LBA39_PR - Neratinib (N) with or without temsirolimus (TEM) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: An inte...

Date 29 September 2014
Event ESMO 2014
Session NSCLC, locally advanced and metastatic
Topics Anticancer Agents
Translational Research
Non-Small Cell Lung Cancer
Basic Principles in the Management and Treatment (of cancer)
Biological Therapy
Presenter Benjamin Besse
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors B. Besse1, J. Soria2, B. Yao3, M. Kris4, B. Chao5, A. Cortot6, J. Mazières7, M.A. Socinski8, L. Horn9, S. Waqar10, F. Barlesi11, J. Gray12, D. Moro-Sibilot13, A. Oton14, E. Quoix15, A. Lalani16, L. McCulloch16, R. Bryce17, L. Gandhi18
  • 1Cancer Medicine, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 2Medicine, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 3Statistics, Puma Biotechnology Inc., Los Angeles/US
  • 4Medical Oncology, Memorial Sloan Kettering Cancer Center, New York/US
  • 5Medical Oncology, Ohio State University, Columbus/US
  • 6Clinique Des Maladies Respiratoires, CHRU de Lille - Hôpital Calmette, Lille/FR
  • 7Unité D'oncologie Cervico-thoracique, CHU de Toulouse Hôpital Larrey, Toulouse/FR
  • 8Medical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh/US
  • 9Medical Oncology, Vanderbilt University, Nashville/US
  • 10Medical Oncology, Washington University, St. Louis/US
  • 11Medical Oncology, Hôpital nord, Marseille/FR
  • 12Medical Oncology, Moffitt Cancer Center, Tampa/US
  • 13Pcmac - Pneumologie - Unité De Consultations, CHU de Grenoble, Grenoble/FR
  • 14Medical Oncology, University of Colorado, Aurora/US
  • 15Service Pneumolgie, Hôpitaux universitaires de Strasbourg Nouvel Hôpital Civil, Strasbourg/FR
  • 16Clinical Sciences, Puma Biotechnology Inc., Los Angeles/US
  • 17Clinical Research And Development, Puma Biotechnology Inc., Los Angeles/US
  • 18Medical Oncology, Dana Farber Cancer Institute, Massachusettes General Hospital, Beth Israel Deaconess Medical Center, Boston/US




Somatic HER2 (ERBB2) mutations occur in approx. 2-4% of pts with NSCLC. In vivo data suggest that combined HER2/mTOR inhibition has synergistic effects in HER2-driven lung tumors [Perera PNAS 2009]. In a phase I study, 5/7 HER2-mutated NSCLC pts showed tumor regression (PR/SD) after treatment with N, an irreversible pan-HER tyrosine kinase inhibitor, and TEM [Gandhi JCO 2014]. The effects of N alone are unknown. This randomized 2-stage phase II study compares N +/- TEM in pts with stage IIIB/IV NSCLC with HER2 somatic mutations.


Pts whose tumors had a documented HER2 mutation were randomized 1:1 to receive oral N 240 mg once daily continuously +/- IV TEM 8 mg/wk (escalated to 15 mg/wk after one 3-wk cycle if tolerated). Addition of TEM was permitted in pts assigned to N alone after progression. High-dose loperamide prophylaxis for diarrhea was mandatory throughout cycle 1. Primary endpoint: overall response rate. Secondary endpoints included: clinical benefit rate, progression-free survival, safety. If > = 2 of 13 pts in each arm have a response at 12 wks in stage 1, a further 26 pts per arm will be enrolled in stage 2. EudraCT ID: 2012-004743-68.


27 pts were enrolled (N, n = 13; N + TEM, n = 14) in stage 1 with approx. 12 wks between randomization of last pt and data cut-off. Baseline characteristics (n = 27): male/female 52%/48%; median age 65 yr; never smokers 63%. Two pts, both in N + TEM arm, had not received prior anticancer medications. Stage 1 results are shown in table. In all pts (n = 27), most common all-grade adverse events (AEs): diarrhea (n = 24), constipation (13), nausea (13), dyspnea (11), asthenia (11), vomiting (11); most common grade 3/4 AEs: dyspnea (4), diarrhea (3; grade 3 only), vomiting (3), nausea (2).

Stage 1 Neratinib (N = 13) Neratinib + Temsirolimus (N = 14)
Overall response rate,* n (%) [90% CI] 0 (0) [0-21] 3** (21) [6-47]
Partial response, n 0 3
Stable disease ( > = 12 weeks), n 4 6
Median PFS, months (95% CI) 2.9 (1.4-NE) 4.0 (2.9-9.8)
Treatment-emergent diarrhea, n (%)
All-grade diarrhea 10 (77) 14 (100)
Grade 3 diarrhea 1 (8) 2 (14)
* RECIST, version 1.1. ** Two confirmed responses; both pts had not received any prior anticancer medications. Abbreviations: CI, confidence interval; NE, not estimable; PFS, progression-free survival.


N + TEM met the efficacy criteria for stage 1 and has been expanded into stage 2. Diarrhea was not a limiting toxicity with aggressive upfront management.


B. Besse: Research grants from Puma; B. Yao, A. Lalani, L. McCulloch and R. Bryce: Employed by Puma Biotechnology Inc (study sponsor). All other authors have declared no conflicts of interest.