crizotinib and Adenocarcinoma--Bronchiolo-Alveolar

This phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC.. Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day -14 and -7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level -1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated.. Twenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level -1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level.. The MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Papillary; Crizotinib; Erlotinib Hydrochloride; Female; Follow-Up Studies; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Pyrazoles; Pyridines; Survival Rate; Tissue Distribution

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.. 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.. 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.. 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.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cohort Studies; Crizotinib; ErbB Receptors; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Quinazolinones; Receptor Protein-Tyrosine Kinases; Survival Rate