8 september 2017: Bron: The Lancet

Immuuntherapie met het vaccin rindopepimut faalt bij hersentumoren met een glioblastoom multiforme.

Dat ons projectvoorstel Utopie of Uitdaging zin heeft bewijst maar weer eens een grote fase III studie gepubliceerd in The Lancet. Immuuntherapie naast temodal - temozolomide met een vaccin (rindopepimut) gericht op de epidermal growth factor receptor (EGFR) mutatie EGFRvIII (30 % van glioblastoma patienten hebben die mutatie) bij nieuw gediagnosteerden van een hersentumor glioblastoma Multiforme waarbij na operatie weinig of geen zichtbaar rest tumorweefsel aantoonbaar is en de EGFR mutatie hadden, geeft geen enkel verschil in mediane overall overleving in vergelijking met alleen temodal - temozolomide.

Hersentumor Glioblastoma Beeld van een glioblastoom plus vocht eromheen

De studie werd uitgevoerd bij totaal 745 patiënten in 165 ziekenhuizen in 22 landen. Patiënten werden gerandomiseerd en blind ingedeeld in rindopepimut en temozolomide (n = 371) of controlegroep (placebo vaccin) en temozolomide (n = 374).

Studie werd uitgevoerd in periode van april 2012 tot december 2014 en gepubliceerd in The Lancet.

De overall overleving was exact geljik: 20.1 maanden in de rindopepimut groep vs 20.0 maanden in de controle groep (hazard ratio = 1.01, P = .93). Onder alle patienten in de "intent-to-treat" populatie, mediane overall overleving (OS) was 17.4 maanden vs 17.4 maanden in controlegroep (HR = 0.89, P = .22).

Ook was er weinig verschil in de bijwerkingen:

De meest voorkomende graad 3 of 4 bijwerkingen waren in de rindopepimut groep thrombocytopenia (9% vs 6% in controle groep), vermoeidheid (2% vs 5%), hersenvocht (2% vs 3%), wegvallen / epileptie aanvallen (2% vs 2%), en hoofdpijn (2% vs 3%). Ernstige bijwerkingen (>4) bleken epileptie aanvallen (5% vs 6%) en hersenvocht (2% vs 3%). 1 patient overleed aan de gevolgen van een longembolie die door de onderzoekers werd gezien als gerelateerd aan rindopepimut.

Onder de 745 patiënten, hadden 405 patiënten minimaal restweefsel, waarvan 195 patiënten waren ingedeeld in de rindopepimut groep en 210 in de controle groep. 338 patiënten hadden wel aantoonbaar resttumorweefsel.

Je vraagt je dan wel af waarom op basis van welke studiersultaten de FDA deze studie versneld goedkeurde

Hebben de onderzoekers gesjoemeld of heeft de FDA niet goed gekeken naar de eerdere studieresultaten? Het lijkt erop.

Rindopepimut

Rindopepimut (Rintega(R)) is an immunotherapy treatment under investigation, which works by targeting EGFRvIII, and reducing its ability to contribute to cancer growth. Rindopepimut is a peptide vaccine that binds to the corresponding 13-amino acid (molecules that make up proteins) “mutant vIII epitope,” which is connected to a carrier protein, KLH (for antibody production), which stimulates the immune system. Peptide vaccines are rapidly cycled and degraded in the body and therefore have minimal deleterious side effects. Peptides are naturally occurring biological molecules, which are made up of short chains of amino acids bonded together by peptide bonds (amine bonds). This peptide vaccine Rindopepimut, consists of using a peptide from the original pathogen, the cancer producing tumor in this case, to stimulate an immune response to fight the tumor. With the three Phase 2 trials of Rindopepimut (ACTIVATE, ACT II, and ACTIII) that have been carried out, the vaccine has been shown to inhibit the growth of EGFRvIII- expressing tumors in mouse models, suggesting that Rindopepimut has the capacity to improve both overall survival, and average survival without any progression of tumors. The vaccine seemingly initiates such a large immune response that 67% of patients who received Rindopepimut injectionss for 3 months or longer showed no visible expression of EGFRvIII. In addition, a Phase 3 study is underway, ACT IV, in newly diagnosed GBM, and a Phase 2 study, called ReACT for recurrent GBM patients. These studies are showing promising results, with noticeable increases in immune responses and health outcomes after just 3-4 months. These developments represent exciting steps in a process for immunotherapy to play a greater role in improving health outcomes, and especially for enabling immunotherapy treatment in brain cancer.

FDA Breakthrough Therapy Designation

As Rindopepimut has shown improvement in clinical outcomes over available therapy options, the FDA intends to speed up the development and review process of this drug through a “Breakthrough Therapy Designation.” The Breakthrough Therapy designation aims to accelerate the progress, analysis and review of Rindopepimut, which has the capacity to make huge advances in the treatment of such a severe and life threatening condition such as GBM.

Het volledige studierapport: Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial is tegen betlaing in te zien.

Hier het abstract van de studie:

In newly diagnosed EGFRvIII-positive glioblastoma, the addition of rindopepimut to temozolomide did not improve survival in patients with minimal residual disease.

Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial

Source: DOI: http://dx.doi.org/10.1016/S1470-2045(17)30517-XDr Prof Michael Weller, MD

Correspondence information about the author Dr Prof Michael Weller

Email the author Dr Prof Michael Weller

Nicholas Butowski, MD

David D Tran, MD

Lawrence D Recht, MD

Michael Lim, MD

Hal Hirte, MD

Lynn Ashby, MD

Laszlo Mechtler, MD

Samuel A Goldlust, MD

Fabio Iwamoto, MD

Jan Drappatz, MD

Donald M O'Rourke, MD

Mark Wong, MD

Prof Mark G Hamilton, MD

Gaetano Finocchiaro, MD

Prof James Perry, MD

Prof Wolfgang Wick, MD

Jennifer Green, BS

Yi He, PhD

Christopher D Turner, MD

Michael J Yellin, MD

Tibor Keler, PhD

Thomas A Davis, MD

Prof Roger Stupp, MD

Prof John H Sampson, MD

for the

ACT IV trial investigators^†

^†Investigators who participated in this trial are listed in the appendix

Background

Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.

Methods

In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m² for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm² post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.

Findings

Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease , and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut.

Interpretation

Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.