49% of the combination group and 45% of the monotherapy group. The most frequent TRAEs in the combination arm versus the monotherapy arm were fatigue (47% vs. 49%), pruritus (29% vs. 8%), diarrhea (25% vs. 37%), and rash (25% vs. 9%).

TRAEs led to treatment discontinuation in 21% of patients who received nivolumab plus ipilimumab and 12% of those who received sunitinib. There was on treatment-related death in the combination arm, which was a 79-year male patient with grade 4 hepatic failure and grade 3 febrile neutropenia. No deaths were reported in the sunitinib arm.

The efficacy and safety data from CheckMate 214 led the investigators to recommend nivolumab plus ipilimumab as a frontline treatment option for patients with sRCC.

“The data presented here show that with 42 months’ minimum follow-up, nivolumab plus ipilimumab offers the potential to achieve durable responses, high ORR and CR rates, and OS benefit, supporting this combination as a standard of care for first-line treatment in patients with

clear-cell sRCC and [poor- to intermediate-risk disease],” wrote Tannir et al.

_References:

_{Tannir NM, Signoretti S, Choueri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Published online September 1, 2020. Accessed September 8, 2020. doi: 10.1158/1078-0432.CCR-20-2063}