A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer

Abstract

An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m 2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P ¼ 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther; 15(9); 2251-8. Ó2016 AACR.

89Zr-mAb3481 PET for HER3 tumor status assessment during lapatinib treatment

“…Similar to the results of this study, gastric cancer patients showed unaltered HER3 mRNA levels after lapatinib plus capecitabine therapy; however, elevated HER3 mRNA levels at baseline did correlate with an increased response rate to the combination. 28 In ovarian cancer, low HER3 mRNA levels represented a more sensitive phenotype for the HER2 dimerization blocking mAb pertuzumab and gemcitabine treatment. 29 Identification of tumor HER3 levels and heterogeneity might therefore pose an attractive option for patient stratification.…”

Targeting EGFR in Esophagogastric Cancer

“…Numerous EGFR-targeting phase II studies evaluated cetuximab (24-37), panitumumab (38,39), nimotuzumab (40,41), lapatinib (42,43), erlotinib (44,45), gefitinib (46), matuzumab (47), and icotinib (48) in mEGC patients ( Table 1). As a monotherapy in an unselected population, cetuximab had modest benefit with FIGURE 1 | Schematic of EGFR and its downstream pathways with monoclonal antibodies exerting their effects at the extracellular domain, and small molecule inhibitors inhibiting phosphorylation intracellularly.…”

“…Numerous EGFR-targeting phase II studies evaluated cetuximab ( 24 – 37 ), panitumumab ( 38 , 39 ), nimotuzumab ( 40 , 41 ), lapatinib ( 42 , 43 ), erlotinib ( 44 , 45 ), gefitinib ( 46 ), matuzumab ( 47 ), and icotinib ( 48 ) in mEGC patients ( Table 1 ). As a monotherapy in an unselected population, cetuximab had modest benefit with an ORR of 5% and a median progression-free survival (mPFS) of 4.0 months in these patients—including one patient with an 11.3 month PFS—which suggested that a small subset of patients benefits from EGFR-directed therapy ( 36 ).…”

Perspectives of HER2-targeting in gastric and esophageal cancer

“…The results in gastric cancer are contrasted by the data in breast cancer where lapatinib in combination with capecitabine improved time to progression with a hazard ratio of 0.49 in trastuzumab-resistant metastatic or locally advanced HER2-positive breast cancer 75 . More recently, an exploratory phase II biomarker-embedded trial combined lapatinib and capecitabine as first-line treatment of advanced gastric and gastroesophageal junction adenocarcinoma independent of HER2 expression 76 . The combination was well tolerated with a median OS of 6.3 months.…”