Clinical Strategies in HER2-positive Resistant Breast Cancer


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The approval of trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) dramatically changed the treatment landscape for women with HER2-positive disease.

Trastuzumab, lapatinib, and pertuzumab are HER2-targeted monoclonal antibodies; T-DM1 is an antibody-drug conjugate that delivers treatment at the tumor site. As with other agents, resistance develops and strategies have emerged that provide additional options for these patients.7,8

Data from the phase 3 ALTERNATIVE study showed that women receiving lapatinib and trastuzumab were at a  reduced risk for disease progression compared with women receiving trastuzumab only.9

Postmenopausal women enrolled in the study had HER2-positive, HR-positive metastatic breast cancer, which progressed on neoadjuvant or first-line trastuzumab plus chemotherapy. Patients were excluded if they were candidates for chemotherapy. 

Of 369 women enrolled in the study, data were presented for 355.

For the primary endpoint, the combination of trastuzumab and lapatinib was superior to trastuzumab: median PFS was 11 months for the combination arm and 5.7 months for the trastuzumab arm. With a hazard ratio of 0.62, the combination was superior to trastuzumab (P = .0064).

Data from ALTERNATIVE suggest that dual HER2 blockade has the potential to offer an effective chemotherapy-sparing option in a subgroup of patients with HER-positive, HR-positive metastatic breast cancer without aggressive disease who are not candidates for chemotherapy.

Results from the phase 3 MARIANNE study (ClinicalTrials.gov Identifier: NCT01120184) showed, however, that T-DM1 or T-DM1 plus pertuzumab was not superior to standard first-line therapy with a taxane plus trastuzumab. T-DM1 plus pertuzumab was not superior to T-DM1 alone.10

Updated data reported at this meeting showed that OS followed a similar pattern as PFS. T-DM1 or T-DM1 plus pertuzumab was not significantly better than a taxane plus trastuzumab. Similar observations were noted when patients who received T-DM1 and/or pertuzumab after progressing on hormone therapy were censored from the analysis.

The report suggested, however, that while the median “OS was similar across treatment arms, a median OS of 53.7 months and fewer grade [3 or worse adverse events] (vs other arms) supports T-DM1 as an effective and tolerable alternative first-line treatment for HER2-positive [metastatic breast cancer] patients.”