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Florida Society of Clinical Oncology

New Approved Therapies for Metastatic Triple Negative

Julie Gralow, MD, FACP, FASCO Chief Medical Officer American Society of Clinical Oncology (ASCO)

© 2021 American Society of Clinical Oncology (ASCO). All Rights Reserved Worldwide. TNBC is NOT One Disease! Molecular Subtyping of Triple Negative Breast Cancer (TNBC) Basal-like Immuno-activated • Majority of TNBC • TP53 mutations in >90% • Higher frequency of HRD Basal-like Immuno-suppressed • TP53 mutations in >90% • Lower TILs Mesenchymal • Lower genomic complexity • PIK3CA pathway activation Luminal Androgen Receptor • Lower genomic complexity • PIK3CA, AKT1, NF1, GATA3, CHH1 mutations • Lower ILs

Lehmann et al 2011, Burstein et al 2015, Reis-Filho et al 2016, Bareche et al 2018 Drugs for Triple Negative Breast Cancer

• Chemotherapy • PARP inhibitors in BRCA1/2+ ▪ Platinum agents more sensitive in ▪ Studies beyond BRCA1/2 TNBC • Androgen Receptor Targeted • Antibody Drug Conjugates Agents ▪ ▪ Bicalutamide, Enzalutamide, • Inhibitors Abiraterone ▪ ▪ Sacituzumab Govitecan

Sacituzumab: antibody against Trop-2 (glycoprotein overexpressed on > 90% of TNBC, plus other breast cancer subtypes) Antibody-Drug SN-38: chemotherapy (active metabolite of ) Conjugates in

Triple Negative SN-38 more Humanized Breast Cancer potent than anti-Trop-2 parent antibody compound

• FDA accelerated approval metastatic TNBC 5/20 (full approval 4/21) • FDA accelerated approval locally advanced/metastatic urothelial cancer 4/21 ASCENT: Randomized Phase III Trial of Sacituzumab Govitecan vs Treatment of Physician Choice in TNBC Bardia A et al, ESMO 2020 abstract LBA17

• Metastatic triple Sacituzumab govitecan negative breast cancer N= 529 10 mg/kg IV days 1 and 8 every 21 days • > 2 lines chemotherapy in metastatic setting R Treatment of Physician Choice Capecitabine Eribulin Primary endpoint: PFS Vinorelbine Gemcitabine ASCENT: Randomized Phase III Trial of Sacituzumab Govitecan vs Treatment of Physician Choice in Metastatic TNBC Bardia A et al, ESMO 2020 abstract LBA17

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• Main toxicities: neutropenia, anemia, • Median PFS: 5.6 versus 1.7 months, p <0.0001 diarrhea, fatigue • OR: 35% versus 5% • Ongoing studies: Neoadjuvant/adjuvant • Median OS: 12.1 versus 6.7 months, p <0.0001 TNBC, ER+ breast cancer, combinations with other targets, other cancers Anti-PD-1/PD-L1 antibodies approved in TNBC Immune Checkpoint Atezolizumab • Approved in PD-L1+ metastatic TNBC Inhibitors in Triple Negative Pembrolizumab • Approved in PD-L1+ metastatic TNBC Breast Cancer • Also approved in solid tumors with TMB high (≥10 mut/Mb) Immune Checkpoint Inhibitors in TNBC: Atezolizumab

• Impassion 130 (Schmid P et al, NEJM 2018) – positive trial ▪ 1st-line metastatic ▪ Nab- +/- atezolizumab ▪ Improved PFS in PD-L1+ (41% of tumors) ▪ Final OS could not be formally tested due to statistical considerations of protocol • Impassion 131 (Miles D et al, ESMO 2020) – negative trial ▪ 1st-line metastatic ▪ Paclitaxel +/- atezolizumab ▪ Did not meet primary endpoint

• Impassion 031 (Mittendorf E et al, Lancet 2020) ▪ Neoadjuvant therapy ▪ Nab-paclitaxel followed by AC +/- 1 year atezo ▪ Improved pCR rates with atezo, irrespective of PD-L1 status Immune Checkpoint Inhibitors in TNBC: Pembrolizumab

• KEYNOTE 355 Trial (Cortes J et al, Lancet 2020) – positive trial ▪ 1st-line metastatic ▪ Chemo +/- pembrolizumab (nab-paclitaxel, paclitaxel, gemcitabine/) ▪ Improved PFS in PD-L1+ ▪ Final OS not yet reported

• KEYNOTE 522 Trial (Schmid P et al, NEJM 2020) ▪ Neoadjuvant therapy ▪ Paclitaxel/Carbo followed by AC +/- pembrolizumab x 1 year ▪ Improved pCR rates with pembro, irrespective of PD-L1 status ▪ Reviewed by FDA/ODAC 2/21 - accelerated approval deferred April 27-29, 2021: Oncologic Drugs Advisory Committee (ODAC) Meeting • Updates on 6 accelerated approvals for immune checkpoint inhibitors with confirmatory trials that have not verified clinical benefit

• Atezolizumab in combination with nab-paclitaxel for locally advanced/metastatic TNBC expressing PD-L1 • Pembrolizumab for locally advanced/metastatic urothelial carcinoma Atezolizumab for locally advanced/metastatic urothelial carcinoma • Pembrolizumab for locally advanced/metastatic gastric or GE junction adenocarcinoma • Pembrolizumab for previously treated with • for hepatocellular carcinoma previously treated with sorafenib • Note also: 4 voluntary withdrawals in 2020 in small cell and IMpassion130 Phase III Trial: Nab-paclitaxel +/- Atezolizumab in Triple Negative Breast Cancer Schmid P et al, NEJM Oct 2018

N=902 patients Nab-paclitaxel 100 mg/m2 weekly 3 out of 4 weeks + Placebo day 1 • Metastatic breast cancer and 15 • No prior treatment for metastatic disease • ER/PR/HER2 negative Nab-paclitaxel 100 mg/m2 • Stratified by PD-L1 status weekly 3 out of 4 weeks + Atezolizumab 840 mg day 1 and 15 IMpassion130 Phase III Trial: Nab-paclitaxel +/- Atezolizumab in Triple Negative Breast Cancer Schmid P et al, NEJM Oct 2018 1st Interim Analysis: 12.9 months of followup

PFS PFS Placebo OS OS Atezo Atezo Placebo ITT 7.2 mo 5.5 mo 21.3 mo 17.6 mo P=0.002 P=0.08 PD-L1 + 7.5 mo 5.0 mo 25 mo 15.5 mo (40.9% of patients) P<0.001 Formal testing not conducted

PD-L1 - 5.6 mo 5.6 mo IMpassion130 Phase III Trial: Nab-paclitaxel +/- Atezolizumab in Triple Negative Breast Cancer: Final OS Data Emmens LA et al, ESMO 2020 LBA16

Final OS analysis: 18.8 months follow-up

• OS ITT – 21.0 vs 18.7 months • OS PD-L1+ – 25.4 vs 17.9 months, HR 0.67 • OS boundary for statistical significance not crossed in ITT population, which precluded further formal testing in the PD-L1-positive group IMpassion130 Phase III Trial: Nab-paclitaxel +/- Atezolizumab in Triple Negative Breast Cancer Schmid P et al, NEJM Oct 2018

Toxicities Nab-paclitaxel + Nab-paclitaxel + Atezolizumab Placebo Discontinued due to AE 15.9% 8.2% Grade 3, 4 adverse event (most common: 48.7% 42.2% neutropenia, anemia, fatigue, neuropathy) Serious adverse event 22.8% 18.3%

Immune-related hypothyroidism 17.3% 4.3% Pneumonitis 3.1% 0.2% Pembrolizumab in Metastatic Breast Cancer with High Tumor Mutational Burden (TMB): Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study Alva AS et al, J Clin Oncol 2021 • Eligibility ▪ Metastatic breast cancer ▪ High tumor mutational burden • Treatment: ▪ Pembrolizumab monotherapy: either 2 mg/kg or 200 mg infusions every 3 weeks • Primary end point: disease control (objective response or stable disease > 16 weeks) • Results: ▪ 28 patients enrolled with TMB ranging from 9 to 37 mut/Mb ▪ Disease Control: 37% (95% CI, 21 to 50) ▪ Objective Response: 21% (95% CI, 8 to 41) ▪ Median PFS: 10.6 weeks (95% CI, 7.7 to 21.1) ▪ Median OS: 30.6 weeks (95% CI, 18.3 to 103.3) ▪ No relationship observed between PFS and tumor mutational burden, PD-L1 status not collected Environmental factors (UV, radiation, chemicals)) DNA DAMAGE Normal physiology Cell Death (DNAChemotherapy, replication) Radiotherapy Replication Lesions PARP Inhibitors • Base excision repair Double Strand Breaks PARP1 • Homologous recombination DNA Adducts/Base Damage in Triple Single Strand Breaks BRCA1/BRCA2 • Base excision repair Negative Breast • Base excision repair PARP1 Cancer PARP1 • Combination of BRCA mutation and PARP inhibitor leads to synthetic lethality (cell death) • PARP inhibitors olaparib and talazoparib FDA approved in metastatic breast cancer • “BRCA-like” TNBC with homologous recombination deficiency (HRD) may be vulnerable to PARP inhibition Phase III OlympiAD Trial: Olaparib versus Physician’s Choice Chemotherapy in Metastatic BRCA-mutated Breast Cancer Robson M et al, NEJM 2017

N=302 patients • Metastatic breast Olaparib 300 mg BID Olaparib Chemo cancer • Germline BRCA PFS 7.0 mo 4.2 mo HR 0.58, p < mutation + 2:1 0.001 • HER2 negative Physician’s Choice of Response 60% 29% • Prior treatment with Chemo OS 19.3 mo 19.6 mo anthracycline and (Capecitabine, Vinorelbine, (interim) taxane Eribulin) Phase III EMBRACA Trial: Talazoparib vs Physician’s Choice Chemotherapy in Metastatic BRCA-mutated Breast Cancer Litton J et al, NEJM 2018

N= 431 patients

Talazoparib 1 mg po daily Talazoparib Chemo • Metastatic or locally PFS 8.6 mo 5.6 mo HR 0.54, advanced breast p = <0.0001 cancer 2:1 Response 62.6% 27.2% P < 0.001 • Germline BRCA1/2 mutation + Physician’s choice: OS 22.3 mo 19.5 mo P = 0.105 • HER2 negative capecitabine, eribulin, (interim) gemcitabine, vinorelbine PARP Inhibitors in Metastatic Breast Cancer

Consider germline genetic testing for metastatic patients: • Patients who meet guidelines for genetic testing based on age and family history • All triple negative • ER+ when thinking of switching to chemo

• Additional studies of PARP inhibitors ongoing: • Adjuvant germline BRCA1/2+ breast cancer • OlympiA trial press release 2/21 : “IDMC concluded that trial crossed superiority boundary for iDFS at planned interim analysis” • Patients with germline mutations in other DNA repair genes • Tumors with somatic mutations in BRCA1/2 and other DNA repair genes • TNBC with “BRCAness” features (HRD) PARP Inhibitors Beyond BRCA1/2 TBCRC 048: Phase II Trial of Olaparib in Metastatic Breast Cancer with Germline (other than BRCA1/2) or Somatic Mutations in DNA Repair Genes Tung N et al, J Clin Oncol 2020

Many Additional (but less common) DNA • 54 metastatic breast cancer patents Repair Genes • Germline or somatic mutations in DNA repair genes: – ATM, ATR, BARD1, BRIP1, CHEK2, FANCA/C/D2/E/F/M, MRE11A, NBN, PALB2, PTEN, RAD50/51C/51D • Somatic mutations in BRCA1/2 • Treated with single agent olaparib • Responses seen in: – Somatic BRCA1/2 mutations – Germline PALB2 mutations • These groups continue to enroll SWOG S1416 Study: Randomized Phase II Trial of +/- Veliparib in Metastatic TNBC and BRCA+ Breast Cancer Sharma P et al, ASCO 2020 abstract 1001

Triple Negative or BRCA1/2+ Metastatic Breast Cisplatin q3 weeks + Veliparib Cancer

335 patients Cisplatin q3 weeks

Germline BRCA1/2 testing and assays for “BRCAness” (HRD) performed SWOG S1416: Cisplatin +/- Veliparib in Metastatic TNBC and BRCA+ Breast Cancer Germline BRCA testing (323 patients evaluable)

Germline BRCA mutation Germline BRCA mutation positive (37) negative (286) No benefit for addition of veliparib (underpowered) BRCAness Biomarker Analysis • HRD score • Somatic mutations in BRCA 1/2 • Non-BRCA germline HR mutations • BRCA1 promoter methylation

Non-BRCAness Group BRCAness Group (101) Unable to classify (75) (110) Significant benefit in PFS for No benefit for addition No benefit for addition addition of veliparib of veliparib of veliparib TBCRC 011: Phase II Study of Bicalutamide (150 mg) in Metastatic AR+ TNBC Gucalp A et al, Clin Cancer Res 2013 Androgen Receptor Phase II Study of Enzalutamide in Therapy in Advanced AR+ Triple Negative Breast Triple Negative Cancer Breast Cancer Traina T et al, J Clin Oncol 2018 Phase II Study of Abiraterone + Prednisone in Metastatic AR+ TNBC Bonnefoi et al, Ann Oncol 2016 Therapies for Metastatic Triple Negative Breast Cancer

• Sacituzumab Govitecan antibody-drug conjugate ▪ Active agent • Immune checkpoint inhibitors ▪ Predictors of response? PD-L1, TMB/MSI-high, TILS, etc ▪ Which chemo combination? Do steroids matter? • PARP inhibitors ▪ Assess germline BRCA (and PALB2?) status in metastatic patients ▪ Activity seen in somatic BRCA mutations ▪ Possible future role for HRD testing in TNBC? • Androgen receptor targeted agents ▪ Consider staining for AR