Treatment Combination May Be Effective for Antitumor Activity in Advanced Sarcoma

A phase II clinical trial published in JAMA Oncology suggested that treatment with talimogene laherparepvec (T-VEC) in combination with pembrolizumab (Keytruda) was correlated with antitumor activity in advanced sarcoma across a range of sarcoma histologic subtypes, with a manageable safety profile.¹

Given these results, researchers currently plan to further evaluate T-VEC in combination with pembrolizumab for patients with angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS), and epithelioid sarcoma. A neoadjuvant cohort of patients with localized, operable UPS and MFS is also being explored.

“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,” the authors wrote. 

In this cohort of 20 patients with locally advanced or metastatic sarcoma for whom at least 1 standard systemic therapy had failed, patients received pembrolizumab intravenously and T-VEC injected into palpable tumor sites on day 1 of each 21-day cycle. The study met its primary end point of evaluating the best objective response rate (ORR) at 24 weeks, determined by RECIST, version 1.1, criteria. The best ORR was 30% (n = 6; 95% CI, 12%-54%). A delayed response was observed in 1 patient at 32 weeks, bringing the overall ORR to 35% (n = 7; 95% CI, 15%-59%).

The median duration of response was 56.1 weeks, indicating a durable disease control. The responses were among 5 histologic subtypes, consisting of UPS, MFS, epithelioid sarcoma, cutaneous angiosarcoma, and unclassified sarcoma. Sixty percent of the patients in the study had previously received 3 or more prior lines of therapy. The researchers noted that this finding supports the rationale that patients with sarcoma should be enrolled in immunotherapy trials earlier in their course of treatment. 

The incidence of grade 3 treatment-related adverse events was low (4 patients [20%]), and there were no grade 4 treatment-related adverse events or treatment-related deaths.

Six of the 8 (75%) patients enrolled with recurrent, locally advanced disease achieved a partial response (PR). Response in distant, noninjected sites was shown among the patients with stage IV and recurrent locally advanced disease. The authors indicated that this finding underscores the merit of continuing to explore T-VEC plus pembrolizumab for metastatic sarcoma as well. 

The researchers also indicated the need to develop prognostic biomarkers. In this study, the patients underwent pretreatment and posttreatment tumor biopsies, with only 1 patient demonstrating PD-L1-positive disease at baseline; however, this patient achieved a PR. The majority (94%) of the posttreatment tumor samples were PD-L1 positive, and 4 patients experienced a PR, while the rest experienced stable or progressive disease. 

Moreover, responsive patients’ tumors had a higher tumor-infiltrating lymphocyte (TIL) score and in all response patients, across multiple subtypes, pretreatment samples had aggregates of CD3⁺/CD8⁺ TILs at the infiltrating tumor edge. This discovery was consistent with prior reports of patients with melanoma treated with pembrolizumab, in which the responsive patients had increased TILs at the tumor edge.

According to the Seattle Cancer Care Alliance, each year about 13,000 people in the US are diagnosed with soft tissue sarcoma and an estimated 3,500 are diagnosed with bone cancer. Collectively, all types of sarcoma represent 1% of all new cancer cases.²

Reference:

1. Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab: A Phase 2 Clinical Trial. JAMA Oncology. doi:10.1001/jamaoncol.2019.6152.

2. Seattle Cancer Care Alliance. Sarcoma facts. Seattle Cancer Care Alliance website. Published 2020. seattlecca.org/diseases/sarcoma/sarcoma-facts. Accessed January 24, 2020.