A phase lb trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib
Por:
Moran, T, Palmero, R, Provencio, M, Insa, A, Majem, M, Reguart, N, Bosch-Barrera, J, Isla, D, Costa, EC, Lee, C, Puig, M, Kraemer, S, Schnell, D and Rosell, R
Publicada:
1 jun 2017
Resumen:
Objectives: Dysregulation 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 methods: Patients 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.
Results: Thirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40 mg/day and sirolimus 5 mg/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 30 mg and sirolimus 1 mg. 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.
Conclusion: The 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. (C) 2017 Elsevier B.V. All rights reserved.
Filiaciones:
:
Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol Badalona, Dept Med Oncol, Badalona, Spain
Univ Autonoma Barcelona, Carretera Canyet S-N, Barcelona 08916, Spain
Palmero, R:
Hosp Duran & Reynals, Catalan Inst Oncol, Dept Med Oncol, Barcelona, Spain
Provencio, M:
Autonomous Univ Madrid, Dept Med Oncol, Hosp Puerta de Hierro, Med, Madrid, Spain
Insa, A:
Univ Valencia, Hosp Clin, Dept Med Oncol, Valencia, Spain
Majem, M:
Hosp Santa Creu & Sant Pau, Dept Med Oncol, Barcelona, Spain
Reguart, N:
ICMHO, Hosp Clin, Dept Med Oncol, Barcelona, Spain
Bosch-Barrera, J:
Hosp Dr Josep Trueta, Catalan Inst Oncol, Dept Med Oncol, Girona, Spain
Isla, D:
Univ Hosp Lozano Blesa, Hosp Lozano Blesa, Dept Med Oncol, Avda S Juan Bosco 15, Zaragoza 50009, Spain
:
Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol Badalona, Dept Med Oncol, Badalona, Spain
Univ Autonoma Barcelona, Carretera Canyet S-N, Barcelona 08916, Spain
Lee, C:
Boehringer Ingelheim Ltd, Bracknell, Berks, England
Puig, M:
Boehringer Ingelheim SA, Med Dept R&D, Clin Res Oncol, Sant Cugat Del Valles, Spain
Kraemer, S:
Boehringer Ingelheim GmbH & Co KG, Reims, France
Schnell, D:
Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany
:
Germans Trias & Pujol Hlth Sci Inst & Hosp, Catalan Inst Oncol, Canc Biol & Precis Med Program, Badalona, Spain
Quiron Dexeus Univ Hosp, Dr Rosell Oncol Inst, Barcelona, Spain
Mol Oncol Res Fdn MORe, Barcelona, Spain
Univ Autonoma Barcelona, Campus Can Ruti,Carretera Canyet S-N, Barcelona 08916, Spain
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