breast cancer immunotherapy - cme...

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Breast Cancer Immunotherapy

Karen S. Anderson MD PhD

Gayle Brinkenhoff Symposium2019


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


OUTLINE

• Define and discuss updates in immunotherapy of breast cancer.

• Review currently established therapies.

• Review toxicities and management of immunotherapies

• Discuss emerging therapeutic targets


Breast Cancer immunotherapy trials

• Atezolizumab + nab-

paclitaxel improves PFS for

PD-L1+ TNBC• IMpassion130, NEJM 2018

Vonderheide, Clin Cancer Res 2017



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



Bayraktar, J Carcinog 2019


Breast Cancer is Immunogenic, Sometimes

Tumor infiltrating lymphocytes associated with improved outcomes

Primarily present in TNBC, Her2+ tumors


Vaccine

Radiation

Viral therapy

Adoptive T cell

Cytokines

Strategies


TONIC trial:

Voorwerk et al, Nat Med 2019

Doxorubicin, cisplatin

induce more IO favorable

microenvironments


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


Pembrolizumab in Patients With Advanced Triple-Negative Breast

Cancer: Phase Ib KEYNOTE-012 Study


Single-agent atezolizumab: phase I trial• n=116• ORR=24% in first line, 6% in second line• median duration of response: 21 months


• Fatigue• Cough• Shortness of breath• Nausea• Pruritis• Rash• Vitiligo• Decreased appetite

Checkpoint Blockade: Side Effects

• Pneumonitis• Colitis• Hepatitis• Nephritis• Endocrine gland failure


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


IMpassion130:

• Randomized phase III trial, n=902

• First-line metastatic TNBC

• Nab-paclitaxel +/- atezolizumab

New England Journal of Medicine, 2018


Adverse Events


Atezolizumab + Nab-PaclitaxelPD-L1+

PFS

OS

25 vs 15.5 month OS, PD-L1+


Atezolizumab + Nab-Paclitaxel


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


9p24.1 Amplification includes JAK2, PD-L1 and PD-L2

(PDJ Amplicon)

9p24.1 Amplification

Barrett MT, Oncotarget 2015


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


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)


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


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


Neoantigen-Vaccine Strategy Neoepitope Prediction Pipeline

Cell research, 2017.


Neoepitopes are Widely Present in Breast Cancer: TCGA

Narang et al, BMC Cancer 2018


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


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


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

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