Guideline Recommendation Favors Doublet Over Triplet Therapy in ccRCC

Targeted Therapies in OncologyFebruary I, 2024
Volume 13
Issue 2
Pages: 77

New guideline favors doublet therapy over triplet for metastatic renal clear cell cancer due to lower toxicity. COSMIC-313 trial shows improved progression-free survival with triplet therapy but significant adverse events.

A new guideline update recommends the continued use of doublet therapy over triplet therapy for all patients with metastatic renal clear cell cancer (ccRCC) because of the increased toxicity associated with triplet therapy. The recommendation is based on the data from the COSMIC-313 trial (NCT03937219), which reported increased progression-free survival (PFS) using the triplet therapy of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy), meeting its primary end point. However, the triplet combination produced significant toxicity, resulting in grade 3 or 4 adverse events (AEs) in 79% of patients in the experimental arm compared with 56% of patients receiving nivolumab and ipilimumab plus placebo in the control arm.1

“For patients diagnosed with ccRCC, the incorporation of data from the COSMIC-313 trial is not expected to influence current practices or treatment selection. Our approach continues to rely on the International Metastatic Renal Cell Carcinoma Database Consortium clinical risk stratification to identify suitable candidates for either dual immunotherapy or the combination of VEGF inhibitors with immunotherapy tablets. Health care professionals are advised to consider these clinical criteria when evaluating treatment options for their patients with doublets still the mainstay of our upfront treatments,” Tian Zhang, MD, MHS, explained in an interview with Targeted Therapies in Oncology. Zhang is an associate professor in the Department of Internal Medicine and a medical oncologist at Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center in Dallas.


In the phase 3, double-blind COSMIC-313 trial, 855 patients with advanced renal cell carcinoma (RCC) who were previously untreated were randomly assigned into 2 arms.

In the experimental arm, 428 patients received 40 mg of cabozantinib daily plus 3 mg/kg of body weight of nivolumab and 1 mg/kg of ipilimumab every 3 weeks for 4 cycles. In the control arm, 427 patients received placebo plus the same dose of nivolumab and ipilimumab for the same duration. After 4 weeks of initial treatment, patients in both arms received 480 mg of nivolumab maintenance therapy every 4 weeks for up to 2 years.2

End Points

PFS as the primary end point of the trial was determined by blinded independent review according to RECIST 1.1. This was assessed in the fi rst 550 patients who had been randomly assigned. The secondary end point was overall survival, which was assessed in all patients who had been randomly assigned.1

The probability of PFS at 12 months in the experimental arm was 0.57 (95% CI, 0.50-0.63) compared with 0.49 (95% CI, 0.42-0.55) in the control arm, and the HR for disease progression or death was 0.73% (95% CI, 0.57-0.94; P = .01). In the experimental arm, the median PFS at 14 months was not reached (NR; 95% CI, 14.0-NR) compared with 11.3 months (95% CI, 7.7-18.2) in the control arm.2

Regarding safety, dose modifications due to AEs were more frequent in patients in the experimental arm (91%) than the control arm (71%), as well as dose delays (90% vs 70%, respectively) and dose reductions of cabozantinib or placebo (54% vs 20%).

The most common any-grade AEs were diarrhea (50% vs 23%, respectively), increased alanine aminotransferase (ALT; 49% vs 19%), and increased aspartate aminotransferase (AST; 46% vs 17%).

These were also the most common grade 3 or 4 AEs, with diarrhea experienced by 6% of patients in the experimental arm compared with 4% in the control arm, increased ALT experienced by 27% vs 6%, and increased AST experienced by 20% vs 5%, respectively. In the experimental arm, 29% of patients continued treatment after disease progression vs 41% of patients in the control arm; the median duration of exposure to the treatment was 10.9 months (range, 0.2-28.5) vs 10.3 months (range, 0.1-28.1), respectively.2

Ongoing Phase 3 Trials

COSMIC-313 was the main trial to influence the rapid recommendation; however, Zhang noted that there are 3 ongoing phase 3 trials.

The PDIGREE study (NCT03793166) is designed to answer how best to adapt treatment for responses and optimize sequential treatments currently available to improve outcomes for patients with RCC.3 The LITESPARK-012 trial (NCT04736706) is also evaluating a triplet regimen that consists of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) with or without belzutifan (Welireg) or quavonlimab; it has just closed enrollment.4

Lastly, the PROBE trial (NCT04510597) will evaluate whether the timing of cytoreductive nephrectomy at 3 months will improve the therapeutic benefi t of immunotherapies.5

Patients in this trial receiving immunotherapy doublet therapy will be randomly assigned 1:1 to either receive a cytoreductive nephrectomy on the primary tumor or continue with the systemic therapy, Zhang explained.

“It’s still a dynamic time in the metastatic kidney cancer space, characterized by signifi cant advancements in treatment options leading to improved patient outcomes. Our focus on refining patient selection strategies will be pivotal. As we continue to optimize sequential treatments, we anticipate further enhancements in tailoring therapies to individual patient needs. This phase is promising, yet we’re still awaiting data from ongoing trials,” Zhang concluded.

1. Singer EA, Rumble RB, Rathmell WK, et al; for the Management of Metastatic Renal Clear Cell Cancer Guideline Expert Panel. Management of metastatic renal clear cell cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023;41(33):5184-5186. doi:10.1200/jco.23.01977
2. Choueiri TK, Powles T, Albiges L, et al; COSMIC-313 Investigators. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/nejmoa2212851
3. Zhang T, Ballman KV, Choudhury AD, et al. PDIGREE: an adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol. 2021;39(suppl 6):TPS366. doi:10.1200/ jco.2021.39.6_suppl.tps366
4. Choueiri TK, Powles T, Voss MH, et al. LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Future Oncol. Published online October 26, 2023. doi:10.2217/fon2023-0283
5. Bell H, Co a BH, Salami SS, Kim H, Vaishampayan U. “PROBE”ing the role of cytoreductive nephrectomy in advanced renal cancer. Kidney Cancer J. 2022;6(1):3-9. doi:10.3233/kca-210010
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