Denise A. Yardley, MD Sarah Cannon Research Institute - PowerPoint Presentation

1. Denise A. Yardley, MDSarah Cannon Research InstituteSenior Investigator, Breast Cancer ResearchTennessee Oncology, PLLCNashville, TennesseeKey Ongoing Clinical Trials in HR-Positive/HER2-Negative Early-Stage Breast CancerThis program is supported by educational grants from AstraZeneca, Lilly and Merck Sharp & Dohme Corp.

2. About These SlidesPlease feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patientsWhen using our slides, please retain the source attribution:These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for detailsSlide credit: clinicaloptions.com

3. FacultyDenise A. Yardley, MDSarah Cannon Research InstituteSenior Investigator, Breast Cancer ResearchTennessee Oncology, PLLCNashville, TennesseeDenise A. Yardley, MD, has disclosed that she has received funds for research support paid to her institution from AbbVie, Amgen, BIOMARIN, Biothera Pharmaceuticals, Clovis Pharma, Incyte, Innocrin Pharmaceuticals, Lilly, MacroGenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, NSABP, Pfizer, Roche/Genentech, Tesaro, and Polyphor and that she has received consulting fees paid to her institution from Athenex, bioTheranostics, G1 Therapeutics, Immunomedics, Lilly, Merck, Novartis, Pfizer, and Sanofi-Aventis.

4. Ongoing Questions in Early-Stage Breast CancerHow can we improve outcomes with the CDK4/6 inhibitors in HR+ HER2- early-stage breast cancer?In the adjuvant setting?In the neoadjuvant setting and with residual disease?What can we learn about the antibody–drug conjugates in HR+/HER2- EBC?Sacituzumab govitecan Trastuzumab deruxtecanWill SERDS have a role in the adjuvant setting?Slide credit: clinicaloptions.com

5. Targeting CDK4/6 in High-Risk HR+, HER2- EBC: RationaleWhy do we see mixed results?Negative: PALLAS and PENELOPEPositive: monarchEOngoing: NATALEE, ADAPTlate Possible explanations: monarchEHigher risk patientsContinuous dosingCDK4 > CDK6 activityOtto. Nat Rev Cancer. 2017;17:93. Corona. Drug Des Devel Ther. 2018;12:321. Tripathy. Clin Cancer Res. 2017;23:3251.MCyclin B-CDK1Cyclin A-CDK1Cyclin A-CDK2Cyclin E-CDK2Cyclin D-CDK4Cyclin D-CDK6G0G2G1SPalbociclibRibociclibAbemaciclibR pointBecause cyclin D–CDK4/6 activation occurs downstream of estrogen signaling, ET + CDK4/6 inhibitor combination therapy has synergistic antitumor activity against HR+ BCEstradiolERAIFulvestrantSlide credit: clinicaloptions.com

6. International, randomized, open-label phase III trial in patients with high-risk, N+, HR+/HER2- EBC; prior (neo)adjuvant CT permitted with no distant metastasis and ≤16 mo from surgery30.4% reduction in the risk of developing an iDFS eventAbsolute difference in 3-yr iDFS rates between arms: 5.4% monarchE: Adjuvant Abemaciclib + ET vs ET Alone in High-Risk, Node-Positive, HR+/HER2- EBC: 3-yr iDFS RateHarbeck. Ann Oncol. 2021;32:1571. O’Shaughnessy. ESMO 2021. Abstr VP8-2021.100iDFS (%)Mo0204060800369121518212427303336394245Abemaciclib durationAbemaciclib + ETET aloneiDFS Events, nAbemaciclib + ET 232ET Alone 333HR: 0.696 (95% CI: 0.588-0.823;nominal P = .0001)iDFS (%)Mo70758085909510045423936333027242118151296303-yr rate: 83.4%2-yr rate: 92.7%3-yr rate: 88.8%2-yr rate: 90.0%Patients at Risk, nAbemaciclib + ETET alone2808 2680 2621 2579 2547 2508 2477 2430 1970 1287 919 522 275 67 8 02829 2700 2652 2608 2572 2513 2472 2400 1930 1261 906 528 281 64 10 0Slide credit: clinicaloptions.com

7. NATALEE: Adjuvant Ribociclib + ET in HR+/HER2- EBCMulticenter, randomized, open-label phase III trialRibociclib 400 mg/day (3 wk on/1 wk off) for 3 yr +ET (letrozole or anastrozole)* for 60 mo +Goserelin†ET for 60 mo Pre/postmenopausal women and men with HR+/HER2-, stage II (either N0 with grade 2/3 and/or Ki67 ≥20% or N1), or stage III EBC; prior (neo)adjuvant CT permitted(N = 5101)*Treatment may begin up to 1 yr before study treatment start date. †Premenopausal women and men will also receive goserelin 3.6 mg/28 days.NCT03701334. Slamon. ASCO 2019. Abstr TPS597. Primary endpoint: invasive DFS (STEEP criteria)Key secondary endpoints: recurrence-free survival, distant DFS, OS, PROs, PK, safetySlide credit: clinicaloptions.com

8. ADAPTlate: Delayed Adjuvant Abemaciclib + ET in High-Risk HR+/HER2- EBCMulticenter, randomized, open-label phase III trialGluz. ASCO 2021. Abstr TPS598. NCT04565054. Pre-/postmenopausal women with high-risk, HR+/HER2- EBC; 2-6 yr after primary diagnosis; no distant metastasis; no prior CDK4/6 inhibitors; ECOG PS 0/1(N = 1250)Abemaciclib 150 mg PO BID for 2 yrET per standard of care* for 5-8 yr*Premenopausal patients: AI + GnRH agonist or tamoxifen ± GnRH agonist; postmenopausal patients: AI or taxomifen.ET per standard of care* for 3-6 yrYears 0-2Years 2-82:1Primary endpoint: iDFSSecondary endpoints: OS, distant DFS, occurrence of CNS metastases, QoLSlide credit: clinicaloptions.com

9. Spring. JAMA Oncol. 2016;2:1477.Neoadjuvant ET vs CT: Systematic Review/Meta-analysis of 20 RCTs Through 2015 (N = 3490)AIs showed significantly higher rates of clinical response, radiologic response, and BCS vs tamoxifen; radiologic response rate higher with CT + ET vs ETClinical ResponseSourceOR (95% CI)Alba 20122.11 (0.92-4.82)Palmieri 20140.34 (0.6-1.98)Semiglazov 20070.93 (0.55-1.57)Total1.08 (0.50-2.35)Heterogeneity: x22 = 4.47 (P = .11), I2 = 55%.Test for overall effect: z = 0.19 (P = .85).0.010.11.010100OR (95% CI)FavorsEndocrineFavorsChemotherapyRadiologic ResponseSourceOR (95% CI)Alba 20122.11 (0.92-4.82)Palmieri 20140.83 (0.25-2.74)Semiglazov 20071.28 (0.77-2.14)Total1.38 (0.92-2.07)Heterogeneity: x22 = 1.77 (P = .41), I2 = 0%Test for overall effect: z = 1.54 (P = .12)0.010.11.010100OR (95% CI)Pathologic CRSourceOR (95% CI)Alba 20123.13 (0.12-78.77)Palmieri 2014Not estimatedSemiglazov 20071.84 (0.53-6.47)Total1.99 (0.62-6.39)Heterogeneity: x22 = 0.09 (P = .76), I2 = 0%.Test for overall effect: z = 1.16 (P = .25).0.010.11.010100OR (95% CI)FavorsEndocrineFavorsChemotherapyBreast Conservation ResponseSourceOR (95% CI)Alba 20120.68 (0.30-1.54)Semiglazov 20070.63 (0.36-1.11)Total0.65 (0.41-1.03)Heterogeneity: x22 = 0.03 (P = .87), I2 = 0%Test for overall effect: z = 1.83 (P = .07)0.010.11.010100OR (95% CI)Slide credit: clinicaloptions.com

10. Select Ongoing Trials With CDK4/6 Inhibitors in HR+/HER2- EBC1. Gluz. ASCO 2021. Abstr TPS598. 2. NCT04565054. 3. NCT04293393. 4. Tolaney. ASCO 2021. Abstr TPS596. 5. Slamon. ASCO 2019. Abstr TPS597. 6. NCT03701334. 7. NCT04584853.ParameterADAPTlate1,2CARABELA3eMonarchHER4NATALEE5,6POETIC-A7TreatmentDelayed extended adjuvant abemaciclib followed by ET vs ET aloneNeoadjuvant abemaciclib + letrozole ± LHRH vs AC-TAdjuvant abemaciclib + ET vs placebo plus ETAdjuvant ribociclib + ET vs ET aloneAdjuvant abemaciclib + ET vs ET alonePhaseIIIIIIIIIIIIIIN1250200245051012500Patient populationHR+/HER2-, high-risk EBCHR+/HER2-, intermediate/high-risk EBCHR+/HER2+, LN+ high-risk EBCHR+/HER2- EBCHR+/HER2-, high-risk EBC* *Patients will be selected for endocrine resistance with preoperative aromatase inhibitor therapy.Slide credit: clinicaloptions.com

11. CARABELA: Neoadjuvant Endocrine Therapy vs ChemotherapyRandomized, open-label phase II trial Letrozole 2.5 mg/day +Abemaciclib 150 mg BID ±LHRH (if premenopausal) in 28-day cycles for up to 12 moDoxorubicin 60 mg/m2 + Cyclophosphamide 600 mg/m2 Q21D x 4 cycles followed byPaclitaxel 80 mg/m2 Q1W x 12 wks orDocetaxel 100 mg/m2 Q1W x 4 cyclesWomen with intermediate-/high-risk (Ki67 ≥20%), HR+/HER2- EBC; T2-T4b, N0-N2, M0 (stages IIA, IIB, IIIA, IIIB); if T2N0M0, Ki-67 >30% or Ki-67 20-30% with PgR- ± G3) (N = 200)SurgeryPrimary endpoint: RCBSecondary endpoints: invasive EFS, safety, residual cancer burden, clinical response by MRI, molecular downstaging, changes in Ki-67, rate of PEPI score 0 at surgery, BCS rateNCT04293393.Slide credit: clinicaloptions.com

12. ImmunoADAPT: NeoAdjuvant Avelumab, Palbociclib + ET in ER+ BCRandomized, open-label phase II trialBIOPSYPalbociclib 125 mg PO QD for 21 days on/7 days off +ET*ET*Avelumab 10 mg/kg IV Q14D +ET*Palbociclib 125 mg PO QD for 21 days on/7 days off +Avelumab 10 mg/kg IV Q14D +ET*28-day lead-in (1 cycle)3 cyclesPrimary endpoint: clinical complete responseSecondary endpoints: safetySURGERYAdults with stage II-III ER+ BC; unlikely to be sensitive to ET (ie, PR-, high-grade/Ki-67, high gene expression profile, clinically aggressive presentation); no prior CDK4/6 inhibitors or immune checkpoint inhibitors; ECOG PS 0/1(N = 40)BIOPSY1:2*ET in premenopausal women: tamoxifen (20 mg/d x 28 d) + either goserelin (3.6 mg SC on D1) or leuprolide (3.75 mg IM on D1); ET in postmenopausal women: letrozole (2.5 mg/d).NCT03573648.Slide credit: clinicaloptions.com

13. neoMONARCH: Neoadjuvant Abemaciclib, Anastrozole, and Abemaciclib + Anastrozole in HR+/HER2- BCRNAseq analysis of biopsy samples from multicenter, randomized, open-label phase II trialHurvitz. Clin Cancer Res. 2020;26:566.BIOPSYAbemaciclib + ANZ(n = 74)ANZ(n = 74)Abemaciclib(n = 75)Abemaciclib + ANZAbemaciclib + ANZAbemaciclib + ANZ2-wk lead-in14 wkPrimary endpoint: percent change in Ki-67 from baseline to 2 wk of treatmentSecondary endpoints: pCR, OR, radiologic responseBIOPSYPostmenopausal women with stage I-IIIB HR+/HER2- BC; no prior systemic tx or radiotherapy of current cancer; no prior selective ER modulator(N = 224)BIOPSYStratified by progesterone receptor status and tumor sizeSlide credit: clinicaloptions.com

14. NSABP FB-13: Neoadjuvant Palbociclib + Letrozole + Ovarian Suppression in Premenopausal ER+/HER2- BCMulticenter, open-label phase II trialNCT03628066.Primary endpoint: complete cell cycle arrest (Ki-67 <2.7% at 6 wk)Secondary endpoints: ORR; pCR; correlation between Oncotype DX RS and clinical complete response, pCR, complete cell cycle arrest; surgical intent vs surgery received; estrone levels; estradiol levelsPremenopausal women with HR+/HER2- invasive EBC eligible for neoadjuvant AI and ovarian suppression; Oncotype DX RS <26; breast tumor ≥2.0 cm; no prior ET; ECOG PS 0/1(N = 24)Until 24 wkPalbociclib 125 mg PO (21-d on/7-d off) +Letrozole 2.5 mg PO QD +Goserelin 3.6 mg SC on D1Palbociclib 125 mg PO (21-d on/7-d off) +Letrozole 2.5 mg PO QD +Goserelin 3.6 mg SC on D1Cohort 1: RS <11Cohort 2: RS 11-26Slide credit: clinicaloptions.com

15. Neoadjuvant Endocrine Therapy ± Palbociclib in Operable HR+/HER2- Breast CancerRandomized, double-blind, placebo-controlled phase III trial Coprimary endpoints: PEPI score at 4 mo, EndoPredict Epclin ScoreSecondary endpoints: drop in Ki67 in 4 mo, pCR, rate of BCS, AEsPalbociclib D1-21 every 28-d cycle +ET* x 16 wkPlacebo + ET* x 16 wkWomen with HR+/HER2- BC; tumor >15 mm; Ki-67 14%; any menopausal status; no prior radiotherapy or systemic tx; ECOG PS 0/1(N = 200)*Premenopausal, tamoxifen + OFS; postmenopausal, letrozole.SurgeryNCT03969121.Slide credit: clinicaloptions.com

16. Neoadjuvant CDK4/6 Inhibitors: Are We There Yet?CDK4/6 inhibitors plus ET: potent reduction in Ki-67 as a measure of activity but does this translate to improvement in long term outcomes?ORR: CDK4/6 inhibitors added to ET does not improve ORR or pCR rates vs ET alone or CTRates of pCR or RCB 0-1 are low with addition of CDK4/6 inhibitorsSimilar benefit seen with all CDK 4/6 inhibitors in the advanced disease setting using cross-trial comparisonThere are no head-to-head comparisonsEndpoint: optimum endpoint unknown; not clear that increasing pCR rates and/or rate of RCB 0-1 improves long-term outcomes for luminal cancersWithout long-term outcomes, neoadjuvant CDK4/6 inhibitors remain investigational and clinical trials continueSlide credit: clinicaloptions.com

17. ESR1 Mutations: Primary vs MetastaticJeselsohn. Clin Cancer Res. 2014;20:1757.Patients With Recurring ESR1 Genomic Alterations (%)Frequency of Recurring ESR1 Genomic Alterations in ER+ TumorsEarly MBCLate MBCESR1 alterations increase in frequency with progression and number of treatment lines for ER+ BCLocation of Somatic Point Mutations in ESR1*Mutation observed in primary ER-negative BC.R503W*Frequencies of Genetic Alterations in Primary vs Metastatic Breast CancerFrequency (%)P <.052015105025D538GY537SY537NY537CD538GY537SampY537NPrimary TumorsampAF1DNA binding domainLigand binding domain/AF21100200300400500595aa344insCE380QD538GY537CY537NY537S2015105250403530TP53PIK3CACCND1MCL1MYCFGFR1ESR1ERBB2AKT1NF1PTENPrimaryMetastasisSlide credit: clinicaloptions.com

18. Targeting ESR1 Mutations With SERDsSERDs inhibit cancers through degradation of the estrogen receptor1May have greater activity than AI in resistant cancers with ESR1 mutations2Fulvestrant: potent ER degrader and only FDA-approved SERD3,4Efficacy limited by poor bioavailabilityOral agents may have greater availability and activity in setting of endocrine resistance41. Bardia. ASCO 2017. Abstr 1014. 2. Fribbens. JCO. 2016;34:2961. 3. Fulvestrant PI. 4. Zhang. Oncotarget. 2017;8:103874.Comparative MoA for AI vs SERM vs SERD[1]ER target genes activated, leading to cell proliferationAIAnastrozole, exemestane, letrozoleSERMTamoxifen, toremifene SERDElacestrant (RAD1901), fulvestrantER degradationPFS by ESR1 Mutation Status in ER+ Advanced BC[2]PFS (%)estrogenERERERERERERMoMoPFS (%)ESR1-Mutated BCESR1-WT BC Median PFS, MoExemestane 2.6Fulvestrant- 5.7containing txHazard ratio: 0.52 (95% CI: 0.30-0.92; P = .02) Median PFS, MoExemestane 8.0Fulvestrant- 5.4containing txHazard ratio: 1.07 (95% CI: 0.68-1.67;P = .77)100755025006121824100755025006121824Slide credit: clinicaloptions.com

19. Select Oral SERDs in Clinical Investigation in Adv BCFulvestrant: only FDA-approved SERD, but poor bioavailability may limit efficacy; oral SERDs may achieve higher exposure and better activity11. Zhang. Oncotarget. 2017;8:103874. 2. Jhaveri. Clin Cancer Res. 2021;27:5760. 3. Dees. ESMO 2019. Abstr 3587. 4. Maglakelidze. ASCO 2021. Abstr 1063. 5. Chandarlapaty. ASCO 2021. Abstr 1058. 6. Bidard, JCO. 2022 [Epub]. 7. Jhaveri. SABCS 2019. Abstr PD7-05. 8. Hamilton. ASCO 2020. Abstr 1024. 9. Lim. ASCO 2020. Abstr 1023. SERDStudyNPrior TxmESR1EfficacyAEs in ≥20% of Patients, %LSZ102 ± ribo or alpelisib2Phase I/Ib(NCT02734615)199Median no. tx: 3-4FULV/CDKi: 46.5-60.3%/34.6-60.3%25.0-41.7%LSZ102 only: ORR, 1.3%; CBR: 7.8%; mPFS: 1.8 moLSZ102 + ribo: ORR, 19.9%; CBR, 35.1%; mPFS, 6.2 moLSZ102 + alpelisib: ORR, 7.0%; CBR, 20.9%; mPFS, 3.5 mo Nausea, 50.0-61.1%; diarrhea, 38.6-69.8%; vomiting, 20.6-37.2%Rintodestrant (G1T48) ± palbo3,4Phase I (NCT03455270)107Median no. tx: 3 FULV/CDKi: 84.6%/76.9%50%ORR: 5.3%CBR: 15.8%Fatigue, 30.8%; diarrhea, 26.9%; hot flashes, 26.9%Amcenestrant (SAR439859) ± palbo5Phase I/II (NCT03284957)251Amcenestrant + palbo (n = 39):CDKi/mTORi: 5.1%/2.6%20%ORR: 34.3%CBR: 74.3%Palbociclib TRAEs: fatigue, 30.8%; nausea, 25.6%Elacestrant6Phase III (NCT03778931)47743.4% 2 prior therapiesFULV/CDKi/mTORi: 29.3%/100%/4.2%48%mPFS: 2.8 vs 1.9 mo (SERD vs SOC)12-mo PFS rate: 22.3% vs 9.4%Nausea, 35%Giredestrant (GDC-9545)7Phase I (NCT03916744)75Median no. tx: 1FULV/CDKi: 38%/59%52%CBR: 41%Nausea, 21%; arthralgia, 21%; fatigue, 21%Camizestrant (AZD9833) ± palbo8Phase I (NCT03616587)340Median no. tx: 5FULV/CDKi: 82%/68%45%ORR: 16.3%CBR: 42.3%Visual disturbances: 53%Bradycardia/sinus bradycardia: 45%Giredestrant (GDC-9545) ± palbo9Phase Ia/Ib (NCT03332797)181Median no. tx: 1FULV/CDKi: 11%/17%30%ORR: 13-33%CBR: 55-81%Neutropenia, 44%; fatigue, 26%; diarrhea, 23%; bradycardia, 21%Slide credit: clinicaloptions.com

20. A New Breast Cancer Subtype: HER2-Low Breast CancerImage from Rinnerthaler. Int J Mol Sci. 2019;20:1115. HER2-directed ADCs beyond T-DM1 in breast cancer. Licensed under Creative Commons Attribution 3.0 Unported License (CC BY 3.0).HER2-low BC45% to 55%HER2-negative BC 30% to 40%HER2-positive BC15%HER2-negative BC 30% to 40%Mechanism of Action of HER2-Directed ADCsSlide credit: clinicaloptions.com

21. $Title$HER2-Targeted ADC: Trastuzumab Deruxtecan (T-DXd)High drug:antibody ratio: ~ 8Stable linker-payloadTumor-selectable cleavable linkerHigh potency, membrane-permeable payload with short systemic half-lifeBystander killing effectNakada. Chem Pharm Bull (Tokyo). 2019;67:173. Trail. Pharmacol Ther. 2018;181:126. Ogitani. Cancer Sci. 2016;107:1039.Humanized anti-HER2 IgG1 mAb with same AA sequence as trastuzumabTetrapeptide-based cleavable linkerCysteine residueDrug/linkerTopoisomerase I inhibitor (DXd) payload(an exatecan derivative)HOOFNHOOONNOHOHHNOOOOOOOOOOOOHNNHNHNHNNNFHN✄CysDeruxtecanSlide credit: clinicaloptions.com

22. DESTINY-Breast04 Trastuzumab Deruxtecan (T-DXd) vs TPC in HER2-Low MBC: PFS2201234567891011121314151617181920212223242526272829020406080100MonthsPts at Risk, n373365325295290272238217201183156142118100888171534235322118158441101841661199390736051453432292622151395431111110T-DXd (n=373):TPC (n=184):Patients with HR+ DiseasePts at Risk, n331T-DXd (n=331):3242902652622482181981821651421281078978736448373128171412744110163TPC (n=163):146105858469574843323027242014128432111111001234567891011121314151617181920212223242526272829Months020406080100PFS (%)T-DXd mPFS: 10.1 moTPCmPFS: 5.4 moHR: 0.51 (95% CI, 0.40-0.64); P <0.0001Δ 4.7 moHR: 0.50 (95% CI, 0.40-0.63); P <0.0001Δ 4.8 moTPC mPFS: 5.1 moT-DXdmPFS: 9.9 moAll patients Modi. N Eng J Med. 2022;387:9. Slide credit: clinicaloptions.comPFS (%)

23. TRIO-US B12 “TALENT” Trial of Pre-Operative Trastuzumab Deruxtecan ± AnastrozoleRandomized, multicenter, open-label, 2-stage phase II trialMen or pre-/post-menopausal women with HR+, HER2 low (1+ or 2+ by IHC/FISH-) breast cancer; stage I-II operable; >cT2; previously untreated(N = 58)For both arms, tissue will be acquired from archival tissue or biopsy at baseline, at cycle 1 Days 17-21, and at surgery. Blood samples will be taken at 4 time points for biomarker analysis.Any arm that achieves >2 pCR advances to stage II (enrolling 15 more patients)Arm BT-DXd 5.4 mg/kg IV Q21D + Anastrozole 1 mg PO QD†Arm AT-DXd 5.4 mg/kg IV Q21DHurvitz. ASCO 2021. Abstr TPS603.6 cycles + EOT*SURGERY*EOT 21-28 days after last dose of T-DXd.†GnRH agonist will be added for men and premenopausal women.Primary endpoint: pCR rate (breast and lymph nodes) at definitive surgerySecondary endpoints: AEs, clinical objective response, biomarker analysesSlide credit: clinicaloptions.com

24. TROP2-Targeted Antibody–Drug Conjugate:Sacituzumab GovitecanBystander effect: In acidic tumor microenvironment, SN-38 is released from anti-TROP2 antibody, diffuses into neighboring TROP2-negative cellsSacituzumab govitecan-hziy PI. Tagawa. ASCO 2019. Abstr TPS3153. Goldenberg. Oncotarget. 2015;6:22496. Goldenberg. MAbs. 2019;11:987. Khoury. ASCO 2019. Abstr e14651. Bardia. JCO. 2017;35:2141.Humanized RS7 AntibodyTargets TROP2, an antigen expressed in many epithelial cancers, including mTNBC (88%)Antibody type: hRS7 IgG1κSN-38 PayloadDelivers 136-fold more than parent compound irinotecanUnique chemistry improves solubility, selectively delivers SN-38 to tumorIrinotecan (Topoisomerase Inhibitor)OOOOOOOOOOOOOHONNHNHNNNNHLys-NCH2OSAnti-TROP2 mAbSN-38[]7NOOOHONNOONNIrinotecanSN-38Linker for SN-38High drug-to-antibody ratio (7.6:1)pH-sensitive linker for rapid release of payload at or inside tumorSlide credit: clinicaloptions.com

25. SASCIA: Sacituzumab Govitecan in HER2- EBC at High Relapse Risk After Neoadjuvant CTInternational, open-label, randomized phase III trialNCT04595565.Adults with HER2- primary BC; residual invasive disease after neoadjuvant CT with high risk of recurrence (HR-: any residual invasive disease >ypT1mi; HR+: CPS + EG ≥3 or 2 and ypN+); <16 wk after final surgery or <10 wk after completing RT; ECOG PS 0/1(N = 1200)Sacituzumab govitecan10 mg/kg IV on Days 1, 8 Q3W x 8 cyclesPhysician’s choice of CT* or observationStratified by HR status (positive vs negative), ypN vs ypN0Primary endpoint: invasive DFSSecondary endpoints: OS, distant DFS, locoregional RFI, invasive DFS and OS in subgroups, safety, compliance, PROs*Capecitabine or platinum-based CT x 8 cycles.Slide credit: clinicaloptions.com

26. KEYNOTE-756: Pembrolizumab vs Placebo with NAC and Adjuvant ET in High-Risk ER+/HER2- EBCRandomized, double-blind, placebo-controlled phase III trialPatients with newly diagnosed high-risk, ER+/HER2- EBC; biopsy at screening; no prior tx; ECOG PS 0/1(N = 1140)Paclitaxel80 mg/m2 IV D1, 8, 15PlaceboIV D1 Q3WNCT03725059. Hirshfield. ASBS 2020. Abstr 785859. Paclitaxel80 mg/m2 IV D1, 8, 15Pembrolizumab200 mg IV D1 Q3WCycles 1-4 (12 wk)Cycles 5-8 (12 wk)SurgeryDoxorubicin* or epirubicin† + cyclophosphamide‡Doxorubicin* or epirubicin† + cyclophosphamide‡Neoadjuvant PhaseAdjuvant PhaseCycles 1-9 (27 wk)ET§Pembrolizumab200 mg IV D1 Q3WET§Placebo200 mg IV D1 Q3W*60 mg/m2. †100 mg/m2. ‡600 mg/m2. §Investigator’s choice.Up to 10 yrUp to 10 yrPrimary endpoint: pCR (ypT0/Tis ypN0), EFSSecondary endpoints: pCR (ypT0 ypN0, ypT0/Tis, ypT0/Tis ypN0), OS, HRQoL, safetySlide credit: clinicaloptions.com

27. CheckMate 7FL: Neoadjuvant Nivolumab in ER+/HER2- Breast Cancer Multicenter, randomized, double-blind, placebo-controlled phase III trialPatients with newly diagnosed high-risk, ER+/HER2-, grade 2 (with ER expression 1%-10%) or grade 3 BC; tissue available for assessment; ECOG PS 0/1(N = 1200)Nivolumab 360 mg Q3W +Paclitaxel 80 mg/m2 QWPlacebo 360 mg Q3W +Paclitaxel 80 mg/m2 QWSurgeryNeoadjuvant PhaseAdjuvant PhaseCycles 1-4Cycles 5-8Nivolumab 360 mg Q3W + AC Q3W orNivolumab 240 mg Q2W + AC Q2WNivolumab 480 mg Q4W +ETPlacebo 360 mg Q3W + AC Q3W orPlacebo 240 mg Q2W + AC Q2WPlacebo 480 mg Q4W +ETCycles 1-7NCT04109066. Loi. ASCO 2020. Abstr TPS604.Coprimary endpoints: pCR (ypT0/is ypN0), EFSSecondary endpoints: OS, DFS, DFMS, pCR (ypT0 ypN0 and ypT0/is), ORR, RCB, AEs, QoLSlide credit: clinicaloptions.com

28. SummaryNovel therapies are continuing to be exploredEfforts underway to define the role of CDK4/6 inhibitors in neoadjuvant as well as adjuvant disease settingAdjuvant setting: what patient population, duration, which agent?Neoadjuvant setting: what defines benefit or resistance?SERDs: Will they have a role in EBC? Single agent or in combinations?HER2 low breast cancer: a new subtype that may benefit with T-Dxd and future HER2 low strategies Sacituzumab govitecan in the residual disease setting?Slide credit: clinicaloptions.com

29. Go Online for More CCO Coverage of HER2- EBC!Expert commentary on integrating biomarker testing into the management of HER2- early breast cancerAdditional text modules on key studies in HER2- early breast cancerDownloadable slidesets on key studies in HER2- early breast cancerInteractive Decision Support Tool on HER2- early breast cancer focused on high-risk disease—coming soon! clinicaloptions.com/oncology