Combination Immunotherapy Meets Primary Endpoint in Phase II Clinical Trial in Advanced Sarcoma

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By Ciara Kelly, MBBCh, BAO, MD William Tap, MD Sandra D’Angelo, MD on behalf of the MSK clinical study team

Bill Tap, Chief of MSK's Sarcoma Medical Oncology Service

Bill Tap, Chief of MSK's Sarcoma Medical Oncology Service

The combination immunotherapy of talimogene laherparepvec (T-VEC) and pembrolizumab met its primary endpoint of objective response rate at 24 weeks in our phase II clinical trial in patients with advanced sarcoma. (1)

The best objective response rate (ORR) was 30 percent (95% CI, 12%–54%; n = 6) and the ORR overall was 35 percent (95% CI, 15%–59%; n = 7). These ORRs were well above the objective response rates observed with standard chemotherapy in the first- and second-line setting. (1)

The open-label, single-arm, single-institution trial at Memorial Sloan Kettering Cancer Center (MSK), tested the combination immunotherapy approach in 20 patients with locally advanced or metastatic sarcoma and whose cancer had not responded to at least one prior systemic therapy where available. On the first day of each 21-day cycle, study participants received pembrolizumab intravenously, and T-VEC injected into palpable tumor sites. (1)

The combination was associated with antitumor activity across a range of sarcoma histologic subtypes, with a manageable safety profile. The incidence of grade 3 treatment related adverse events was low at 20 percent (4 patients), and there were no grade 4 adverse events or deaths related to treatment. (1)

Based on these promising results, the trial of T-VEC in combination with pembrolizumab has been expanded to explore activity of this combination therapy in select sarcoma subtypes where responses were observed in the initial cohort examined.

Sarcoma and the Rationale for Combination Immunotherapy

Sarcomas are rare cancers of the bone and soft tissue that originate in mesenchymal cells. (2), (3), (4), (5) Chemotherapy has been the cornerstone of management for advanced sarcoma, but there is a need for more effective treatment options. Standard first-line treatment with doxorubicin or gemcitabine and docetaxel has shown ORRs of about 20 percent (6), and second-line treatment with agents such as pazopanib and trabectedin has shown lower ORRs of about 4 to 10 percent. (7), (8)

Immunotherapy has emerged as an exciting new treatment option during the last decade. (9), (10), (11), (12), (13), (14) The US Food & Drug Administration (FDA) has approved several T-cell immune checkpoint inhibitors for treating a growing list of cancers. (10), (11), (12), (13), (14)

Previous research results suggest that immunotherapy may be an effective treatment strategy for advanced sarcoma. In the SARC028 study, which evaluated the effectiveness of pembrolizumab, the ORR was 18 percent among 40 patients in the initial group with soft tissue sarcoma. A follow-up expansion cohort showed ORRs of 23 percent (9 of 40 patients) among patients with undifferentiated pleomorphic sarcoma (UPS) and 10 percent (4 of 39 patients) among those with liposarcoma (LPS). (15) In the Alliance A091401 noncomparative, phase II study, researchers randomized patients with advanced sarcoma to receive nivolumab or nivolumab and ipilimumab. The ORR for patients in the combination therapy group was 16 percent compared to 5 percent in the monotherapy group. Most patients did not respond, but objective responses were observed in a variety of sarcomas, including UPS, leiomyosarcoma, myxofibrosarcoma, angiosarcoma, and alveolar soft-part sarcoma. (16)

Immune biomarkers differ by sarcoma subtype and may be associated with response to immunotherapy. (3) Investigators have detected immune cell infiltration in genomically complex sarcomas. For example, in the SARC028 study, most (75 percent) of patients with UPS who responded had tumors that were programmed death-ligand 1 (PD-L1) positive. Responses were also observed in patients with PD-L1-negative tumors (two of eight UPS tumors and three of three LPS tumors). (15)

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Study Design

T-VEC is an oncolytic immunotherapy made from a modified human herpes simplex virus type 1. It is designed to self-replicate inside tumor cells and destroy them from within, releasing tumor antigens and promoting both regional and systemic antitumor immunity. (17) The FDA approved T-VEC in 2015 as the first oncolytic virus therapy for the treatment of advanced melanoma that cannot be surgically removed. (18) Pembrolizumab is an anti-PD-1 monoclonal antibody that removes the brakes on cancer cells, allowing T-cells to recognize and destroy tumors. First approved by the FDA in 2014 for treating patients with advanced melanoma, additional indications approved since then include non-small cell lung cancer, head and neck cancer, renal cell carcinoma, and most recently, high-risk bladder cancer. (19)

We tested the combination of T-VEC and pembrolizumab among 20 adult patients treated at Memorial Sloan Kettering Cancer Center between March and December 2017. Participants received both drugs on day one of each 21-day treatment cycle as follows: a 200 mg dose of pembrolizumab intravenously and T-VEC (first dose, ≤4 mL × 106 plaque-forming units [PFU]/mL; second and subsequent doses, ≤4 mL × 108 PFU/mL), injected into palpable tumor sites. Treatment was repeated until patients showed a complete response, progressive disease, unacceptable toxic effects or completed 12 months of study therapy (the trial was later amended to allow patients continue treatment beyond 12 months if deemed to be deriving clinical benefit.). (1)

The primary endpoint was ORR (complete response and partial response) at 24 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 criteria. (20) Secondary endpoints were best ORR determined by immune-related RECIST criteria, (21) progression-free survival (PFS) at 24 weeks, overall survival, and safety. (1)

Tumor biopsies from distant, noninjected tumor sites were performed at baseline and week eight, as feasible. We performed radiographic tumor assessments at baseline, every eight weeks for the first 56 weeks, and every 12 weeks thereafter until disease progression. We looked for tumor-infiltrating lymphocyte (TIL) immune biomarker expression, including PD-L1, PD-1, CD3, CD4, FOXP3, CD8, CD68, CD163, and MHC1. We used the Merck 22C3 antibody to evaluate for the presence of PD-L1 expression. The threshold for positive PD-L1 expression was greater than one percent. (1)

To our knowledge, this is one of the highest ORRs reported in an unselected group of sarcoma patients evaluating the efficacy of combination immunotherapy.
Sandra P. D'Angelo Associate Attending Physician
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Study Results

The median age of study participants was 63.5 years, with a range of 24 to 90 years, and 60 percent were female. Sarcoma histologic subtypes were as follows: leiomyosarcoma (five percent); angiosarcoma (three percent); UPS (two percent); undifferentiated or unclassified sarcoma (three percent); and other (seven percent). A total of 12 patients (60 percent) had received three or more prior lines of therapy, and five patients (25 percent) had received prior treatment with an immune checkpoint inhibitor. (1)

T-VEC plus pembrolizumab showed an ORR of 30 percent at 24 weeks, meeting the study’s primary endpoint. One patient had a delayed response observed at 32 weeks, which increased the ORR to 35 percent. To our knowledge, this is one of the highest ORRs reported in an unselected group of sarcoma patients evaluating the efficacy of combination immunotherapy. (1)

Together with a median response time of 14.4 weeks, these findings suggest that maximal response to therapy may require a prolonged period of time. The median duration of response was 56 weeks, indicating that the drug combination may achieve durable disease control. (1)

Five histologic subtypes of sarcoma responded to the combination therapy: UPS, myxofibrosarcoma, epithelioid sarcoma, cutaneous angiosarcoma, and unclassified sarcoma.

The high ORR observed among patients with locally advanced sarcoma (75%) supports the investigation of T-VEC plus pembrolizumab as neoadjuvant approach in the management of patients with UPS or myxofibrosarcoma. (1)

The mean number of prior lines of therapy among responsive patients was one, supporting the rationale to enroll patients with sarcoma in immunotherapy trials earlier in their course of treatment. We also observed responses in distant, noninjected sites in patients with stage IV and recurrent locally advanced disease, underscoring the importance of continuing to explore this immunotherapy combination for metastatic sarcoma. (1)

Median PFS was 17.1 weeks (95%CI, 12.6 weeks to not estimable). PFS was 70 percent at 12 weeks and 39.4 percent at 24 weeks. At data cutoff, eight patients had died. The median disease-specific survival was 74.7 weeks (3-sided 95% CI, 49 weeks to not estimable). (1)

Tumors in responsive patients had a higher TIL score, and all pretreatment samples across various subtypes of sarcoma had aggregates of CD3*/CD8* TILs at the infiltrating tumor edge. By contrast, samples from nonresponsive patients either before or after therapy showed minimal CD3*/CD8* TIL infiltrates, and all lacked clusters or aggregates of TILs at tumor edges. These findings were consistent with previous reports of patients with melanoma treated with pembrolizumab: responsive tumors showed increased TILs at the tumor edge. (22)

Safety results in our study were consistent with previously reported experience in patients with melanoma. (23) There was a low incidence of grade 3 treatment-related adverse events (20 percent). By comparison, note that the incidence of grade 3 treatment-related adverse events with standard chemotherapy is generally higher than 20 percent. (6), (7), (8), (24), (25)

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Advancing Sarcoma Cancer Care Through Research

Based on the promising results of this phase II study, we expanded the current study to examine T-VEC plus pembrolizumab in patients with select sarcoma subtypes including UPS, myxofibrosarcoma, epithelioid sarcoma and cutaneous angiosarcoma. We will continue to explore immune-related biomarkers to inform the selection of patients most likely to respond as a top priority in the expansion cohort.

MSK experts pioneered immunotherapy over 120 years ago. We are currently conducting more than 170 clinical trials testing immunotherapy approaches as monotherapy or in novel combinations to treat a wide variety of cancers. These trials include the following for patients with sarcoma:

The study was funded by Amgen and Merck. Additional support was provided by Cycle for Survival and the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30 CA00878).

Dr. Kelly reports receiving research funding from Merck and Amgen pertaining to this study; and receiving research funding from Agios Pharmaceuticals and Exicure pertaining to other studies. Dr. D’Angelo reports serving in a consulting or advisory role for Merck, Amgen, Incyte, Nektar, EMD Serono, GlaxoSmithKline, and Immune Design; and receiving travel expenses from Adaptimmune, EMD Serone, and Nektar. For disclosures from other authors, please refer to the paper. (1)

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