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Home , Atezolizumab, Camrelizumab, Sacituzumab govitecan

Inhibitors in Triple-Negative Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

What Are • Proteins on T cells or cancer cells that need to be activated/inactivated to start/stop Immune an immune response (eg, PD-1, PD-L1, CTLA-4) Checkpoints? • Serve as “brakes” that help keep immune responses in check; can prevent T-cell response against cancer cells • Can be blocked by immune checkpoint inhibitors (the “brakes” on the immune system are released and T cells are able to attack and kill cancer cells)

GO Immune checkpoint inhibitors modulate T-lymphocyte responses against cancer by blocking negative regulation of immune responses

PD-1/PD-L1 Checkpoint Tumor Microenvironment Inhibition

PD-1 pathway inhibits Without With signaling downstream of TCR STOP Immunotherapy Immunotherapy GO Anti–PD-1 or anti–PD-L1 monoclonal antibodies • TCR triggered by Tumor block the interaction and presented by tumor cell cell Anti– negative regulation • Negative regulatory receptor PD-L1 MHC PD-1 expressed and PD-L1 Antigen Anti– PD-L1 TCR PD-1 reactively expressed PD-1 • PD-L1 binds to PD-1 Inactivation Activation of T Cell of T Cell

T cell inactivated T cell activated Tumor escape Elimination of tumor cells

Tumor escape Tumor attack

CTLA-4 Checkpoint Lymphoid Tissue Inhibition

CTLA-4 is a negative Without With regulator of costimulation Immunotherapy Immunotherapy STOP GO Anti–CTLA-4 monoclonal required for activation of an antibodies block negative antitumor T cell in a lymph regulation by CTLA-4 node upon recognition of APC tumor antigen Anti– MHC CD80/86 CTLA-4 Antigen antibody TCR CTLA-4

Inactivation Activation of T Cell of T Cell T cell inactivated T cell activated

Tumor escape Elimination of tumor cells

Tumor escape Tumor attack Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

FDA- Approved PD-L1 Inhibitor PD-1 Inhibitor ICIs1

 

Approved in combination Approved in combination with nab- for with chemotherapy for the the treatment of patients treatment of patients with with locally advanced locally recurrent unresectable unresectable or metastatic or metastatic TNBC whose TNBC whose tumors express tumors express PD-L1 (CPS PD-L1 (PD-L1 stained ≥10), as determined by the tumor-infiltrating ICs of any PD-L1 IHC 22C3 pharmDx

Atezolizumab intensity covering ≥1% of the companion diagnostic assay tumor area), as determined by the VENTANA PD-L1 (SP142) companion diagnostic assay

Phase 3 Clinical Trials Neoadjuvant Setting of ICIs in TNBC2 Trial Regimen Status Pembrolizumab + paclitaxel + g NCT03036488 Active, pembrolizumab + (AC or EC) g surgery g KEYNOTE-522 not recruiting pembrolizumab NCT03197935 + nab-paclitaxel g atezolizumab + Active, IMpassion031 AC g surgery g atezolizumab not recruiting NCT02620280 Atezolizumab + nab-paclitaxel + carboplatin g Active, NeoTRIPaPDL1 surgery g AC or EC or FEC not recruiting NCT03281954 Atezolizumab + paclitaxel + carboplatin g GBG 96 Recruiting atezolizumab + (AC or EC) g surgery g atezolizumab GeparDouze

NCT04613674 + chemotherapy Recruiting

NCT03281954 Atezolizumab Recruiting Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Phase 3 Clinical Trials Adjuvant Setting of ICIs in TNBC2 Trial Regimen Status NCT02954874 Pembrolizumab + radiotherapy Recruiting SWOG-S1418 NCT02926196 Active, A-Brave not recruiting NCT03498716 Atezolizumab + paclitaxel g Recruiting IMpassion030 atezolizumab + (AC or EC) g atezolizumab

NCT02954874 Pembrolizumab Recruiting

Phase 3 Clinical Trials Metastatic Setting of ICIs in TNBC2 Trial Regimen Status NCT02425891 Active, Atezolizumab + nab-paclitaxel IMpassion130 not recruiting NCT02819518 Pembrolizumab + [nab-paclitaxel or Active, KEYNOTE-355 paclitaxel or (gemcitabine + carboplatin)] not recruiting NCT03125902 Active, Atezolizumab + paclitaxel IMpassion131 not recruiting NCT03371017 Atezolizumab + Recruiting IMpassion132 [(gemcitabine + carboplatin) or capecitabine] Active, NCT04177108 Atezolizumab + ipatasertib + paclitaxel not recruiting NCT04148911 Atezolizumab + nab-paclitaxel Recruiting EL1SSAR NCT04085276 Toripalimab + nab-paclitaxel Recruiting TORCHLIGHT

NCT04335006 Carelizumab + nab-paclitaxel + Recruiting

NCT04191135 Pembrolizumab + carboplatin + gemcitabine or Recruiting KEYLYNK-009 pembrolizumab + olaparib

1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. 2. https://clinicaltrials.gov. Antibody–Drug Conjugates in Triple-Negative Breast Cancer Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Structure and Mechanism of Action of Antibody–Drug Conjugates

Conjugation site (lysine coupling, cysteine alkylation, enzymatic reaction, etc)

mAb (humanized or Linker fully human) (cleavable or Payload noncleavable) (antimitotic agent)

Key factors • High potency • High cancer-cell specificity • Low immunogenicity • Long circulating life • Low cytotoxicity to off-target cells

6 1 Cell death Binding to cell-surface antigen

5 DNA or microtubule disruption

2 Endocytosis of ADC–antigen complex

4 Release of active payload

3 Lysosomal degradation Antibody–Drug Conjugates in Triple-Negative Breast Cancer Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

FDA- Approved Antibody– Drug Conjugates1

Linker for SN-38  • Hydrolyzable linker for payload release • High drug-to-antibody Approved for the ratio (7.6:1) treatment of patients with unresectable locally advanced or metastatic SN-38 payload TNBC who have received • Metabolite of topo I inhibitor two or more prior systemic • SN-38 more potent Humanized anti- than parent compound, therapies, at least one of TROP2 antibody • Directed toward them for metastatic disease TROP2, an epithelial antigen expressed on many solid cancers

Clinical Trials Phase 3 of ADCs 2 in TNBC Trial Regimen Setting Status

NCT04595565 Sacituzumab govitecan Post-neoadjuvant Recruiting

Clinical Trials Phase 2 of ADCs 2 in TNBC Trial Regimen Setting Status Sacituzumab govitecan ± NCT04468061 Metastatic Recruiting pembrolizumab NCT04230109 Sacituzumab govitecan ± Neoadjuvant Recruiting NeoSTAR pembrolizumab Active, NCT04454437 Sacituzumab govitecan Metastatic not recruiting deruxtecan NCT04699630 Metastatic Recruiting (U3-1402) Locally advanced NCT04225117 Recruiting or metastatic

NCT04504916 VLS-101 Metastatic Recruiting

NCT01042379 Ladiratuzumab vedotin Neoadjuvant Recruiting Antibody–Drug Conjugates in Triple-Negative Breast Cancer Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Clinical Trials Phase 1/2 of ADCs 2 in TNBC Trial Regimen Setting Status

Sacituzumab govitecan + NCT04039230 Metastatic Recruiting talazoparib Sacituzumab govitecan + Metastatic NCT03424005 atezolizumab or ladiratuzumab or inoperable Recruiting Morpheus-TNBC vedotin + atezolizumab locally advanced Ladiratuzumab vedotin + Locally advanced NCT03310957 Recruiting pembrolizumab or metastatic Datopotamab deruxtecan NCT03742102 (DS-1062a) + or Metastatic Recruiting BEGONIA deruxtecan + durvalumab Active, NCT04441099 NBE-002 Metastatic not recruiting Locally advanced NCT03504488 CAB-ROR2-ADC inoperable Recruiting or metastatic Locally advanced NCT04152499 SKB264 inoperable Recruiting or metastatic Locally advanced NCT03729596 MGC018 ± MGA012 Recruiting or metastatic

Clinical Trials Phase 1 of ADCs 2 in TNBC Trial Regimen Setting Status

NCT03992131 Sacituzumab govitecan + Active, Metastatic SEASTAR rucaparib not recruiting Ladiratuzumab vedotin NCT01969643 Metastatic Recruiting (SGN-LIV1A) NCT03401385 Datopotamab deruxtecan TROPION- Metastatic Recruiting (DS-1062a) PanTumor01 Locally advanced NCT03621982 Recruiting (ADCT-301) or metastatic

1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. 2. https://clinicaltrials.gov. Guidance for Immune-Related Adverse Effects Associated With Immunotherapy1-6 Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

What Are irAEs?

• Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic enhancement can also lead to a unique spectrum of immune-related adverse effects (irAEs)

• Pathophysiology of irAEs is not entirely clear, but T-cell, antibody, and cytokine responses may be involved

• irAEs differ significantly from toxicities of chemotherapies and other cancer therapies

• Any organ system can be affected, but more commonly occurring irAEs are pulmonary (pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo), gastrointestinal (, enterocolitis, transaminitis, hepatitis, pancreatitis), and endocrine (thyroiditis, hypophysitis, adrenal insufficiency) irAEs

• irAEs are unpredictable and can present at any time, but they typically start within the first few weeks to months after treatment initiation and can occur after treatment discontinuation

• irAEs can be difficult to differentiate from other etiologies and are often diagnosed by exclusion; other causes should be ruled out, but immunotherapy-related toxicity should always be included in the differential for patients who are receiving or have received immunotherapies

Organ-specific events General events • Skin • Fatigue • Gastrointestinal • Pyrexia, chills • Liver • Infusion reactions • Pulmonary • Endocrine system

Corticosteroids irAEs (autoimmune reactions) Immunotherapy Immune Tolerance

Unchecked Immune Response Guidance for Immune-Related Adverse Effects Associated With Immunotherapy1-6 Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Spectrum of Potential irAEs

Neurologic Neuropathy, meningitis, Ocular Guillain–Barré syndrome, Uveitis/iritis, episcleritis, myasthenia gravis, encephalitis, and blepharitis and transverse myelitis

Endocrine Cardiovascular Primary hypothyroidism, Myocarditis, pericarditis, hyperthyroidism, hypophysitis, arrhythmias, impaired primary adrenal insufficiency, ventricular function with heart and diabetes failure and vasculitis, and venous thromboembolism

Dermatologic Rash/inflammatory Pulmonary dermatitis, bullous dermatoses, Pneumonitis and severe cutaneous adverse reactions

Hematologic Autoimmune hemolytic anemia, Gastrointestinal aTTP, hemolytic uremic Colitis, hepatitis, and hepatic syndrome, aplastic anemia, transaminases lymphopenia, ITP, and acquired hemophilia

Musculoskeletal Renal Inflammatory arthritis, Nephritis myositis, and polymyalgia-like syndrome

Note: This irAE list is not all inclusive Guidance for Immune-Related Adverse Effects Associated With Immunotherapy1-6 Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

How Should irAEs Be Diagnosed and Managed?

There should be a high irAEs are often Depending on severity level of suspicion that diagnosed by exclusion; of irAE, management new symptoms are If appropriate Use of immunosuppressive other causes should be may require treatment related; early immunosuppressive therapy to manage ruled out (including AEs corticosteroid or other recognition, evaluation, treatment is irAEs does not appear to of other therapies used), immunosuppressive and treatment of irAEs used, patients generally impact response to but immunotherapy-related treatment and plus patient education recover from irAEs immunotherapy toxicity should always be interruption or are essential for the included in the differential discontinuation of therapy best outcome

Managed in outpatient/community setting Generally requires hospital admission

Referral to specialist Strong immune suppressive treatment

Steroids (PO/IV): 1-2 mg/kg/d Oral steroids Intravenous steroids prednisone or equivalent, slow taper over 4-6/52

a For some AEs, treatment can Stop treatmenta be restarted after resolution (eg, rash); ICI generally continued with endocrinopathies once managed Symptomatic therapy Treatment Required Increasing Intensity of Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Very severe

Increasing Grade of Side Effect

Multidisciplinary Management of irAEs Is Coordinated by the Oncologist

Pulmonologist Gastroenterologist

Endocrinologist Ophthalmologist

Neurologist Oncologist Rheumatologist

Hematologist Cardiologist

Hepatologist Dermatologist Guidance for Immune-Related Adverse Effects Associated With Immunotherapy1-6 Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Management of Organ-Specific irAEs

Nervous system Ocular

Neurologic. Assessment: neurology consult, Ocular. Assessment: rule out and MRI of brain to rule out CVA and brain consult with ophthalmology. metastases; MRI spine; LP; rule out infection. Management: lubricating eye drops; topical Management: permanent discontinuation; corticosteroid eye drops; decrease local rehab services; IV immunoglobulin. irritants: contact lens, eye makeup, etc.

Endocrine

Adrenal insufficiency. Assessment: more common Cardiovascular with anti–PD-1; monitor ACTH and cortisol. Management: corticosteroids (must start prior to any other hormone replacement) and stress dosing Cardiac. Assessment: ECG, echocardiogram, in trauma. CXR, and cardiology consult. Management: Hypophysitis. Assessment: CMP, glucose, cortisol, blood pressure support and heart rate regulation. ACTH, pituitary panel (TSH, FSH, LH, ACTH, and prolactin); testosterone/estradiol; and MRI of brain with sellar cuts. Management: hormone replacement. Hyperthyroidism. Assessment: monitor TSH and T4. Management: antithyroid: methimazole; beta-blockers. Hypothyroidism. Assessment: monitor TSH and T4. Management: levothyroxine; usually permanent. Pulmonary Type 1 diabetes: Assessment: blood glucose. Management: insulin.

Pneumonitis. Assessment: O2 saturation levels, CT of chest; rule out progression of disease, Dermatologic lymphangitic spread, pulmonary embolism,

and pleural effusion. Management: O2 support, bronchoscopy ± BAL, steroids, and Rash/skin. Assessment: rule out other antibiotic prophylaxis. causes; total body exam (include mucous membranes); measure distribution and skin biopsy. Management: topical moderate-to-high–dose steroids; IV steroids; consult dermatology and infectious disease; if mucosa, consult gynecology, ophthalmology, and urology; Gastrointestinal admission: burn unit.

Colitis. Assessment: rule out infectious causes; stool cultures; rule out perforation; abdominal Hepatic CT and lactoferrin and calprotectin levels. Management: if steroid refractory: ; Assessment: liver enzymes (AST, antispasmodic, antidiarrheal, and fluid support. Hepatic. ALT, ALK, total and direct bilirubin), liver ultrasound, GI consult, and rule out viral syndrome. Management: hold hepatotoxic drugs; mycophenolate 2 mg/kg/d; if refractory: no infliximab.

Musculoskeletal Renal

Musculoskeletal. Assessment: rheumatologic Renal/nephritis. Assessment: serum tests, autoimmune panel (ANA, RF, anti-CCP, creatinine and urinalysis; nephrology ESR, CK, and CRP); imaging and EMG. consult, renal ultrasound, and biopsy. Management: NSAIDs, corticosteroid joint Management: limit nephrotoxic drugs, injections, DMARDs, methotrexate, and PT/OT. antibiotics, NSAIDs, and contrast dye; identify high-risk patients (CRF); and hydration.

1. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 2. https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/supportive-careand-treatment- related-issues#/29866. 3. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 4. Calabrese LH et al. Nat Rev Rheumatol. 2018;14:569-579. 5. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2018/761069s002lbl.pdf. 6. Postow MA et al. N Engl J Med. 2018;378:158-168. Tigerlily Foundation: Breast Cancer Resource Compendium Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Tigerlily Foundation envisions a future where breast cancer diagnosis doesn’t inspire fear, but ignites hope for a future to young women diagnosed with breast cancer to transform s 1 Inspire eek inside and out as they journey through treatment to live their tion s , ms, Tigerlily Founda ds best life going forward s progra oun h it ackgr oug ower women of all b ing hr nd emp fac 2 Empower young women to be advocates for change T te a hose uca at heightened risk, t re d g those o ca e din cess t Breast cancer will no longer be a terminal disease, clu nd those with less ac 3 in ities, a but becomes a chronic disease that will someday par dis be cured

4 End disparities of age, stage, and color, in our lifetime

To educate, advocate for, VISION AIM empower, and support young women, before, during, and after breast cancer Maimah Karmo is the Founder/CEO of the BE SURE TO FOLLOW Tigerlily Foundation TIGERLILY FOUNDATION and a 15-year survivor FOR ALL UP-TO-DATE EVENTS. of breast cancer Her journey with breast cancer MISSION motivated her to create an FOUNDING organization to educate, empower, advocate for, and support other women affected by breast cancer

https://www.tigerlilyfoundation.org/ Tigerlily Foundation: Breast Cancer Resource Compendium Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

My Lifestyle Toolkit https://www.tigerlilyfoundation.org/category/breast-cancer-toolkit/

• Types of breast cancer • Symptoms • Educational Guidebooks • Diagnosis • My Life Newsletters • Genomics • Impact Reports • Treatments • Brochures • Men and breast cancer • Quick Shareables • Breast cancer statistics • Healthcare providers • Glossary of terms Breast Publications Cancer 101

Wellness and Survivorship Prevention • The new normal • Early detection • Quality of life • High risk • Mental health assessment • Clinical trials • Screening and testing • Diet and nutrition • Healthy lifestyle • Caregiver support • Genomics and you: • Research screening for women at high risk • Holistic and integrated health Tigerlily Foundation: Breast Cancer Resource Compendium Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Educational Guidebooks https://www.tigerlilyfoundation.org/breast-cancer-toolkit/educational-guidebooks/

Understanding Triple-Negative Understanding Genetics, BRCA, Breast Cancer Clinical Trials and PARP Inhibitors Guidebook Guidebook Guidebook

My Life Guidebook This guidebook is focused on meeting the needs of young women living with metastatic breast cancer, diagnosed Genomics and You Caregiver under the age of 45 years Guidebook Guidebook Tigerlily Foundation: Breast Cancer Resource Compendium Full abbreviations, accreditation, and disclosure information available at PeerView.com/EKR40

Black women and White women get breast cancer at about the same rate, but Black women are nearly 40% more likely to die of breast cancer

Female Breast Cancer Stage Distribution by Female Breast Cancer Incidence (2012-2016) and Distribution of Breast Cancer Subtypes by Race/Ethnicity, Ages 20 and Older, US, 2012-20161 Death (2013-2017) Rates by Race/Ethnicity, US1 Race/Ethnicity, Ages 20 and Older, US, 2012-20161 Facts Localized Regional Distant Unknown 150 Incidence Mortality HR+/HER2- HR+/HER2+ HR-/HER2+ HR-/HER2- 100 3 3 4 4 2 • Black women are 130.8 5 126.7 100 5 8 6 6 10 Facts 90 more likely to be 120 12 12 10 4 21 6 80 26 28 diagnosed with breast 6 6 • Black women have 80 30 32 10 13 70 33 94.7 93.7 93.2 6 12 13 cancer at later stages 90 lower enrollment in 60 12 and have more 60 clinical trials, which 50 aggressive forms makes it more difficult Percentage 60

40 Percentage Rate per 100,000 40 to design treatments 66 64 • Black women 30 60 58 76 71 56 28.4 70 experience delays 30 61 69 • Black women 20 20.3 14.6 14.0 11.5 20 10 in treatment, long represent only 6.2% intervals between 0 of 0 Non- Non- American Hispanic/ Asian/ Non- Non- American Hispanic/ Asian/ Hispanic Hispanic Indian/ Latina Pacific 0 Hispanic Hispanic Indian/ Latina Pacific screening, and lack White Black Alaska Islander Non- Non- American Hispanic/ Asian/ participants White Black Alaska Islander Native Hispanic Hispanic Indian/ Latina Pacific Native of timely follow-up White Black Alaska Islander The Challenges Native of suspicious results Metastatic breast cancer disproportionately affects black women, yet they often go underrepresented in the conversation on the unique needs of women living with stage IV breast cancer. Due to mistreatment in the clinical trial/scientific/research settings, many Black women have a mistrust of the scientific and healthcare systems, as well as providers, which has resulted in alarming outcomes.

Tigerlily Foundation Initiatives Targeting Disparities in Breast Cancer

ANGEL #KnowMoreDisparities and #PullUpASeat Advocacy Bidirectional Program Conversation Series We pledge to only participate in initiatives—panels, boards, planning committees, programs—that include the experience of Black women; and we commit to taking specific actions to dismantle systemic barriers and end disparities for Black women in our lifetime

Young Women’s MBC Disparities Initiative and BREATHE TV #InclusionPledge Young Women’s MBC Disparities Alliance

1. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf.