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 three 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/m2 (loading = 8 mg/m2) and bevacizumab 15 mg/kg every three weeks, with lapatinib 1250 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.

Salivary gland carcinomas with unusual presentations

“…This warrants radiotherapy as main therapy as shown previously [7][8][9]. HER2-directed therapy has been tested in small series with some effect [10][11][12]. The stabilization of disease in this case supports a role for HER2-directed therapy in HER2positive SDC.…”

Expression pattern of androgen receptor and AR-V7 in androgen-deprivation therapy–naïve salivary duct carcinomas

“…Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 15-50% of SDC. Trastuzumab, a HER2 inhibitor has been tested with some clinical benefit in SDC patients [1,2]. However, controlled studies have not been done, partly due to the rarity of this disease.…”

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

“…Among these factors, vascular endothelial growth factor (VEGF) is pivotal as the primary molecular driver in vasculogenesis (7). Inflammatory and tumor cells secrete VEGF, which binds and activates the VEGF receptor (VRGFR) on the surface of endothelial cells (ECs), stimulating various signaling pathways to accelerate angiogenesis (8)(9)(10). Therefore, the inhibition of tumor angiogenesis via the suppression of VEGF is favorably recommended by clinicians globally.…”