Han, Ji-Youn; Lee, Soo Hyun; Lee, Geon Kook; Yun, Tak; Lee, Young Joo; Hwang, Kum Hui; Kim, Jin Young; Kim, Heung Tae
Cancer chemotherapy and pharmacology
2015Mar ; 75 ( 3 ) :475-83.
PMID : 25552401
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Han, Ji-Youn -
Lee, Soo Hyun -
Lee, Geon Kook -
Yun, Tak -
Lee, Young Joo -
Hwang, Kum Hui -
Kim, Jin Young -
Kim, Heung Tae -
ABSTRACT
PURPOSE: Vorinostat has been shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated non-small cell lung cancer (NSCLC).
METHODS: A 3?+?3 dose-escalation design was used to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Three dose levels were tested: 250?mg/day gefitinib on days 1-28 and 200, 300 or 400?mg/day vorinostat on days 1-7, and 15-21 out of every 28?days. The primary endpoint was median progression-free survival (PFS).
RESULTS: Fifty-two patients were enrolled and treated (43 in phase II). The median age was 59?years, 28 patients were male, 44 had adenocarcinoma, 29 had never smoked, and 36 had undergone one prior treatment. Twenty-two patients exhibited sensitive EGFR mutations. Planned dose escalation was completed without reaching the MTD. The RP2D was 250?mg gefitinib and 400?mg vorinostat. In 43 assessable patients in phase II, the median PFS was 3.2?months; the overall survival (OS) was 19.0?months. There were 16 partial responses and six cases of stable disease. In EGFR-mutant NSCLC, response rate was 77?%, median PFS was 9.1?months, and median OS was 24.1?months. The most common adverse events were anorexia and diarrhea.
CONCLUSIONS: Treatment with 250?mg gefitinib daily with biweekly 400?mg/day vorinostat was feasible and well tolerated. In an unselected patient population, this combination dose did not improve PFS. However, this combination showed a potential for improving efficacy of gefitinib in EGFR-mutant NSCLC (NCT01027676).
Adenocarcinoma/*drug therapy/genetics/pathology; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Hydroxamic Acids/administration & dosage; Lung Neoplasms/*drug therapy/genetics/pathology; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Quinazolines/administration & dosage; Receptor, Epidermal Growth Factor/*genetics; Survival Rate; Treatment Outcome
MESH
Adenocarcinoma/*drug therapy/genetics/pathology, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse, Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Humans, Hydroxamic Acids/administration & dosage, Lung Neoplasms/*drug therapy/genetics/pathology, Male, Maximum Tolerated Dose, Middle Aged, Mutation, Quinazolines/administration & dosage, Receptor, Epidermal Growth Factor/*genetics, Survival Rate, Treatment Outcome
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