Combination Regimens Offer Options in Frontline RCC as Novel Agents Advance Through Pipeline

Katy E. Beckermann, MD

Clinical trial updates presented during the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), including from the phase 3 CheckMate 9ER (NCT03141177) and COSMIC-313 (NCT03937219) studies, have further validated combination regimens as the first-line treatment for patients with advanced renal cell carcinoma (RCC). Because of the numerous options, investigators must carefully consider factors such as sarcomatoid features, disease risk status, and patient fitness when selecting from the current regimens.

“We have several clear ‘right answers’ when it comes to first-line [treatment] for patients with advanced RCC,” Elizabeth M. Wulff-Burchfield, MD, said. “My perspective is that not every efficacy outcome matters for every patient. [For example], in the beginning, if [a patient] is in visceral crisis, then the only outcome that matters is objective response rate [ORR]. It’s OK to let that guide us, but if we have more indolent disease, among other [factors], the possibility of a treatment-free interval can rise in our prioritization. It is [acceptable] to, in addition to knowing the data, prioritize some of the outcomes differently for different patients.”

During an OncLive Peer Exchange filmed during ASCO GU, expert investigators discussed significant updates in the RCC space from the meeting and beyond. They highlighted data from final analyses of CheckMate 9ER and COSMIC-313, discussed treatment selection considerations for patients with treatment-naive disease, and looked forward to results from clinical trials of the investigational agents HC-7366 and CBM588 in the frontline, second line, and beyond.

Nivolumab Forms Basis of Frontline IO Combinations

In first-line RCC, the FDA has approved nivolumab (Opdivo) as a component in 2 combination regimens.^1,2 The first was in April 2018, when frontline nivolumab plus ipilimumab (Yervoy) was approved for patients with intermediate- or poor-risk advanced RCC. In January 2021, nivolumab plus cabozantinib (Cabometyx) was approved in the first line. The approvals were supported by findings from the phase 3 CheckMate 214 (NCT02231749) and CheckMate 9ER trials, respectively.

“We have all of these immunotherapy [IO]–based combinations approved in frontline RCC, but the one that revolutionized the field was [investigated in] CheckMate 214 because [that study] led to the approval of the first IO-based combination and, to date, the only IO/IO regimen in treatment-naive metastatic RCC,” Moshe Ornstein, MD, MA, commented.

At a median follow-up of 99.1 months (range, 91.0-107.3), longterm follow-up data from CheckMate 214 showed that patients who received nivolumab plus ipilimumab (n = 550) achieved a median overall survival (OS) of 52.7 months (95% CI, 45.8-64.5) vs 37.8 months (95% CI, 31.9-43.8) among 546 patients who received sunitinib (Sutent; HR, 0.72; 95% CI, 0.62-0.83).3 The 90-month OS rates were 35.1% vs 24.9%, respectively. The median progression-free survival (PFS) was 12.4 months (95% CI, 9.9-16.8) vs 12.3 months (95% CI, 9.8-15.2), respectively (HR, 0.88; 95% CI, 0.75-1.03).

“Perhaps the most interesting of the updates with this 8-year follow-up is in the favorable-risk population,” Ornstein added. “Originally, the [FDA] approval was for [patients at] intermediate and poor risk, and in the National Comprehensive Cancer Network [NCCN] guidelines, it was a preferred regimen in intermediate- and poor-risk [disease]. But with additional follow-up, we noticed the curves split at approximately 48 months in favor of nivolumab plus ipilimumab, with a median OS in the favorable-risk population of approximately 78 months for the patients who received nivolumab plus ipilimumab vs [approximately] 67 months for [patients at favorable risk who received sunitinib]. The HR was 0.82, although the CI crossed 1. However, it is now one of the preferred regimens in the NCCN guidelines, even in favorable-risk [disease].”

During ASCO GU, investigators presented findings from a post hoc analysis of CheckMate 214, which evaluated kidney injury molecule-1 (KIM1) as a prognostic and predictive biomarker in advanced RCC.⁴ Patients in both the investigational and control arms with high baseline KIM-1 levels experienced worse OS outcomes than those with low (HR, 2.74; 95% CI, 2.14-3.52) or medium (HR, 2.05; 95% CI, 1.62-2.59) baseline levels. Additionally, patients with high baseline KIM-1 in both arms also had worse PFS than patients with KIM-1 low (HR, 1.53; 95% CI, 1.18-1.97) or KIM-1 medium (HR, 1.57; 95% CI, 1.21-2.03) levels.

The panelists then discussed the final follow-up results of CheckMate 9ER presented during ASCO GU.⁵ At a median follow-up of 67.6 months (range, 60.2-80.2) in the intention-to-treat population, the median PFS in the nivolumab plus cabozantinib (n = 323) and sunitinib (n = 328) arms was 16.4 months (95% CI, 12.5-19.3) and 8.3 months (95% CI, 7.0-9.7), respectively (HR, 0.58; 95% CI, 0.49-0.70). The 60-month PFS rates were 13.6% and 3.6%, respectively. The median OS was 46.5 months (95% CI, 40.6-53.8) and 35.5 months (95% CI, 29.2-42.8), respectively (HR, 0.79; 95% CI, 0.65-0.96); the 60-month OS rates were 40.9% and 35.4%, respectively.

“Cabozantinib is one of the preferred TKIs [tyrosine kinase inhibitors], and in the refractory setting, we see a lot of combinations using it as a backbone,” Pedro C. Barata, MD, MSc, FACP, noted.

Wulff-Burchfield added, “My overall impression [of the CheckMate 9ER update] was that it was very affirming to the data we have seen previously. This regimen is clearly superior to sunitinib [in terms of PFS]. One thing that stands out to me is how the hazard ratio is evolving in a different direction for patients with favorable-risk disease[compared with what we saw in] CheckMate 214. [These data] affirm that these are VEGF-driven tumors. Sunitinib is VEGF targeted, as is cabozantinib, even though cabozantinib has a broader mechanism of action. [These data] do not give us an obvious solution of a one-size-fits-all approach for our favorable-risk patients, but they certainly cement [this regimen] in the canon for first-line [therapy] in the overall population.”

In COSMIC-313, investigators added cabozantinib to ipilimumab and nivolumab in the frontline RCC setting.⁶ Patients were randomly assigned 1:1 to receive the triplet (n = 428) or placebo plus nivolumab and ipilimumab (n = 427). The primary end point was PFS per RECIST 1.1 and OS is the secondary end point.

Data from the final analysis presented during ASCO GU demonstrated that patients who received the triplet achieved a median PFS of 16.6 months (95% CI, 14.0-22.6) vs 11.2 months (95% CI, 9.3-14.0) for those in the placebo arm (HR, 0.82; 95% CI, 0.69-0.98). The 24-month PFS rates were 44% and 37%, respectively. The median OS was 41.9 months (95% CI, 34.8-47.9) with the triplet vs 42.0 months (95% CI, 34.9-53.1) with placebo (HR, 1.02; 95% CI, 0.85-1.23; P = .08366). The 36-month OS rate in both arms was 54%.

Following encouraging data from the phase 2 LITESPARK-003 (NCT03634540) and phase 1/2 LITESPARK-024 (NCT05468697) studies, which examined the HIF-2α inhibitor belzutifan (Welireg) in combination with cabozantinib or palbociclib (Ibrance), respectively, investigators have initiated the phase 3 LITESPARK-012 study (NCT04736706) to evaluate belzutifan as a triplet component.⁷ The trial is examining pembrolizumab (Keytruda) plus lenvatinib (Lenvima) with or without belzutifan or quavonlimab for the frontline treatment of patients with advanced clear cell RCC (ccRCC).

LITESPARK-012 is an open-label, multicenter study that will enroll approximately 1653 adults with advanced or metastatic ccRCC with measurable disease per RECIST 1.1 and a Karnofsky performance score of at least 70%. Eligible patients will be randomly assigned 1:1:1 to receive belzutifan plus pembrolizumab and lenvatinib (arm A); coformulated pembrolizumab and quavonlimab plus lenvatinib (arm B); or pembrolizumab plus lenvatinib (arm C). The coprimary end points are PFS and OS per RECIST 1.1 in arms A vs C and B vs C.

“We have learned a lot about how to manage adverse effects in a triplet arm,” Katy E. Beckermann, MD, said. “We might see better exposure to the TKI and get better benefits. I’m excited to see [LITESPARK-012] read out. All of us want to see more cures in the frontline. There are a couple of [other] ongoing frontline trials that are about to start [enrolling] looking at triplet combinations of various immunotherapy regimens. I am looking forward to seeing those open and start enrolling.”

When selecting a treatment regimen in the frontline, Ornstein noted that patients with a visceral crisis who need an immediate response should usually be treated with an IO/TKI combination. He added that PD-L1 testing is largely not appropriate when selecting a frontline regimen; he often chooses the CheckMate 214 regimen for patients with sarcomatoid features because of poor historical outcomes with TKI therapy in this population.

“[In patients without] clear sarcomatoid histology, I’m not convinced that any of these IO/TKI regimens are better for any specific site of disease,” Ornstein explained. “Lenvatinib plus pembrolizumab has good data in [metastases of the] liver and bone, [as does] cabozantinib. We’re trying to tease out these subgroup analyses to see if we can determine which specific regimen can target which specific disease [type]. In summary, in sarcomatoid disease, I’m leaning toward an IO/IO combination. If patients need an [immediate] response, I’m giving an IO/TKI, focusing on [which] TKI [is appropriate for] a specific patient and for the favorable-risk population, I’m comfortable using all of them. I appreciate that ipilimumab plus nivolumab is now in the NCCN guidelines [in the favorable-risk group] because it makes it more available from an insurance perspective.”

Novel Agents Attract Attention in Multiple Disease Settings

Following their discussion of the frontline treatment landscape, the panelists shifted their conversation to highlight ongoing clinical trials of the investigational agents HC-7366 and CBM588. HC-7366 is a first-in-class GCN2 serine/threonine kinase activator, which investigators hypothesize can be combined with belzutifan to treat patients with ccRCC who experience disease progression.⁸ CBM588 is a live bacterial agent containing a strain of Clostridium butyricum, which has shown the potential to boost clinical outcomes in combination with immune checkpoint inhibition.⁹

HC-7366 is being evaluated as monotherapy and in combination with belzutifan in patients with advanced or metastatic ccRCC in a phase 1b study (NCT06234605).8 To be eligible for the monotherapy arm, patients must have received 1 to 4 prior lines of therapy, including belzutifan or another HIF-2α inhibitor. In the combination arm, patients need to have received 1 to 3 prior lines of therapy for metastatic disease, including at least 1 anti–PD-1/anti– PD-L1 agent and a VEGF TKI. The primary end points are establishing the maximum tolerated and recommended phase 2 doses, and safety and tolerability. At the time of ASCO GU, enrollment was ongoing into 2 combination cohorts and a monotherapy cohort.

In another phase 1 trial (NCT06399419), CBM588 is being examined in combination with nivolumab and ipilimumab in adult patients with metastatic RCC with a clear cell or sarcomatoid component who have received no prior systemic therapy for RCC beyond 1 prior adjuvant/neoadjuvant therapy for resectable RCC.9 The primary objective is to determine the regimen’s safety and tolerability, and efficacy will be secondarily assessed.

CBM588 is also under evaluation in combination with cabozantinib and nivolumab in another phase 1 trial (NCT05122546); the study is enrolling patients with treatment-naive RCC with a clear cell, papillary, and/or sarcomatoid component.10 Patients were randomly assigned 2:1 to receive the triplet (n = 20) or cabozantinib plus nivolumab (n = 10).

Updated study data presented at ASCO GU showed that patients in the investigational arm achieved a median PFS of 19.7 months compared with 13.4 months in the control arm (HR, 0.74; 95% CI, 0.25-2.23; P = .59). Moreover, the ORRs were 84% and 20%, respectively. The study authors added that there were no additional toxicity signals and that the further development of CBM588 should be prioritized.

“We’ve seen data regarding antibiotic use for patients with RCC and how that impacts not only their gut microbiome but their efficacy outcomes as well,” Wulff-Burchfield said. “I’m looking forward to hearing more from [these studies of CBM588].”

References

1. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed March 13, 2025. https://www. fda.gov/drugs/resources-information-approved-drugs/fdaapproves-nivolumab-plus-ipilimumab-combination-intermediateor-poor-risk-advanced-renal-cell
2. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed March 13, 2025. https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-approves-nivolumab-plus-cabozantinibadvanced-renal-cell-carcinoma
3. Tannir NM, Albigès L, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol. 2024;35(11):1026-1038. doi:10.1016/j. annonc.2024.07.727
4. Xu W, Vemula SV, Motzer R, et al. Evaluation of circulating kidney injury marker-1 (KIM-1) as a prognostic and predictive biomarker in advanced renal cell carcinoma (aRCC): post-hoc analysis of CheckMate 214. J Clin Oncol. 2025;43(suppl 5):437. doi:10.1200/JCO.2025.43.5_suppl.437
5. Motzer R, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): final follow-up results from the CheckMate 9ER trial. J Clin Oncol. 2025;43(suppl 5):439. doi:10.1200/JCO.2025.43.5_suppl.439
6. Albiges L, Motzer R, Trevino S, et al. Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC): final results of COSMIC-313. J Clin Oncol. 2025;43(suppl 5):438. doi:10.1200/ JCO.2025.43.5_suppl.438
7. 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. 2023;19(40):2631-2640. doi:10.2217/fon-2023-0283
8. Shah N, Bupathi M, Garmezy B, et al. A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). J Clin Oncol. 2025;43(suppl 5):TPS609. doi:10.1200/JCO.2025.43.5_suppl.TPS609
9. Agarwal R, Ebrahimi H, Zengin ZB, et al. Dose finding study of CBM588 in combination with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma: a phase I study. J Clin Oncol. 2025;43(suppl 5):TPS611. doi:10.1200/ JCO.2025.43.5_suppl.TPS611
10. Ebrahimi H, Meza LA, Dizman N, et al. Cabozantinib (cabo) and nivolumab (nivo) with or without CBM588 in patients with metastatic renal cell carcinoma: updated clinical outcomes of a phase I study. J Clin Oncol. 2025;43(suppl 5):543. doi:10.1200/ JCO.2025.43.5_suppl.543