A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer. Invest New Drugs 2015 Feb;33(1):177-86
Date
10/18/2014Pubmed ID
25323060Pubmed Central ID
PMC4297242DOI
10.1007/s10637-014-0173-7Scopus ID
2-s2.0-84921384013 (requires institutional sign-in at Scopus site) 20 CitationsAbstract
PURPOSE: Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates.
EXPERIMENTAL DESIGN: Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types). Patients received lapatinib daily for 21 days, and bevacizumab and trastuzumab every 3 weeks. Correlates included HER2 extracellular domain levels (ECD) and single nucleotide polymorphisms (SNPs).
RESULTS: Ninety-four patients were treated (median = four prior systemic therapies). The most common related adverse events ≥ grade 2 were diarrhea (n = 33, 35 %) and hypertension (n = 10, 11 %). The recommended phase 2 dose was trastuzumab 6 mg/m(2) (loading = 8 mg/m(2)) and bevacizumab 15 mg/kg every 3 weeks, with lapatinib 1,250 mg daily (full FDA-approved dose of each drug). One patient (1 %) achieved a complete response (CR); eight (9 %), a partial response (PR) (includes breast (n = 7, one of which was HER2 2+ by IHC) and salivary ductal carcinoma (n = 1); and 14 (15 %), stable disease (SD) ≥6 months (total SD ≥ 6 months/PR/CR =23 (25 %). All patients with PR/CR received prior trastuzumab +/- lapatinib. SD ≥ 6 months/PR/CR rate and time to treatment failure (TTF) correlated with elevated baseline HER2 ECD (N = 75 patients tested) but not with HER2 SNPs.
CONCLUSIONS: Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy.
Author List
Falchook GS, Moulder S, Naing A, Wheler JJ, Hong DS, Piha-Paul SA, Tsimberidou AM, Fu S, Zinner R, Janku F, Jiang Y, Huang M, Parkhurst KL, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Quinazolines
Receptor, ErbB-2
Trastuzumab
Treatment Outcome