Ulka Vaishampayan, MD, FASCO, discusses different novel therapies in development for renal cell carcinoma.
Novel multikinase inhibitors, HIF-2α inhibitors, and microbiome-impacting agents have the potential to build upon standard-of-care regimens in renal cell carcinoma (RCC) and improve outcomes for patients, according to Ulka Vaishampayan, MD, FASCO.
In a presentation given during the 19th Annual New York GU Cancers Congress®, an event hosted by Physician’s Education Resource® (PER®), in New York, New York, Vaishampayan discussed novel therapies and treatment approaches in RCC, including HIF-2α inhibitors, microbiome-impacting agents, and immunotherapies.1
Vaishampayan is the Beverly S. Mitchell, MD Research Professor of Cancer Research, a professor of internal medicine and ambulatory care clinical chief at the University of Michigan Medical School, as well as director of the Phase 1 Program and coleader of the Translational and Clinical Research Program at the University of Michigan Rogel Cancer Center.
Vaishampayan began her presentation by discussing the multitargeted kinase inhibitor zanzalintinib (XL092). The agent is being evaluated as monotherapy and in combination with atezolizumab (Tecentriq) in patients with locally advanced or metastatic solid tumors in the phase 1b STELLAR-001 trial (NCT03845166).
“Zanzalintinib is relatively similar to cabozantinib [Cabometyx], but with a shorter half-life and some [other] differences that may make it a broad-spectrum [agent],” she commented.
At a median follow-up of 8.3 months, findings from an expansion cohort of STELLAR-001 presented during the 2023 International Kidney Cancer Symposium: North America revealed that patients with clear cell RCC who received zanzalintinib monotherapy (n = 32) achieved an objective response rate (ORR) of 38% and a disease control rate (DCR) of 88%.2 Among patients who previously received cabozantinib (n = 17), the ORR and DCR were 24% and 94%, respectively. The ORR and DCR were 57% and 86%, respectively, in patients who were cabozantinib naive.
Vaishampayan noted that zanzalintinib is being examined in combination with nivolumab (Opdivo) in the randomized phase 3 STELLAR-304 study (NCT05678673).3 The study is enrolling patients with previously untreated, unresectable, advanced, or metastatic non–clear cell RCC. Patients will be randomly assigned 2:1 to receive the combination or sunitinib [Sutent]. The dual primary end points are progression-free survival (PFS) and ORR per RECIST 1.1 criteria by blinded independent central review.
“You may argue that the control arm [should be] cabozantinib, but we will await the results of this study,” Vaishampayan said.
Vaishampayan began her presentation by highlighting the progress that has been observed with HIF-2α inhibitors in RCC. The phase 3 LITESPARK-011 (NCT04586231) study evaluated the selective HIF-2α inhibitor belzutifan (Welireg) in combination with lenvatinib (Lenvima) in patients with clear cell RCC after anti–PD-(L)1 therapy.4
Findings from LITESPARK-011, which were presented during the
Although the overall survival (OS) data did not reach statistical significance at the time of the presentation, a trend in favor of the combination arm emerged (HR, 0.85; 95% CI, 0.68-1.05; 1-sided P = .06075). The 12- and 24-month OS rates in the combination arm were 79.7% and 62.8%, respectively; the corresponding rates in the control arm were 77.7% and 55.4%, respectively. The ORR in the combination arm was 52.6% (95% CI, 47.3%-57.7%) compared with 40.2% (95% CI, 35.2%-45.3%) in the control arm, representing an estimated difference of 12.4% (95% CI, 5.3%-19.3%). The respective complete response rates were 5.4% and 1.1%.
Findings from LITESPARK-011 supported the FDA’s acceptance of a supplemental new drug application seeking the approval of belzutifan plus lenvatinib for the treatment of adult patients with RCC with a clear cell component following treatment with a PD-1 or PD-L1 inhibitor in February 2026.5
“Lenvatinib plus belzutifan [is] not FDA approved yet, but it showed very promising results,” Vaishampayan said. “This is another combination that we may have to incorporate, and I wonder if lenvatinib plus belzutifan becomes the second line [standard of care].”
Another HIF-2α inhibitor, casdatifan (AB521), is under evaluation in combination with cabozantinib in the phase 3 PEAK-1 trial (NCT07011719).6 The study is comparing the combination with cabozantinib monotherapy for the treatment of patients with advanced or metastatic clear cell RCC who have experienced disease progression on or after a prior anti–PD-L1 agent. The primary end point of the trial is PFS per RECIST 1.1 criteria, as assessed by blinded independent central review (BICR); results from the study have not been reported to date.
Vaishampayan noted that in the phase 3 LITESPARK-012 study (NCT04736706), investigators evaluated pembrolizumab (Keytruda) plus lenvatinib, with or without belzutifan or quavonlimab, as frontline therapy for patients with advanced clear cell RCC.7 The primary end points were PFS by RECIST 1.1 criteria per BICR and OS. Results from the trial are awaiting readout, she said.
Vaishampayan concluded her presentation by discussing ongoing efforts to improve the outcomes of currently available agents in RCC using cytoreductive nephrectomy and microbiome-impacting agents. In the ongoing phase 3 SWOG 1931/PROBE trial (NCT04510597), investigators are examining the effect of adding surgery to a standard-of-care (SOC) immunotherapy-based combination in patients with metastatic RCC.8
“The principle behind this is that neoadjuvant immunotherapy with the primary in place has [produced] much better outcomes than removing the primary and then giving immune checkpoint therapy,” Vaishampayan said. “The idea is that we have a much larger antigen spread, and we’re likely to stimulate the immune response much better when we leave the primary in place and give immune checkpoint therapy.”
In terms of microbiome-impacting therapy, Vaishampayan noted that the live biotherapeutic product CBM588 has shown promise in combination with nivolumab and ipilimumab (Yervoy) for the treatment of patients with metastatic RCC with clear cell and/or sarcomatoid histology. Findings from a phase 1 trial (NCT03829111) demonstrated that patients in the CBM588 group (n = 19) experienced a median PFS of 12.7 months compared with 2.5 months among those who received only nivolumab plus ipilimumab (n = 10; HR, 0.15, 95% CI, 0.05-0.47; P < .001).9 The median OS in both arms was not reached.
“[This approach] came from an observation that [individuals] on antibiotics or prolonged antibiotic therapy during immune checkpoint therapy were not showing as good of a response as those who were not on antibiotics,” Vaishampayan said. “That has led us to create the [phase 3] SWOG S2419 BioFront trial [NCT07383441], which is using any of the immune checkpoint–based regimens in the frontline setting with/without the biotherapeutic. We have chosen CBM588 because there were adequate preliminary data. That study will be activated very soon and will be available throughout the country.”
Disclosures: Vaishampayan received research support from Merck. She also received consulting fees and honoraria from Bayer, BMS, Exelixis, Merck, Novartis, and Pfizer.
