Investigators Debate Frontline Doublet Vs Triplet Therapy in RCC


Rana M. McKay, MD, and Yousef Zakharia, MD, debate the pros and cons of doublet vs triplet combination therapies in the frontline setting for patients with renal cell carcinoma.

Rana M. McKay, MD

Rana M. McKay, MD

Although doublet immune-oncology (IO) regimens are the standard of care in the frontline treatment of renal cell carcinoma (RCC), triplet immunotherapy has shown to be effective in the first-line setting for patients, leading to a debate of whether triplet regimens increase efficacy or decrease safety and tolerability.

During a debate at the 2022 International Kidney Cancer Symposium, Yousef Zakharia, MD, a medical oncologist and clinical associate professor of internal medicine-hematology, oncology, and blood and marrow transplantation in the Department of Internal Medicine at University of Iowa Health Care, gave a presentation favoring doublet IO for first-line RCC. In opposition, Rana M. McKay, MD, a medical oncologist, and associate clinical professor of medicine at UC San Diego Health, presented a case in favor of triplet IO.1

Less is More

According to Zakharia, doublet combinations are the golden standard in first-line RCC, but a case can be made for triplet therapy in select subgroups. Patients who may benefit from a triplet regimen upfront are those with intermediate-/poor-risk RCC, and those with sarcomatoid features.

“Whether IO/IO or IO/TKI, doublets remain the standard of care in first-line setting. Triplet combinations, even if [they] becomes FDA approved, I would like to have very careful conversations with my patients. We would like to see more survival data and I'm hopeful for the future, we will be discussing more biomarker-driven arguments,” said Zakharia, during his presentation.

Multiple clinical trials have shown that combining multiple IO agents or combining IO agents with tyrosine kinase inhibitors (TKIs) provide good survival and responses in first-line RCC. In comparison with the use of single-agent pembrolizumab (Keytruda) as studied in KEYNOTE-427 (NCT02853344), in CheckMate-214 (NCT02231749), KEYNOTE-426 (NCT02853331), and CHECKMATE-9ER (NCT03141177), and CLEAR (NCT02811861), the median progression-free survival (PFS) with doublet therapy ranged from 11.6 months to 17.5 months vs 6.9 months with single-agent pembrolizumab. Zakharia’s argument in favor of doublet therapy was supported by results from CheckMate-214.


The phase 3, randomized, open-label CheckMate-214 study assessed 1096 patients with previously untreated advanced clear-cell RCC (ccRCC). The patients were randomly assigned 1:1 to received 3 mg/kg nivolumab (Opdivo) in combination with 1 mg/kg ipilimumab (Yervoy; ipi/nivo) or 50 mg sunitinib (Sutent) monotherapy. The coprimary end points evaluated in the study were overall survival (OS), objective response rate (ORR), and PFS in the intermediate- to poor-risk group.2

Overall, 550 patients were treated with doublet IO therapy and 546 received single-agent sunitinib. There were 425 patients in the doublet IO arm and 422 patients in the sunitinib arm who had intermediate- to poor-risk disease.

At a median follow-up of 25.2 months in the intermediate- to poor-risk subgroup population, the 18-month OS rate was 75% (95% CI, 70%–78%) with the combination vs 0% (95% CI, 55%–65%) with sunitinib. Median OS was not reach with IO therapy compared with 26.0 months in the sunitinib arm (HR, 0.63; P < .001). The ORR in the IO arm was 42% vs 27% with sunitinib (P < .001), and complete responses were observed in 9% and 1%, respectively. Ipi/Nivo showed a median PFS of 11.6 months compared with 8.4 months in the sunitinib arm (HR, 0.82; P = .03). The results did not cross the threshold for significant PFS improvement.

Ninety-three percent of patients who received the IO doublet experienced treatment-related adverse events (TRAEs) vs 97% of the sunitinib arm, and the TRAEs were high-grade in 46% vs 63%, respectively. TRAEs led to treatment discontinuation in 22% of the doublet IO arm vs 12% of the IO monotherapy arm.

“The other landmark CheckMate-214 has set up, nowadays, is the 5-year overall survival. In intermediate- and poor-risk [disease], you're seeing that, at 5 years, 43% of those patients are still alive…You might argue these patients are technically cured with ipi/nivo,” explained Zakharia. “We have a median overall survival of 47 months. This is very intriguing, and the data gets even more intriguing in sarcomatoid features,” he added.

In the sarcomatoid population, median follow-up was 42 months in a post hoc analysis of CheckMate-214. In 139 patients, the median OS was not reached (NR) in the doublet IO arm (95% CI, 25.2-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). The median PFS in patients with sarcomatoid RCC was 26.5 months with doublet IO vs 5.1 months with single-agent IO (HR, 0.54; 95% CI, 0.33-0.86; P = .0093).3

Zakharia noted that any newly-launched study of pembrolizumab plus axitinib (Inlyta) and selenomethionine may offer hope for triplet combination use for RCC in the future. As of now, he says, using less upfront is better.

Rationale for More Agents Upfront

McKay explained that there is evidence to support the use of triplet therapy in RCC. Research shows that combining the IO combination of ipi/nivo with the TKI, cabozantinib (Cabometyx), prolongs PFS and decreases the rate of progressive disease while increasing responses compared with doublet IO. Research also shows that the triplet therapy has a manageable safety profile.

“The IO/VEGF TKIs are a winner in the short game. They have great upfront responses of over 50%. The PFS is great, but we're still kind of lacking data on long-term durability and whether we cure patients with IO/VEGF therapy. With ipi/nivo, the Achilles heel of that regimen is at the primary [progressive disease] rate, [which] is around 20%. However, what we all hope for our patients is that we can cure them potentially. There's a tail on the curve, which we've seen with over 5 years of follow-up data, the PFS curves hold steady right at 30%,” explained McKay during her presentation.

Data supporting McKay’s argument were from the global, double-blind, randomized phase 3 COSMIC-313 study (NCT03937219).


COSMIC-313 included 855 patients who were randomized 1:1 to receive cabozantinib with ipi/nivo (n = 428) or ipi/nivo alone (n = 427). Of the patients enrolled, 75% of the triplet arm were classified as intermediate- to poor-risk compared with 25% of the doublet arm.4

The median PFS observed was not reached with the triplet regimen (95% CI, 14.0–NE) compared with 11.3 months (95% CI, 7.7–18.2) in the doublet arm (HR 0.73, 95% CI, 0.57–0.94; P = .013). Additionally, objectives responses were observed in 43% (95% CI, 37.2%–49.2%) of the triplet arm vs 36% (95% CI, 30.1%–41.8%) with the doublet. The median duration of response was NR in either treatment arm.

The triplet regimen led to grade 3/4 TRAEs in 73% of patients compared with 41% in the doublet arm. TRAEs led to discontinuation of all treatment components in 12% of the triplet arm vs 5% of the doublet arm.

McKay posed a question, saying, “How can we get the best of both worlds with wins in the short game and wins in the long game? How can we decrease the [progressive disease] rate [and] potentially offer long-term durability, and offer upfront primary tumor reduction?” She asked. McKay explained that this is where triplet therapy comes into play.


1. Zakharia Y and McKay, R. Debate 3: Doublet or Triplet as first-line treatment in kidney cancer case presentation. Presented at: 2022 International Kidney Cancer Symposium. November 4-5, 2022; Austin, TX.

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018; 378:1277-1290
doi: 10.1056/NEJMoa1712126

3. 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. Clin Cancer Res. 2021; 27(1): 78–86. doi: 10.1158/1078-0432.CCR-20-2063

4. Choueiri TK, Powles TB, Albiges L, et al. LBA8 - Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Ann Oncol. 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089

Related Videos
Karl Semaan, MD, MSc
Bradley McGregor, MD, discusses findings from a phase 1b study of abemaciclib  in clear cell renal cell carcinoma.
Toni K. Choueiri, MD
Neil J. Shah, MBBS
Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team; co-director, Kidney Cancer Program; professor, vice chair, Academic Affairs, Department of Medical Oncology & Therapeutics Research, City of Hope
Vivek Subbiah, MD
Marijo Bilusic, MD, PhD
Joshua Linscott, MD
Petros Grivas, MD, PhD
Sujith Samarasinghe, MD