Phase II Randomized Study of CMB305 and Atezolizumab Compared With Atezolizumab Alone in Soft-Tissue Sarcomas Expressing NY-ESO-1

Abstract

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?

“…A phase I trial including 24 sarcoma patients only showed partial response in 1 patient and stable disease in 13 patients [109]. In line with these findings, a sequential phase II trial that explored the combination of this NY-ESO-1 vaccine with anti-PD-L1 treatment in 45 sarcoma patients observed a partial response and stable disease in one and 23 patients, respectively [110]. To further improve T cell activation upon antigen presentation by dendritic cells, combination therapy of TCR gene therapy and vaccination is currently being explored in the clinic (https://clinicaltrials.gov/ Identifier: NCT03450122.…”

Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1): A Promising Cancer Testis Antigen

“…In recent decades, several targeted immunotherapies for carcinogenic CTAs have been developed, and these immunotherapies have been tested in preclinical and early clinical environments. At present, most clinical studies have focused on the treatment of melanoma-associated antigen A (MAGEA) and New York esophageal squamous cell carcinoma-1 (NY-ESO-1), including cancer vaccines targeting CTAs to prevent tumor occurrence and development, and monoclonal antibodies against CTAs and CAR-T designed based on CTAs [ 65 - 73 ]. Due to the late discovery of KK-LC-1, the reported treatments include vaccines, photodynamic therapy combined with new photosensitizers and TCR-T therapy ( Fig.…”

Immunotherapy for Sarcoma: A Work in Progress

“…The immune correlates noted with increased T-cell and antibody responses could be due to CMB305 alone as was seen in the phase Ib trial. Therefore, improvement in OS in those exhibiting immune responses (see Fig 4 in Chawla et al 21 ) could be attributed to CMB305 alone. Even with the promising 2 PRs in the combination arm, the LV305 phase I study described above, which lacked the G305 adjuvant, produced a sustained PR.…”

“…Therefore, this vaccination strategy produced B- and T-cell immune reactions on the cellular level that translated to stability but not tumor response. In the context of CMB305 producing a stable phenotype, in the article that accompanies this editorial Chawla et al 21 attempted to further boost the vaccine response comparing atezolizumab with a combination of atezolizumab with CMB305 in NY-ESO-1–expressing SS and MRCLS in a randomized phase II trial. They are commended for completing a study in two rare sarcomas using a novel strategy to advance previous treatment findings.…”

“…In the article that accompanies this editorial, Chawla et al 21 have reported the results of their trial assessing the efficacy of CMB305 plus atezolizumab or atezolizumab alone in patients with NY-ESO-1–expressing synovial or myxoid round cell liposarcoma. The relevance of this study furthers the data using novel immunotherapeutic strategies, which generate B- and T-cell responses for two rare sarcomas that can serve as a foundation for future trials.…”