Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, with temozolomide (TMZ) in recurrent glioblastoma (rGBM)

Abstract

Background: ABT-414 is a first-in-class ADC that selectively targets EGFR amplification (amp) to deliver a potent microtubule cytotoxin (monomethyl auristatin F) inside the tumor cells. Almost 50% of GBMs harbor EGFR amp. ABT-414 monotherapy has shown preliminary efficacy in EGFR amp rGBM. Here we report safety and efficacy of ABT-414 + TMZ in EGFR amp rGBM at the recommended phase 2 dose. Methods: Adults with rGBM harboring centrally-confirmed EGFR amp, adequate end-organ function, and KPS >70 were eligible. To isolate the effects of ABT-414 from TMZ, all patients ( pt)s were TMZ refractory, defined as a recurrent/progressive disease <3 months from last TMZ. Pts received ABT-414 1.25 mg/kg IV on days 1 and 15, and TMZ 150-200 mg/m2 on days 1-5 of 28-day cycles, until progression (RANO). Results: As of March 1, 2016, 32 pts were treated following 1 (n = 21), 2 (n = 8), or >3 (n = 1) prior therapies. The most common adverse events (AE)s (≥25% pts) were blurred vision (53%), photophobia (34%), headache (34%), fatigue (31%) and constipation (25%). Grade 3/4 AEs included (>1 pt) keratitis (16%), ataxia, decreased platelet count, hemiparesis and thrombocytopenia (6% each). Seizure was the most common serious AE, occurring in 13% pts. Neurologic AEs were generally attributed to the underlying tumor. No dose-limiting toxicities were observed. Best radiographic responses in 31 pts with available imaging data were: 3 (10%) partial responses (PR), 18 (58%) stable disease (SD), and 10 (32%) progressive disease (PD). Pts with PD were allowed a repeat resection as clinically indicated. Four of them were found to have all or mainly treatment effect rather than active recurrence on histologic analysis; the progression-free survival (PFS), response, and 6 month-PFS rates will be updated after clarifying their outcomes. Conclusions: In this TMZ refractory population, ABT-414 demonstrated 10% PR and 58% SD rates, although histology of tissue resected for presumed recurrence remains to be clarified, which may increase rate of disease control. No new safety events were observed and ocular toxicity was the most common AE. A global, randomized trial of ABT-414 alone or with TMZ, vs. TMZ or lomustine, is underway in rGBM (NCT02343406).