In a single-institution phase II study reported in JAMA Oncology, Kelly et al found that the combination of talimogene laherparepvec (T-VEC) and pembrolizumab produced durable responses in patients with previously treated advanced sarcoma.
As noted by the investigators, T-VEC has been found to increase tumor-specific immune activation by increasing antigen presentation and T-cell priming. It was hypothesized that T-VEC in combination with pembrolizumab might increase tumor-infiltrating lymphocyte infiltration and programmed cell death ligand 1 expression, and thereby increase antitumor activity in this setting.
Study Details
In the study, 20 patients at Memorial Sloan Kettering Cancer Center with locally advanced or metastatic sarcoma with failure of at least one prior standard systemic therapy received pembrolizumab at 200 mg plus an injection of T-VEC into palpable tumor sites on day 1 of 21-day cycles. The first dose of T-VEC was ≤ 4 mL × 106 plaque-forming units (PFU); subsequent doses were ≤ 4 mL × 108 PFU/mL. Histologic subtypes of sarcoma included leiomyosarcoma (n = 5), angiosarcoma (n = 3), undifferentiated pleomorphic sarcoma (n = 2), undifferentiated or unclassified sarcoma (n = 3), and other (n = 7). The primary endpoint was objective response rate at 24 weeks on Response Evaluation Criteria in Solid Tumors, version 1.1.
KEY POINTS
- A response was observed in 35% of patients and in five histologic subtypes of sarcoma.
- The median duration of response was 56 weeks.
Responses
The overall response rate at 24 weeks was 30% (partial response in six patients), meeting the criterion for a promising response rate. An additional patient achieved response after 24 weeks, yielding an overall response rate of 35%. Stable disease was observed in an additional seven patients, yielding a disease control rate of 70%.
Responses were observed in five histologic subtypes, consisting of cutaneous angiosarcoma of head and neck (n = 2), undifferentiated pleomorphic sarcoma (n = 2), myxofibrosarcoma (n = 1), epithelioid sarcoma (n = 1), and unclassified sarcoma (n = 1). Median time to response was 14.4 weeks (range = 6.6–31.9 weeks). Median duration of response was 56.1 weeks (range = 49.4–87.0 weeks).
At the time of analysis, five patients had completed the 12-month maximum duration of study therapy and four remained in the study. Two patients had no disease progression while not receiving treatment, and two resumed study treatment and regained stable disease after having progression off treatment.
Adverse Events
The most common treatment-related adverse events of any grade were fatigue (80%), fever (45%), chills (45%), and nausea (30%). Grade 3 treatment-related adverse events occurred in four patients (20%) and consisted of pneumonitis (n = 1), anemia (n = 1), fever (n = 1), and hypophosphatemia (n = 1). There were no grade 4 treatment-related adverse events and no treatment-related deaths.
The investigators concluded, “In this phase II clinical trial, treatment with T-VEC plus pembrolizumab was associated with antitumor activity in advanced sarcoma across a range of sarcoma histologic subtypes, with a manageable safety profile. This combination therapy met its predefined primary study endpoint; further evaluation of T-VEC in combination with pembrolizumab for patients with select sarcoma subtypes is planned.”
Ciara M. Kelly, MBBCh BAO, MD, of the Department of Sarcoma Oncology, Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was funded by Amgen and Merck. Additional support was provided by Cycle for Survival. For full disclosures of the study authors, visit jamanetwork.com.
