Adding Lapatinib to Paclitaxel Does Not Improve Survival as Second-Line Therapy in Asian Patients With HER2-Positive Advanced Gastric Cancer


Key Points

  • The addition of lapatinib to paclitaxel did not improve overall survival or progression-free survival.
  • Improvements in efficacy were observed with the combination in patients with no history of gastrectomy and in those with IHC 3+ score.

Weekly paclitaxel is used as second-line treatment in advanced gastric cancer, including HER2-positive disease, in Asian countries. In the phase III TyTAN trial in Asian patients reported in the Journal of Clinical Oncology, Satoh et al assessed the addition of the anti-HER2 agent lapatinib (Tykerb) to paclitaxel in this setting. Although overall response rate was improved with the combination, no significant improvements were observed in overall survival or progression-free survival.

Study Details

In the trial, 261 patients with advanced gastric cancer who were HER2-positive by fluorescence in situ hybridization (FISH) were randomly assigned to receive second-line therapy with lapatinib at 1,500 mg once daily plus weekly paclitaxel at 80 mg/m2 (n = 132) or paclitaxel alone (n = 129). The primary endpoint was overall survival in the intent-to-treat population.

The combination and paclitaxel groups were generally balanced for age (median, 61 and 62 years), sex (77% and 79% male), country (eg, Japan for 39% and 37%, China for 34% and 39%, South Korea for 17% and 19%), Eastern Cooperative Oncology Group performance status (0 in 45% and 37%, 1 in 55% and 63%), HER2 immunohistochemistry (IHC) score (0/1+ in 36% and 35%, 2+ in 12% in both, 3+ in 52% and 53%), gastrectomy status (none in 42% and 43%, yes–pylorus removed in 50% and 49%), disease stage at initial diagnosis (IV in 96% and 94%), type of gastric cancer (diffuse in 34% in both, intestinal in 43% and 42%), prior therapy (chemotherapy in 100% in both, surgery in 58% and 57%, biologic therapy in 5% and 6%, immunotherapy in 3% and 2%, radiotherapy in 5% in both), and prior trastuzumab (Herceptin) therapy (6% and 5%). 

No Survival Difference in Total Population

Median overall survival was 11.0 months in the combination group vs 8.9 months with paclitaxel alone (hazard ratio [HR] = 0.84, P = .1044. Median progression-free survival (HR = 0.85, P = .2441) and median time to progression (HR = 0.84, P= .2163) were both 5.5 vs 4.4 months. Overall response rate was 27% vs 9% (odds ratio = 3.85, P < .001). Response duration was 7.4 vs 5.1 months.

Treatment after progression occurred in 58% of the lapatinib/paclitaxel group and 64% of the paclitaxel group, including chemotherapy in 55% and 55%, radiotherapy in 8% and 16%, biologic therapy in 5% and 12%, and surgery in 4% and 8%.

Subgroup Benefits

In subgroup analyses, progression-free surival was significantly prolonged with the combination vs paclitaxel among patients with no history of gastrectomy (HR = 0.63, P = .0360) and both overall survival (HR = 0.59, P = .0176) and progression-free survival (HR = 0.54, P = .0101) were prolonged with the combination vs paclitaxel in patients with IHC 3+ score. In addition, both overall survival (9.7 vs 7.6 months, P = .0351) and progression-free survival (7.2 vs 4.7 months, P = .0077) were significantly prolonged with the combination vs paclitaxel among Chinese patients.


For adverse events of any grade, diarrhea (77%), alopecia (67%), and neutropenia (65%) were the most common with lapatinib/paclitaxel and alopecia (57%), neutropenia (50%), and leukopenia (42%) were the most common with paclitaxel alone. Grade 3 or 4 adverse events occurred in 84% of the combination group and 54% of the paclitaxel group, with the most common in the combination group being neutropenia (57% vs 31% in the paclitaxel group), leukopenia (29% vs 10%), and diarrhea (18% vs 2%). Febrile neutropenia occurred in 7% vs 2%. Adverse events led to permanent discontinuation of treatment in 16% vs 9%. Diarrhea, alopecia, neutropenia, and leukopenia were more common in Japanese vs Chinese patients.

The investigators concluded, “Lapatinib plus paclitaxel demonstrated activity in the second-line treatment of patients with HER2 FISH-positive IHC 3+ advanced gastric cancer but did not significantly improve [overall survival] in the intent-to-treat population.”

Yung-Jue Bang, MD, PhD, of Seoul National University College of Medicine, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by GlaxoSmithKline. For full disclosures of the study authors, visit

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