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Combined Pan-HER and ALK/ROS1/MET Inhibition with Dacomitinib and Crizotinib in Advanced Non-Small Cell Lung Cancer:
Pasi A Jänne1, Alice T Shaw2, D Ross Camidge3
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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.
Insights
This phase I trial combined dacomitinib and crizotinib for advanced non-small cell lung cancer, but showed limited antitumor activity and significant toxicity in patients with EGFR mutations.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Advanced non-small cell lung cancer (NSCLC) remains a significant clinical challenge.
- Targeted therapies, including epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) inhibitors, have revolutionized NSCLC treatment.
- Investigating novel drug combinations is crucial for overcoming resistance mechanisms and improving patient outcomes.
Purpose of the Study:
- To evaluate the safety and activity of dacomitinib (a pan-HER inhibitor) combined with crizotinib (a MET/ALK inhibitor) in advanced NSCLC.
- To determine the recommended phase II dose (RP2D) of this combination therapy.
- To explore potential correlations between tumor biomarkers and treatment response.
Main Methods:
- A phase I dose-escalation study enrolled 70 patients with advanced NSCLC who progressed on prior therapies.
- Dacomitinib and crizotinib doses were escalated to identify the maximum tolerated dose (MTD).
- Safety, tolerability, and preliminary antitumor activity were assessed, alongside biomarker analysis (EGFR mutations, MET amplification, HER/MET expression).
Main Results:
- The MTD was established as dacomitinib 30 mg once daily plus crizotinib 200 mg twice daily.
- Grade 3/4 treatment-related adverse events occurred in 43% of patients, with diarrhea being most common.
- Limited partial response (1%) was observed; 46% had stable disease. No clear association between biomarkers and activity was found.
Conclusions:
- The combination of dacomitinib and crizotinib demonstrated limited antitumor efficacy in advanced NSCLC.
- The regimen was associated with substantial toxicity, particularly gastrointestinal and dermatological adverse events.
- Further investigation into this specific combination for NSCLC is not supported by these findings.
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