1. Fuerst, Mark L.

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Updated results for the CheckMate 9ER trial support the combination of nivolumab plus cabozantinib as a potential first-line treatment option for patients with advanced renal cell carcinoma (RCC).

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Previously, in the open-label, randomized, multi-national Phase III CheckMate 9ER trial of first-line nivolumab plus cabozantinib versus sunitinib for patients with metastatic or advanced RCC, the dual combination demonstrated superiority after a minimum follow-up of 10.6 months. The 651 patients were randomized to nivolumab 240 mg IV every 2 weeks, plus cabozantinib 40 mg orally daily (323 patients) or sunitinib 50 mg orally for 4 weeks of 6-week cycles (328 patients) for first-line treatment until disease progression or unacceptable toxicity. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR, 55.7% vs. 27.1%) were all significantly improved with nivolumab plus cabozantinib versus sunitinib. The safety profile was consistent of individual drug components.


"Long-term updates establish durability of clinical benefits with immunotherapy-based regimens, and there is historical unmet need for improved treatment options among advanced RCC patients with sarcomatoid features," said lead author Robert Motzer, MD, Kidney Cancer Section Head of the Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology, at Memorial Sloan Kettering Cancer Center at the 2021 ASCO Genitourinary Cancers Symposium (Abstract 308). "Dual checkpoint inhibition with nivolumab plus ipilimumab recently showed long-term efficacy benefits in patients with sarcomatoid features of RCC, and some benefits have been reported with immuno-oncology plus antiangiogenic regimens relative to older treatments."


Motzer presented updated analyses with first-line nivolumab plus cabozantinib, as well as outcomes in advanced RCC patients with sarcomatoid features, an aggressive histologic subtype associated with poor prognoses.


Updated Results

With a median follow-up of 2 years (23.5 months), nivolumab plus cabozantinib continued to show superior PFS, ORR, and OS versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up.


The combination doubled median PFS (17 months vs. 8.3 months), the trial's primary endpoint, compared to sunitinib. Nearly twice as many patients responded to the combination versus sunitinib (54.8% vs. 28.4%). The combination maintained improvements in OS, demonstrating a 34 percent reduction in the risk of death compared to sunitinib.


In an exploratory analysis, the combination was associated with a disease control rate (including complete response, partial response, and stable disease) of 88.2 percent versus 69.9 percent with sunitinib. The complete response rate, also exploratory, for the combination was 9.3 percent compared to 4.3 percent with sunitinib.


Among patients treated with the combination, 6.6 percent discontinued both agents due to TRAEs, 9.7 percent discontinued nivolumab only, and 7.2 percent discontinued cabozantinib only.


In an exploratory subgroup analysis of 75 patients with sarcomatoid features, at a median follow-up of 18.1 months, the combination of nivolumab plus cabozantinib showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64 percent versus sunitinib, and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22%).


"Notable PFS, OS, and ORR benefits were observed with nivolumab plus cabozantinib versus sunitinib in the subgroup of patients without sarcomatoid RCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently higher with nivolumab plus cabozantinib versus sunitinib regardless of sarcomatoid status," said Motzer.


Quality-of-Life Improvements

Another presentation at the meeting described patient-reported outcomes of quality of life from the CheckMate 9ER trial (Abstract 285). At a median follow-up of 18.1 months, the exploratory analysis found patients treated with nivolumab plus cabozantinib experienced less treatment burden, with decreased risk of confirmed deterioration across most measurements versus suntinib, including FKSI-19 total, disease-related symptoms (DRS), DRS-physical (DRS-P), DRS-emotional (DRS-E), functional well-being (FWB), and EQ-5D-3L visual analog scale (VAS) scores.


Lead author David Cella, MD, Chair of the Department of Medical Social Sciences at Northwestern University, said: "Patients reported statistically significant health-related quality of life (HRQoL) benefits with nivolumab plus cabozantinib versus sunitinib. Treatment with nivolumab plus cabozantinib significantly reduced the risk of deterioration in HRQoL scores, including in disease-related symptoms of kidney cancer. These results suggest that the superior efficacy of nivolumab plus cabozantinib over sunitinib comes with the additional benefit of improved HRQoL."


Mark L. Fuerst is a contributing writer.