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A phase Ib 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.
Lung Cancer 2017; 108:154-160LC

Abstract

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 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.

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. CLINICALTRIALS.

GOV IDENTIFIER

NCT00993499.

Authors+Show Affiliations

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.Medical Oncology Department, Catalan Institute of Oncology, Hospital Duran i Reynals, Barcelona, Spain. Electronic address: rpalmero@iconcologia.net.Medical Oncology Department, Hospital Puerta de Hierro, Medicine Autonomous University of Madrid, Spain. Electronic address: mprovenciop@gmail.com.Medical Oncology Department, Hospital Clinico Universitario de Valencia, Valencia, Spain. Electronic address: amelia_insa@ono.com.Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Electronic address: MMajem@santpau.cat.Medical Oncology Department, Hospital Clinic ICMHO, Barcelona, Spain. Electronic address: nreguart@clinic.ub.es.Medical Oncology Department, Catalan Institute of Oncology, Hospital Dr. Josep Trueta, Girona, Spain. Electronic address: jbosch@iconcologia.net.Medical Oncology Department, Hospital Lozano Blesa, University Hospital Lozano Blesa, Avda. S. Juan Bosco nº 15, 50009, Zaragoza, Spain. Electronic address: lola.isla@gmail.com.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: ecarcereny@iconcologia.net.Boehringer Ingelheim Ltd., Bracknell, Berkshire, UK. Electronic address: chooi.lee@boehringer-ingelheim.com.Clinical Research-Oncology, Medical Department R&D, Boehringer Ingelheim S.A., Sant Cugat del Vallès, Spain. Electronic address: marta.puig@boehringer-ingelheim.com.Boehringer Ingelheim, Reims, France. Electronic address: sandrine.kraemer@boehringer-ingelheim.com.Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. Electronic address: david.schnell.ext@boehringer-ingelheim.com.Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Badalona, Spain; Dr. Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain; Molecular Oncology Research Foundation (MORe), Barcelona, Spain; Universitat Autònoma de Barcelona (UAB) Campus Can Ruti, Carretera de Canyet s/n, 08916 Badalona, Barcelona, Spain. Electronic address: rrosell@iconcologia.net.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Multicenter Study

Language

eng

PubMed ID

28625629

Citation

Moran, Teresa, et al. "A Phase Ib 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." Lung Cancer (Amsterdam, Netherlands), vol. 108, 2017, pp. 154-160.
Moran T, Palmero R, Provencio M, et al. A phase Ib 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. Lung Cancer. 2017;108:154-160.
Moran, T., Palmero, R., Provencio, M., Insa, A., Majem, M., Reguart, N., ... Rosell, R. (2017). A phase Ib 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. Lung Cancer (Amsterdam, Netherlands), 108, pp. 154-160. doi:10.1016/j.lungcan.2017.03.009.
Moran T, et al. A Phase Ib 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. Lung Cancer. 2017;108:154-160. PubMed PMID: 28625629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A phase Ib 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. AU - Moran,Teresa, AU - Palmero,Ramón, AU - Provencio,Mariano, AU - Insa,Amelia, AU - Majem,Margarita, AU - Reguart,Noemí, AU - Bosch-Barrera,Joaquim, AU - Isla,Dolores, AU - Costa,Enric Carcereny, AU - Lee,Chooi, AU - Puig,Marta, AU - Kraemer,Sandrine, AU - Schnell,David, AU - Rosell,Rafael, Y1 - 2017/03/22/ PY - 2016/11/15/received PY - 2017/03/17/revised PY - 2017/03/20/accepted PY - 2017/6/20/entrez PY - 2017/6/20/pubmed PY - 2018/3/27/medline KW - Afatinib KW - Epidermal growth factor receptor KW - Non-small cell lung cancer KW - Sirolimus SP - 154 EP - 160 JF - Lung cancer (Amsterdam, Netherlands) JO - Lung Cancer VL - 108 N2 - 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 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. 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. CLINICALTRIALS. GOV IDENTIFIER: NCT00993499. SN - 1872-8332 UR - https://www.unboundmedicine.com/medline/citation/28625629/A_phase_Ib_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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169-5002(17)30263-5 DB - PRIME DP - Unbound Medicine ER -