Axitinib-pembrolizumab combination shows promise in advanced alveolar soft part sarcoma

WAILEA, Hawaii — The combination of axitinib and pembrolizumab demonstrated early evidence of activity among patients with advanced alveolar soft part sarcoma and other soft tissue sarcomas, according to phase 2 study results presented at the Connective Tissue Oncology Society Annual Meeting.

“The combination [also] is well tolerated, with expected rates of autoimmune toxicities,” Breelyn A. Wilky, MD, associate professor of medicine at Sylvester Comprehensive Cancer Center at University of Miami, said during a presentation.

Single-agent checkpoint inhibitors induce impressive responses in about 20% of patients with soft tissue sarcoma. Monotherapy with the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) induced a 19% overall response rate in a phase 2 study of patients with advanced soft tissue sarcomas.

High vascular endothelial growth factor expression and hypoxia have been linked to poor prognosis in sarcoma, and anti-VEGF tyrosine kinase inhibitors are the most active drugs for alveolar soft part sarcoma, according to study background.

Wilky and colleagues hypothesized that VEGF blockade administered concurrently with anti-PD-1 checkpoint inhibition would optimize the sarcoma microenvironment and improve responses.

Researchers conducted a single-arm, open-label, single-institution phase 2 trial to assess the combination of the anti-VEGFR TKI axitinib (Inlyta, Pfizer) and pembrolizumab.

Researchers enrolled 30 patients (median age, 44.5 years; range, 19-77; 57% white) with radiographically progressing advanced or metastatic soft tissue sarcoma. The most common subtypes were alveolar soft part sarcoma (n = 10; 33%), high-grade undifferentiated pleomorphic sarcoma (n = 5; 17%) and uterine leiomyosarcoma (n = 4; 13%).

Twenty-eight patients (93%) had metastatic disease and two (7%) had locally advanced disease.

Twenty-four patients had undergone one to three prior lines of systemic therapy; the other six were treatment naive.

All patients had adequate end-organ function and performance status. Most patients received at least one prior standard line of chemotherapy.

Study participants received axitinib 5 mg orally twice daily, with intrapatient dose escalation according to predefined toxicity thresholds. They also received concurrent pembrolizumab 200 via IV every 21 days.

All patients underwent mandatory tumor biopsies and peripheral blood sampling at baseline, at 12 weeks and upon progression as part of correlative immunoprofiling.

PFS at 12 weeks served as the primary endpoint. Secondary endpoints included toxicity, objective response rate, clinical benefit rate, PFS and OS.

Twenty-nine patients received at least one cycle of treatment. In this group, researchers reported a 12-week PFS rate of 48%. Five patients (17%) achieved partial response and nine patients (31%) achieved stable disease, equating to a 48% clinical benefit rate.

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In the subset of nine patients with alveolar soft part sarcoma, four (44%) achieved partial response and three (33%) achieved stable disease, equating to a 78% clinical benefit rate.

Among the 20 patients with other subtypes, one (5%) achieved partial response and six (30%) achieved stable disease, equating to a clinical benefit rate of 35%.

Researchers observed prolonged responses among early patients with alveolar soft part sarcoma and soft tissue leiomyosarcoma. Median duration of response was 29.3 weeks (95% CI, 18.4-66.1) for those with stable disease or better at 12 weeks.

Wilky and colleagues reported median PFS of 15.9 weeks in the entire cohort; median PFS was not reached among those with alveolar soft part sarcoma and 13.2 weeks among patients with other histologies.

Median OS in the full cohort was not reached; 12-month OS was 60%.

The most common adverse events were fatigue (any grade, 70%; grade 3/grade 4, 0%), generalized or tumor pain (63% and 0%), oral mucositis (63% and 3%), nausea/vomiting (57% and 7%) and diarrhea (50% and 3%).

Researchers determined two adverse events, one case of grade 3 spontaneous pneumothorax and one case of grade 4 hypertriglyceridemia, were attributable to axitinib. Six drug-related serious adverse events or immune related toxicities were attributable to pembrolizumab. They included two cases of grade 3 seizure, and one case each of grade 3 arthritis/joint effusion, grade 2 type 1 diabetes mellitus, grade 3 colitis and grade 3 transaminitis.

Fourteen patients tolerated axitinib dose escalation above the FDA-approved starting level of 5 mg twice daily in combination with pembrolizumab; 45% of patients required at least one axitinib dose reduction; and 28% of patients required at least one axitinib dose hold of 3 to 5 days. – by Mark Leiser

For more information:

Wilky BA, et al. Abstract 2762964. Presented at: Connective Tissue Oncology Society Annual Meeting; Nov. 8-11, 2017; Maui.

Disclosure: Wilky reports research funding from Merck and Pfizer, as well as other financial relationships with Agenus, Eli Lilly, Janssen and Novartis.