A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer.

Abstract

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.

• Authors: Gerald S Falchook, Stacy Moulder, Aung Naing, Jennifer J Wheler, David S Hong, Sarina A Piha-Paul, Apostolia M Tsimberidou, Siqing Fu, Ralph Zinner, Filip Janku, Yunfang Jiang, Mei Huang, Kristin L Parkhurst, Razelle Kurzrock
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 1 Pg. 177-86 (Feb 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25323060 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal, Humanized
• Quinazolines
• Lapatinib
• Bevacizumab
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Bevacizumab
• Female
• Humans
• Lapatinib
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, genetics, metabolism)
• Quinazolines (administration & dosage, adverse effects)
• Receptor, ErbB-2 (genetics, metabolism)
• Trastuzumab
• Treatment Outcome