Marizomib in combination with temozolomide-based radiochemotherapy for newly diagnosed glioblastoma

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Published: 11 Jun 2021
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Dr Patrick Roth - University Hospital Zurich, Zurich, Switzerland

Dr Patrick Roth speaks to ecancer in an online interview for ASCO 2021 about a phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.

He explains that glioblastoma still has a very poor prognosis despite intense research efforts and comprehensive standard treatment.

Dr Roth reports that the data obtained from the interim analysis shows no survival benefit from the addition of marizomib and an increase in adverse events, leading to enrollment for the trial ending. He discusses analysis that is still ongoing.

We conducted a randomised phase III trial for patients with newly diagnosed glioblastoma. As many people will know, glioblastoma is a disease which still has a very poor prognosis despite intense research efforts and despite quite comprehensive standard treatment which consists of surgery, radiation therapy and alkylating chemotherapy. In this phase III trial we explored the addition of marizomib, a novel proteasome inhibitor, to the standard of care and compared it to standard of care alone.

This is a multi-centre trial running at roughly 70 sites in Europe, in Canada and the US. The coordinating institution is EORTC and we did this trial in collaboration with CCTG. We enrolled 749 patients who were randomised on the two study arms. Enrolment started in summer 2018 and lasted until August 2020. Following a pre-planned interim analysis patient enrolment was stopped, however at the time we had already reached basically the target sample size. So we ended up with 749 patients.

The primary endpoint of the trial was overall survival and actually based on the data obtained within the interim analysis we did not see a survival benefit conferred by the addition of marizomib. In other words, there was no difference between the standard arm and the experimental arm with a median overall survival of approximately 15.6 and 15.8 months in the two treatment arms with a hazard ratio of 0.99. Similarly there was no difference in progression free survival. These are the key findings of the trial which is, therefore, unfortunately a negative trial.

We also looked at the safety of this combination and saw more adverse events associated with the treatment in the experimental group. There was particularly a higher frequency of neurological and psychiatric adverse events in the marizomib group which was another reason for the IDMC to recommend that the enrolment is stopped.

We are working on additional analyses such as detailed survival analyses, also taking into consideration the MGMT promoter methylation status. We are working on several exploratory analyses and we have an ongoing translational research programme. But at this point no further patients will be treated with marizomib, obviously.

This is unfortunately another negative phase III trial in the glioblastoma field which is something we’ve seen many times before, unfortunately, despite some encouraging observations in previous smaller trials. So it’s very clear that we need to understand this data in detail, understand why the drug did not confer survival benefit, understand how we design clinical trials in the future to avoid such large trials which then turn out to be negative. So evaluating more advanced study concepts will probably be a key step in the future.

We are grateful, of course, for all the patients who were willing to participate in the trial, their relatives and, of course, I’d like to thank all investigators across the world for their participation in the trial.