Vocimagene Amiretrorepvec Plus Flucytosine vs Standard of Care Following Tumor Resection in Patients With Recurrent High-Grade Glioma
abstract
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New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma.
Objective
To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC).
Design, Setting, and Participants
A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma.
Interventions
Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab.
Main Outcomes and Measures
The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS.
Results
All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group.
Conclusions and Relevance
Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points.
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Additional Info
Disclosure statements are available on the authors' profiles:
Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial
JAMA Oncol 2020 Oct 29;[EPub Ahead of Print], TF Cloughesy, K Petrecca, T Walbert, N Butowski, M Salacz, J Perry, D Damek, D Bota, C Bettegowda, JJ Zhu, F Iwamoto, D Placantonakis, L Kim, B Elder, G Kaptain, D Cachia, Y Moshel, S Brem, D Piccioni, J Landolfi, CC Chen, H Gruber, A Rao, D Hogan, W Accomando, D Ostertag, TT Montellano, T Kheoh, F Kabbinavar, MA VogelbaumFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Cloughsey et al, in this issue of JAMA Oncology, report the overall survival (OS) results of a well-conducted, large, international, multicenter, randomized trial of resection followed by either standard of care (SOC) or intraoperative injection of Toca 511 followed by multiple cycles of oral 5-flucytosine (the Toca 511/FC cohort), which was conducted from November 30, 2015, to December 20, 2019. Patients at first or second recurrence of glioblastoma or anaplastic astrocytoma underwent resection followed by Toca 511 (an investigational γ retroviral replicating vector encoding a transgene for an optimized yeast cytosine deaminase, an enzyme that converts 5-fluorocytosine into 5-fluorouracil in the tumor), if randomized to the experimental arm (n = 202). The SOC control group received investigators’ choice of single salvage therapy, either lomustine, temozolomide, or bevacizumab (n = 201). With a median follow-up of 22.8 months, the median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (HR, 1.06; 95% CI, 0.83–1.35; P = .62). Further, the secondary endpoints of durable response rate, duration of response, durable clinical benefit rate, and 12-month OS were not different between the two cohorts.
So, clearly, this innovative trial, which had demonstrated clinical activity in prior uncontrolled trials, did not improve OS or other efficacy endpoints in glioblastoma/ anaplastic astrocytoma patients at first/ second relapse. Preplanned subgroup analysis in various prespecified cohorts, however, did demonstrate some interesting findings.
In patients at second recurrence (n = 60), median OS was 21.8 months for the Toca 511/FC group (n = 28) and 11.1 months for the SOC group (n = 32; (HR, 0.43; 95% CI, 0.21–0.87; P = .02, but not significant when adjusted for multiplicity). In further exploratory post hoc subset analyses in the second recurrence subpopulation, improved survival was noted for patients with IDH1-mutated tumors, as well as anaplastic astrocytoma, but with very small numbers. These subgroups with a trend toward superior survival showed more robust baseline immune cells and reduced immune suppressive cells, providing the hypothesis that, perhaps for such immune-mediated therapies to be successful, a higher baseline level of immune robustness might be a prerequisite.
A second important observation in this study was that the median numbers of therapeutic cycles on the experimental arm was low, perhaps explaining the lack of therapeutic benefit observed in the trial. This underscores the observation that the overall dismal outcome in recurrent high-grade glioma whose natural history is frequently driven by rapid tumor progression, most modestly effective therapies, especially those dependent on relatively slower immune-mediated therapeutic mechanisms, would have little to no opportunity to expose the tumor to effective cell-killing doses. This has been seen in other immunotherapy studies such as the CheckMate 143 study of nivolumab and bevacizumab in recurrent glioblastoma. Analogous to prior clinical experience, this recurrent disease trial also showed that deep sustained responses were seen in those patients who are exposed to the Toca 511 and Toca FC for a longer duration. The subset analysis for benefit demonstrated that patients who had not progressed fairly rapidly and therefore had the ability to receive an adequate dose of drug were most likely to show survival benefit. The second recurrence population, among whom there was an improvement in survival for patients with IDH1-mutant tumors and patients with anaplastic astrocytoma, has a notably better prognosis, in part because these are slower growing tumors, and there may be more potential to respond to therapy that may stimulate a local immune response.
These findings raise a critically important question. If such therapeutics fail to show OS benefit in the recurrent GBM population, should they therefore not be tested in the newly diagnosed setting? We have significant prior experience in neuro-oncology where trials that were negative in the recurrent glioblastoma setting led to the approval of the same therapy when tested in the newly diagnosed context. Examples include temozolomide, carmustine wafers, and Optune. Even radiotherapy has produced no survival benefit in recurrent GBM (NRG Oncology/RTOG 1205) but is categorically proven to improve survival in the newly diagnosed setting in several trials. In fact, to date, no therapy has ever increased survival in the recurrent glioblastoma setting.
This limitation could broadly be applicable to several novel immunotherapies being tested in the recurrent malignant glioma population, underscoring the important observation that failure of efficacy in the recurrent malignant glioma setting should not be the primary decision-driver for limiting testing of such therapies in the newly diagnosed setting where the likelihood of exposing the tumor to more therapeutic intensity in a less immunocompromised milieu exists.