What is the clinical trial that established the efficacy of lapatinib (Tykerb) in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer?

Clinical Trial Establishing Lapatinib Efficacy in Metastatic HER2-Positive Breast Cancer

The pivotal phase III trial that established lapatinib's efficacy in metastatic HER2-positive breast cancer randomized 399 patients who had progressed after anthracyclines, taxanes, and trastuzumab to receive either lapatinib 1,250 mg daily plus capecitabine 2,000 mg/m²/day (days 1-14 every 21 days) versus capecitabine alone at 2,500 mg/m²/day, demonstrating a significant improvement in time to progression from 18.6 weeks to 27.1 weeks (HR 0.57, P=0.00013). 1

Trial Design and Patient Population

• This was a randomized, phase III trial that enrolled patients with HER2-overexpressing (IHC 3+ or IHC 2+ confirmed by FISH) locally advanced or metastatic breast cancer who had progressed after prior treatment including anthracyclines, taxanes, and trastuzumab 1

• The median age was 53 years, with 14% older than 65 years, and 91% were Caucasian 1

• Ninety-seven percent had stage IV disease, 48% were ER+ or PR+, and 95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation 1

• Approximately 95% of patients had received prior treatment with anthracyclines, taxanes, and trastuzumab 1

Primary Efficacy Results

• The primary endpoint was time to progression (TTP), defined as time from randomization to tumor progression or death related to breast cancer 1

• Based on independent assessment, the combination arm achieved a median TTP of 27.1 weeks versus 18.6 weeks with capecitabine alone (HR 0.57,95% CI 0.43-0.77, P=0.00013) 1

• Investigator assessment showed similar results with median TTP of 23.9 weeks versus 18.3 weeks (HR 0.72,95% CI 0.56-0.92, P=0.00762) 1

• The objective response rate was 23.7% with the combination versus 13.9% with capecitabine alone by independent assessment 1

Overall Survival Data

• At the initial efficacy analysis, overall survival data were immature (32% events), leading to study unblinding and crossover of patients from capecitabine alone to the combination 1

• After an additional 2 years of follow-up, median overall survival was 75.0 weeks with lapatinib plus capecitabine versus 65.9 weeks with capecitabine alone (HR 0.89,95% CI 0.71-1.10, P=0.21) 1

• The survival analysis was confounded by the crossover design, with 76% mortality in the combination arm versus 82% in the capecitabine-alone arm 1

Current Clinical Context and Guideline Recommendations

• The NCCN guidelines recognize lapatinib in combination with capecitabine or trastuzumab as options for patients with HER2-positive disease after progression on a trastuzumab-containing regimen 2

• A subsequent phase III trial demonstrated that trastuzumab plus lapatinib improved progression-free survival from 8.1 weeks to 12 weeks (P=0.008) compared to lapatinib monotherapy in heavily pretreated patients with disease progression on trastuzumab 2

• The EMILIA trial later showed that T-DM1 was superior to lapatinib plus capecitabine, with median PFS of 9.6 months versus 6.4 months (HR 0.65, P<0.001) and improved overall survival (HR 0.62, P=0.0005), establishing T-DM1 as the preferred second-line option 2

Important Safety Considerations

• The most common adverse events with lapatinib plus capecitabine include diarrhea (67%), palmar-plantar erythrodysesthesia syndrome (76%), nausea, vomiting, and stomatitis 3

• Grade 3 or 4 adverse events occurred in 57% of patients receiving lapatinib plus capecitabine versus 41% with T-DM1 in the EMILIA trial 2

• Aggressive supportive management is required for severe diarrhea, including IV fluids, octreotide, empiric fluoroquinolone therapy, and comprehensive metabolic monitoring 4

Current Treatment Positioning

• While the original phase III trial established lapatinib plus capecitabine as an effective option after trastuzumab progression, newer agents have since demonstrated superior efficacy 1

• Trastuzumab deruxtecan is now the preferred treatment option for patients who have progressed after trastuzumab, with a 12-month PFS rate of 75.8% versus 34.1% with T-DM1 (HR 0.28, P=7.8×10⁻²²) 4

• Lapatinib remains a reasonable option in resource-limited settings or when newer HER2-targeted therapies are unavailable, particularly in patients with negative prognostic factors who have received prior trastuzumab, pertuzumab, and T-DM1 5, 6