HER-2阳性乳腺癌辅助治疗赫赛汀基础上再加上拉帕替尼？

Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial

Piccart-Gebhart M, Holmes E, Baselga J, et alJ Clin Oncol. 2015 Nov 23. [Epub ahead of print]

Study Summary

Dual anti-HER2 therapy with monoclonal antibodies increases the pathologic complete response in the neoadjuvant setting, but the role of lapatinib added to trastuzumab in the adjuvant setting remains unclear.

In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO trial), conducted between 2007 and 2011, over 8000 women from around the world were randomly assigned to 1 year of adjuvant therapy with trastuzumab alone or in sequence with lapatinib (T→ L) or their combination. The primary endpoint was disease-free survival (DFS). The initial protocol included an additional randomization to lapatinib alone, but this arm of the study was closed in 2011 and patients were offered adjuvant trastuzumab.

With a median follow-up of 4.5 years, a 16% reduction in the hazard of a DFS event was observed with the combination, but this effect was modest, not statistically significant, and of little clinical significance in consideration of the additional toxicity (diarrhea, cutaneous rash, hepatic toxicity). The combination also produced a modest reduction in the hazard rate of DFS, with no detectable effect on the incidence of central nervous system (CNS) relapse, which is a major problem for patients with this subset of breast cancer.

The results of this study failed to show superior outcomes for dual antibody therapy given on this schedule, although there was a nonsignificant improvement in DFS in a group that had exceptionally good outcomes. One year of trastuzumab remains standard of care.

Viewpoint

The ALTTO trial was an incredible undertaking, involving thousands of women with early-stage HER2-positive breast cancer. At the time of design, there were great hopes placed on lapatinib, in part due to reports of CNS penetration, a better cardiac safety record, and it being an oral medication. Since then, trials have cast doubts on the efficacy of lapatinib,^[1,2]although the modest efficacy of lapatinib + trastuzumab was confirmed, compared with trastuzumab alone.^[3]

Where does this leave us on the question of dual HER2 blockade?

The ALTTO investigators cite results from the CLEOPATRA (Clinical Evaluation Of Pertuzumab and Trastuzumab) trial^[4]that showed a 6-month benefit in progression-free survival and 15-month improvement in overall survival for those treated with the combination of trastuzumab and pertuzumab. In addition, the ExteNet study,^[5]presented by Chan and colleagues at the 2015 annual meeting of the American Society of Clinical Oncology, showed encouraging results in the use of neratinib for extended adjuvant therapy after trastuzumab-based adjuvant therapy. Novel immune-based approaches are currently being investigated and are likely to create more options to improve the cure rate for HER2-positive disease. Investigators continue searching for the right combination of agents and the right schedule of administration. It may be that more antibodies or combination therapies will ultimately become the standard of care, and the future may see personalized regimens geared to an individual patient's estimated tolerance and the expectation of clinical benefit.

In his editorial accompanying the published study, Dr George Sledge referred to the ALTTO trial as a detour on the road to a cure.^[6]This seems an appropriate analogy. Given the progress being made in the use of small molecules (such as neratinib) and immune-based approaches (checkpoint inhibitor monoclonal antibodies and anti-CD137 combined with trastuzumab), we will probably be traveling new avenues in the treatment and potential cure of HER2-positive disease.