Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab
Authors: Ciara M. Kelly, Cristina R. Antonescu, Timothy Bowler, Rodrigo Munhoz, Ping Chi, Mark A. Dickson, Mrinal M. Gounder, Mary Louise Keohan, Sujana Movva, Reena Dholakia, Hamza Ahmad, Matthew Biniakewitz, Mercedes Condy, Haley Phelan, Margaret Callahan, Phillip Wong, Sam Singer, Charlotte Ariyan, Edmund K. Bartlett, Aimee Crago, Sam Yoon, Sinchun Hwang, Joseph P. Erinjeri, Li-Xuan Qin, William D. Tap, Sandra P. D’Angelo
Journal: JAMA Oncology (2020)

<h3>Importance</h3> Patients with advanced sarcoma have limited treatment options. Talimogene laherparepvec (T-VEC) has been shown to increase tumor-specific immune activation via augmenting antigen presentation and T-cell priming. <h3>Objective</h3> To examine whether T-VEC in combination with pembrolizumab is associated with increased tumor-infiltrating lymphocyte infiltration and programmed death-ligand 1 expression and thus with increased antitumor activity in patients with locally advanced or metastatic sarcoma. <h3>Design, Setting, and Participants</h3> This open-label, single-institution phase 2 interventional trial of T-VEC plus pembrolizumab enrolled 20 patients with locally advanced or metastatic sarcoma between March 16 and December 4, 2017, for whom at least 1 standard systemic therapy had failed. The median duration of therapy was 16 weeks (range, 7-67 weeks). Reported analyses include data through December 14, 2018. <h3>Intervention</h3> Patients received pembrolizumab (200-mg flat dose) intravenously and T-VEC (first dose, ≤4 mL × 10<sup>6</sup>plaque-forming units [PFU]/mL; second and subsequent doses, ≤4 mL × 10<sup>8</sup>PFU/mL) injected into palpable tumor site(s) on day 1 of each 21-day cycle. <h3>Main Outcomes and Measures</h3> The primary end point was objective response rate (ORR; complete response and partial response) at 24 weeks determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, criteria. Secondary end points included best ORR by immune-related RECIST criteria, progression-free survival rate at 24 weeks, overall survival, and safety. <h3>Results</h3> All 20 patients (12 women [60%]; median age, 63.5 years [range, 24-90 years]) were evaluable for response. The study met its primary end point of evaluating the best ORR at 24 weeks determined by RECIST, version 1.1, criteria; the best ORR was 30% (95% CI, 12%-54%; n = 6). The ORR overall was 35% (95% CI, 15%-59%; n = 7). The incidence of grade 3 treatment-related adverse events was low (4 patients [20%]). There were no grade 4 treatment-related adverse events or treatment-related deaths. <h3>Conclusions and Relevance</h3> In this phase 2 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 end point; further evaluation of T-VEC in combination with pembrolizumab for patients with select sarcoma subtypes is planned. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT03069378