US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments

Abstract

Purpose The outcome and proportion of patients with bone-only (BO) metastatic breast cancer (MBC) has not been well described. We sought to describe the differential outcomes of patients with BO MBC in clinical trials and explore whether there was a discrepancy in radiographic reads between investigator and blinded independent central review. Methods We pooled and analyzed data on 10,521 patients from 13 prospective trials submitted for MBC treatment in initial or supplemental New Drug or Biologics License Applications from 2005. Three subsets were evaluated: BO, bone with other metastases (BWO), and no bone metastases (NBM). Early discordance rate and late discordance rate were calculated from 3,733 and 2,813 patients subject to a blinded independent central review, respectively. Results Bone metastases were identified in 49% (range: 42% to 73%) of patients across trials. BO disease was present in 12.5% (range: 4% to 26%), dependent on subtype. Investigator-assessed progression-free survival (PFS) and overall survival (OS) for the pooled trials demonstrated improved outcomes for the BO subgroup compared with other subgroups (BO v BWO PFS hazard ratio [HR], 0.64; 95% CI, 0.591 to 0.696; BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61; BO v NBM OS HR, 0.68; 95% CI, 0.61 to 0.76). The BO subgroup has a higher early discordance rate and lower late discordance rate than the BWO and NBM subgroups. Conclusion To our knowledge, this review is the largest analysis to date of the BO subgroup of MBC and suggests this subgroup may have a distinct natural history. There also seems to be a difference in how the local investigators assessed progression events in the BO subgroup when compared with the other two groups.

Trial registration: ClinicalTrials.gov NCT00333775 NCT00262067 NCT00721409 NCT01740427 NCT01942135 NCT00863655 NCT00388726 NCT00099437 NCT00082433 NCT00073528.

Figures

Fig 1.

Kaplan-Meier estimates of progression-free survival (PFS), and overall survival (OS) in pooled patients (n = 3,911) with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer treated with first-line therapy (including hormonal therapy or chemotherapy) by bone metastases subtype: bone only (n = 567), no bone metastases (n = 1,309), and bone with other metastases (n = 2,035).

Fig 2.

Kaplan-Meier estimates of progression-free survival (PFS), and overall survival (OS) in pooled patients (n = 1,172) with hormone-receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer treated with second-line therapy (including hormonal therapy or chemotherapy) by bone metastases subtype: bone only (n = 249), no bone metastases (n = 291), and bone with other metastases (n = 632).

Fig 3.

Kaplan-Meier estimates of progression-free survival (PFS), and overall survival (OS) in pooled patients (n = 1,983) treated with third-line chemotherapy by bone metastases subtype: bone only (n = 134), no bone metastases (n = 900), and bone with other metastases (n = 949).