TRIPLE-B

Primary:

• Validate the BRCA-like test* in predicting differential progression free survival (PFS) according to RECIST v1.1 definitions for measurable and non-measurable disease with first line alkylating and platinum agents (± antibody add-on) when compared to paclitaxel (± antibody add-on) in TNBC

Secondary:

• Test whether the addition of atezolizumab to chemotherapy will result in more objective responses and a higher proportion of patients who are free of progression at 6 months and at 12 months
• Analyze whether PD-L1 status (immunohistochemistry) in either tumor cells or tumor infiltrating immune cells predicts for potential differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
• Analyze whether intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL) predict for differential PFS benefit of atezolizumab added to fist line palliative chemotherapy in TNBC
• Evaluate whether an alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS in BRCA-like TNBC
• Evaluate whether paclitaxel is more effective than an alkylating regimen as first line chemotherapy regarding PFS in non-BRCA-like TNBC
• To define whether different TNBC molecular subtypes- based on RNA –expression analysis – predict for differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
• To define whether pretreatment LDH level predicts for differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
• To define biomarkers that can predict for a PFS advantage of carboplatin-cyclophosphamide (CC) as first line palliative chemotherapy in TNBC
• To define biomarkers that can predict for a PFS advantage of paclitaxel as first line palliative chemotherapy in TNBC
• To define biomarkers that can predict for a benefit of addition of atezolizumab to first line palliative chemotherapy in TNBC
• Evaluation of PFS after cross-over to the other chemotherapy regimen with atezolizumab (PFS2)
• Evaluation of ORR, proportion of patients that is free of progression at 6 months and at 12 months after cross-over to the other chemotherapy regimen with atezolizumab
• Evaluate whether addition of atezolizumab to chemotherapy in first line is more beneficial than when added in second line
• Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS and evaluation of overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR) for all atezolizumab-related questions
• Evaluate clinically relevant toxicity of all study regimens
• Evaluate preliminary efficacy by PFS and OS in subgroups of patients treated before amendment 3 with carboplatin/cyclophosphamide or paclitaxel with or without bevacizumab
• Evaluate putative predictive potential of BRCA-like status in various subgroups defined by treatment regimen received before amendment 3 (to be analyzed only after the main outcome of the trial, to avoid an extra interim analysis on the primary outcome).

* BRCA-like status determined by array comparative genomic hybridization (aCGH), multiplex ligase-dependent probe amplification (MLPA), or next generation sequencing (NGS); BRCA-like test positive when the genomic profile resembles that of BRCA-mutated breast cancers (BRCA-like genomic profile, derived from BRCA1 or BRCA2 mutation), or when the tumor is BRCA1-mutated, BRCA2-mutated, the patient is a BRCA1 and/or BRCA2 germline mutation carrier, or has a BRCA1 promoter hypermethylation.