Quality-adjusted survival analysis of first-line treatment of hormone-receptor-positive HER2+ metastatic breast cancer with letrozole alone or in combination with lapatinib

Abstract

Aim:

Compare first-line lapatinib plus letrozole (L + Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2 + metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period.

Methods:

The area under survival curves for each treatment group was partitioned into distinct health states of varying utility: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period following disease progression until death or end of follow-up (REL). The utility-weighted sum of the mean health state durations was derived for each group. The threshold utility analysis evaluates how varying utility values across the states affects Q-TWiST differences between groups, although the method is limited by not varying utilities within each health state.

Results:

The primary analysis population was the HER2 + subgroup (n = 219). There was no significant difference between treatments in mean duration of grade 3/4 adverse events prior to progression (L + Let = 1.95 weeks; Let = 2.14 weeks; P = 0.90). Using utility weights of 0.5 for TOX and REL, L + Let was favored for quality-adjusted survival by 8.8 weeks (P = 0.09). The Q-TWiST difference between treatment groups ranged from 8 to 9.5 weeks, favoring combination therapy for all hypothetical utility levels, but none of the comparisons were statistically significant at P = 0.05.

Conclusions:

No significant differences were found between L + Let versus Let in mean duration of severe adverse events. Quality-adjusted survival was favored for the combination treatment arm for all utility levels examined when toxicity was defined by grade 3/4 AEs, but differences between groups were not statistically significant.

Trial registration: ClinicalTrials.gov identifier: NCT00073528.

Keywords::

• Breast cancer
• HER2
• Lapatinib
• Letrozole
• Metastatic
• Q-TWIST
• quality-adjusted

Transparency

Declaration of funding

The EGF30008 study and the Q-TWiST analysis were funded by GlaxoSmithKline.

Declaration of financial/other relationships:

Be.S. and Bi.S. are employees of RTI Health Solutions which receives research funding from multiple pharmaceutical companies; M.M.A. and L.O’R. are employees of GSK and own stocks; J.M. was an employee of GSK when this work was conducted; S.J. receives research funding from GSK.

CMRO peer review reviewers have disclosed any relevant financial relationships to the Editors.

Acknowledgements

We thank the patients who participated in the study and their families; the medical, nursing, and research staff at the study centers; the independent data and safety monitoring committee; the monitors, clinical operations staff, data managers, statisticians, and programmers at GlaxoSmithKline.