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The phase III CLEOPATRA study assessed the use of pertuzumab and trastuzumab with docetaxel as a first-line treatment for patients with HER2-positive metastatic breast cancer. Based on the demonstrated of a median overall survival of 56.5 months in this study. This benefit equated to a 15.7 month overall advantage compared with trastuzumab and chemotherapy, which is unprecedented in terms of first-line metastatic survival in any subset.
As a result, this triplet is now considered the standard of care in this setting, notes Joyce O’Shaughnessy, MD. This compelling data has also led to the examination of the triplet combination in the adjuvant setting. A taxane is needed with pertuzumab and trastuzumab, as was seen in the CLEOPATRA trial, says Debu Tripathy, MD. Whether docetaxel and paclitaxel are interchangeable in this setting has not been established, he adds. Smaller pilot studies have assessed the use of paclitaxel and shown fewer initial responses and comparable times to progression.
The MARIANNE study evaluated 1095 individuals with previously untreated advanced HER2-positive breast cancer who received either T-DM1 (ado-trastuzumab emtansine) alone, T-DM1 with pertuzumab, or trastuzumab with chemotherapy. However, in this study, dual blockade with trastuzumab in combination with pertuzumab did not show superiority, as similar progression-free survival (PFS) was seen among the 3 arms, states Edith Perez, MD. In the T-DM1/pertuzumab arm, the median PFS was 15.2 months versus 13.7 months with trastuzumab and a taxane and 14.1 months with T-DM1 alone.
T-DM1 was designed to be a highly toxic molecule that is designed to deliver a targeted payload of chemotherapy directly to HER2-expressing cells, says Tripathy. Trastuzumab is thought to inhibit signaling and work through an immune mechanism, he adds, although its mechanism of action is not fully understood. However, the in T-DM1, this mechanism could be slightly different, which could explain the lack of synergy with pertuzumab in the MARIANNE study.
The BOLERO-1 study represents another disappointing study for patients with HER2-positive metastatic breast cancer. In this study, frontline treatment with everolimus (Afinitor) combined with trastuzumab and paclitaxel failed to delay disease progression versus trastuzumab and paclitaxel alone in patients with HER2-positive advanced breast cancer. However, among HR-negative patients, PFS was 20.27 months with everolimus compared with 13.08 months with placebo (HR = 0.66; 95% CI, 0.48-0.91; P = .0049). Based on these findings, if you can get insurance coverage for everolimus, O’Shaughnessy suggests that adding it could be a beneficial treatment in the HR-negative setting.