Research Continues for Best Immunotherapy Order in Advanced RCC


Even with the increase of immunotherapy utilization to treat patients with advanced renal cell carcinoma, more research is needed to determine in which order to administer it as later lines of therapy.


As the use of immunotherapy becomes more prevalent to treat patients with advanced renal cell carcinoma (RCC), evidence demonstrating the benefit of sequencing these agents in a specific order is limited, an expert said.

Dr. Robert J. Motzer, 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, discussed this topic during a presentation during the 2023 Kidney Cancer Research Summit (KCRS).

“National Comprehensive Cancer Network members are struggling to try and establish what the best care (is) for patients (with advanced RCC) who have had immunotherapy ,” Motzer said. “For the most part, there really are very little high-level evidence data to support one program after another.”

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, patients with advanced or metastatic RCC with a clear cell component were treated with the TKI Cometriq (cabozantinib) as a single agent. Patients with disease progression following treatment with Yervoy (ipilimumab) plus Opdivo (nivolumab) were assigned to cohort A (60 patients) and those who experienced progression after receiving a checkpoint inhibitor plus a VEGFR TKI (28 patients) were assigned to cohort 2. The primary focus of the trial was overall response rate (percentage of patients with a complete or partial response to treatment), progression-free survival, safety and tolerability.

Findings from the interim analysis study presented at 2023 ASCO GU showed that the overall response rate in the overall population was 29.5%, including 1.2% of patients who experienced a complete response (disappearance of all signs of cancer). In cohort A, the overall response rate was 31.7%, with no complete responses, and the overall response rate was 25% in cohort B, with a complete response rate of 4%. Patients experienced disease progression rates of 17.1%, 15.8% and 20%, in the overall, cohort A, and cohort B populations, respectively.

“Regardless of how long a patient had been on the prior first-line therapy, they appeared to benefit from (Cometriq), 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.”

Motzer then transitioned to the phase 3 CONTACT-03 trial, which evaluated the safety and efficacy of Tecentriq (atezolizumab) plus Cometriq compared with that of Cometriq 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 Tecentriq plus Cometriq (263 patients) or Cometriq alone (259 patients). Researchers focused on several areas including progression-free survival and overall survival.“In my opinion, the abstract of the year was the CONTACT-03 trial,” Motzer noted before highlighting the findings of the trial.

Data from the trial presented at the 2023 ASCO Annual meeting and published in the Lancet showed that the median progression-free survival in the combination and monotherapy was 10.6 months vs 10.8 months, respectively. Moreover, the median overall survival was 25.7 months compared with nonevalulable (meaning more than half of patients were alive at the time this was assessed), respectively.

The confirmed objective response rate was 40.5% in the combination arm compared with 40.9% in the monotherapy arm, which included two complete responses. Most patients in both arms still had an ongoing response at data cutoff (50.5% vs 52.9%) and the median duration of response was 12.7 months and 14.8 months.

“For the most part, the patients who went on the first-line (treatment) had had (Yervoy) plus (Opdivo), 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 (Opdivo) 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, which examined the combination of Welireg (belzutifan) plus Lenvima (lenvatinib) 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%.

Moreover, findings from the phase 2 LITESPARK-003 trial showed that combining Welireg plus Cometriq for the treatment of patients with advanced ccRCC who previously received immunotherapy led to promising antitumor activity with a tolerable safety profile. Among efficacy-evaluable patients (52 patients), 45 experienced a reduction in target lesion size. The most common any-grade side effects were anemia (85%), fatigue (71%) and hand-foot syndrome (54%).

“Perhaps the safety profile will be better with (Lenvima/Welireg), but I believe either one of these are very interesting combinations moving forward,” Motzer said of the two studies.

Planned trials of subsequent therapies

The phase 3 MK-6482 is comparing the safety and efficacy of Welireg with that of everolimus among patients with ccRCC who have undergone a maximum of three prior lines of therapy, including a PD-1/L1 inhibitor and a VEGFR inhibitor. Approximately 736 patients will be randomly assigned Welireg or everolimus. The coprimary end points are progression-free survival and overall survival.

Litespark-011 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 two prior lines of therapy. Approximately 708 patients will be randomly assigned Welireg plus Lenvima or Cometriq. Again, the coprimary end points are progression-free survival and overall survival.

Finally, the phase 3 TiNIVo2 trial is enrolling patients with recurrent or metastatic RCC with prior immunotherapy exposure who have progressed on up to two prior regimens and have not been treated with more than one prior TKI. Approximately 326 patients will be randomly assigned the VEGFR inhibitor Fotivda (tivozanib) plus Opdivo or Fotivda monotherapy. The primary end point is progression-free survival, with overall survival, overall response rate, duration of response and safety serving as additional end points.

“(Cometriq) 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, 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.”

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