Expert Compares Frontline Immunotherapy Studies in RCC

Robert J. Motzer, MD

Three game-changing immunotherapy trials have transformed the treatment paradigm in frontline clear cell renal cell carcinoma (RCC). At the 37th Annual CFS^®, Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, compared the findings from the three studies.

The 3 phase III randomized trials all 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 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 with nivolumab/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.”

References

1. Motzer R. First-line metastatic renal cell carcinoma: what is the right choice? Presented at 37th Annual CFS^®. 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. bit.ly/32pYknC. Published August 5, 2019. Accessed November 7, 2019.

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