Motzer Makes Sense of Pivotal IO Trials in Frontline RCC

Immunotherapy combination regimens have revolutionized the first-line treatment paradigm for patients with clear cell renal cell carcinoma, explained Robert J. Motzer, MD, at the <em>37th Annual</em> CFS.

Robert Motzer, MD

Immunotherapy combination regimens have revolutionized the first-line treatment paradigm for patients with clear cell renal cell carcinoma (RCC), explained Robert J. Motzer, MD, at the37th AnnualCFS®.1

The game-changing data have come from 3 phase III randomized trials, all of which had a control arm of single-agent sunitinib (Sutent): the CheckMate 214 trial2(n = 1096) exploring nivolumab (Opdivo) plus ipilimumab (Yervoy); the KEYNOTE-426 trial3(n = 861) assessing pembrolizumab (Keytruda) plus the tyrosine kinase inhibitor (TKI) axitinib (Inlyta); and JAVELIN Renal 1014(n = 886), which explored avelumab (Bavencio) plus axitinib.

Cross-Trial Comparison

To compare the studies, Motzer, kidney cancer section head of the Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York, highlighted several measures of comparison in the intent-to-treat populations across the 3 trials.

Follow-up: Follow-up data are longest for nivolumab/ipilimumab at over 2 years (25.2 months). Follow-up is at about 1 year with pembrolizumab/axitinib (12.8 months) and avelumab/axitinib (12.0 months).

Response: The objective response rate (ORR) was slightly lower with nivolumab/ipilimumab (39%) compared with pembrolizumab/axitinib (59%) and avelumab/axitinib (51%). Motzer noted that the high ORR is a “salient feature” of TKI/immunotherapy combinations. However, complete response rate was higher with the dual immunotherapy regimen of nivolumab/ipilimumab (10.2%), compared with pembrolizumab/axitinib (5.8%) and avelumab/axitinib (3.4%).

Progression-Free Survival (PFS): The median PFS for nivolumab/ipilimumab versus sunitinib was 12.4 versus 12.3 months, respectively (HR, 0.98); 15.1 versus 11.1 months (HR, 0.69) with pembrolizumab/axitinib; and 13.8 versus 8.4 months (HR, 0.69) with avelumab/axitinib. Motzer said the longer median PFS with pembrolizumab/axitinib was “probably related to the TKI, since PFS seems to be most impacted by TKIs.”

Overall Survival (OS):Motzer explained that an OS benefit with nivolumab/ipilimumab (HR, 0.68) and pembrolizumab/axitinib (HR, 0.53) versus sunitinib has been demonstrated; however, the OS data are still not mature for avelumab/axitinib.

“For many oncologists, overall survival benefit trumps others, and so, for the most part, in choosing one treatment versus another in community practice, it’s been nivolumab/ipilimumab versus pembrolizumab/axitinib,” said Motzer.

Nivolumab/Ipilimumab Versus Pembrolizumab/Axitinib

Given the OS benefit demonstrated withnivolumab/ipilimumab versus pembrolizumab/axitinib, Motzer compared the CheckMate 214 and KEYNOTE-426 trials head to head.

A key component when comparing these trials, Motzer noted, is disease risk classification as determined by baseline characteristics. Risk evaluation categorizes patients’ status as either favorable, intermediate, or poor.

Among intermediate- and poor-risk patients, the data for the regimens in the 2 trials are similar. The ORR with nivolumab/ipilimumab was 42% versus 55.8% with pembrolizumab/axitinib. Complete response was higher with the nivolumab regimen at 9% versus 4.8%, respectively. Median PFS was 11.6 versus 12.6 months in the 2 arms, respectively. Motzer said both showed a “really good OS benefit,” with a 12-month OS rate of 80% (HR, 0.63) and 87% (HR, 0.52), respectively.

In favorable-risk patients in KEYNOTE-426, pembrolizumab/axitinib improved outcomes compared with sunitinib. In CheckMate 214, however, the ORR in the favorable-risk group was higher for single-agent sunitinib (52%) than nivolumab/ipilimumab (29%). The median PFS (25.1 vs 15.3 months) was also higher with sunitinib and the hazard ratio for OS was 1.45.

Motzer noted that with long-term follow-up, however, outcomes improve with nivolumab/ipilimumab in the favorable-risk group. Survival outcomes become similar between the 2 arms and the “durable complete response rate becomes higher with nivolumab/ipilimumab compared with sunitinib,” said Motzer.

Motzer also briefly touched on safety with the 2 trials, but did not note any differences that would heavily impact his treatment choice.

What Is the Optimal Choice?

Based on the data he presented, Motzer said that for intermediate- and poor-risk patients, “Nivolumab/ipilimumab or pembrolizumab/axitinib are both good choices and the primary choices that I offer my patients. It’s often an individual decision for the risks/benefits of one versus the other with each patient.”

He added, “All things aside, I tip toward nivolumab/ipilimumab in these patients because of the fact that data are more mature and [positive] quality-of-life data are available.”

Regarding the favorable-risk population, Motzer cited the National Comprehensive Cancer Network (NCCN) Guidelines.5“For patients who have favorable-risk disease, the preferred treatment according to NCCN is either pembrolizumab/axitinib or single-agent TKI; but, I also think nivolumab/ipilimumab is a possibility here if the patient and doctor feel the safety profile is acceptable.”


  1. Motzer R. First-line metastatic renal cell carcinoma: what is the right choice? Presented at 37th Annual CFS&reg;. November 6-8, 2019. New York, New York.
  2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Engl J Med.2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
  3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med.2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.
  4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med.2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.
  5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Kidney Cancer, version 2.2020. NCCN website. Published August 5, 2019. Accessed November 7, 2019.