Randomized, Double-Blind, Placebo-Controlled Phase II Study of Yeast-Brachyury Vaccine (GI-6301) in Combination with Standard-of-Care Radiotherapy in Locally Advanced, Unresectable Chordoma

Abstract

Background Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial‐to‐mesenchymal transition. GI‐6301 is a recombinant, heat‐killed Saccharomyces cerevisiae yeast‐based vaccine targeting brachyury. A previous phase I trial of GI‐6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI‐6301 vaccine plus radiation. Materials and Methods Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo‐controlled trial. Patients received three doses of GI‐6301 (80 × 107 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity. Results Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive‐free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7–37.5 months) and 25.9 months (95% CI, 9.2–30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38–2.71). Vaccine was well tolerated with no vaccine‐related serious adverse events. Preexisting brachyury‐specific T cells were detected in most patients in both arms. Most patients developed T‐cell responses during therapy, with no difference between arms in frequency or magnitude of response. Conclusion No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual. Implications for Practice Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast‐brachyury vaccine (GI‐6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.

Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer

“…While limited clinical trials of brachyury-targeting cancer vaccines have yet to demonstrate efficacy, this phase 1 study is unique as the first intravenous administration of a brachyury-targeting vaccine and the second intravenous administration of any cancer vaccine. 24 43 The immunogenicity induced by intravenous administration of MVA-BN-brachyury-TRICOM in the current study is comparable to that obtained with SC administration of MVA-brachyury-TRICOM vaccine in the phase 1 dose-finding study and a second phase 1 study employing MVA-brachyury-TRICOM as the priming vaccine and FPV-brachyury-TRICOM as the booster vaccine. 25 26 This may be due to the small number of patients evaluated, the heterogenicity of patients enrolled in these studies, and the varied time points in which research bloods were evaluated for immune assessments.…”

“… 23 A phase 2 study (NCT02383498) of the S. cerevisiae yeast-brachyury vaccine in combination with radiation therapy in chordoma did not meet its primary efficacy endpoint. 24 The next vaccine to undergo human trials was MVA-brachyury-TRICOM, an MVA vector-based vaccine expressing the transgenes for brachyury and three human T cell costimulatory molecules: B7.1, ICAM-1, and LFA-3, designated as TRICOM. After the phase 1 dose-finding trial (NCT02179515), a second phase 1 study (NCT03349983) employed a heterologous ‘prime and boost’ strategy with MVA-brachyury-TRICOM as the priming vaccine and fowlpox virus (FPV)-brachyury-TRICOM (FPV-brachyury) as the booster vaccine.…”

Loss of SMARCB1 promotes autophagy and facilitates tumour progression in chordoma by transcriptionally activating ATG5

“… 40 , 41 , 42 Our findings provide a preclinical basis for clinical trials of autophagy inhibitors, although further in vivo validation and development of other underlying autophagy‐related agents are warranted. Moreover, considering the deficiency of satisfactory chemotherapies and targeted therapies for chordoma to date, 1 , 3 , 6 , 7 , 8 , 43 on the basis of our preclinical data, we speculate that the use of autophagy inhibitors combined with anti‐cancer therapies may resolve this plight in chordoma.…”

“… 1 Additionally, conventional chemotherapeutic drugs have a limited effect on patient survival. 5 Although clinical trials of potential target agents, which include imatinib, apatinib and a Brachyury vaccine, have been carried out recently, 6 , 7 , 8 the results are unsatisfactory and the outcomes of chordoma patients remain dismal. Thus, identification of promising biomarkers and therapeutic targets in chordoma is urgent.…”

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

“…While significantly increased levels of interferon-γ and IL-12 were observed, indicating an increased immune response, only one patient out of 35 showed a partial response to the vaccine [111]. A vaccine against advanced chordoma, in which the tumor-associated antigen brachyury is targeted, has recently finished a phase II trial [112]. Unfortunately, no significant differences were found in the overall response between the treated and control group.…”