Doublet and Triplet Combinations Continue to Challenge Monotherapy in Advanced RCC

Yousef Zakharia, MD

Randomized clinical trials in renal cell carcinoma (RCC) have brought several multi-drug combinations into the treatment paradigm in recent years. However, there is limited research comparing the efficacy and safety of these regimens, according to Yousef Zakharia, MD.

Recently at medical meetings across the United States and globally, the question of whether to use doublet immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations or triplet combinations has been raised. Although this question cannot be answered through debates and panel discussions, data from the CheckMate-214 study (NCT02231749) and the COSMIC-313 study (NCT03937219) offer hints, according to Zakharia, clinical associate professor, director of the phase I program, and co-leader of the Genitourinary Oncology Program at University of Iowa Hospitals & Clinics

Checkmate-214 is a phase 3, randomized, open-label, study of nivolumab (Opdivo) plus ipilimumab (Yervoy) vs sunitinib (Sutent) in patients with previously untreated, advanced, or metastatic RCC. Patients were randomized 1:1 to received nivolumab 3 mg/kg plus ipilimumab mg/kg, every 3 weeks for 4 cycles (standard dose). This dosing was followed by treatment with nivolumab 3 mg/kg every 2 weeks. In the comparator arm, patients were given sunitinib 50 mg once daily for 4 weeks, followed by 2 weeks off.¹

According to 5-year follow-up results, doublet therapy with nivolumab/ipilimumab demonstrated a favorable overall survival (OS) compared with sunitinib (HR, 0.46;95% CI 0.29-0.71; P = .0004; as well as PFS improvement compared with sunitinib (HR, 0.50;95% CI 0.32-0.80; P = .0036).

A better objective response rate (ORR) was also demonstrated with nivolumab/ipilimumab (61%) compared with sunitinib (23%; P < .0001). The median duration of response (DoR) was not reached with the doublet vs 25 months with sunitinib. Complete responses occurred in 23% of the doublet arm vs only 6% of the sunitinib arm. Efficacy favored the doublet arm regardless of PD-L1 expression, and across subgroups.

Treatment-related adverse events (AEs) were observed in 93% of the doublet arm vs 97% of the monotherapy arm. AEs were grade 3 or higher in 46% of the doublet arm vs 63% of the sunitinib arm. Treatment discontinuation was observed in 22% of the doublet arm vs 12%of the monotherapy arm. There were 8 deaths in the nivolumab/ipilimumab arm vs 4 in the sunitinib arm.²

COSMIC-313 is a randomized, double-blind, phase 3 study that is investigating cabozantinib (Cabometyx) with nivolumab, and ipilimumab vs nivolumab/ipilimumab in previously untreated, advanced/metastatic RCC of intermediate- or poor-risk. Patients in the study were randomized to receive cabozantinib 40 mg once daily with standard doses of nivolumab plus ipilimumab followed by nivolumab, every 4 weeks. Nivolumab was administered in the study for up to 2 years.³

Interim findings from COSMIC-313 showed improved PFS and consistent safety. Specifically, in 855 patients, the median PFS was not reached with the triplet combination (95% CI, 14.0–not estimable) vs 11.3 months with the doublet combination (95% CI, 7.7–18.2), meeting the primary end point of the study (HR, 0.73; 95% CI, 0.57-0.94; P = .013. The PFS benefit was carried over to the prespecified subgroups.

In terms of response, cabozantinib with nivolumab/ipilimumab showed an ORR of 43% (95% CI, 37.2%-49.2%) compared with 36% (95% CI, 30.1%-41.8%) in the doublet arm. The median DoR was not reached in either arm.

Safety results from COSMIC-313 showed grade 3/4 occurred 73% of the triplet arm vs 41% of the doublet arm. In addition, 1% of patients in each arm experience grade 5 treatment-emergent AEs. Twelve percent of the triplet arm discontinued treatment due to AEs compared with 5% of the doublet arm.

In an interview with Targeted Oncology™, Zakharia discussed evidence supporting both doublet and triplet therapy for the treatment of previously untreated, advanced/metastatic RCC, including in patients with intermediate- to- poor-risk disease and/or sarcomatoid features.

TARGETED ONCOLOGY: Can you discuss the standard first-line intermediate- to poor-risk RCC?

Zakharia: The current standard of care is either a immunotherapy combination with ipilimumab, nivolumab, or with immunotherapy plus TKI regimen, and we have 3 different regimens that are almost routinely used in the first-line setting. The reassuring is that all these IO/TKI regimens are showing consistent efficacy results and almost similar toxicity profiles, so we can’t say 1 regimen is better than the other. It basically becomes more of provider preference.

There are some subtle differences between those regimens that might make us pick 1 over another in clinic. But in a big picture, there are no huge differences.

What key points should an oncologist takeaway from the CheckMate-214 study?

In Checkmate-214, the efficacy of the combination of ipilimumab and nivolumab was more pronounced in the intermediate- and poor-risk features. That study has currently the longest follow-up of almost 5 years now, and it has basically set up and landmark for our long-term overall survival of over 40% with a median overall survival of 47 months. We are achieving a nice tail of the curve, meaning those patients who benefit from this treatment tend to benefit for a prolonged period of time, which is a nice feature of immunotherapy.

Specifically, we have seen more intriguing and interesting efficacy signals in the sarcomatoid patient population who tend to be more aggressive, or those tumors that tend to be more aggressive tumors with sarcomatoid features. The efficacy we are seeing with the combination of ipilimumab and nivolumab is outstanding for this challenging patient population. I would argue a lot of us in the field of kidney cancer utilize the ipilimumab/nivolumab combination as a preferred treatment choice for patients with intermediate-risk features like sarcomatoid histology.

There is an unanswered question of whether doublet or triplet combinations are most optimal for first-line intermediate- to poor-risk RCC. What are your thoughts on this question?

Regarding triplet vs doublet therapy, the interim analysis of COSMIC-313 study was positive. This was comparing the triplet of ipilimumab, nivolumab, and cabozantinib vs ipilimumab/nivolumab, with a primary end point of PFS.

The triplet did improve PFS in the intention-to-treat population. More so, it was in the intermediate-risk patient population. The downside, I would argue, of that regimen is an adverse event profile, and the lack of overall survival data. Certainly, we will need longer follow-up to see how the overall survival is going to pan out. As I mentioned, the toxicity profile, mainly the hepatitis, liver toxicity, and diarrhea, are discouraging.

Randomized clinical trials will help answer these questions better. Certainly, COSMIC-313 was an important study to conduct and it is the first study to use doublet therapy as a control arm. It taught us a lot, but is it ready to change practice in clinic? I would say it is still too early. Certainly, I would hope that the encouraging efficacy signal that we saw on the interim analysis is persistent. Also, I hope that the overall survival signal will turn out to be a positive signal here, so that our patients can benefit from this combination.

_REFERNCES:

_{1. Tannir Nm Signoretti S, Choueiri TK, McDermott DF, et al. Efficacy and safety of nivolumab plus ipilimumab (N+I) versus sunitinib (S) for first-line treatment of patients with advanced sarcomatoid renal cell carcinoma (sRCC) in the phase 3 CheckMate 214 trial with extended 5-year minimum follow-up. J Clin Oncol. 2022;40(6):352-352. doi:10.1200/JCO.2022.40.6_suppl.352}

_{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. Choueiri TK, Powles TB, Albige 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. doi:10.1016/annonc/annonc1089}