ASCO 2018: A Phase 3, Randomized, Open-label Study of Nivolumab Combined with Cabozantinib vs Sunitinib in Patients with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma

Chicago, IL ( Current standard of care for advanced or metastatic renal cell carcinoma (RCC) includes a collection of agents targeting the vascular endothelial growth factor (VEGF) pathway, anchored by the tyrosine kinase inhibitors sunitinib and sorafenib. Other agents affecting this pathway encompass the first, second and even third-line options. Unfortunately, these medications are not curative and are effectively not cytotoxic. Cytotoxic chemotherapy has proven ineffective in this disease space.

Immune checkpoint inhibitors have been gaining significant traction across all malignancies, demonstrating durable long-term cures in a subset of patients. RCC, in particular, due to a high tumor mutational burden, may be an optimal target for therapy.

Biomarker studies suggest that promotion of an immune suppressive tumor microenvironment can contribute to anti-VEGF therapy resistance and point to a rationale for combining anti-VEGF therapy with immunotherapy.

As such, in this study, the authors combine cabozantinib and nivolumab. Cabozantinib (CABO) is a tyrosine kinase inhibitor which also targets the VEGF receptor, MET and the TAM receptor family, has shown immunomodulatory properties suggestive of synergistic effects with immune checkpoint inhibitors. Nivolumab is a programmed death-1 (PD-1) inhibitor. A recent phase 1 study demonstrated that the combination showed encouraging antitumor activity in pretreated patients with metastatic RCC and other advanced genitourinary tumors (Nadal et al. ASCO GU 2018).

Study Design: Randomized, Open-label, Multi-national study
Key inclusion criteria:
Patients with advanced or metastatic RCC
Patients must have measurable disease with a clear-cell component
No prior systemic therapy for RCC
Tumor must be screened for PD-L1 expression (<=1%, >1%, indeterminate)
KPS >= 70%
They must have had an evaluable tumor biopsy

Key exclusion criteria: Active CNS metastases and autoimmune disease, EF <50%

Trial Design: Randomized Phase III Clinical Trial
Randomized 1:1 to either nivolumab plus cabozantinib or sunitinib (standard of care)
Stratification factors for randomization: International Metastatic RCC Database Consortium (IMDC) risk score, PD-1 ligand 1 (PD-L1) tumor expression, and geographic region
Treatment will continue until disease progression or unacceptable toxicity (maximum nivolumab treatment of 2 years)
Efficacy assessments (CT/MRI imaging) will be performed at baseline, week 12 and every 6 weeks until week 60. After that, every 12 weeks until progression.

In terms of outcomes, the primary endpoint is progression-free survival by blinded independent central review (BICR) in all randomized patients. Secondary endpoints include overall survival and objective response rate by BICR in all randomized patients, and safety/tolerability in all treated patients.

Enrollment for this study has already began (August 2017). The target is 580 randomized patients. Complete enrollment expected by 1st quarter of 2019. Study sites included are depicted below:

image 16

image 16bSummary of Study design

Presented by: Toni K. Choueiri, MD

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA