Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab

Abstract

IMPORTANCEPatients 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.OBJECTIVE 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. DESIGN, SETTING, AND PARTICIPANTSThis 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.INTERVENTION Patients received pembrolizumab (200-mg flat dose) intravenously and T-VEC (first dose, Յ4 mL × 10 6 plaque-forming units [PFU]/mL; second and subsequent doses, Յ4 mL × 10 8 PFU/mL) injected into palpable tumor site(s) on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURESThe 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. RESULTSAll 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. CONCLUSIONS AND RELEVANCEIn 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.

Newcastle Disease Virus at the Forefront of Cancer Immunotherapy

“…Indeed, combination of NDV with systemic anti-CTLA-4, anti-PD-1, or anti-PD-L1 resulted in enhanced rejection of bilateral tumors and prolonged animal survival compared to either treatment alone, an effect that was seen in multiple tumor types [51,54]. These findings highlight that intratumoral therapy with NDV can be an effective strategy to drive systemic efficacy of immune checkpoint inhibitors and have now been confirmed across a number of oncolytic viruses [61][62][63][64][65][66][67][68][69][70][71][72][73], including early clinical studies of immune checkpoint inhibitors in combination with T-VEC [61,74,75].…”

The Biology of Myxofibrosarcoma: State of the Art and Future Perspectives

“…The results of successful immunotherapy trials using an anti-PD-1 antibody and combination anti-PD-1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) showed that a significant number of UPS experienced a reduction in tumor size. A phase II study of single-agent pembrolizumab (anti-PD-1 antibody) in multiple sarcoma types showed an objective response rate of 40% in UPS [90, 91]. A separate trial involving nivolumab alone and in combination with ipilimumab demonstrated responses in UPS [92].…”

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

“…3 4 Soft tissue sarcomas (STSs) represent a histologically diverse family of tumors for which the benefits of immunotherapy have been incremental. [5][6][7][8] For example, the SARC028 Trial, one of the largest clinical trials evaluating the efficacy of checkpoint therapy for metastatic or unresectable soft tissue and bone sarcomas, 5 identified an objective response rate of 18% in patients with STS, with the most promising results observed in patients with undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. As a result, checkpoint blockade therapy remains unapproved for patients with STS, and the search for successful immunotherapy regimens remains a significant unmet need.…”