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

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/m2 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/m2 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.

Informative Simultaneous Confidence Intervals in Hierarchical Testing

SummaryBackground and Objectives: In clinical trials involving multiple tests it is often difficult to obtain informative simultaneous confidence intervals (SCIs). In particular in hierarchical testing, no quantification of effects is possible for the first tested (and most important) hypothesis after its rejection. Our goal is a construction of SCIs that are always informative.Methods: We present an approach where the level is split after rejection of each hypothesis to obtain an informative confidence bound. The splitting weights are continuous functions of the parameters. Our method is realizable by a simple algorithm and is illustrated by an intuitive graphical representation.Results: We show theoretically and by an example that the new SCIs always provide information when a hypothesis is rejected. The power to reject the first hypothesis is not smaller than for the classical fixed-sequence procedure. The price for the extra information is a small power loss in the hypotheses proceeding the most important one.Conclusions: Given the substantial gain in information, a small loss of power for the non-primary hypotheses seems often acceptable. Especially in the context of non-inferiority trials, this method is a useful alternative. The flexibility in the choice of the weight functions makes the procedure attractive for applications.