Combination Sitravatinib and Nivolumab Boosts Outcomes in Advanced Kidney Cancer

By Marilynn Larkin

April 28, 2022

NEW YORK (Reuters Health) - In patients with advanced clear cell renal cell carcinoma (ccRCC), an optimal sitravatinib dose combined with a fixed dose of nivolumab improved outcomes in a phase 1-2 trial.

"A surprising finding was that patients treated with the higher dose of sitravatinib (120 mg) consistently reported better quality of life after three months of therapy compared with patients treated with the lower dose (80 mg)," Dr. Pavlos Msaouel of the University of Texas MD Anderson Cancer Center in Houston told Reuters Health by email. "For this reason, we ended up choosing 120 mg as the initial sitravatinib dose for the further development in clinical trials."

"Most early phase trials establish drug dosage based only on toxicity," he noted. "However, our trial established the dose of sitravatinib in combination with nivolumab after taking into account toxicity, efficacy, and quality of life. This...approach yields more reliable dosage decisions for further development, and can be used for early drug development across disease settings."

However, he added, "The combination is still under investigation and should not be used outside of clinical trials. Further phase 2 and phase 3 clinical trials are ongoing to investigate the combination...across different cancers."

Cancer immunotherapy with anti-PD-L1 antibodies can benefit and even cure some patients with advanced ccRCC, but many patients end up relapsing over time, Dr. Msaouel and colleagues explain in Science Translational Medicine. This resistance occurs in part due to the accumulation of immune-suppressing myeloid cells in the tumor environment.

However, preclinical studies suggested that sitravatinib can counteract the accumulation of immune-suppressing myeloid cells and improve responses to immunotherapy. Therefore, the team conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab - an anti-PD-L1 therapy - in 42 immunotherapy-naïve patients with ccRCC refractory to prior antiangiogenic therapies.

The combination achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80% of patients still alive after a median follow-up of 18.7 months. No unexpected toxicities occurred.

Further, eight of 11 patients with liver metastases showed durable responses - reductions in tumor size that lasted more than six months.

The baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with the response to the combination. In addition, correlative studies showed a reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib.

The authors write, "The broad applicability of this regimen has led to the subsequent activation of phase 2 and 3 clinical trials using the sitravatinib dose of 120 mg established in the present study in combination with nivolumab."

Dr. Matthew Zibelman, an associate professor in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, commented on the study in an email to Reuters Health. "While the correlative data showing changes in the tumor microenvironment with sitravatinib is a potential proof-of-concept for improved efficacy in combination with nivolumab," he said, "it is difficult to know in this single-arm trial how this combination would compare to other already available TKI/IO combination approaches."

"Sitravatinib is not yet FDA-approved or commercially available, and would need to be compared to a standard-of-care treatment in a randomized trial before applying this combination in the clinic," he added.

The study was funded in part by Mirati Therapeutics (San Diego, California), which is developing sitravatinib.

SOURCE: Science Translational Medicine, online April 20, 2022.