Faculty Bibliography

Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

Background: Based on findings from IMpassion130, international guidelines now recommend atezolizumab (A) + nab-paclitaxel (nP) for patients (pts) with locally advanced or metastatic TNBC (mTNBC) whose tumours express PD-L1 on tumour-infiltrating immune cells (IC). Here we report prespecified final OS and long-term safety results.
Method(s): The study design and final PFS analysis have been reported (Schmid NEJM 2018). Pts were randomised 1:1 to A + nP or placebo (P) + nP. Co-primary endpoints were PFS (tested in parallel in ITT and PD-L1+ pts) and OS (tested hierarchically in ITT and, if significant, in PD-L1+ pts).
Result(s): As of 14 April 2020, 666/902 pts (73.8%) had died; median OS follow-up was 18.8 mo (IQR, 8.9-34.7 mo). 6% of pts in the A + nP arm and 2% in the P + nP arm remained on any treatment. OS data are in the table. 460 A + nP arm pts and 430 P + nP arm pts were safety evaluable, of whom 8% and 3%, respectively, received nP for up to 24 mo. Similarly, 5% in the A + nP arm received nP for >= 24 mo (vs 1% in the P + nP arm). Respectively, 51% vs 43% had a G 3-4 AE; = 1% per arm had a G 5 AE (no new G 5 AEs since last analysis; no patterns seen); 24% vs 19% had a serious AE, and 59% vs 42% had an AE of special interest (G 3-4 in 8% vs 5%). No confirmed or suspected COVID-19 AEs were reported. 19% in the A + nP arm and 8% in the P + nP arm had an AE leading to treatment discontinuation (most commonly due to neuropathy); in 18% and 8%, respectively, AEs led to nP discontinuation, and in 8% and 1%, AEs led to A or P discontinuation.
Conclusion(s): While OS differences for A + nP vs P + nP in the IMpassion130 ITT population were not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed in PD-L1+ pts (7.5-mo median OS improvement). A + nP remained safe and tolerable with longer follow-up. Results from this final and mature OS analysis are consistent with prior interim analyses. [Formula presented] Clinical trial identification: NCT02425891. Editorial acknowledgement: Medical writing assistance for this abstract was provided by Ashley J. Pratt, PhD, CMPP of Health Interactions, Inc. Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd.
Funding(s): F. Hoffmann-La Roche, Ltd. Disclosure: H. Iwata: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, uncompensated IMpassion130 study steering committee member, editorial support: Roche; Non-remunerated activity/ies, editorial support: Chugai; Honoraria (self), Advisory/Consultancy: Novartis; AstraZeneca; Pfizer; Eli Lilly; Daiichi Sankyo. L. Emens: Honoraria (self): AbbVie; Amgen; Celgene; Chugai; Gritstone; MedImmune; Peregrine; Shionogi; Syndax; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Bayer; MacroGenics; Replimune; Vaccinex; Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, editorial support, uncompensated IMpassion130 study and KATE2 study steering committee chairs: Genentech/Roche; Shareholder/Stockholder/Stock options, Potential for stock in future: Molecuvax; Research grant/Funding (institution), Licensing/Royalties: Aduro Biotech; Research grant/Funding (institution): Breast Cancer Research Foundation; Research grant/Funding (institution): Bolt Therapeutics, Corvus, US Dept of Defense, EMD Serono, Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Translational Breast Cancer Research Consortium, Tempest, HeritX. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), uncompensated advisory/consulting: BMS; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, uncompensated advisory/consulting, editorial support: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution), uncompensated advisory/consulting: Merck; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Novartis. C.H. Barrios: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Novartis; Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Boehringer Ingelheim; GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution), editorial support: Roche/Genentech; Research grant/Funding (institution): Eli Lily; 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; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Astellas, BioMarin; Advisory/Consultancy: Eisai, Bayer; Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy: Merck Sharp and Dohme; Research grant/Funding (institution): Abraxis BioScience, AB Science, Asana BioSciences, Medivation, Exelexis, ImClone Systems, LEO Pharma, Millennium. V. Dieras: Advisory/Consultancy, editorial support: Roche/Genentech; Advisory/Consultancy: Pfizer; Eli Lilly; Novartis; Daiichi Sankyo; AstraZeneca; AbbVie; MSD; Seattle Genetics; Odonate. S. Loi: Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Novartis; Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution), Unpaid consultant: Merck; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, Unpaid consultant, editorial support: Roche/Genentech; 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: AstraZeneca; Advisory/Consultancy, Consulting fees paid to institution: Aduro Biotech. H.S. Rugo: Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, editorial support: Roche/Genentech; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Merck; Research grant/Funding (institution): OBI; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Plexxikon; 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, Non-remunerated activity/ies, editorial support: 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. E.P. Winer: Honoraria (self): Eli Lilly; Honoraria (self), Advisory/Consultancy: Leap; Honoraria (self): 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; Non-remunerated activity/ies, editorial support: Roche. S. Patel: Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche/Genentech. V. Henschel: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche. A. Swat: Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche. M. Kaul: Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche/Genentech. L. Molinero: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Use patent to disclose with Roche/Genentech, editorial support: Roche/Genentech. S.S. Chui: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Use patent to disclose with Roche/Genentech, editorial support: Roche/Genentech. P. Schmid: Research grant/Funding (institution), Spouse/Financial dependant: Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Spouse/Financial dependant, Non-remunerated activity/ies, editorial support, uncompensated steering committee member: F. Hoffmann-La Roche; Honoraria (self): Medscape; Honoraria (self), Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Merck; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bayer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Celgene; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Puma; Honoraria (self): GI Therapeutics; Research grant/Funding (institution): OncoGenex.
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Background: IMpassion130 is a phase 3 study evaluating atezolizumab (A) + nab-paclitaxel (nP) vs placebo (P) + nP as 1L treatment for patients with mTNBC. A+nP significantly improved PFS in PD-L1+ patients. This exploratory post-hoc analysis evaluated the analytical concordance of SP142 with 2 other PD-L1 IHC assays, and their ability to predict clinical activity.
Method(s): Available samples were evaluated for PD-L1 status using VENTANA SP142 or SP263 IHC assays (immune cells [IC] >=1%, SP142+ or SP263+) or Dako PD-L1 IHC 22C3 assay (combined propor-tion score [CPS] >=1, 22C3+) by central laboratory in a biomarker-evalu-able population (BEP).
Result(s): The BEP consisted of 614 patients (68% of ITT). PD-L1+ prev-alence was 46% for SP142+, 81% for 22C3+, and 75% for SP263+. The overall percentage agreement (OPA) of SP142 with 22C3 and SP263 was 69% and 63%, respectively. PPAs of 98% for both assays suggests SP142+ patients are captured by the other two tests, while negative per-centage agreements were < 45%. The PFS and OS HR (95% CI) in SP142+ patients were 0.60 (0.47, 0.78) and 0.74 (0.54, 1.01) respec-tively; 0.68 (0.56, 0.82) and 0.78 (0.62, 0.99) in 22C3+ patients, respec-tively; and 0.64 (0.53, 0.79) and 0.75 (0.59, 0.96) in SP263+ patients, respectively. Subgroup outcomes indicate the PFS and OS benefit with A+nP in SP263+/SP142- or 22C3+/SP142- was smaller than in double-positive subgroups (table).
Conclusion(s): At the evaluated cutoffs, 22C3 and SP263 assays identi-fied more patients with PD-L1+ tumours. The patients in the SP142 PD-L1+, derived the greatest clinical benefit with A+nP. (Figure Presented)

Background: Based on findings from IMpassion130, international guidelines now recommend atezolizumab (A) + nab-paclitaxel (nP) for patients (pts) with locally advanced or metastatic TNBC (mTNBC) whose tumours express PD-L1 on tumour-infiltrating immune cells (IC). Here we report prespecified final OS and long-term safety results.
Method(s): The study design and final PFS analysis have been reported (Schmid NEJM 2018). Pts were randomised 1:1 to A + nP or placebo (P) + nP. Co-primary endpoints were PFS (tested in parallel in ITT and PD-L1+ pts) and OS (tested hierarchically in ITT and, if significant, in PD-L1+ pts).
Result(s): As of 14 April 2020, 666/902 pts (73.8%) had died; median OS follow-up was 18.8 mo (IQR, 8.9-34.7 mo). 6% of pts in the A + nP arm and 2% in the P + nP arm remained on any treatment. OS data are in the Table. 460 A + nP arm pts and 430 P + nP arm pts were safety evaluable, of whom 8% and 3%, respectively, received nP for up to 24 mo. Similarly, 5% in the A + nP arm received nP for >= 24 mo (vs 1% in the P + nP arm). Respectively, 51% vs 43% had a G 3-4 AE; = 1% per arm had a G 5 AE (no new G 5 AEs since last analysis; no patterns seen); 24% vs 19% had a serious AE, and 59% vs 42% had an AE of special interest (G 3-4 in 8% vs 5%). No confirmed or suspected COVID-19 AEs were reported. 19% in the A + nP arm and 8% in the P + nP arm had an AE leading to treatment discontinuation (most commonly due to neuropathy); in 18% and 8%, respectively, AEs led to nP discontinuation, and in 8% and 1%, AEs led to A or P discontinuation.
Conclusion(s): While OS differences for A + nP vs P + nP in the IMpassion130 ITT population were not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed in PD-L1+ pts (7.5-mo median OS improvement). A + nP remained safe and tolerable with longer follow-up. Results from this final and mature OS analysis are consistent with prior interim analyses. [Formula presented] 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(s): F. Hoffmann-La Roche, Ltd. Disclosure: L.A. Emens: Honoraria (self): AbbVie, Amgen, Celgene, Chugai, Gritstone, MedImmune, Peregrine, Shionogi, Syndax; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca, Bayer, MacroGenics, Replimune, Vaccinex; Travel/Accommodation/Expenses: Bristol Myers Squibb, Genentech/Roche, Novartis; Research grant/Funding (institution): Aduro Biotech, AstraZeneca, The Breast Cancer Research Foundation, Bristol Myers Squibb, Bolt Therapeutics, Corvus, The US Department of Defense, EMD Serono, Genentech, Maxcyte, Merck, The National Cancer Institute, The NSABP Foundation, Roche, The Transl; Licensing/Royalties: Aduro; Advisory/Consultancy: Roche. S. Adams: Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Merck, Amgen, BMS, Novartis, Celgene, Daiichi Sankyo. C.H. Barrios: Advisory/Consultancy: Boehringer- Ingelheim; Advisory/Consultancy: GSK; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/ Consultancy, Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Non-remunerated activity/ies: Bayer; Research grant/ Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Mylan; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): Biomarin; 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): Exelixis, Research grant/Funding (institution): ImClone Systems, Research grant/Funding (institution): LEO Pharma; Research grant/Funding (institution): Millennium; Advisory/Consultancy: Merck Sharp and Dohme; Advisory/Consultancy: AstraZeneca. V.C. Dieras: Honoraria (self), Advisory/Consultancy: Roche/Genentech, Pfizer, Lilly, Novartis, Daiichi Sankyo, AstraZeneca, AbbVie, Seattle Genetics, Odonate, MSD. H. Iwata: Honoraria (self), Advisory/Consultancy: Chugai; Honoraria (self), Advisory/Consultancy: Novartis, AstraZeneca, Pfizer, Lilly, Daiichi-Sankyo, Eisai, Kyowa Kirin; Non-remunerated activity/ies: MSD, Bayer, BI, Nihon, Kayaku, Sanofi. S. Loi: Research grant/Funding (institution), Non-remunerated activity/ies: Novartis, BMS, Roche-Genentech, Merck; Research grant/Funding (institution): Puma, Eli Lilly, Pfizer; Unpaid consultant: Seattle Genetics; Unpaid consultant: Pfizer; Unpaid consultant: Novartis; Unpaid consultant: BMS; Unpaid consultant: AstraZeneca; Unpaid consultant: Roche/Genentech; Advisory/Consultancy (institution): Aduro Biotechnology. H.S. Rugo: Research grant/Funding (institution): Pfizer, Novartis, Lilly, Genentech/Roche, Merck, OBI, Eisai, Plexxikon, Immunomedics; Research grant/Funding (institution), Travel/Accommodation/Expenses: Macrogeneics, Daiichi; Travel/Accommodation/Expenses: Puma, Mylan, Genentech/Roche, Novartis, Pfizer; Honoraria (self): Celltrion. A. Schneeweiss: Research grant/Funding (institution): Celgene, Roche, AbbVie, Molecular Partner; Advisory/Consultancy: Roche AstraZeneca; Travel/Accommodation/Expenses: Celgene, Roche, Pfizer; Honoraria (self): Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly. E.P. Winer: Honoraria (self): Lilly, Genentech, Infinite MD, Carrick Therapeutics, GSK, Jounce, Genomic HEalth, Merck, Seattle Genetics; Honoraria (self), Leadership role: Leap. S. Patel: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. V. Henschel: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. A. Swat: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. M. Kaul: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. L. Molinero: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. S.Y. Chui: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech/Roche. P. Schmid: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Spouse/Financial dependant, spouse - consulting for Genentech: Roche; Honoraria (self): Medscape; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): GI Therapeutics; Honoraria (self): Health Interactions; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Merck; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bayer; Advisory/Consultancy: EISAI; Advisory/Consultancy: Celegence; Advisory/Consultancy: Puma; Research grant/Funding (institution), Spouse/Financial dependant, spouse - consulting for Genentech: Genentech; Research grant/Funding (institution): Oncogenex.
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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.
Method(s): 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.
Result(s): 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]).
Conclusion(s): 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(s): 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. Dieras: 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.
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PURPOSE/OBJECTIVE:mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear. EXPERIMENTAL DESIGN/METHODS:mutation status. Furthermore, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated. RESULTS:) in these models. CONCLUSIONS:mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor.

BACKGROUND:Metastatic triple-negative breast cancer (mTNBC) is incurable. A key treatment goal is providing palliation while maintaining patients' health-related quality of life (HRQoL). IMpassion130 demonstrated progression-free survival benefit with atezolizumab + nab-paclitaxel (A + nP) versus placebo + nab-paclitaxel (Pl + nP) in first-line treatment of mTNBC patients with programmed death-ligand 1 positive (PD-L1+) tumors. We report data on patient-reported outcomes (PROs), which capture patient perspectives of treatment. PATIENTS AND METHODS/METHODS:) on days 1, 8, and 15 of each 28-day cycle until progression or intolerance. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and its Breast Cancer Module (QLQ-BR23) on day 1 of each cycle, at end of treatment, and every 4 weeks during 1 year of follow-up. Time-to-deterioration (TTD) in HRQoL (first ≥10-point decrease from baseline lasting two cycles) was a secondary end point. Exploratory end points included TTD in functioning and mean and mean change from baseline scores in HRQoL, functioning, and disease- and treatment-related symptoms. RESULTS:Baseline completion of PROs was 92% (QLQ-C30) and 89% (QLQ-BR23) and remained >80% through cycle 20 in intent-to-treat (ITT) and PD-L1+ patients. No differences between arms in median TTD in PD-L1+ patients were observed for HRQoL {hazard ratio (HR) 0.94 [95% confidence interval (CI) 0.69-1.28]} or physical [HR 1.02 (95% CI 0.76-1.37)] or role [HR 0.77 (95% CI 0.57-1.04)] functioning. Mean baseline scores for A + nP versus Pl + nP for HRQoL (67.5 versus 65.0) and physical (82.8 versus 79.4) and role (73.7 versus 71.7) functioning were comparable between arms and throughout the course of treatment, with no clinically meaningful (≥10 point) changes from baseline until patients discontinued treatment. No differences in clinically meaningful worsening in treatment symptoms (fatigue, diarrhea, or nausea/vomiting) were observed between arms. Results in ITT patients were similar. CONCLUSIONS:A + nP as first-line treatment for mTNBC delayed progression without compromising patients' day-to-day functioning or HRQoL or worsening treatment symptoms. CLINICALTRIAL. GOV IDENTIFIER/UNASSIGNED:NCT02425891.

Background: PD-1/PD-L1 checkpoint blockade in combination with chemotherapy has improved outcomes in triple-negative breast cancer, but its role in hormone receptor-positive (HR+) metastatic breast cancer (MBC) is less clear. We report the results of the HR+ cohort of a HER2-negative MBC trial.
Method(s): Prospective phase 2 trial where 20 HR+/HER2- MBC patients (pts) received nab-paclitaxel (A) (100mg/m2 IV d1/8, q 3 wks) and pembrolizumab (P) (200mg IV d1, q 3 wks, starting with cycle 2). Eligibility: ER/PR >=1%, HER2 negative, maximum of 2 lines of cytotoxic therapy for MBC, pts could have received prior endocrine and/or targeted therapy. Primary endpoint: best overall response rate (BORR) by RECIST v1.1; secondary endpoints: safety, PFS, clinical benefit rate (CBR), duration of response (DOR), and overall survival (OS). Biomarker analyses are ongoing.
Result(s): In this 20-patient cohort, the median age was 56 (34-75), median lines of cytotoxic chemotherapy was 1 (0-2), 70% (14/20) were ER>10%, 80% (16/20) received prior hormone therapy, and 60% (12/20) received prior CDK 4/6 inhibitors. BORR was partial response (PR) in 5/20, stable disease (SD) in 7/20, and progressive disease (PD) in 7/20. CBR was 35% (7/20). Median PFS was 5.6 mos (95%CI 2.07-8.18), median OS 15.7 mos (95%CI 3.88-27.70) and median DOR was 3.9 mos (95%CI 2.07-not yet reached). Out of 5 pts who achieved PR, 4 (80%) received prior CDK 4/6 inhibitors. The most common related adverse events (AE) were anemia (50%), diarrhea, nausea and ALT abnormalities (40% each). 14 pts experienced grade 3 AEs, the most common being neutropenia, 1 pt had grade 4 AEs (pneumonitis, blood/lymphatics, hyponatremia), and no grade 5 AEs. [Formula presented]
Conclusion(s): P plus A was efficacious with PR in 5/20 and SD in 7/20 pts with a manageable toxicity profile. Importantly, responses were observed in patients previously treated with CDK 4/6 inhibitors. Further investigation of this regimen in HR+/HER2- MBC is warranted. Clinical trial identification: NCT02752685. Legal entity responsible for the study: NYU Langone Health.
Funding(s): Merck (drug-pembrolizumab and financial funding); Celgene (drug-nab-paclitaxel). Disclosure: F. Muggia: Advisory/Consultancy, Member of data safety monitoring committee of Pembrolizumab trials run by Merck: Merck. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), consultant (uncompensated): Merck; Research grant/Funding (institution): Celgene. All other authors have declared no conflicts of interest.
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Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer. TILs can be easily assessed on hematoxylin and eosin stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Since TILs and PD-L1 are parts of an immunological spectrum in breast cancer, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immune-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with breast cancer. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in breast cancer. This article is protected by copyright. All rights reserved.

BACKGROUND:Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer. METHODS:of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891. FINDINGS/RESULTS:Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018). INTERPRETATION/CONCLUSIONS:Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. FUNDING/BACKGROUND:F Hoffmann-La Roche and Genentech.