title: Phase I/II study of gefitinib (Iressa(®)) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  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).
authors.affiliation: Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea, jymama@ncc.re.kr.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Han
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Geon Kook
authors.initials: GK
authors.lastname: Lee
authors.forename: Tak
authors.initials: T
authors.lastname: Yun
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Kum Hui
authors.initials: KH
authors.lastname: Hwang
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Heung Tae
authors.initials: HT
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D011799:Quinazolines; D000077337:Vorinostat; D066246:ErbB Receptors; D000077156:Gefitinib