1290P - Phase I trial of irreversible pan-ErbB inhibitor dacomitinib (DAC) in combination with ALK/MET inhibitor crizotinib (CRIZ) in previously treated adv...

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Drug Development
Non-Small-Cell Lung Cancer, Metastatic
Presenter Pasi Janne
Authors P.A. Janne1, A. Shaw2, G. Giaccone3, R. Camidge4, S.M. Shreeve5, Z. Goldberg5, Y. Tang6, B. Solomon7
  • 1Thoracic Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 2Cancer Center, Massachusetts General Hospital, Boston/US
  • 3Medical Oncology Branch, National Cancer Institute, US-20892 - Bethesda/US
  • 4University of Colorado Cancer Center, Aurora/US
  • 5Research And Development, Pfizer Oncology, La Jolla/US
  • 6Reseach And Development, Pfizer Oncology, La Jolla/US
  • 7Oncology, Peter MacCallum Cancer Centre, Melbourne/AU

Abstract

Objectives

EGFR T790M and MET amplification are acquired resistance mechanisms to erlotinib and gefitinib. We evaluated the feasibility of combining dac and criz to overcome this resistance.

Methods

Dose escalation was followed by an expansion phase comprising two planned cohorts: A) dac/criz and B) dac followed by dac/criz at progression. Biopsy at study entry was mandatory in the dose expansion cohorts. Dose escalation phase included patients (pts) with advanced NSCLC who had progressed after ≥1 line of chemotherapy or targeted therapy. Expansion phase included pts who had developed acquired resistance to the first generation EGFR tyrosine kinase inhibitors (TKI) erlotinib or gefitinib. Dose escalation of both agents continued until dose limiting toxicity (DLT). Endpoints included safety, best overall objective response rate (ORR), progression free survival, and biomarkers in tumor and blood that are potentially predictive for antitumor activity.

Results

Currently, 30 NSCLC pts have enrolled and are evaluable for safety (dose escalation: 25; expansion: 5). Characteristics: M/F: 13/17; mean age: 57; ECOG PS 0/1/2: 7/21/2; Caucasian/Asian: 26/4; never/former smokers: 11/19; prior therapies 1/2/ > 3: 7/9/14; prior EGFR TKI/crizotinib: 28/5; EGFR mutant/WT: 17/3; ALK-positive (ALK+): 5; HER2-positive: 1. DLTs were mucositis (n = 1/6) at dac 30 mg qd/criz 250 mg bid, diarrhea (n = 1/6) and elevated ALT (n = 1/6) at dac 45 mg qd/criz 200 mg bid, and nausea (n = 1/6) at dac 45 mg qd/criz 250 mg qd. The dose used for the expansion phase was dac/criz: 30mg qd/200mg bid. 28 pts were evaluable for response: 2 unconfirmed partial responses (1 EGFR/ALK WT; 1 ALK+), 14 stable disease, 6 progressive disease and 6 indeterminate. Dose expansion is ongoing in both cohorts.

Conclusions

Dac and criz can be combined with a manageable toxicity profile. Clinical activity has been observed in erlotinib, gefitinib and crizotinib treated pts. Dose expansion and correlation with predictive tumor biomarkers including EGFR T790M and MET amplification is underway.

Disclosure

P.A. Janne: Advisory relationship with Boehringer-Ingelheim, Roche, Genentech, Abbott, AstraZeneca, Pfizer, Sanofi and Teva Other remuneration received from LabCorp.

A.T. Shaw: Advisory relationship with Pfizer, Ariad, Chugai, Novartis and Daiichi-sankyo Received research funding from AstraZeneca and Novartis.

D.R. Camidge: Advisory relationship with Pfizer Honoraria received from Pfizer.

S.M. Shreeve: Employed as a Director by Pfizer and has stock ownership with Pfizer.

Z. Goldberg: Employed as a Medical Director by Pfizer and has stock ownership with Pfizer.

Y. Tang: Employed as a Manager by Pfizer and has stock ownership with Pfizer.

B. Solomon: Advisory relationship with Pfizer Received research funding from Pfizer.

All other authors have declared no conflicts of interest.