Lessons from breast cancer trials of HER2-kinase inhibitors.

The clinical development of the HER2-specifi c monoclonal antibody trastuzumab is an oncology success story. Adding trastuzumab to chemotherapy markedly improves survival for patients with both early and advanced HER2-positive breast cancer. Despite this success, trastuzumab regimens are not eff ective in all patients, and in patients with metastatic disease, tumors inevitably progress. However, trastuzumab provides benefi t even after progression. This was fi rst shown in a study in which patients with metastatic disease that had progressed with a trastuzumab-based regimen were randomly assigned to receive capecitabine alone or capecitabine plus trastuzumab. Trastuzumab continuation signifi cantly improved time to progression compared with capecitabine alone. An alternative approach to HER2-targeting is the use of small molecule tyrosine kinase inhibitors such as lapatinib (which has been approved by the US Food and Drug Administration), and the investigational drugs afatinib, neratinib, and ONT-380. Lapatinib was approved on the basis of a study showing that capecitabine and lapatinib improved progression-free survival compared with capecitabine alone in patients who had previously progressed on trastuzumab. Lapatinib was also directly compared with trastuzumab in MA.31, a trial of predominantly trastuzumab-naive patients (82%) randomly assigned to fi rst-line treatment with a taxane and either lapatinib or trastuzumab; the lapatinib group had inferior progression-free survival and more toxic eff ects compared with the trastuzumab group. An unanswered question is how lapatinib or any other tyrosine kinase inhibitor compares with trastuzumab in patients after progression with trastuzumab. Nadia Harbeck and colleagues report the results of the fi rst study that addresses this question. The LUX-Breast 1 trial compared afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients whose cancer had progressed on one line of trastuzumab. The data monitoring committee stopped the study because it had a low likelihood of showing superiority of afatinib for progression-free survival, and overall survival was greater in the trastuzumab group than in the afatinib group (hazard ratio 1·48 [95% CI 1·13–1·95]; p=0·0048). In addition, the afatinib regimen was associated with greater toxic eff ects. Superfi cially, the LUX-Breast 1 trial seems to be just another study showing that a tyrosine kinase inhibitor has inferior outcomes and greater toxic eff ects compared with trastuzumab. But one could argue that the results of this trial were unexpected. Unlike lapatinib, which reversibly inhibits EGFR and HER2, afatinib is a highly potent and irreversible inhibitor of all kinase-competent HER proteins (EGFR, HER2, and HER4). In addition, afatinib blocks all heterodimers and homodimers of the HER family. Preclinical studies suggest that signalling through heterodimers, most notably HER2–HER3, is an important mechanism of trastuzumab resistance. Thus, the LUX-Breast 1 investigators had a strong rationale for comparing afatinib with trastuzumab. Finally, one could argue that the study design favoured afatinib because the patient population had all previously progressed on trastuzumab. Despite these points favouring afatinib, the study was negative. Faced with these surprising data, it is useful to take a step back and ask what broader lesson can be learned from these results. One potential explanation for the consistent superiority of trastuzumab over tyrosine kinase inhibitors is trastuzumab’s ability to act through mechanisms aff ecting immunity, rather than solely as a HER2 signalling inhibitor. Evidence to support this contention includes preclinical studies showing that the ability of trastuzumab to activate antibody-dependent cell-mediated cytotoxicity is crucial for its effi cacy in vivo. Several clinical studies also suggest an immunomodulatory component to trastuzumab activity. Patients with tumours enriched for gene signatures of immunity benefi t more from adjuvant trastuzumab than do patients who have tumors without such signatures. The presence of many tumour-infi ltrating lymphocytes also predicts benefi t of trastuzumab, although not all studies are concordant. Trastuzumab’s ability to act via immune-related mechanisms could explain its unique benefi t across multiple lines of treatment. These data do not rule out a potential role for tyrosine kinase inhibitors for treating breast cancer. Combinations of tyrosine kinase inhibitors with trastuzumab, as well as other targeted drugs, are being explored. In addition, a phase 3 study has shown that 1 year of treatment with the irreversible Lancet Oncol 2016