Alongside pancreatic cancer, the aggressive brain cancer glioblastoma (GBM) is one of the toughest cancers out there. Now, AbbVie is yet another biopharma learning that lesson firsthand.
The odds were against the company from the start, given the large level of flops against this difficult-to-to-treat disease, alongside the difficulty of getting an antibody-drug conjugate (ADC) to hit its survival goals.
According to the National Brain Tumor Society, for the most common form of primary malignant brain tumors, glioblastoma multiforme, the five-year relative survival rate is a dismal 5.6% with a median survival of around 15 months.
GBMs are also quick to develop, with the tumors made up of different cells, and have a high recurrence rate of 90%. Most treatments are surgery, where possible, and chemo/radiotherapy.
Roche’s multi-indicated cancer blockbuster Avastin, which is designed to block a protein called vascular endothelial growth factor, is one of the few targeted drugs to be approved for glioblastoma multiforme, although European regulators have rejected it in the past for not being good enough.
The R&D path to treat this terrible disease is littered with failures, most recently coming from BMS’ checkpoint inhibitor Opdivo earlier this month. Brain tumors are a dismal story, and AbbVie has become the latest victim to this plot.
It was testing its experimental ADC depatuxizumab mafodotin (Depatux-M, previously known as ABT-414), which goes after the mutation epidermal growth factor receptor (EGFR) or mutant EGFRvIII, which is also the target of some older cancer meds.
In a phase 3 test, known as INTELLANCE-1, the med was used in newly diagnosed GBM patients whose tumors had EGFR: It showed no survival benefit, and given its poor showing, an Independent Data Monitoring Committee recommended it should be axed. “Enrollment in all ongoing Depatux-M studies has been halted,” the company said.
"Glioblastoma patients and their caregivers face a devastating disease for which there are few therapeutic options. While we are disappointed that Depatux-M did not demonstrate a survival benefit in the INTELLANCE-1 study, we remain committed to discovering and developing therapies to address some of the most debilitating cancers," said Michael Severino, M.D., vice chairman and president at AbbVie.
The test was being done in collaboration with the RTOG Foundation, an independent, nonprofit cancer research organization. Full, detailed results from the failed test will be published at a later medical conference and in a journal, the biopharma added in a brief update. Shares in AbbVie dipped into the red by 0.6% in trading Friday.
This also knocks back AbbVie’s late-stage cancer R&D even further, after the calamity that was Rova-T. AbbVie’s once highly lauded cancer drug, bought from a nearly $10 billion biobucks deal with Stemcentrx in 2016, in January ended up costing the company an additional $4 billion in an impairment charge.
Last year, AbbVie said would stop enrollment in a phase 3 trial of Rova-T in lung cancer patients. The decision came after a data monitoring committee found patients taking Rova-T had worse survival rates than patients in the control arm.
This was the latest setback in a round of poor showings from AbbVie after it abandoned its plans to seek an accelerated FDA approval for Rova-T as a third-line treatment for relapsed or refractory small cell lung cancer.
This also adds to a recent spate of poor results for ADCs, which have seen failures for a number of drugs over the past few years. ADCs take the form of an antibody, linker and drug—generally a toxin—and are designed to deliver a cell-killing payload to malignant tissues while limiting exposure to healthy tissues.
Despite hundreds of clinical trials, only a handful have been made available to patients, notably Pfizer’s recently reintroduced Mylotarg for acute myeloid leukemia, Seattle Genetics/Takeda’s Hodgkin lymphoma therapy Adcetris and Roche’s Kadcyla for breast cancer.
The reason so few make it to market is ADCs are complex drugs with numerous potential pitfalls that can impact safety, including the selectivity of the targeting antibody, the stability of the ADC in the body and the efficiency with which the cytotoxic payload is taken up into cells, which can lead to off-target side effects.
Just over a year ago, ADC Therapeutics abandoned one of its ADCs, HER2-targeting drug ADCT-502, after it became clear in a phase 1 trial that it would not be able to take the dose high enough to have a therapeutic effect without tolerability issues.
AbbVie had before Rova-T terminated an early-stage trial of an ADC for solid tumors, one of the candidates acquired as part of its ill-fated takeover of Stemcentrx.
In the summer of 2017, a pivotal trial of Bayer’s ADC anetumab ravtansine also missed its primary endpoint, failing to improve progression-free survival in mesothelioma patients.
And in March, a phase 3 trial of ImmunoGen’s ADC mirvetuximab soravtansine missed its primary endpoint, failing to extend progression-free survival by more than chemotherapy, driving investors to wipe 50% off its stock price. It now has to redo that phase 3 if it wants FDA approval.
It’s not been all bad news, however, with Daiichi getting nearly $7 billion in a deal with AstraZeneca for its anti-HER2 ADC [fam-] trastuzumab deruxtecan (DS-8201), which hit its main goal in a pivotal midstage test this month.