Updated Findings Show Sustained OS Benefit With Nivolumab/Ipilimumab Combo in Frontline RCC

Nizar M. Tannir, MD

In updated 30-month follow-up data from the phase III CheckMate-214 trial, nivolumab (Opdivo) combined with low-dose ipilimumab (Yervoy) sustained strong responses and a survival benefit as a frontline treatment for patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC).¹

According to the findings, which will be presented during the upcoming 2019 Genitourinary Cancers Symposium, the combination demonstrated a 30-month overall survival (OS) rate of 60% with the immunotherapy combination versus 47% with sunitinib in the intermediate- and poor-risk population (HR, 0.66; 95% CI, 0.54-0.80;P<.0001). The objective response rates (ORRs) were 42% versus 29% (P= .0001), respectively, including complete response (CR) rates of 11% versus 1%. Among the responders, 52% of patients receiving nivolumab/ipilimumab had a response duration &ge;18 months compared with 28% of patients on the TKI arm.

Among all randomized patients (intent-to-treat [ITT] population) the 30-month OS rate was 64% with the immunotherapy combination versus 56% with sunitinib (HR 0.71; 95% CI, 0.59-0.86;P= .0003). The ORR in the ITT population was 41% versus 34% (P= .015), respectively, including CR rates of 11% versus 2%.

No new safety signals emerged at the long-term follow-up, with safety data remaining consistent with both the primary study analysis and historical data with these agents in RCC.

&ldquo;The results from this 30-month follow-up from the CheckMate-214 study are meaningful as they continue to demonstrate that in patients with advanced renal cell carcinoma, a population with considerable unmet treatment needs, there is potential for long-term survival benefits with the combination of nivolumab and ipilimumab,&rdquo; CheckMate-214 investigator Nizar M. Tannir, MD, FACP, department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said in a statement.

In the open-label trial, patients were randomized 1:1 to receive the combination of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 2 weeks off in every cycle (n = 425) or sunitinib at 50 mg once daily for a 4-weeks-on/2-weeks-off schedule (n = 422). After completion of 4 doses with the combination, nivolumab was given 240 mg intravenously every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes until disease progression or unacceptable toxicity.

Patients enrolled on the study had advanced or metastatic disease with no prior therapy. In the 1096 patients in the ITT population, 23% were considered favorable risk, 61% as intermediate risk, and 17% as poor risk in each arm. Additionally, about one-fourth in the ITT population had PD-L1 expression &ge;1%. Among the 847 patients in the intermediate- or poor-risk groups, 79% were classified as intermediate risk and 21% as poor risk in each treatment arm. Approximately one-quarter of patients in each arm had PD-L1 expression &ge;1%.

The coprimary endpoints were OS, ORR, and progression-free survival (PFS) as determined by an independent radiographic review committee in intermediate- and poor-risk patients.

In the primary data analysis, the nivolumab/ipilimumab combination demonstrated a 37% reduction in the risk of death versus sunitinib in intermediate- and poor-risk patients with advanced RCC, regardless of PD-L1 expression status (HR, 0.63; 99.8% CI, 0.44-0.89;P<.0001).²The median OS in these patients was not yet reached (95% CI, 28.2 months-not estimable) versus 25.9 months, respectively. In the overall population, 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).

However, favorable-risk patients had a significantly higher confirmed ORR with sunitinib versus nivolumab/ipilimumab at 52% versus 29% (P=.0002) and a significantly longer PFS (25.1 vs 15.3 months;P<.0001). Across the full ITT population, the ORRs were 39% and 32% (P= .0191) in the nivolumab/ipilimumab and sunitinib groups, respectively.

In the ITT population, the median PFS was not improved (12.4 vs 12.3 months; HR, 0.98; 99.1% CI, 0.79-1.23;P= .8498). The median PFS in the intermediate- and poor-risk group was 11.6 months with the combination versus 8.4 months with sunitinib (HR, 0.82; 99.1% CI, 0.64-1.05;P= .0331). APvalue of .009 was required for significance.

The overall safety profile was consistent with prior trials of nivolumab/ipilimumab. Adverse events (AEs) leading to discontinuation of treatment occurred in 22% of patients receiving nivolumab/ipilimumab 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 arm, the most common grade 3/4 AEs were hypertension (16%), fatigue (9%), and palmar-plantar erythrodysesthesia syndrome (9%). There were 7 treatment-related deaths in the combination group and 4 in the sunitinib group.

Based on the primary CheckMate-214 data analysis, the FDA approved the combination of nivolumab and ipilimumab in April 2018 as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.

References:

1. Tannir NM, Ar&eacute;n Frontera, Hammers HJ, et al. Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).J Clin Oncol. 2019;37 (suppl; abstr 547).
2. Motzer RJ, Tannir NM, McDermott DF, Frontera OA, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Eng J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.

Moreover, the combination was associated with an ORR of 41.6% (95% CI, 36.9%-46.5%;P<.0001) versus 26.5% for sunitinib (95% CI, 22.4-31.0) in the intermediate- and poor-risk patient populations. The median duration of response was not yet reached for the combination (95% CI, 21.8 to NE) versus 18.2 months for sunitinib (95% CI, 14.8-NE).