Dual therapy with the investigational oral tyrosine kinase inhibitor (TKI) apatinib plus anti-PD-1 checkpoint blockade was safe and yielded modest activity in soft-tissue sarcoma, a phase I open-label trial showed.
Among 30 patients with various solid tumors, treatment with apatinib plus nivolumab (Opdivo) led to responses in 13.3% (95% CI 3.8-30.7), all of which were partial responses, and a disease control rate (response plus stable disease) of 76.7% (95% CI 57.7-90.1), reported Sant Chawla, MD, of the Sarcoma Oncology Research Center in Beverly Hills, California.
Median progression-free survival in the cohort was 7.2 months (95% CI 5.3-9.0), according to findings presented at the virtual Connective Tissue Oncology Society annual meeting.
“Our results demonstrate the potential clinical benefit of apatinib — this is an oral TKI inhibitor — in combination with nivolumab in unresectable and metastatic solid tumors, with obviously observed response in sarcomas,” Chawla concluded. “There was no additive toxicity or unexpected side effects of this combination.”
Two-thirds of patients in the study had sarcoma, and responses were seen among those with classical leiomyosarcoma, angiosarcoma, and undifferentiated pleomorphic sarcoma.
“Some of the responses were long-lasting,” said Chawla.
Grade ≥3 treatment-emergent adverse events (AEs) occurred in 76.7% of the cohort, which including anemia in 16.7%, as well as fatigue, hypertension, nausea, and asthenia in 10% each. The treatment discontinuation rate was 30%, as was the rate of dose reductions for toxicity. There were two deaths due to AEs.
Nivolumab alone has shown limited antitumor activity in sarcoma, said Chawla. In one study of 12 patients with advanced uterine leiomyosarcoma, for example, none responded to single-agent nivolumab. Yet a study of 23 sarcoma patients showed some partial response with the drug.
Apatinib (also known as rivoceranib) is a highly selective inhibitor of VEGFR2 approved as a later-line therapy for gastric cancer in China. In preclinical lung cancer models, the combination of apatinib plus nivolumab showed synergistic activity surpassing the single agents alone.
Chawla said that while the response rate of 13% is “very encouraging,” whether these are being driven by anti-PD-1 therapy or apatinib is not entirely unclear. “Additional studies are indicated in this group of patients,” he said.
The current phase I trial started with a dose-escalation phase, where 10 patients received apatinib doses ranging from 400 mg to 700 mg per day, along with nivolumab at a standard dose of 240 mg every 2 weeks. During dose expansion, 20 patients received a daily 700 mg dose of apatinib plus nivolumab, with some patients getting a reduced dose of the immunotherapy (200 mg every 2 weeks).
Leiomyosarcoma was the most common cancer type in the study (n=9), followed by synovial sarcoma (n=4), gastric cancer (n=3), chondrosarcoma (n=3), cervical cancer (n=2), and osteosarcoma (n=2), with cholangiocarcinoma, undifferentiated pleomorphic sarcoma, and liposarcoma in one patient each.
Patients had a median age of 53 years, 90% were white, 50% were women, and all had an Eastern Cooperative Oncology Group performance status of 1. Half had received at least three prior lines of therapy, with 16% having been previously treated with two lines of therapy, and 24% having one or fewer prior treatments.
Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.
The study was funded by Elevar Therapeutics.
Chawla disclosed relationships with Amgen, Roche, GlaxoSmithKline, Ignyta, TRACON Pharma, Karyopharm, SARC, Janssen, Inhibrx, Immix, and Aadi Bioscience.