Background:

Progression free-survival (PFS) is the dominant endpoint in phase 3 randomized controlled trials (RCTs) in women with metastatic breast cancer (MBC), and requires the ability to measure target lesions. It is unknown whether treatment effect on PFS is consistent among patients with measurable and non-measurable disease.

Methods:

We searched MEDLINE, EMBASE and COCHRANE for phase 3 RCTs in MBC that reported outcomes in subgroups with non-measurable (or bone only disease, if not reported explicitly) and measurable disease. Data were extracted and a single hazard ratio (HR) and 95% confidence intervals (CI) were computed to compare the individual trial treatment effect in non-measurable versus measurable disease. Data were then pooled in a meta-analysis. We repeated the analysis comparing bone only to non-bone only disease and performed subgroup analyses based on drug mechanism of action.

Results:

Of 82 RCTs that enrolled patients with non-measurable disease, 16 trials comprising 8516 patients were eligible for analysis. All included RCTs used PFS or time to progression as primary endpoints. There was no difference in pooled treatment effect between patients with non-measurable and measurable disease (HR 1.01, 95% CI 0.89-1.15, p=0.82). However, compared to non-bone only disease, a significantly greater effect on PFS was seen in those with bone only disease (HR 0.82, 95% CI 0.70-0.98, p=0.03). Subgroups analyses according to drug mechanism are shown in Table 1

Intra-study comparison, according to evaluated drug mechanism

Cohort/ Investigational drug No. studies included Measurable HR (95% CI) Non measurable HR (95% CI) Intra- study comparison HR (95% CI) P – for intra-study comparison 
All 16 0.69 (0.65-0.73) 0.72 (0.64-0.80) 1.01 (0.89-1.15) 0.82 
Chemotherapy 0.99 (0.87-1.13) 0.67 (0.44-1.02) 0.73 (0.44-1.21) 0.22 
Endocrine treatment 0.86 (0.77-0.96) 0.94 (0.80-1.10) 1.13 (0.92-1.40) 0.23 
Signal transduction inhibitors 0.52 (0.48-0.57) 0.41 (0.33-0.50) 0.74 (0.59-0.94) 0.01 
Anti-angiogenetic agents 0.66 (0.59-0.73) 0.84 (0.67-1.04) 1.34 (1.05-1.71) 0.02 
Cohort/ Investigational drug No. studies included Measurable HR (95% CI) Non measurable HR (95% CI) Intra- study comparison HR (95% CI) P – for intra-study comparison 
All 16 0.69 (0.65-0.73) 0.72 (0.64-0.80) 1.01 (0.89-1.15) 0.82 
Chemotherapy 0.99 (0.87-1.13) 0.67 (0.44-1.02) 0.73 (0.44-1.21) 0.22 
Endocrine treatment 0.86 (0.77-0.96) 0.94 (0.80-1.10) 1.13 (0.92-1.40) 0.23 
Signal transduction inhibitors 0.52 (0.48-0.57) 0.41 (0.33-0.50) 0.74 (0.59-0.94) 0.01 
Anti-angiogenetic agents 0.66 (0.59-0.73) 0.84 (0.67-1.04) 1.34 (1.05-1.71) 0.02 

CI- confidence interval, HR- hazard ratio

. Compared to patients with measurable disease, there was a greater effect on PFS in those with non-measurable disease in RCTs of signal transduction inhibitors and endocrine therapy (HR 0.74, 95% CI 0.59-0.94, p=0.01). There was a lesser effect on PFS in patients with non-measurable disease in RCTs of antiangiogenic drugs (HR 1.34, 95% CI 1.05-1.71, p=0.02). Comparable effect on PFS was shown in RCTs evaluating endocrine therapy and chemotherapy.

Conclusions:

There is variability in treatment effect on PFS in patients with measurable and non-measurable disease. There is greater effect on PFS in RCTs of endocrine therapy and signal transduction inhibitors and in patients with bone only disease. Standardization of PFS determination in patients with non-measurable and bone only disease is warranted.

Citation Format: Goldvaser H, Ribnikar D, Fazelzad R, Seruga B, Templeton AJ, Ocana A, Amir E. Influence of non-measurable disease on progression-free survival in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-17-02.