Knowledge Gap Remains for Sequencing of Later-Line Treatments of Advanced RCC


Although the use of immunotherapy treatment approaches continues to become more prevalent in advanced renal cell carcinoma, high-level evidence showing benefit of sequential administration of these agents are limited.

Robert J. Motzer, MD

Robert J. Motzer, MD

Although the use of immunotherapy treatment approaches continues to become more prevalent in advanced renal cell carcinoma (RCC), high-level evidence showing benefit of sequential administration of these agents are limited, according to a presentation given during the 2023 Kidney Cancer Research Summit (KCRS).1

“National Comprehensive Cancer Network members are struggling to try and establish what the best care for patients [with advanced RCC] who have had immunotherapy,” Robert J. Motzer, MD, section head of the Kidney Cancer, Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation. “For the most part, there really are very little high-level evidence data to support one program after another.”1

During his presentation, Motzer outlined key findings from ongoing trials of subsequent line treatments for advanced RCC presented during the 2023 ASCO Annual Meeting and the 2023 Genitourinary Cancers Symposium (ASCO GU). Motzer then discussed planned phase 3 trials in the space and shared his vision for the treatment of RCC in the future.

Select ongoing trials of immunotherapy approaches in second-line or later

In the phase 2 CaboPoint trial (NCT03945773), patients with advanced or metastatic RCC with a clear cell component were treated with the TKI cabozantinib (Cometriq) as a single agent. Patients with disease progression following treatment with ipilimumab (Yervoy) plus nivolumab (Opdivo) were assigned to cohort A (n = 60) and those who experienced progression after receiving a checkpoint inhibitor plus a VEGFR TKI (n = 28) were assigned to cohort 2. Both cohorts received cabozantinib at a dose of 60 mg daily; the primary end point was overall response rate (ORR) by RECIST 1.1 criteria in cohort A and secondary end points included ORR in cohort B, ORR for both cohorts, progression-free survival (PFS), and safety and tolerability.2

Findings from the interim analysis study presented at 2023 ASCO GU showed that the ORR in the overall population was 29.5% (95% CI, 20.3%-40.2%), including 1.2% of patients who experienced a complete response (CR). In cohort A, the ORR was 31.7% (95% CI, 20.3%-45.0%), with no CRs, and the ORR was 25.0% (95% CI, 10.7%-44.9%) in cohort B, with a CR rate of 4.0%. Patients experienced disease progression rates of 17.1%, 15.8%, and 20.0%, in the overall, cohort A, and cohort B populations, respectively.2

“Regardless of how long a patient had been on the prior first-line therapy, they appeared to benefit from cabozantinib, at least [in terms of] response rate in the trial,” Motzer said. “This was an early look at that trial. It helps us set the stage for prospective studies in this new era to establish the optimal therapy.”1

Motzer then transitioned to the phase 3 CONTACT-03 trial (NCT04338269), which evaluated the safety and efficacy of atezolizumab (Tecentriq) plus cabozantinib compared with that of cabozantinib monotherapy among patients with advanced or metastatic clear cell or non–clear cell RCC with or without a sarcomatoid component who experienced radiographic progression on or after previous treatment with an immune checkpoint inhibitor. Patients were randomly assigned to receive atezolizumab 1200 mg intravenously every 3 weeks plus daily cabozantinib at a dose of 60 mg (n = 263) or cabozantinib alone (n = 259). The coprimary end points were PFS and overall survival (OS).3 “In my opinion, the abstract of the year was the CONTACT-03 trial,” Motzer noted before highlighting the findings of the trial.1

Data from the trial presented at the 2023 ASCO Annual meeting and published in the Lancet showed that the median PFS in the combination and monotherapy was 10.6 months (95% CI, 9.8-12.3) vs 10.8 months (95% CI, 10.0-12.5), respectively (HR, 1.03; 95% CI, 0.83-1.28; P = .78). Moreover, the median OS was 25.7 months (95% CI, 21.5-not evaluable [NE]) compared with NE (95% CI, 21.1-NE), respectively (HR, 0.94; 95% CI 0.70-1.27; P = .69).3

Per central review, the confirmed objective response rate was 40.5% (95% CI, 34.5%-46.8%) in the combination arm compared with 40.9% (95% CI, 34.8%-47.3%) in the monotherapy arm, which included 2 CRs. Most patients in both arms still had an ongoing response at data cutoff (50.5% vs 52.9%) and the median duration of response (DOR) was 12.7 months (range, 2.1+ to 22.9+) and 14.8 months (range, 2.3+ to 25.6+).3

“For the most part, the patients who went on the first-line [treatment] had had ipilimumab plus nivolumab, there were very few patients who had first-line TKI-immunotherapy combinations,” Motzer said. “And there was a rather large proportion of patients that fell into the old paradigm where they had a TKI first and then went on to get an immunotherapy. Many of the patients just had nivolumab before going on to the study. I do think it changed the needle a little bit towards patients who would benefit from a TKI and perhaps watered down those that might benefit from an immunotherapy. Nevertheless, the results were clear as day: there wasn’t a benefit for this approach of an early switch from immunotherapy therapy to TKI plus a PD-L1 inhibitor.”

Moving into findings from the phase 1/2 KEYMAKER-U03B study (NCT04626518), which examined the combination of belzutifan (Welireg) plus lenvatinib (Lenvima) in with advanced clear cell RCC (ccRCC) after progression on a PD-1/PD-L1 and VEGF inhibitor, Motzer noted that preliminary findings presented at the 2023 ASCO Annual Meeting showed that the combination displayed early efficacy. Twenty-one of 25 patients experienced any reduction from baseline in target lesions, with 15 achieving a reduction of greater than 30%.4

Moreover, findings from the phase 2 LITESPARK-003 trial (NCT03634540) showed that combining belzutifan plus cabozantinib for the treatment of patients with patients with advanced ccRCC who previously received immunotherapy led to promising antitumor activity with a tolerable safety profile. Among efficacy-evaluable patients (n = 52), 45 experienced a reduction in target lesion size. The most common any-grade adverse effects (AEs) were anemia (85%), fatigue (71%), and palmar plantar erythrodysesthesia (54%).5

“Perhaps the safety profile will be better with lenvatinib/ belzutifan, but I believe either one of these are very interesting combinations moving forward,” Motzer said of the 2 studies.1

Planned trials of subsequent therapies

The phase 3 MK-6482 (NCT04195750) is comparing the safety and efficacy of belzutifan with that of everolimus among patients with ccRCC who have undergone a maximum of 3 prior lines of therapy, including a PD-1/L1 inhibitor and a VEGFR inhibitor. Approximately 736 patients will be randomly assigned 1:1 to receive belzutifan 120 mg daily or everolimus 10 mg daily. The coprimary end points are PFS and OS.6

Litespark-011 (NCT04586231) is another phase 3 trial that will enroll patients with ccRCC. Eligible patients must have previously undergone treatment with a PD-1/PD-L1 inhibitor and have a maximum of 2 prior lines of therapy. Approximately 708 patients will be randomly assigned 1:1 to receive belzutifan 120 mg daily plus lenvatinib 20 mg daily or cabozantinib 60 mg daily. Again, the coprimary end points are PFS and OS.7

Finally, the phase 3 TiNIVo2 trial (NCT04987203) is enrolling patients with recurrent or metastatic RCC with prior immunotherapy exposure who have progressed on up to 2 prior regimens and have not been treated with more than 1 prior TKI. Approximately 326 patients will be randomly assigned 1:1 to receive the VEGFR inhibitor tivozanib (Fotivda) at a dose of 0.89 mg daily for 3 weeks on/1 week off plus nivolumab 480 mg every 28 days or tivozanib monotherapy at a dose of 1.34 mg daily for 3 weeks on/1 week off. The primary end point is PFS, with OS, ORR, DOR, and safety serving as additional end points.8

“Cabozantinib is becoming the de facto standard of care, although there really isn’t the phase 3 benefit of that drug over others in this particular setting,” Motzer said. “The phase 3 trials that I think should be on the radar screen are MK-6482, Litespark-011, and TiNIVo2. [There is] also the [phase 3] PDIGREE trial [NCT03793166], which I didn’t cover because of timing and is a little bit of a different study. That’s an adaptive approach [and a] study being run through our cooperative group. In terms of the vision for [future treatment of] RCC, it’s really the integration of novel agents and technology to optimize our care.”


  1. Motzer RJ. Subsequent line treatments for advanced disease. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023; Boston, MA.
  2. Albiges L, Powles T, Sharma A, et al. CaboPoint: interim results from a phase 2 study of cabozantinib after checkpoint inhibitor (CPI) therapy in patients with advanced renal cell carcinoma (RCC). J Clin Oncol. 2023;41(suppl 6):606. doi:10.1200/JCO.2023.41.6_suppl.606
  3. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. Published online June 2, 2023. doi:10.1016/S0140-6736(23)00922-4
  4. Albiges L, Beckermann K, Miller WH, et al. Belzutifan plus lenvatinib for patients (pts) with advanced clear cell renal cell carcinoma (ccRCC) after progression on a PD-1/L1 and VEGF inhibitor: preliminary results of arm B5 of the phase 1/2 KEYMAKER-U03B study. J Clin Oncol. 2023;41(suppl 16):4553. doi:10.1200/JCO.2023.41.16_suppl.4553
  5. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 2023;24(5):553-562. doi:10.1016/S1470-2045(23)00097-9
  6. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). Updated August 1, 2022. Accessed July 14, 2023.
  7. A study of belzutifan (MK-6482) in combination with lenvatinib versus cabozantinib for treatment of renal cell carcinoma (MK-6482-011). Updated July 7, 2023. Accessed July 14, 2023.
  8. Choueiri TK, Albiges L, Hammers HJ, et al. TiNivo-2: a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor. J Clin Oncol. 40(suppl 6):TPS405. doi:10.1200/JCO.2022.40.6_suppl.TPS405
Related Videos
Vivek Subbiah, MD
Marijo Bilusic, MD, PhD
Joshua Linscott, MD
Petros Grivas, MD, PhD
Sujith Samarasinghe, MD
Suzanne Trudel, MSc, MD
Consuelo Bertossi, MD
Michael R. Grunwald, MD, FACP
Manali Kamdar, MD
Ibrahim Aldoss, MD