title: A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer.
abstract: This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA. Massimo.Cristofanilli@fccc.edu
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.forename: Stephen R D
authors.initials: SR
authors.lastname: Johnston
authors.forename: Alexey
authors.initials: A
authors.lastname: Manikhas
authors.forename: Henry L
authors.initials: HL
authors.lastname: Gomez
authors.forename: Oleg
authors.initials: O
authors.lastname: Gladkov
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.forename: Sufia
authors.initials: S
authors.lastname: Safina
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Alvarez
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Rubin
authors.forename: Sulabha
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Suman
authors.initials: S
authors.lastname: Redhu
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Trudeau
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D000077341:Lapatinib; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007191:Indazoles; D000077341:Lapatinib; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; C516667:pazopanib; C508053:ERBB2 protein, human