Abstract 296P
Background
Immune checkpoint inhibitors can stimulate immune responses to tumour neoantigens. Tumour mutational burden (TMB), a surrogate for neoantigen load, is associated with improved outcomes following immunotherapy in several cancers. In IMpassion130, atezolizumab (A) + nab-paclitaxel (nP) showed improved progression-free survival (PFS) and clinically meaningful overall survival (OS) benefit vs. placebo + nP in PD-L1+ metastatic triple-negative breast cancer (TNBC; Schmid P, et al. N Engl J Med. 2018;379:2108-2121). The goal of this exploratory, retrospective study was to evaluate TMB as a potential biomarker of clinical activity with A + nP in a randomised data set.
Methods
TMB (FoundationOne) and PD-L1 (VENTANA SP142 assay; positivity defined as immune cells [IC] stained with PD-L1 on ≥1% of tumour area) were assessed centrally in the biomarker-evaluable population (BEP). PFS and OS (co-primary endpoints) were analysed using Cox proportional hazards models and adjusted for study stratification factors. Objective response rate (ORR) was assessed by RECIST 1.1.
Results
The BEP comprised 579 patients (64% of ITT population). Median TMB was 4.39 mutations/megabase (Mut/Mb; range, 0-46.51). TMB and PD-L1 IC levels were not correlated (Spearman correlation = 0.0174). Increasing TMB was associated with improved PFS in the overall BEP (highest quartile [Q3; 7.02 Mut/Mb] HR, 0.56 [95% CI: 0.38, 0.81]), driven by PD-L1+ cases (HR, 0.31 [95% CI: 0.17, 0.57] vs. 0.84 [95% CI: 0.48, 1.47] for PD-L1− cases). Similar observations were seen for ORR. Notably, TMB was not linked to OS benefit with A + nP in the overall BEP or in PD-L1− BEP, but higher TMB was associated with OS benefit in PD-L1+ BEP (HR for all TMB quartiles, 0.71 [95% CI: 0.52, 0.97]; Q1 HR, 0.69 [95% CI: 0.49, 0.98]; Q2 HR, 0.59 [95% CI: 0.37, 0.92]; Q3 HR, 0.37 [95% CI: 0.15, 0.90]).
Conclusions
In this exploratory analysis, TNBC tumours had low TMB overall, and TMB was not correlated with PD-L1 status. Although TMB may be associated with improved outcomes with A + nP, clinical benefit was observed only in patients with PD-L1+ tumours.
Clinical trial identification
NCT02425891.
Editorial acknowledgement
Medical writing assistance for this abstract was provided by Ashley J. Pratt, PhD, of Health Interactions, and funded by F. Hoffmann-La Roche, Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche, Ltd.
Funding
F. Hoffmann-La Roche, Ltd.
Disclosure
L.A. Emens: Full/Part-time employment, current: University of Pittsburgh/UPMC; Full/Part-time employment, 2001-2008: Johns Hopkins University; Full/Part-time employment, 2012-2016: FDA-CTGTAC; Officer/Board of Directors, non-profit: SITC; Honoraria (self), Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Co-chair IMpassion130 Steering Committee, Chair KATE2 Steering Committee: Roche/GNE; Leadership role, Chair TRIO-025 DSMB: Trio/Syndax; Leadership role, Steering committee member: Ambiance Trial; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Meyers Squibb; Honoraria (self), Advisory/Consultancy: Celgene; Advisory/Consultancy, no compensation: eTHeRNA; Honoraria (self), Advisory/Consultancy: MedImmune; Shareholder/Stockholder/Stock options, Potential for stock in future: Molecuvax; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy: Peregrine; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Replimmune; Honoraria (self): Syndax; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Vaccinex; Research grant/Funding (institution), Licensing/Royalties, IND Licensing/vaccine <25K: Arduro Biotech; Research grant/Funding (institution): Breast Cancer Research Foundation; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Department of Defense; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): HeritX, Inc.; Research grant/Funding (institution): Maxcyte; Research grant/Funding (institution): Merck; Research grant/Funding (institution), (separate relationships, ran out of lines): National Cancer Institute, NSABPFoundation, Translational Breast Cancer Research Consortium. L. Molinero: Research grant/Funding (institution), Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Roche/GNE. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), Uncompensated consultant/advisory role: BMS; Advisory/Consultancy, Research grant/Funding (institution), Uncompensated consultant/advisory role: Genentech; Advisory/Consultancy, Research grant/Funding (institution), Uncompensated consultant/advisory role: Merck; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis. H.S. Rugo: Honoraria (institution), Research grant/Funding (institution), Travel/Accommodation/Expenses, & Editorial Support: Genentech/Roche; Honoraria (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (institution): Eli Lilly; Honoraria (institution): Merck; Honoraria (institution): OBI; Honoraria (institution): Eisai; Honoraria (institution): Plexxikon; Honoraria (institution), Travel/Accommodation/Expenses: MacroGenics; Travel/Accommodation/Expenses: Puma; Travel/Accommodation/Expenses: Mylan; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self): Celltrion. A. Schneeweiss: Honoraria (self), Research grant/Funding (institution): Celgene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Molecular Partners; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): Tesaro; Honoraria (self): Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: Pfizer. V. Diéras: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche/GNE; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Odonate. H. Iwata: Honoraria (self), Advisory/Consultancy, Leadership role, Research grant/Funding (institution), uncompensated member of the steering committee for the IMpassion130 trial & Editorial Support: Roche; Non-remunerated activity/ies, Editorial Support: Chugai; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo. C.H. Barrios: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Roche/GNE; Research grant/Funding (institution): Ely Lilly; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Mylan; Research grant/Funding (institution): Merrimack; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): BioMarin; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Abraxis Bioscience; Research grant/Funding (institution): AB Science; Research grant/Funding (institution): Asana BioSciences; Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): ImClone Systems; Research grant/Funding (institution): LEO Pharma; Research grant/Funding (institution): Millennium; Advisory/Consultancy: Eisai; Advisory/Consultancy: Bayer. E.P. Winer: Honoraria (self): Eli Lilly; Honoraria (self), Advisory/Consultancy: Leap; Honoraria (self), Research grant/Funding (institution): Genentech; Honoraria (self): Infinite MD; Honoraria (self): Carrick Therapeutics; Honoraria (self): GlaxoSmithKline; Honoraria (self): Jounce; Honoraria (self): Genomic Health; Honoraria (self): Merck; Honoraria (self): Seattle Genetics. C-W. Chang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche. S.Y. Chui: Research grant/Funding (institution), Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche/GNE. P. Schmid: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Spouse/Financial dependant, uncompensated steering committee member for the IMpassion130 trial. Spouse has a consulting role: Roche/GNE; Research grant/Funding (institution): Oncogenex; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): MedScape; Honoraria (self): GI Therapeutics; Advisory/Consultancy: Merck; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bayer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Celgene; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Puma. S. Loi: Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Unpaid Consultant: BMS; Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Merck; Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Roche/GNE; Research grant/Funding (institution): Puma; Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Pfizer; Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Unpaid consultant: Seattle Genetics; Advisory/Consultancy, Unpaid consultant: AZ; Advisory/Consultancy, Fees paid to institution: Aduro Biotech. All other authors have declared no conflicts of interest.