Randomized Phase III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Who Experienced Disease Progression During or After Trastuzumab-Based Therapy

Abstract

Purpose To assess the efficacy and safety of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy and received a prior taxane. Patients and Methods Patients were randomly assigned to arm A: trastuzumab 8 mg/kg → 6 mg/kg once every 3 weeks plus capecitabine 1,250 mg/m twice a day (2 weeks on, 1 week off, every 3 weeks); or arm B: pertuzumab 840 mg → 420 mg once every 3 weeks plus trastuzumab at the same dose and schedule as arm A plus capecitabine 1,000 mg/m on the same schedule as arm A. The primary end point was independent review facility-assessed progression-free survival (IRF PFS). Secondary end points included overall survival (OS) and safety. Hierarchical testing procedures were used to control type I error for statistical testing of IRF PFS, OS, and objective response rate. Results Randomly assigned (intent-to-treat) populations were 224 and 228 patients in arms A and B, respectively. Median IRF PFS at 28.6 and 25.3 months' median follow-up was 9.0 v 11.1 months (hazard ratio, 0.82; 95% CI, 0.65 to 1.02; P = .0731) and interim OS was 28.1 v 36.1 months (hazard ratio, 0.68; 95% CI, 0.51 to 0.90). The most common adverse events (all grades; incidence of ≥ 10% in either arm and ≥ 5% difference between arms) were hand-foot syndrome, nausea, and neutropenia in arm A, and diarrhea, rash, and nasopharyngitis in arm B. Conclusion The addition of pertuzumab to trastuzumab and capecitabine did not significantly improve IRF PFS. An 8-month increase in median OS to 36.1 months with pertuzumab was observed. Statistical significance for OS cannot be claimed because of the hierarchical testing of OS after the primary PFS end point; however, the magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer. No new safety signals were identified.

Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis

“…The monoclonal antibody pertuzumab (Perjeta ® ; Roche-treatment in combination with trastuzumab and chemotherapy) [24,25] was included in the NMA for completeness despite not being approved in this patient group. The primary endpoint analysis of the failed PHEREXA trial showed pertuzumab to increase PFS, but was not statistically significant, when added to trastuzumab plus capecitabine [26].…”

Phase II Study of Weekly Paclitaxel with Trastuzumab and Pertuzumab in Patients with Human Epidermal Growth Receptor 2 Overexpressing Metastatic Breast Cancer: 5-Year Follow-up

“…The high PFS in patients who were treated in the second‐line setting in our study was not seen in PHEREXA, although this was a small group and cross trial comparison cannot be done . In PHEREXA, capecitabine with trastuzumab ± pertuzumab was evaluated in patients with HER2‐positive MBC in the second‐line setting after disease progression during or after trastuzumab‐based therapy . Overall, the median PFS was 11.1 months in the dual antibody arm, which was not significantly better than 9.0 months seen in the control arm, but interim OS was 36.1 months versus 28.1 months, in favor of the pertuzumab‐containing arm.…”

“…Progression‐free survival was also sustained with a median PFS of 20.0 months (95% CI 8.5–33.0) for patients with one prior treatment. The high PFS in patients who were treated in the second‐line setting in our study was not seen in PHEREXA, although this was a small group and cross trial comparison cannot be done . In PHEREXA, capecitabine with trastuzumab ± pertuzumab was evaluated in patients with HER2‐positive MBC in the second‐line setting after disease progression during or after trastuzumab‐based therapy .…”

Review A meta-analysis of the efficacy and safety of additional anti-HER2-targeting drugs in HER2-positive advanced breast cancers

“…Studies have shown that compared with single-anti-HER2-targeting treatment, dual-anti-HER2targeting drugs increase the number of patients who achieve complete pathological remission [15,41] and could signi cantly reduce previously generated cardiotoxicity. However, a study by Urruticoechea et al [42] showed that the addition of pertuzumab to trastuzumab and capecitabine did not signi cantly improve PFS as assessed by independent review agencies. It is that the use of this drug is also controversial.…”