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Breast Cancer Immunotherapy
Karen S. Anderson MD PhD
Gayle Brinkenhoff Symposium2019
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Potential Conflicts of Interest
• Immunomedics: Advisory Board
• Merck: Sponsored research (ASU) and clinical trial funding
• Lilly: Speaker, unrestricted CME education support
• ProvistaDx: consultant, stock options
• GemNeo: advisory board, stock options
• FlexBioTech: Founder, stock options
• I hold patent applications on breast cancer biomarkers; none of
which are FDA approved for clinical use
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OUTLINE
• Define and discuss updates in immunotherapy of breast cancer.
• Review currently established therapies.
• Review toxicities and management of immunotherapies
• Discuss emerging therapeutic targets
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Breast Cancer immunotherapy trials
• Atezolizumab + nab-
paclitaxel improves PFS for
PD-L1+ TNBC• IMpassion130, NEJM 2018
Vonderheide, Clin Cancer Res 2017
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Breast Cancer immunotherapy trials
Study Details Drug
NCT02730130 Phase II mTNBC Pembrolizumab + XRT
Keynote-162 Phase I/II mTNBC Niraparib +
Pembrolizumab
TONIC Phase II adaptive
mTNBC (XRT, doxo,
cyclophos, cisplatin first)
Nivolumab
GeparNuevo Phase II primary TNBC Durvalumab TAC
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Breast Cancer immunotherapy trials
Bayraktar, J Carcinog 2019
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Breast Cancer is Immunogenic, Sometimes
Tumor infiltrating lymphocytes associated with improved outcomes
Primarily present in TNBC, Her2+ tumors
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Vaccine
Radiation
Viral therapy
Adoptive T cell
Cytokines
Strategies
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TONIC trial:
Voorwerk et al, Nat Med 2019
Doxorubicin, cisplatin
induce more IO favorable
microenvironments
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Breast Cancer Immunotherapy
Multiple clinical trials are ongoing: vaccines, adoptive T cells, CAR T cells, MAb/ADC therapy, checkpoint therapy
Ideal patients:
Adjuvant setting with minimal residual disease
High PD-L1
High mutational burden?
Prevention
Many therapies may be synergistic with checkpoint blockade
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Pembrolizumab in Patients With Advanced Triple-Negative Breast
Cancer: Phase Ib KEYNOTE-012 Study
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Single-agent atezolizumab: phase I trial• n=116• ORR=24% in first line, 6% in second line• median duration of response: 21 months
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• Fatigue• Cough• Shortness of breath• Nausea• Pruritis• Rash• Vitiligo• Decreased appetite
Checkpoint Blockade: Side Effects
• Pneumonitis• Colitis• Hepatitis• Nephritis• Endocrine gland failure
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Conclusions:
• Triple negative breast cancer has the highest rate of PD-L1 expression and mutational burden
• PD-1/PD-L1 checkpoint blockade has evidence of durable responses in a subset of TNBC patients
• Synergy with chemotherapy and targeted therapy is being evaluated
• Biomarkers are needed to determine who will respond to checkpoint blockade
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IMpassion130:
• Randomized phase III trial, n=902
• First-line metastatic TNBC
• Nab-paclitaxel +/- atezolizumab
New England Journal of Medicine, 2018
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Adverse Events
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Atezolizumab + Nab-PaclitaxelPD-L1+
PFS
OS
25 vs 15.5 month OS, PD-L1+
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Atezolizumab + Nab-Paclitaxel
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Summary
• Atezolizumab has efficacy in first line PD-L1+ metastatic TNBC combined with nab-paclitaxel
• Single-agent PD1/PD-L1 targeted therapies have ~5-10% ORR for TNBC
• Pembrolizumab had activity with paclitaxel in neoadjuvant setting (ISPY2) for TNBC
• Targeted vaccine trials are underway
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9p24.1 Amplification includes JAK2, PD-L1 and PD-L2
(PDJ Amplicon)
9p24.1 Amplification
Barrett MT, Oncotarget 2015
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Detection of JAK2/PD-L1 Amplification
• Tumor samples from 326 subjects
• High level amplification defined as log2ratio >1
• Low level (gain) defined as log2ratio <1 and >0
Tumor Total Number Percent Amplified
TNBC 41 29.3%
ER+ breast cancer 8 0%
Her2+ breast cancer 15 0%
Glioblastoma 44 4.5%
Colorectal cancer 68 3.0%
Pancreatic cancer 150 0%
Barrett et al, Oncotarget 2015
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PD-L1 amplification in TNBC is associated with:
Overall Survival
Lower overall survival at 5 years
25.0% vs. 69.0%, p=0.004
Median follow up is 4.7 years (range 0.9-12.0 years)
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Conclusions:
• High level amplification of chromosome 9p24.1 involving the PD-L1, PD-L2, and JAK2 loci (PDJ) was observed in up to 25% of TNBCs at diagnosis
• Amplification is associated with worse prognosis
• The level of amplification is consistent with genomic drivers such as Her2 and Myc
• This may represent a subset of TNBCs that are sensitive to JAK2 or PD-L1 blockade
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Adoptive Cell Therapy
• Zacharakis et al, Nature Medicine, 2018
• Heavily pre-treated patient with ER+ stage IV breast cancer
• 62 mutations identified
• TILS to four proteins (SLC3A2, KIAA0368, CADPS2 and CTSB)
• Pembrolizumab given
• 22 months NED
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Neoantigen-Vaccine Strategy Neoepitope Prediction Pipeline
Cell research, 2017.
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Neoepitopes are Widely Present in Breast Cancer: TCGA
Narang et al, BMC Cancer 2018
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Sacituzumab (IMMU-132) in TNBC
• Trop-2 is expressed in >90% of TNBC
• Antibody-drug conjugate with irinotecan metabolite
• ORR=45.4%
• PFS=5.5 months, OS=13 months
• Accelerated approval denied
• Pulmonary toxicity observed
Bardia et al, NEJM 2019
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Summary
• Adjuvant vaccination for breast cancer remains under active investigation
• Targets include neo-epitope vaccines and overexpressed antigens
• Emerging therapies:
• Adoptive cell therapy
• Oncolytic viral therapy
• Antibody-drug conjugates
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Acknowledgements
• The Arizona Breast Cancer Interest Group “AZ BIG”• Barbara A. Pockaj, MD
• Michael T. Barrett, PhD
• Amylou C. Dueck, PhD
• Ann E. McCullough, MD
• Donald W. Northfelt, MD
• Arizona Translational Research in Immuno-Oncology (AZ-TRIO)
• Our patients