Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial

Andrew B Lassman, Martin J van den Bent, Hui K Gan, David A Reardon, Priya Kumthekar, Nicholas Butowski, Zarnie Lwin, Tom Mikkelsen, Louis B Nabors, Kyriakos P Papadopoulos, Marta Penas-Prado, John Simes, Helen Wheeler, Tobias Walbert, Andrew M Scott, Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J Ansell, Earle Bain, Kyle D Holen, David Maag, Ryan Merrell, Andrew B Lassman, Martin J van den Bent, Hui K Gan, David A Reardon, Priya Kumthekar, Nicholas Butowski, Zarnie Lwin, Tom Mikkelsen, Louis B Nabors, Kyriakos P Papadopoulos, Marta Penas-Prado, John Simes, Helen Wheeler, Tobias Walbert, Andrew M Scott, Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J Ansell, Earle Bain, Kyle D Holen, David Maag, Ryan Merrell

Abstract

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.

Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.

Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.

Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Figures

Fig. 1
Fig. 1
Best response and time on therapy. The best responses as determined by the investigator using RANO criteria and time on depatux-m therapy are shown for 60/60 patients (analysis included 1 patient each with SD and PD without measurable disease at baseline).
Fig. 2
Fig. 2
Best percentage change in tumor size. The percent change in target lesion from baseline are shown for 56/58 patients who had measurable disease at baseline and at least one post-baseline measurement. Best tumor percent change is defined as the maximum reduction/minimum increase from baseline in tumor size. Values were determined per investigator measurements.

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Source: PubMed

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