Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

January 23, 2020
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Talimogene laherparepvec-pembrolizumab combination appears safe, effective in advanced sarcoma

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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.

Fibrosarcoma, malignant tumor of fibroblasts, one of soft tissue sarcomas, light micrograph, photo under microscope 
Talimogene laherparepvec plus pembrolizumab showed antitumor activity in patients with advanced sarcomas.
Source: Adobe

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).

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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.