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

ABSTRACT: 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.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).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.Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy.

SUBMITTER: Falchook GS

PROVIDER: S-EPMC4297242 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Falchook Gerald S GS Moulder Stacy S Naing Aung A Wheler Jennifer J JJ Hong David S DS Piha-Paul Sarina A SA Tsimberidou Apostolia M AM Fu Siqing S Zinner Ralph R Janku Filip F Jiang Yunfang Y Huang Mei M Parkhurst Kristin L KL Kurzrock Razelle R

Investigational new drugs 20141018 1

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 domai ...[more]

PMID: 25323060

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Project description:BackgroundThe anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy.MethodsIn this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg [DOSAGE ERROR CORRECTED], subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358.Findings154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1-59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4-37·5]; difference 21·1%, 9·1-34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1-32·3]) and the trastuzumab (difference -4·8%, -17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]).InterpretationDual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting.FundingGlaxoSmithKline.

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

Publications

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

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