AbbVie pulls phase 3 ADC trials in glioblastoma after survival miss

AbbVie is the latest company to have an investigational drug for glioblastoma multiforme (GBM) – an aggressive form of brain cancer – fail at the final hurdle.

The drugmaker’s antibody-drug conjugate Depatux-M (depatuxizumab mafodotin), previously known as ABT-414, proved unable to improve overall survival in the phase 3 INTELLANCE-1 study and has been abandoned on the advice of its data monitoring committee.

The trial compared Depatux-M to placebo on top of standard treatment with radiotherapy and chemotherapy with temozolomide in newly-diagnosed patients with glioblastoma expressing higher levels of EGFR.

The comprehensive miss means AbbVie has now stopped enrolling patients in all its studies of depatuxizumab mafodotin, and the programme joins an increasing body of drugs that have failed to move the needle in glioblastoma.

That includes several small-molecule and antibody-based EGFR inhibitors, including ImClone/Eli Lilly’s Erbitux (cetuximab), Roche/Astellas’ Tarceva (erlotinib) and AstraZeneca’s Iressa (gefitinib), whose failures were attributed to a failure to cross the blood brain barrier.

Depatux-M consists of an antibody targeted to EGFR, with a cytotoxic payload that is released inside tumour cells and causes them to die.

This is the second phase 3 trial of the drug to end in failure. At an ASCO meeting in 2017 AbbVie reported results from the INTELLANCE-2 trial of Depatux-M plus temozolomide in relapsed GBM, revealing a trend to improved outcomes versus temozolomide alone, although this did not reach statistical significance.

GBM has also proved resistant even to the newer cancer immunotherapies, with Bristol-Myers Squibb’s PD-1 inhibitor Opdivo (nivolumab) the latest to strike out in a phase 3 study.

Aside from chemotherapy the only improvements to treatment in recent years have included Roche’s VEGF-targeted antibody Avastin (bevacizumab), given a green light by the FDA in 2009, although it was subsequently rejected in Europe on the grounds of a lack of evidence for its efficacy.

There are around 300,000 or so GBM cases diagnosed every year in the US, and patients have very few treatment options. Survival times are close to the worst of any cancer, with a median survival of only around six months from diagnosis and just 5% of patients still alive after five years.

One of the reasons for the preponderance of late-stage failures is that patients enrolled into GBM trials tend to be very carefully selected at the phase 2 assessment stage, excluding those with a poor prognosis. That creates an inflated efficacy that is not borne out in less-selective phase 3 trials.

The INTELLANCE-1 trial was conducted in collaboration with the RTOG Foundation, an independent, non-profit cancer research organisation that specialises in trials that include radiation therapy. Full results from the failed test will be presented at a later medical conference.

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