• Teresa Moran, Ramón Palmero, Mariano Provencio, Amelia Insa, Margarita Majem, Noemí Reguart, Joaquim Bosch-Barrera, Dolores Isla, CostaEnric CarcerenyECMedical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona (UAB), Carretera de Canyet s/n, 08916 Badalona, Barcelona, Spain. Electronic address: ec, Chooi Lee, Marta Puig, Sandrine Kraemer, David Schnell, and Rafael Rosell.
• Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona (UAB), Carretera de Canyet s/n, 08916 Badalona, Barcelona, Spain. Electronic address: mmoran@iconcologia.net.
• Lung Cancer. 2017 Jun 1; 108: 154-160.

ObjectivesDysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non-small-cell lung cancer (EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib.Materials And MethodsPatients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics.ResultsThirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40mg/day and sirolimus 5mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30mg and sirolimus 1mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination.ConclusionThe combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. CLINICALTRIALS.Gov IdentifierNCT00993499.Copyright © 2017 Elsevier B.V. All rights reserved.

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