Original Article
Non–Small Cell Lung Cancer
Combined Pan-HER and ALK/ROS1/MET Inhibition with Dacomitinib and Crizotinib in Advanced Non–Small Cell Lung Cancer: Results of a Phase I Study

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Abstract

Introduction

This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non–small cell lung cancer.

Methods

Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose; secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers.

Results

Seventy patients were treated in the dose-escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths; none were considered treatment related. One patient (1%) had a partial response; 46% had stable disease. Most of the tumor samples analyzed had activating epidermal growth factor receptor gene (EGFR) mutations (18 of 20 [90%]); 50% (10 of 20) had a concurrent resistance mutation. Only one sample showed MMNG HOS Transforming gene (MET) amplification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity.

Conclusion

The combination of dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non–small cell lung cancer and was associated with substantial toxicity.

Keywords

Non–small cell
Dacomitinib
Crizotinib
EGFR TKI resistance
Biomarkers

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Disclosure: Dr. Jänne reports receiving grants and research support from Astellas and AstraZeneca; receiving consulting fees from Astra Zeneca, Roche, Genentech, Merrimack, Chugai, and Clovis Oncology; and holding stock in Gatekeeper. Dr. Shaw reports receiving grants and personal fees from Pfizer, Novartis, Ariad, Chugai, Genentech, Daiichi-Sankyo, and Ignyta. Dr. Camidge reports receiving consulting fees from Pfizer. Drs. Shreeve, Tang, Goldberg, Martini, Xu, and James were employees of Pfizer at the time this work was conducted and held Pfizer stock. Dr. Solomon reports receiving consulting fees from Pfizer, Novartis, Roche, Merck Sharpe & Dohme, AstraZeneca, and BMS; receiving research funding from Pfizer; holding patent/intellectual property with Biodesix; and receiving travel, accommodation, and other expenses from Roche and AstraZeneca. The remaining author declares no conflict of interest.