Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003)

Abstract

Purpose: Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes.

Patients and methods: Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored.

Results: Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2).

Conclusion: Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.

Trial registration: ClinicalTrials.gov NCT00470704.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

Progression-free survival (PFS) for (A) cohort 1, no prior trastuzumab in the advanced setting (n = 40), and (B) cohort 2, up to two lines of chemotherapy including trastuzumab for metastatic breast cancer (n = 45). Overall survival (OS) for (C) cohort 1 and (D) cohort 2. Shaded areas depict the 95% CIs.

Fig 2.

Relationship between change in maximum standardized uptake value (ΔSUVmax) and objective response by RECIST v1.0. Paired [18F]fluorodeoxyglucose positron emission tomography/computed tomography scan data were available for 82 patients at week 1 and for 76 patients at week 8. One patient's best overall response was not evaluable and was excluded from the figure. Dashed lines denote European Organisation for Research and Treatment of Cancer cutoffs for metabolic response (−25%) and progression (+25%). Color codes indicate objective response for each patient according to RECIST v1.0. (A) Cohort 1 and (B) cohort 2 ΔSUVmax at week 1 v baseline. (C) Cohort 1 and (D) cohort 2 ΔSUVmax at week 8 v baseline. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Fig 3.

Association between week-1 metabolic response by [18F]fluorodeoxyglucose positron emission tomography (PET) /computed tomography and progression-free survival (PFS). Patients were grouped according to those with a partial metabolic response (PMR) by European Organisation for Research and Treatment of Cancer criteria, defined as > 25% decrease in maximum standardized uptake value relative to baseline v those with either stable metabolic disease (SMD) or progressive metabolic disease (PMD). PFS was calculated from the date of the landmark (week 1). (A) Cohort 1 patients with a week-1 PMR had a median PFS of 8.8 months (95% CI, 5.3 to 29.1 months) and those without a week-1 PMR had a median PFS of 1.6 months (95% lower CI, 1.4 months). (B) Cohort 2 patients with a week-1 PMR had a median PFS of 5.3 months (95% CI, 5.1 to 7.9 months) and those without a week-1 PMR had a median PFS of 3.2 months (95% CI, 1.6 to 5.3 months).

Fig A1.

Waterfall plots of change in maximum standardized uptake value (ΔSUVmax) relative to baseline. Dashed lines denote European Organisation for Research and Treatment of Cancer cutoffs for metabolic response (−25%) and progression (+25%). Asterisks denote patients who were considered metabolic progressors on the basis of new lesion(s). (A) Cohort 1 and (B) cohort 2 ΔSUVmax at week 1 v baseline; (C) cohort 1 and (D) cohort 2 ΔSUVmax at week 8 v baseline. PMD, progressive metabolic disease; SMD, stable metabolic disease; PMR, partial metabolic response.

Fig A2.

Relationship between percentage change in maximum standardized uptake value (SUVmax) at week 1 and best percentage change of target lesions. Each individual patient is plotted according to percentage change in SUVmax by [18F]fluorodeoxyglucose positron emission tomography/computed tomography (CT) comparing baseline and week 1 on the y-axis and according to best percentage change in sum of longest dimensions of target lesions relative to baseline by CT imaging on the x-axis. Seven patients were considered RECIST nonresponders despite reductions of more than 30% in the sum of target lesions. Of these patients, six had an initial partial response that was not confirmed on subsequent imaging 8 weeks later: one had stable disease > 24 weeks and one had stable disease on initial restaging and more than 30% on second restaging but in the setting of a new lesion and was therefore deemed a nonresponder.