Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2

Abstract

Background:To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab.Methods:In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m−2) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated.Results:Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3′ (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3–4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3–4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30–40% compared with DL1.Conclusion:The MTD LPT 1000 mg/VNR 22.5 mg m−2 (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.

A Phase II Randomized Study of Lapatinib Combined With Capecitabine, Vinorelbine, or Gemcitabine in Patients With HER2-Positive Metastatic Breast Cancer With Progression After a Taxane (Latin American Cooperative Oncology Group 0801 Study)

“…The combination of L with C resulted in an ORR of 49% (95% CI, 34.8%-63.4%), which compares with an ORR of 11.1%-51.9% in the published data. 7,[18][19][20][21][22] The ORR was 56% for V (95% CI, 40%-70.4%), in the upper range of previously published data (20%-40%) for V combined with L. 9,11,12 Response rates of 51% to 59.3% were reported when combining V, in different doses, with trastuzumab. 23,24 The LG arm had an ORR of 41% (95% CI, 27%-56.8%), comparable to previously published data for the combination of G with trastuzumab (30%-62%).…”

“…These PFS and OS rates are well matched with those from other studies of LC and LV in similar populations. 9,11,12 The OS in the LG arm was shorter (11.9 months) than that in the other arms, which might be explained by the greater proportion of younger patients, hormone receptor-negative tumors, previous treatment for metastatic disease, and, possibly, postprogression therapy.…”

“…These results are similar to those from previous reports. 7,9,11,12 Hand-foot syndrome developed in 57% of patients (24% with grade 3-4) in the LC arm. As anticipated, both the LV and the LG regimens had lower rates (2% and 11%, respectively) of this AE.…”

“…A number of studies have suggested that the LV combination is effective and safe for patients with HER2 þ recurrent or MBC. [9][10][11][12] Gemcitabine (G) is a nucleoside metabolic inhibitor that kills cells undergoing DNA synthesis and blocks the progression of cells through the G 1 /S-phase boundary. As a single agent, G is active in second-and third-line treatment for patients with MBC.…”

Lapatinib-Based Therapy for Women With Advanced/ Metastatic Her2 Positive Breast Cancer

“…Similar results were reported in the subset of patients with HER2 overexpressed disease from another trial [17]. Response to combined L and vinorelbine (LV) is reported in 31 and 14% of patients in phase I and single arm phase II trials [18,19]. A phase II study randomized 37 patients to LC and 75 patients -to LV.…”