CANCER IMMUNOTHERAPY 101The Era of Immuno-Oncology in

Triple-Negative Breast Cancer

PRACTICE AID

Access the activity, “The Era of Immuno-Oncology in TNBC: Navigating Evidence in Early-Stage and Advanced Disease, Practicalities of Integration, and Implications for Breast Surgeons,” at PeerView.com/JBC40

WithoutImmunotherapy

WithImmunotherapy

MHCAntigen

TCR PD-1PD-L1

Anti–PD-L1

Anti–PD-1

TumorCell

Tumor escape

Inactivationof T Cell

Activationof T Cell

Elimination oftumor cells

WithoutImmunotherapy

WithImmunotherapy

MHC CD80/86

CTLA-4

Anti–CTLA-4Antibody

APC

AntigenTCR

Inactivationof T Cell

Activationof T Cell

Tumor escape Elimination oftumor cells

Immune Checkpoint Inhibition in the Treatment of Cancer1

Immunecheckpoints

Proteins on T cells or cancer cells that need to beactivated/inactivated to start/stop an immune response

Examples include PD-1, PD-L1, CTLA-4

Serve as “brakes” that help keep immune responses incheck; can prevent T-cell response against cancer cells

Can be blocked by immune checkpoint inhibitors The “brakes” on the immune system are releasedand T cells are able to attack and kill cancer cells

PD-1/PD-L1 Checkpoint Inhibition2 CTLA-4 Checkpoint Inhibition2

CTLA-4 is a negativeregulator of

costimulation requiredfor activation of anantitumor T cell in a

lymph node uponrecognition of

tumor antigen

PD-1 pathway inhibitssignaling downstream of TCR:

TCR triggered by antigenpresented by tumor cell à

negative regulatoryreceptor PD-1 expressed à

PD-L1 reactively expressed àPD-L1 binds to PD-1

Tumor microenvironment Lymphoid tissue

Anti–PD-1or anti–PD-L1monoclonalantibodiesblock the

interaction andnegative

regulation

Anti–CTLA-4monoclonal

antibodies blocknegative

regulation byCTLA-4

T cell inactivated

Tumor escape

T cell activated

Tumor attack

T cell inactivated

Tumor escape

T cell activated

Tumor attack

STOP GO STOP GO

CANCER IMMUNOTHERAPY 101The Era of Immuno-Oncology in

Triple-Negative Breast Cancer

PRACTICE AID

APC: antigen-presenting cell; CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; MHC: major histocompatibility complex; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1; TCR: T-cell receptor; TIL: tumor-infiltrating lymphocyte; TNBC: triple-negative breast cancer.1. Ribas A, Wolchock JD. Science. 2018;359:1350-1355. 2. Adapted from: Soularue E et al. Gut. 2018;67:2056-2067. 3. de la Cruz-Merino L et al. Clin Trans Oncol. 2019;21:117-125. 4. Vikas P et al. Cancer Manag Res. 2018;10:6823-6833. 5. Tecentriq (atezolizumab) Prescribing Information. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf. 6. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm633065.htm.

Access the activity, “The Era of Immuno-Oncology in TNBC: Navigating Evidence in Early-Stage and Advanced Disease, Practicalities of Integration, and Implications for Breast Surgeons,” at PeerView.com/JBC40

Rationale for Immunotherapy in TNBC3,4

FDA Approval ofImmunotherapy in TNBC5,6

First approval in breast cancer

FDA granted accelerated approval to atezolizumab in combination with nab-paclitaxel for adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1–stained, tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test

More to come!

Immune Checkpoint InhibitorsUnder Investigation in TNBC

Anti–PD-1 inhibitors: PembrolizumabNivolumab

Anti–PD-L1 inhibitors:Atezolizumab Durvalumab Avelumab

Anti–CTLA-4 inhibitors:Ipilimumab Tremelimumab

TNBC tumors with a highly invasivecharacteristic express a large amount of PD-L1and a high degree of TILs compared with other

subtypes of breast cancer

Implicates immunogenic nature of TNBC

Rationale for testing/use of immunotherapiesin TNBC

More aggressive forms of breast cancer have somedegree of host immunity, but it appears to decreaseas the tumors progress and become more resistant

(eg, advanced, heavily pretreated TNBC)

Reduction in body’s immune response to the cancer

Immunotherapy may be more effective in earlier

stages of TNBC

Rationale for testing/use of immunotherapiesin neoadjuvant or adjuvant settings

Multimodal therapy may enhance the activity ofimmunotherapies in TNBC and other subtypes

of breast cancer

Combination or sequential strategies withchemotherapies, targeted therapies, other

immunotherapies with nonredundantmechanisms of action, vaccines, surgery,

radiation, and cryotherapy are being explored

Access the activity, “The Era of Immuno-Oncology in TNBC: Navigating Evidence in Early-Stage and Advanced Disease, Practicalities of Integration, and Implications for Breast Surgeons,” at PeerView.com/JBC40

SELECTION OF KEY CANCER IMMUNOTHERAPY CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1

PRACTICE AID

Atezolizumab + nab-paclitaxel atezolizumab + AC surgery atezolizumab

vs placebo + nab-paclitaxel placebo + AC surgery

NCT03197935 IMpassion031

Phase 3 Anti–PD-L1

Atezolizumab + paclitaxel + carboplatin atezolizumab + (AC or EC) surgery atezolizumab

vs placebo + paclitaxel + carboplatin placebo + (AC or EC)

surgery placebo

NCT03281954 GBG 96-GeparDouze

Phase 3

Anti–PD-L1

Atezolizumab + nab-paclitaxel + carboplatin surgery AC or EC or FEC

vs nab-paclitaxel + carboplatin surgery AC or EC or FEC

NCT02620280 NeoTRIPaPDL1 Phase 3

Anti–PD-L1

NCT03036488a KEYNOTE-522 Phase 3

Anti–PD-1

Durvalumab durvalumab + nab-paclitaxel durvalumab + EC surgery

vs placebo placebo + nab-paclitaxel placebo + EC surgery

NCT02685059 GeparNuevo

Phase 2 Anti–PD-L1

Pembrolizumab + nab-paclitaxel pembrolizumab + EC surgery

NCT03289819 NIB

Phase 2 Anti–PD-1

Olaparib durvalumab + olaparib surgery

NCT03594396 Phase

1/2 Anti–PD-L1

Pembrolizumab + radiotherapy boost surgery

NCT03366844 Anti–PD-1 Phase 1/2

Nivolumab surgery vs

nivolumab + doxorubicin surgery

NCT03815890 BELLINI

Phase 2 Anti–PD-1

Nivolumab + ipilimumab core biopsy/cryoablation surgery nivolumab

vs surgery

NCT03546686

Phase 2

Anti–PD-1 + anti–CTLA-4

Neoadjuvant Setting

Pembrolizumab + paclitaxel + carboplatin pembrolizumab + (AC or EC) surgery pembrolizumab

vs placebo + paclitaxel + carboplatin placebo + (AC or EC)

surgery placebo

Access the activity, “The Era of Immuno-Oncology in TNBC: Navigating Evidence in Early-Stage and Advanced Disease, Practicalities of Integration, and Implications for Breast Surgeons,” at PeerView.com/JBC40

SELECTION OF KEY CANCER IMMUNOTHERAPY CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1

PRACTICE AID

Pembrolizumab + radiotherapyvs

observation + radiotherapy(for residual disease after neoadjuvant chemo and surgery)

NCT02954874 SWOG-S1418

Phase 3 Anti–PD-1

Avelumabvs

observation(after surgery, neo- or adjuvant chemo, and radiotherapy if indicated)

NCT02926196 A-Brave

Phase 3 Anti–PD-L1

Atezolizumab + paclitaxel → atezolizumab + (AC or EC) → atezolizumab

vs paclitaxel → AC or EC

NCT03498716 IMpassion030

Phase 3 Anti–PD-L1

Nivolumabvs

capecitabinevs

nivolumab + capecitabine(for residual disease after neoadjuvant chemo and surgery)

NCT03487666 OXEL

Phase 2

Anti–PD-1

Adjuvant Setting

Nivolumab + ipilimumab + radiotherapyvs

capecitabine + radiotherapy(for residual disease after neoadjuvant chemo and surgery)

NCT03818685BreastImmune03

Phase 2

Anti–PD-1 + anti–CTLA-4

Atezolizumab + capecitabinevs

capecitabine(for residual disease after neoadjuvant chemo and surgery)

NCT03756298

Phase 2 Anti–PD-1

Access the activity, “The Era of Immuno-Oncology in TNBC: Navigating Evidence in Early-Stage and Advanced Disease, Practicalities of Integration, and Implications for Breast Surgeons,” at PeerView.com/JBC40

SELECTION OF KEY CANCER IMMUNOTHERAPY CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1

PRACTICE AID

Atezolizumab + nab-paclitaxelvs

placebo + nab-paclitaxel

NCT02425891 IMpassion130

Phase 3 Anti–PD-L1

Atezolizumab + paclitaxelvs

placebo + paclitaxel

NCT03125902 IMpassion131

Phase 3 Anti–PD-L1

Pembrolizumab + [nab-paclitaxel or paclitaxel or (gemcitabine + carboplatin)]

vsplacebo + [nab-paclitaxel or paclitaxel or (gemcitabine + carboplatin)]

NCT02819518 KEYNOTE-355

Phase 3 Anti–PD-1

Metastatic/Advanced Setting

Pembrolizumab

NCT02447003 KEYNOTE-086Phase 2

Anti–PD-1

1st line

1st line

1st line

Durvalumab + tremelimumab → durvalumab

NCT02536794Phase 2

Anti–PD-L1 + anti–CTLA-4

1st line 1st line

Atezolizumab + [(gemcitabine + carboplatin) or capecitabine]

vs placebo + [(gemcitabine + carboplatin) or capecitabine]

NCT03371017 IMpassion132

Phase 3 Anti–PD-L1

1st line

Pembrolizumab vs

capecitabine or eribulin or gemcitabine or vinorelbine

NCT02555657 KEYNOTE-119

Phase 3 Anti–PD-1

≥2nd line

Pembrolizumab + doxorubicin → pembrolizumab

NCT02648477Phase 2

Anti–PD-1 Pembrolizumab + nab-paclitaxel

NCT02752685Phase 2

Anti–PD-1

1st line 1st line

Pembrolizumab + carboplatin + gemcitabinevs

carboplatin + gemcitabine

NCT02755272

Phase 2 Anti–PD-1

Pembrolizumab + cyclophosphamide

NCT02768701

Phase 2 Anti–PD-1

1st line 1st line

a Continued in adjuvant setting. 1. https://clinicaltrials.gov.AC: doxorubicin + cyclophosphamide; chemo: chemotherapy; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; EC: epirubicin + cyclophosphamide; FEC: fluorouracil + epirubicin + cyclophosphamide; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1.

Access the activity, “The Era of Immuno-Oncology in TNBC: Navigating Evidence in Early-Stage and Advanced Disease, Practicalities of Integration, and Implications for Breast Surgeons,” at PeerView.com/JBC40

SELECTION OF KEY CANCER IMMUNOTHERAPY CLINICAL TRIALS IN TRIPLE-NEGATIVE BREAST CANCER1

PRACTICE AID

Olaparib → durvalumab + olaparib

NCT03801369Phase 2

Anti–PD-1

Pembrolizumab + carboplatin + nab-paclitaxel

NCT03121352Phase 2

Anti–PD-1

Pembrolizumab + radiotherapy NCT02730130

Phase 2 Anti–PD-1

Metastatic/Advanced Setting (Cont’d)

Nivolumab + romidepsin + cisplatin

NCT02393794Phase

1/2 Anti–PD-1

1st/2nd line

1st-3rd line

≥2nd line

Pembrolizumab + eribulin mesylate

NCT02513472 ENHANCE-1 Anti–PD-L1

≥1st line 1st-3rd line

Atezolizumab + cobimetinib + paclitaxelvs

atezolizumab + cobimetinib + nab-paclitaxelvs

cobimetinib + paclitaxelvs

placebo + paclitaxel

NCT02322814

Phase 2

Anti–PD-L1

1st line

Pembrolizumab + lenvatinib NCT03797326 LEAP-005

Phase 2Anti–PD-1

≥2nd line

Durvalumab + paclitaxel → durvalumab

NCT02628132Anti–PD-1

≥2nd line

Radiotherapy → nivolumab vs

doxorubicin → nivolumab vs

cisplatin → nivolumab vs

cyclophosphamide → nivolumab vs

nivolumab

NCT02499367 TONIC

Phase 2 Anti–PD-1

2nd-4th line

Phase1/2

Phase1/2