Background: Precision medicine is a promising tool in oncology. Depatux-M is a new antibody-drug conjugate, consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The Intellance2/EORTC 1410 phase II trial, showed interesting results for Depatux-M and TMZ combination in EGFR-amplified glioblastoma (GBM) patients (PTS) at first recurrence after RT and TMZ. In our study, we investigated clinical outcome and safety of this combination used in recurrent GBM PTS as “compassionate use”. Methods: In this prospective observational study, PTS were enrolled from 7 centres of AINO. Major inclusion criteria were: histologically confirmed diagnosis of GBM, 1 or more prior systemic therapies, ECOG PS ≤ 2 and EGFR-amplified (analyzed by FISH). According to original schedule, patients received Depatux-M 1.25 mg/kg every two weeks combined with TMZ until disease progression or unacceptable toxicity. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. Results: From October 2018 to June 2019, we enrolled 36 PTS: median age was 57, ECOG PS 0-1 in 88% of PTS, MGMTmet in 64%, 42% received the treatment as second-line therapy and 27% underwent further chemotherapy at progression. At the time of analysis, 13 PTS (36%) had died and 27 PTS (75%) had progressed. Median OS was 8.7ms (95%CI not available), 6ms OS was 68%; median PFS was 2.3ms (95% CI 1.8 – 2.8), 6ms PFS was 37%. All PTS were evaluable for response: disease control rate was 47%: stable disease was reported in 36% and partial response in 11% of PTS. Drug-related adverse events led to dose reductions of Depatux-M in 17% of PTS, in 28% was delayed and in 8% was permanently discontinued. The most frequent grade 3-4 adverse events were ocular toxicity in 67% and haematological toxicity in 17% of PTS; no death was considered drug-related. Conclusions: We report the first “real world” experience of Depatux-M plus TMZ in recurrent GBM. We showed encouraging clinical benefit, despite most patients were treated beyond the second-line of therapy. Overall the results are closed to those reported in previous phase II trial. Although toxicity was higher than expected, it was manageable and only a small group of patients discontinued the treatment due to serious adverse events