The combination of nivolumab (Opdivo) plus the investigational drug sitravatinib improved progression-free survival (PFS) in patients with pretreated metastatic clear-cell renal-cell carcinoma (RCC) and the historical disease control rates compared with nivolumab alone, according to the results of a phase 1/2 clinical trial reported at the 2020 Genitourinary Cancers Symposium.
The objective response rate (ORR) was 39% (15 of 38 patients), whose disease progressed after 2 lines of antiangiogenic therapy. The median PFS was 10.3 months.
Although these data are preliminary, the ORR compared favorably with historical ORRs seen in this setting with nivolumab (25%), cabozantinib (Cabometyx; 17%-21%), and everolimus (Afinitor; 3%-5%).
“Responses tended to be durable. With a median follow-up of 17.7 months, the median overall survival has not been reached, and currently 30 of 38 patients are alive. The combination has an acceptable safety profile,” said lead investigator Pavlos Msaouel, MD, PhD, Assistant Professor, Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, TX.
Sitravatinib is a novel tyrosine kinase inhibitor (TKI) that targets a unique group of receptor tyrosine kinases, including TAM, split family receptors, and c-MET. According to Dr Msaouel, sitravatinib may also enhance the effects of immunotherapy “through multiple mechanisms,” such as improving tumor perfusion, depleting immunosuppressive cells from the tumor microenvironment, and increasing T-cell priming.
Based on preliminary studies suggesting that sitravatinib can manipulate T-cell trapping, the investigators combined the new TKI with nivolumab. The study included 40 patients, and efficacy was defined as not having progressive disease within 6 weeks of treatment initiation. The investigators plan to evaluate quality of life and perform multiple correlative analyses.
The dose-escalation phase involved 4 dose levels of sitravatinib (60, 80, 120, and 150 mg daily) combined with standard-dose nivolumab. The patients were evaluated every 6 weeks during the first year of treatment, then every 12 weeks until progressive disease or unacceptable toxicity. Sitravatinib was given for 2 weeks, and nivolumab was started on day 15.
The dose of sitravatinib 120 mg daily plus nivolumab will be explored in future studies and in other tumor types as well as in RCC. All patients (N = 40) were evaluable for safety and 36 were evaluable for efficacy at the time of the meeting presentation.
The most common sites of metastasis were the lymph nodes (67.5%), lung (52.5%), bone (32.5%), and liver (27.5%). Almost 88% of the patients received 1 previous therapy, with a median duration of 10.8 months.
The best confirmed ORR was 39%, and the rate of clinical benefit was 92%. “Responses tended to be durable,” Dr Msaouel said.
The most common adverse events were diarrhea (N = 29) not associated with immune-related colitis; fatigue (N = 27), and elevated liver enzymes (N = 5). In all, 4 patients discontinued treatment because of adverse events, and 21 patients required dose reductions, 15 of which occurring within 12 weeks of starting treatment.
“This tells us that the 12-week window is enough to capture the vast majority of dose-limiting toxicities,” Dr Msaouel said.
Daniel M. Geynisman, MD, Assistant Professor, Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, agreed that the response rates in the study were “really good results,” but he added that more follow-up is needed.
“Sitravatinib is very active in RCC but has a lot of overlap with the targets of cabozantinib. How different is this drug from cabozantinib? If the answer is ‘not much,’ then what is the added value?” Dr Geynisman said.
Other drugs, including tivozanib (Fotivda), axitinib (Inlyta), and lenvatinib (Lenvima), have been combined with a checkpoint inhibitor in patients with metastatic RCC.
“There is a hint in these studies that no matter which TKI you combine with a checkpoint inhibitor, you get responses and disease control rate in second line [in RCC],” he said.