459P - Progression-free survival (PFS) assessment by local investigators versus blinded independent central review (BICR) in randomized clinical trials (RCTs) in metastatic breast cancer (MBC): Is it really needed?

Background

In RCTs, BICR is used to minimize the heterogeneity and risk of bias associated with radiological response evaluation by local investigators. However, BICR adds costs and complexity in trial management, which questions its practical utility. We aimed to assess the discrepancy index between PFS assessment by local investigators and by BICR in RCTs of MBC.

Methods

A systematic search of PubMed, Embase, Cochrane databases and conference proceedings (ASCO, SABCS and ESMO meetings) was performed up to January 4, 2023. All RCTs published from 2000 to 2022, including MBC patients treated in first or second-line, and reporting PFS assessed by local investigators and BICR were included (PROSPERO - CRD42021229865). The agreement between hazard ratios (HRs) of PFS assessed by local investigators and BICR was measured using intraclass correlation coefficient (ICC). A discrepancy index, defined as the ratio of BICR-assessed HR by the corresponding investigator-assessed HR, was calculated for each trial to quantify the level of agreement in the estimated effect.

Results

A total of 24 studies with 13,338 patients were included in the analysis. Among them, 19 (79%) were in first line, 18 (75%) were phase III trials and 23 (96%) had PFS as primary endpoint. The overall combined discrepancy index was 0.97 (95%CI 0.85-1.10; ICC = 0.831, p-value <0.001) suggesting no statistically significant difference in PFS assessment by local investigators vs BICR. This result was consistent across all subgroups analyzed (the table). Table: 459P

Discrepancy index and 95% confidence intervals in the overall population and in subgroups

Conclusions

The good concordance between local investigator and BICR assessments supports the reliability of local investigator-assessed PFS as primary endpoint for RCTs in MBC. The resources used for BICR might be reallocated to other areas, such as translational research, decreasing the burden of clinical trial conduction.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Molinelli: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Writing Engagement: Lilly; Financial Interests, Personal, Other, support to attend medical conferences: Gilead. E. Agostinetto: Financial Interests, Personal, Invited Speaker: Eli Lilly, Sandoz, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Gilead; Financial Interests, Personal, Other, support to attend medical conferences: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, AstraZeneca . D. Martins Branco: Financial Interests, Personal, Advisory Board, (14/01/2021): Janssen; Financial Interests, Personal, Advisory Board, (22/03/2021): Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker, (03/02/2022 and 23/09/2022): AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, (18/06/2021): Novartis; Financial Interests, Personal, Other, Meeting/travel grant (11/02/2021): Merck Sharp & Dohme; Financial Interests, Personal, Other, Meeting/travel grant (07/12/2021).: Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an observational research project.: Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an investigator-initiated clinical trial (NCT05075538).: F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Other, Work for Institut Jules Bordet as academic partner medical advisor in two industry-sponsored clinical trials (NCT01358877 and NCT03498716): F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Other, Institutional funding for an investigator-initiated clinical trial (NCT03339843): Eli Lilly; Non-Financial Interests, Member of Board of Directors: Associação de Investigação e Cuidados de Suporte em Oncologia - Portuguese MASCC affiliate; Non-Financial Interests, Leadership Role, Portuguese Young Oncologists Committee Chair: November 2020 - May 2022: Sociedade Portuguesa de Oncologia; Non-Financial Interests, Leadership Role, Oncology Committee Chair: January 2020 - January 2021: Health Parliament Portugal; Other, Employment of non-household immediate family member: F. Hoffmann-La Roche Ltd. G. Nader Marta: Financial Interests, Personal, Other, support to attend medical conferences: Bayer, Roche and AstraZeneca. M. Piccart: Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly, MSD, Novartis, Pfizer; Financial Interests, Personal, Other, Consultant: Camel-IDS/Precirix; Financial Interests, Personal, Advisory Board: Immunomedics, Menarini, Odonate, Seattle Genetics, Immutep, SeaGen, Gilead, NBE Therapeutics, Frame Therapeutics; Financial Interests, Personal, Advisory Board, Consultant and invited speaker: Roche-Genentech; Financial Interests, Personal, Member of Board of Directors, Scientific Board: Oncolytics; Financial Interests, Institutional, Research Grant: AstraZeneca, Immunomedics, Lilly; Financial Interests, Institutional, Funding: Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Coordinating PI, 2-year research grant paid to my Institution: Gilead. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, SeaGen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Local PI: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Steering Committee Member, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Steering Committee Member, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Steering Committee Member, AURORA: Breast International Group; Financial Interests, Steering Committee Member, Olympia: AstraZeneca; Financial Interests, Personal, Other, Travel grant: AstraZeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. All other authors have declared no conflicts of interest.