Abstract P4-14-23: A phase I/II study of the combination of lapatinib and oral vinorelbine in HER2 positive metastatic breast cancer
Authors: Chen TW-W , Yeh D-C , Chao T-Y , Lin C-H , Chow LW-C , Hsieh Y-Y , Huang S-M , Cheng A-L , Huang C-S , Lu Y-S 
Published: May 2016

Abstract
Background The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is appealing due to the convenience of oral combinations, but the overlapping toxicities may be of concern. A phase I/II study was designed to understand the tolerability and efficacy of this combination treatment.
Methods Female MBC patients (pts) with HER2 positive, but regardless of ER status, were eligible. In the phase I part, pts refractory to HER2-targeted treatment or chemotherapy were eligible. In the phase II part, only pts who had not exposed to HER2-targted treatment in the metastatic setting were eligible. Hormonal treatments were not allowed during the study for ER positive pts. Lapatinib was given once daily and oral vinorelbine was given on days 1 and 8 of a 21-day cycle. A 3+3 standard dose escalation rule was applied in phase I part (Table 1). The maximum tolerated dose (MTD) was the highest dose level with less than 33% of pts experiencing dose limiting toxicity (DLT) and will used as starting dose for phase II part. The primary endpoint of the phase II part was progression-free survival (PFS). Tumor response was assessed according to RECIST 1.1. Pt number estimation in the phase II part was based on Simon 2 stage design.
Results From 2009 Jun to 2013 Feb, a total of 46 pts were enrolled in phase I (n=15) and II (n=31) parts. The median age was 52.8 (range 34.3-84.0) and the median follow-up time was 39.2 months (range 6.1-62.2). Twenty-eight (60.9%) pts were ER positive. In the phase I part, 2 pts in dose level III had DLTs (Grade 3 neutropenia and grade 3 diarrhea (n=1), prolonged neutropenia delaying next cycle treatment (n=1)). Other common ≥40% grade 1/2 adverse events (AE) in the first-cycle include diarrhea (80.0%), skin rash (66.7%), fatigue (60.0%), and vomiting (40.0%). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the phase II part, 11 pts had intra-patient dose escalation of vinorelbine from 50 to 60 mg/m2 after first-cycle if no major toxicities were noted. Grade 3/4 AEs in the first-cycle include neutropenia, diarrhea, and infection in 12.9%, 3.2% and 3.2%, respectively. Grade 1/2 AEs were similar to the phase I results. Persistent treatment (in 8 cycles) increased the rate of grade 3/4 neutropenia (22.6%) and ALT/AST elevation (6.5%).The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) pts had PR, and the clinical benefit rate (CBR) was 38.7%. A higher dose (level III vs. level II) of vinorelbine was not associated with a better CBR (p=0.71), PFS (p=0.73), or OS (p=0.11). Among pts who had disease progression records, 13.2% (5/38) had brain metastasis progression. Long-term disease control (under treatment for more than 2 years) were achieved in 13.0% (6/46, 2 ER positive, 4 ER negative) pts.
Conclusion The combination of lapatinib 1000 mg and oral vinorelbine 60 mg/m2 was general tolerable with manageable toxicities. Clinical efficacy was demonstrated with long-term responders observed.
Table 1 Vinorelbine D1 & D8/21-day cycleLapatinib Daily/21-day cycleNo. of pt recruitedNo. of pt with grade 3/4 toxicities in first-cycle mg/m2mgN=15(I)+31(II)NLevel 030100030Level I40100030Level II5010006+206(II)Level III6010003+112(I)Level IV60125000
Citation Format: Chen TW-W, Yeh D-C, Chao T-Y, Lin C-H, Chow LW-C, Hsieh Y-Y, Huang S-M, Cheng A-L, Huang C-S, Lu Y-S. A phase I/II study of the combination of lapatinib and oral vinorelbine in HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-23.