1248P - A phase Ib open label clinical trial of continuous once daily oral afatinib (A) plus sirolimus (S) in patients (pts) with EGFR mutation positive (E...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer Agents
Non-Small Cell Lung Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Biological Therapy
Presenter Teresa Moran
Citation Annals of Oncology (2014) 25 (suppl_4): iv426-iv470. 10.1093/annonc/mdu349
Authors T. Moran1, R. Palmero2, M. Provencio Pulla3, A. Insa4, M. Majem5, N. Reguart6, J. Bosch-Barrera7, D. Isla8, C.P. Lee9, S. Kraemer10, D. Schnell11, R. Rosell12
  • 1Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona, Barcelona/ES
  • 2Medical Oncology, Catalan Institute of Oncology, Hospital Duran i Reynals, Barcelona/ES
  • 3Medical Oncology, Hospital Puerta de Hierro, Madrid/ES
  • 4Medical Oncology, Hospital Clinico Universitario de Valencia, Valencia/ES
  • 5Oncology, Hospital de Sant Pau, 08025 - Barcelona/ES
  • 7Medical Oncology, Catalan Institute of Oncology, Hospital Doctor Josep Trueta, 17007 - Girona/ES
  • 8Servicio De Oncologia, Hospital Clínico Universitario Lozano Blesa, Zaragoza/ES
  • 9Clinical Research Department, Boehringer Ingelheim Ltd., RG12 8YS - Bracknell/GB
  • 10Biostatistics And Data Management, Boehringer Ingelheim Corporation, Reims/FR
  • 11Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/DE
  • 12Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona, Barcelona/ES



Preclinical data show that A, an irreversible ErbB family blocker, combined with an mTOR inhibitor such as S, may restore sensitivity in EGFR M+ NSCLC pts who progress after E/G. This trial was conducted to identify the maximum tolerated dose (MTD) of A + S.


Pts with stage IIIB/IV NSCLC who failed ≥1 prior treatment, and whose tumour was EGFR M + , or negative/unknown, but had progressive disease after response or stable disease (SD) for ≥6 months on prior E/G were eligible. Pts received run-in treatment with sirolimus for 8 days before starting the combination therapy. Definition of MTD was initially based on dose-limiting toxicities (DLTs) in cycle (C) 1 (28 days) but with an amendment this was extended to C1 and 2. EGFR mutation was assessed (from blood and archival tumour) and PK sampling was performed. Tumour assessment was performed at week 4, 8, 12, then every 8 weeks.


39 pts were treated: median age 61y (range: 32-81); male: 15; ECOG 0/1/2: 16/21/1; adeno/squamous/large cell carcinoma: 33/3/3. All had prior E/G; 32 had ≥1 prior chemotherapy. Median treatment duration: 103 days (range: 10-367). Pts were treated at 6 dose levels (A, mg/S, mg): 30/1 (n = 12), 40/1 (n = 3), 30/3 (n = 9), 30/5 (n = 9), 30/10 (n = 3), 40/5 (n = 3), with 30/1 defined as MTD. DLTs (C1 and 2) were seen in 12 pts (Table). The most frequent (≥20%, all grades) drug-related adverse events were: diarrhoea, mucositis, rash, asthenia, decreased appetite and nausea. The best response was partial response (PR) in 4 pts (2 at 30/5, 2 at 40/5); 23 had stable disease (SD) (median duration [days]: 105, range: 51-337). PK, tumour and blood mutation results will be presented.

DLTs (grade [n]) by dose level

30/1 40/1 30/3 30/5 30/10 40/5
Diarrhoea G3 (1) G3 (1) G3 (2)* G3 (1)
Mucositis G3 (1) G3 (2) G3 (1) G3 (2)
Raised CPK G4 (1)

*1 pt had G3 diarrhoea, asthenia, anorexia and iliac fossa pain.


A + S combination had limited tolerability in pts with EGFR M+ NSCLC progressing on E/G mainly due to overlapping DLTs of diarrhoea and mucositis. A 30 mg + S 1 mg was defined as MTD. PRs were observed at doses exceeding MTD; SD was observed at all doses.


M. Majem: Membership on an advisory board for Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer; N. Reguart: Membership on an advisory board for Roche, Lilly, Boehringer Ingelheim and Pfizer; C.P. Lee: Employee of Boehringer Ingelheim; S. Kraemer: Employee of Boehringer Ingelheim; D. Schnell: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.