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.
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
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.
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).
Clinical trial identification
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A.B. Lassman: Comp./Res.Support:VBI Vaccines, SapienceTh., CorticeBioSci., Oxigene, prIMEOnc., AbbVie, Genentech, Regeneron, Amgen, Novartis, Karyopharm, Celldex, NWBiotherapeutics, Plexxicon, Pfizer, Agenus, Medimmune, BoehringerIngelheim, Angiochem, Novocure, Stemline, E-Th., Millennium. M. van den Bent: Received honoraria from Roche, Abbvie, Celldex, Novocure, Merck Ag, Cavion, Actelion, BMS, Blue Earth Diagnostics; received research funding from AbbVie and Roche. H.K. Gan: Has an investigator-initiated study with AbbVie; received travel support and research funding from AbbVie; received honoraria from AbbVie, Pfizer and Merck Serono; affiliated with the Ludwig Institute for Cancer Research. D.A. Reardon: Received honoraria/consulting/advisory role: Abbvie, BMS, Cavion, Celldex, Inovio, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron, Stemline Therapeutics; speakers' bureau: Roche, Merck; research funding: Incyte, Midatech, Celldex. P. Kumthekar: Received Honoraria for advisory role with AbbVie within the last 12 months. N. Butowski: Received honoraria from and has a consulting or advisory role with, Roche/Genentech, Medicenna, VBL Therapeutics, Omniox, Celldex; is involved in speakers' bureaus with Roche and Merck; received research funding Insys. L.B. Nabors: Serve on a Scientific Advisory Board for Cavion. K.P. Papadopoulos: Received research funding from AbbVie, MedImmune, Daiichi Sankyo, GlaxoSmithKline, Onyx, Sanofi, Novartis. J. Simes: Employed at an institute that received funding for the trial; also received co‐funding for an investigator‐initiated trial from AbbVie. E. Gomez, H-J. Lee, L. Roberts-Rapp, H. Xiong, E. Bain, K. Holen: Employed by AbbVie and may own AbbVie stock. R. Merrell: Advisory Board for AbbVie. All other authors have declared no conflicts of interest.