Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.
Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J
Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported.
Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed.
Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.
Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover.
This data from the Sam Antonio Breast Cancer Symposium last month showed that heavily pre-treated patients including prior trastuzumab (Herceptin) who received a combination of two HER-2 inhibitors, trastuzumab and lapatinib (Tykerb) improved their survival by 4.5 months over lapatinib alone:
The EGF104900 study included 296 women and resulted in an overall survival rate of 56% in patients randomized to lapatinib (1,000mg/day) plus trastuzumab compared to 41% in those assigned to lapatinib (1,500mg/day) alone.
Presently, trastuzumab is approved for first treatment of HER-2 positive breast cancer and lapatinib is given in second line once Herceptin fails. It is interesting that there wasn't a Herceptin only arm, only a lapatinib only arm, but then the patients had previously progressed on trastuzumab therapy.
Previous studies with Herceptin and anthracyclines have shown an increase in cardiotoxicity associated with mainly with doxorubicin. There was no suggestion of a cardiac safety issue with the HER-2 combination therapy in this study.
Lapatinib and trastuzumab target HER-2 through different mechanisms, which may account for the apparent additive effect in combination. Previous preclinical and animal studies have suggested synergistic benefits for the combination, including enhanced apoptosis, anti-proliferative effects and downregulation of survivin.
This is the first study to show a survival improvement for any anti-HER2 agent taken beyond first line therapy. It validates the concept that trastuzumab is an important drug to maintain through disease progression beyond initial therapy in patients who have previously done well on combined chemotherapy and HER-2 regimens before developing disease progression.