Talimogene laherparepvec-pembrolizumab combination appears safe, effective in advanced sarcoma
Talimogene laherparepvec in combination with pembrolizumab demonstrated antitumor activity among patients with advanced sarcoma across a range of histologic subtypes, according to results of a single-arm phase 2 study published in JAMA Oncology.
The regimen also appeared safe.
“Sarcomas are rare cancers of mesenchymal origin, [and] chemotherapy remains the cornerstone of management for advanced sarcoma,” Ciara M. Kelly, MD, MBBCh, BAO, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “There is a need for more effective treatment options for sarcomas. Immunotherapy has emerged as a revolutionary oncologic therapy during the last decade. A significant focus of research has centered on T-cell immune checkpoint inhibitors, which are now approved for treatment of several cancers.”
Previous studies have shown that talimogene laherparepvec (Imlygic, Amgen), a herpes simplex virus-1-derived oncolytic immunotherapy often referred to as T-VEC, increases tumor-specific immune activation by augmenting antigen presentation and T-cell priming.
Kelly and colleagues sought to determine whether combining T-VEC with the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda, Merck) would increase tumor-infiltrating lymphocyte infiltration and PD-L1 expression, thereby enhancing antitumor activity.
The study included 20 patients (median age, 63.5 years; range, 24-90; 60% women) with locally advanced or metastatic sarcoma who had at least one previous systemic therapy.
Researchers administered pembrolizumab at a flat dose of 200 mg IV and T-VEC by intratumoral injection at no more than 4 mL x 106 plaque-forming units [PFU]/mL for the first dose and no more than 4 mL x 108 PFU/mL for each subsequent dose. Treatment administration occurred on day 1 of each 21-day cycle.
Objective response rate at 24 weeks determined by RECIST version 1.1 criteria served as the study’s primary endpoint. Secondary endpoints included best ORR by immune-related RECIST criteria, PFS at 24 weeks, OS and safety.
Median duration of therapy was 16 weeks (range, 7-67).
Results showed an ORR at 24 weeks of 30% (95% CI, 12-54; n = 6). One patient with cutaneous angiosarcoma experienced a delayed response at 32 weeks, leading to an overall ORR of 35% (95% CI, 15-59; n = 7).
Median time to response was 14.4 weeks (range, 6.6-31.9), with a median duration response of 56.1 weeks (range, 49.4-87).
Researchers observed partial responses in cutaneous angiosarcoma of head and neck (n = 2), undifferentiated pleomorphic sarcoma (n = 2), myxofibrosarcoma (n = 1), epithelioid sarcoma (n = 1) and sarcoma unclassified (n = 1).
Results also showed median PFS of 17.1 weeks (95% CI, 12.6-not estimable) and 12-week PFS of 70% (95% CI, 52.5-93.3).
Eight patients had died by data cutoff. Median disease-specific survival was 74.7 weeks (95% CI, 49-not estimable).
Four patients experienced grade 3 treatment-related adverse events, including pneumonitis, anemia, fever and hypophosphatemia. No grade 4 adverse events or treatment-related deaths occurred.
A lack of adequate tumor material for all patients, as well as the lack of a control group, served as limitations to this study.
“This phase 2 study of T-VEC and pembrolizumab for patients with advanced sarcoma met its primary endpoint,” Kelly and colleagues wrote. “Continued exploration of immune-related biomarkers to inform the future selection of patients with sarcomas most likely to benefit from this treatment remains a priority for the expansion cohort.” – by John DeRosier
Disclosures: Kelly reports research funding from Amgen, Agios Pharmaceuticals, Exicure and Merck. Please see the study for all other authors’ relevant financial disclosures.