Dr. Vincent Xu, a genitourinary oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, presented and discussed the kidney cancer clinical updates from the ESMO 2022 which he described as a “huge conference for kidney cancer”.
Highly awaited results from the COSMIC-313 phase III trial showed that triplet therapy with cabozantinib, nivolumab, and ipilimumab has superior PFS compared to the current standard of care with nivolumab plus ipilimumab in patients with IMDC intermediate or poor risk advanced renal cell carcinoma (aRCC).[1]
Belzutifan has clinically meaningful antitumor activity with a manageable safety profile in aRCC and von Hippel-Lindau (VHL) disease, according to the results of the LITESPARK-003 and LITESPARK-004 trial phase II studies.[2],[3]
Has the COSMIC-313 trial potential to become practice-changing?
The COSMIC-313 is a randomised phase III trial assessing the role of triplet therapy with cabozantinib, nivolumab, and ipilimumab as first-line treatment for patients with aRCC. Patients with previously untreated clear-cell aRCC of IMDC intermediate or poor risk were randomly assigned to receive cabozantinib (40 mg) or matched placebo. All patients received nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) for 4 cycles followed by nivolumab (480 mg). Nivolumab was given for a maximum of 2 years.[1]
“This is the first phase III trial that used a modern compared arm, comparing cabozantinib plus nivolumab plus ipilimumab, a triplet combination, with placebo plus nivolumab plus ipilimumab.” – dr. Xu elaborated.
The study’s primary endpoint was progression-free survival (PFS), which was improved significantly (HR 0.73, 95% CI, 0.57–0.94; p=0.013).[1] “The PFS was improved for triplet therapy with a pretty convincing hazard ratio of 0.73.” – Dr. Xu added.
In subgroup analyses, Dr. Xu highlighted that patients with intermediate-risk disease appeared to benefit more than those with poor-risk disease.[1]
“This triplet combination is the first triplet that ever shows PFS superiority against doublet. However, we do not have any overall survival (OS) data, so I think it is fair to say that how OS data depends on this triplet will really inform whether this triplet will or will not fit in first-line clinical practice.” – dr. Xu concluded.
Are belzutifan trial results continue to be promising?
“The other key news is about belzutifan.” – he continued.
Belzutifan presents a new drug class. It has been identified as a first-in-class HIF-2α inhibitor that has been approved for patients with VHL disease who require therapy for RCC, CNS hemangioblastomas, or pancreatic neuroendocrine tumours (pNET).[3]
The results from the LITESPARK-003 and LITESPARK-004 trials demonstrated that belzutifan does have activity in both DLC and sporadic clear-cell kidney cancer.[2],[3]
Cohort 1 of the LITESPARK-003 phase II study evaluated the combination of belzutifan (120 mg orally once daily) and cabozantinib (60 mg orally once daily) as first-line treatment for aRCC.[2] “This combination had an impressive overall response rate (ORR) of 57% and disease control rate (DCR) of 94%.” – he highlighted.
All patients with available scans had a reduction in target lesion size. The median PFS was 30.3 months (95% CI, 9.4 to not reached) and the median OS was not reached (12-month OS 96%).[2]
“This is the first combination that does not about immunotherapy in the first line space with this kind of results.” – dr. Xu added.
The LITESPARK-004 phase II study evaluated belzutifan (120 mg once daily) in patients with germline VHL alteration.[3]
“These results continue to be extremely impressive.” – he continued. After the median follow-up of 37.8 months, the ORR was 64%. A total of 56 of 61 (92%) patients experienced a reduction in target lesion size. Significant results were observed in pNET patients with the ORR of 91% and CNS hemangioblastomas patients with the ORR of 44%.[3]
“We continue to see a significant reduction in the need for surgical procedures in these patients with VCH disease.” – Dr. Xu said for these findings.
CONCLUSIONS:
- The COSMIC-313 is the first trial that demonstrated the benefit of triplet therapy compared to the current standard of care in patients with aRCC. However, there are many unanswered questions that have to be addressed prior to actual clinical use.[1]
- The results of Cohort 1 LITESPARK-003 phase II showed that the combination of belzutifan and cabozantinib has manageable safety and promising antitumor activity in treatment-naïve patients with aRCC.[2]
- According to the LITESPARK-004 trial, belzutifan continues to have clinically meaningful antitumor activity with durable responses and manageable safety profile in VHL disease-associated RCC, pNET, and CNS and retinal hemangioblastomas.[3]
The full dr. Xu’s presentation can be found here:
REFERENCE:
- https://www.urotoday.com/conference-highlights/esmo-2022/esmo-2022-kidney-cancer/139522-esmo-2022-invited-discussant-lba8.html (access:18.01.2023.)
- https://www.urotoday.com/conference-highlights/esmo-2022/esmo-2022-kidney-cancer/139501-esmo-2022-1447o-phase-2-study-of-belzutifan-plus-cabozantinib-as-first-line-treatment-of-advanced-renal-cell-carcinoma-cohort-1-of-litespark-003.html (access:18.01.2023.)
- https://www.urotoday.com/conference-highlights/esmo-2022/esmo-2022-kidney-cancer/139495-esmo-2022-belzutifan-a-hif-2-inhibitor-for-von-hippel-lindau-vhl-disease-associated-neoplasms-36-months-of-follow-up-of-the-phase-2-litespark-004-study.html (access:18.01.2023.)