Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer

Marie-Laure Tanguy,Francois-Clement Bidard,Fréderique Berger,Luc Cabel,Jean-Yves Pierga,Alexia Savignoni

doi:10.1038/s41523-018-0068-4

Abstract

Palbociclib, ribociclib, and abemaciclib have been investigated in combination with aromatase inhibitors as first-line therapy for metastatic hormone receptor-positive breast cancer (PALOMA-2, MONALEESA-2 and MONALEESA-7, MONARCH-3 trials, respectively); pivotal trials led to absolute median progression-free survival (PFS) gain of about 15 months. We aimed to estimate, for each trial, the statistical power to demonstrate a significant gain in overall survival (OS). Power was calculated with Freedman’s formula. Given the allocation ratio and the number of events, power was computed as a function of hazard ratio. We focused on four specific hazard ratio values (0.94, 0.89, 0.81, and 0.77), which are estimated to correspond to absolute 3, 6, 12, and 15 months gain in OS, respectively. For these calculations, the type I error rate was stated at 5% with a two-sided test, and we assumed that the risk of death was constant over time. PALOMA-2 and MONALEESA trials have an almost similar power despite different allocation ratios, while MONARCH-3 has a more limited power. Overall, the power of the four trials to demonstrate a statistically significant improvement in OS is less than 70% if the prolongation in median OS is ≤12 months, whatever the OS data maturity. This analysis shows that OS results are jeopardized by limited powers, and a meta-analysis might be required to demonstrate OS benefit. Conversely, if a significant OS improvement is observed in some but not at all trials, this discrepancy might be more attributable to chance than to a truly different drug efficacy.

Highlights

Endocrine therapies are the cornerstone of hormone receptorpositive (HR+) HER2-negative (HER2−) breast cancer treatment at both early and metastatic stages
We observed that PALOMA-2 and MONALEESA trials have an almost similar power, MONALEESA trials displaying a marginally increased power
We showed that MONARCH-3 is less powerful than PALOMA-2, MONALEESA-2, and MONALEESA-7 trials, and that these three latter trials have an almost similar power; the small difference in power between them is explained by the difference in treatment allocation ratio: 2:1 in the PALOMA-2 trial vs 1:1 in the MONALEESA trials, the three trials having enrolled a similar number of patients

Summary

Introduction

Endocrine therapies are the cornerstone of hormone receptorpositive (HR+) HER2-negative (HER2−) breast cancer treatment at both early and metastatic stages. In 2012, results of BOLERO-2, a randomized placebo-controlled phase 3 conducted in patients with HR+ HER2− MBC progressing under first-line nonsteroidal AI, have been reported.[2] This trial compared the efficacy of a steroidal AI (exemestane) to that of a combination of exemestane and everolimus, a mTOR inhibitor. In that second-line setting, despite a 4.6-month prolongation in median PFS, adding everolimus to exemestane did not confer a statistically significant improvement in the overall survival (OS): HR = 0.89, 95% CI [0.73; 1.10].3. This negative result increased the concerns about the limited cost-effectiveness of everolimus in that setting.[4,5]

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Conclusion