Phase I/II study of HSP90 inhibitor AUY922 and Erlotinib for EGFR-Mutant lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors Journal Article
| Authors: | Johnson, M. L.; Yu, H. A.; Hart, E. M.; Weitner, B. B.; Rademaker, A. W.; Patel, J. D.; Kris, M. G.; Riely, G. J. |
| Article Title: | Phase I/II study of HSP90 inhibitor AUY922 and Erlotinib for EGFR-Mutant lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors |
| Abstract: | Purpose: AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment. Patients and Methods: All patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximumtolerated dose. The primary end point of the phase II trial was complete plus partial response rate. Results: In phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junctional cardiac rhythm). Common drug-related adverse events were diarrhea, skin rash, hyperglycemia, and night blindness. All patients treated at maximum-tolerated dose (n = 25) were evaluable for response. The partial response rate was 16% (four of 25 patients; 95% CI, 5% to 36%) and was independent of tumor T790M status. Conclusion: Partial responses were observed, but the duration of treatment with AUY922 and erlotinib was limited by toxicities, especially night blindness. This phase II study of AUY922 and erlotinib did not meet its primary end point. © 2015 by American Society of Clinical Oncology. |
| Keywords: | adult; clinical article; controlled study; treatment response; aged; middle aged; gene mutation; overall survival; drug tolerability; fatigue; neutropenia; erlotinib; area under the curve; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; monotherapy; side effect; treatment duration; cancer patient; drug megadose; drug eruption; multiple cycle treatment; phase 2 clinical trial; amino acid substitution; heart disease; mucosa inflammation; thrombocytopenia; myalgia; epidermal growth factor receptor; lung cancer; tumor biopsy; cetuximab; alanine aminotransferase blood level; arthralgia; aspartate aminotransferase blood level; drug dose escalation; hyperglycemia; hypomagnesemia; alanine aminotransferase; aspartate aminotransferase; bilirubin; chemotherapy induced emesis; hypoalbuminemia; hypokalemia; hyponatremia; lung adenocarcinoma; clinical evaluation; glucose blood level; colitis; threonine; glucose; loperamide; maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; visual disorder; bilirubin blood level; metabolic disorder; methionine; epidermal growth factor receptor kinase inhibitor; circadian rhythm; afatinib; night blindness; chemotherapy induced anemia; human; male; female; priority journal; article; luminespib; elimination half-life |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 33 |
| Issue: | 15 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2015-05-20 |
| Start Page: | 1666 |
| End Page: | 1673 |
| Language: | English |
| DOI: | 10.1200/jco.2014.59.7328 |
| PROVIDER: | scopus |
| PUBMED: | 25870087 |
| PMCID: | PMC4881377 |
| DOI/URL: | |
| Notes: | Export Date: 3 August 2015 -- Source: Scopus |
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