1 Florida Society of Clinical Oncology New Approved Therapies for Metastatic Triple Negative Breast Cancer 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 ▪ Sacituzumab Govitecan ▪ Bicalutamide, Enzalutamide, • Immune Checkpoint Inhibitors Abiraterone ▪ Atezolizumab ▪ Pembrolizumab 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 irinotecan) 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 R • 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-paclitaxel +/- 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/carboplatin) ▪ 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 hepatocellular carcinoma previously treated with sorafenib • Nivolumab for hepatocellular carcinoma previously treated with sorafenib • Note also: 4 voluntary withdrawals in 2020 in small cell lung cancer and bladder cancer 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