Module 9: HER2-Positive and Triple-Negative BC - PowerPoint Presentation

1. Module 9: HER2-Positive and Triple-Negative BC

2. Percent with PatientsNumber of Patients (Median)ER-positive, HER2-negative breast cancer for whom you ordered a genomic assay9214Metastatic ER-positive, HER2-negative breast cancer9610HER2-positive breast cancer currently receiving neoadjuvant or adjuvant treatment887TNBC currently receiving neoadjuvant or adjuvant treatment1005Metastatic HER2-positive breast cancer924ER-positive, HER2-negative breast cancer receiving adjuvant therapy1003Metastatic TNBC923Metastatic HER2-negative breast cancer with a BRCA germline mutation462

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4. Invasive Disease-Free SurvivalFreedom from Distant RecurrenceMonths since randomizationFreedom from distant recurrence (%)Invasive disease-free survival (%)Months since randomizationvon Minckwitz G et al. N Engl J Med 2019;380(7):617-28. KATHERINE: T-DM1 for Residual Invasive HER2-Positive Breast Cancer

5. KATHERINE: First Invasive DFS Events ^Patients who experience additional IDFS event(s) within 61 days of their first IDFS event are reported in the category according to the following hierarchy: [1] Distant recurrence; [2] Locoregional recurrence; [3] Contralateral breast cancer; [4] Death without prior event. *CNS metastases as component of distant recurrence (isolated or with other sites). Geyer CE Jr et al. San Antonio Breast Cancer Symposium 2018;Abstract GS1-10.1.10.4Patients (%)TrastuzumabT-DM122.212.215.910.54.61.30.40.3CNS*(4.3)CNS* (5.9)11.64.6TrastuzumabT-DM1

6. APHINITY: Clinical Benefit of Adjuvant Dual HER2 Blockade in Combination with ChemotherapyPiccart M et al. San Antonio Breast Cancer Symposium 2019;Abstract GS1-04.OS difference after 74.1 months of median FU did not yet reach statistical significanceLN = lymph node; HR = hormone receptorHazard ratio for IDFSin the ITT population and subgroups based on lymph node & hormone receptor statusIDFS at 6 years from randomization(APHINITY updated descriptive analysis)PopulationPrimary analysismedian FU 45.4 months; 2017Updated analysismedian FU 74.1 months; 2019Pertuzumab armPlacebo armAbsolute benefitITT0.810.7690.6%87.8%2.8%LN-positive0.770.7287.9%83.4%4.5%LN-negative1.131.0295.0%94.9%0.1%HR-positive0.860.7391.2%88.2%3.0%HR-negative0.760.8389.5%87.0%2.5%

7. ATEMPT: Adjuvant T-DM1 Versus Trastuzumab/ Paclitaxel for Stage I HER2-Positive Breast Cancer Tolaney SM et al. San Antonio Breast Cancer Symposium 2019;Abstract GS1-05.T-DM1THNNo. of events3-y DFSNNo. of events3-y DFSOverall3831097.7%114792.8%Hormone receptor (HR) status HR+289897.5%Not reported HR-94298.5%Tumor size T <1cm163298.5%Not reported T ≥1cm220897.1%

8. ExteNET: Neratinib After Trastuzumab-Based Adjuvant Therapy in HER2-Positive Breast Cancer Martin M et al. Proc ESMO 2017;Abstract 149O; Lancet Oncol 2017;18(12):1688-1700.5-Year Invasive Disease-Free Survival

9. ExteNET: 5-Year Invasive Disease-Free Survival by Hormone Receptor StatusMartin M et al. Proc ESMO 2017;Abstract 149O; Lancet Oncol 2017;18(12):1688-1700.

10. Second Annual Miami General Medical Oncology SymposiumFebruary 22, 2020Charles E Geyer Jr, MDDeputy DirectorHouston Methodist Cancer CenterHouston, TexasNew Agents in HER2-Positive Metastatic Breast Cancer

11. Disclosures11Advisory Committee (Uncompensated) Daiichi Sankyo Inc, Genentech, a member of the Roche Group, Roche Laboratories Inc, Seattle Genetics Contracted Research Genentech, a member of the Roche Group, Roche Laboratories Inc Paid Travel AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Genentech, a member of the Roche Group, Roche Laboratories Inc Writing Assistance AbbVie Inc, Genentech, a member of the Roche Group, Roche Laboratories Inc

12. HER2-Positive Breast Cancer Case Study59 y/o female presented to PCP on 06/13/2019 complaining of right-sided sacroiliac pain of several weeks duration. Exam unremarkableCMP remarkable for AST/ALT of 194/301 with TB of 0.8 and Alk Phos of 206Abdominal ultrasound on 06/20/2019 demonstrated multiple hepatic metastasesCT of chest, abdomen and pelvis on 06/21/2019 demonstrated extensive hepatic and skeletal metastasesCharles E Geyer, Jr

13. HER2-Positive Breast Cancer Case StudyBreast imaging performed on 06/24/2019Diagnostic mammogram Breast parenchyma heterogeneously dense. Outer left breast demonstrates linear and branching calcifications in a segmental distribution measuring 3.8 x 3.2 x 3.0 cm. Partially obscured 1.1 cm mass associated with the calcifications.No suspicious mammographic findings in right breast.Bilateral whole breast sonography Hypoechoic irregular mass at 4:00 position mid depth measuring 1.2 x 0.9 x 0.5 cm representing sonographic correlate to mass seen on mammogram. No solid or cystic masses of concern identified in right breast.Breast biopsy performed on 06/25/2019Grade 3 invasive ductal carcinomaER/PR - negativeHER by IHC - 3+Ki67 - 35%TILs - 8% of stromaCharles E Geyer, Jr

14. HER2-Positive Breast Cancer Case StudyLiver biopsy performed on 07/09/2019Metastatic adenocarcinoma consistent with breast primaryER/PR - negativeHER by IHC - 3+CMP on 07/11/2019AST/ALT - 580/281Alk Phos - 1400TB - 7.7On 7/12/2019 started on trastuzumab, pertuzumab and paclitaxel initially at 50 mg/m2 per weekOn 7/22/2019 labs showedAST/ALT 89/75, Alk Phos 700, TB 4.0H/H 6.8/21.2, platelet count 23,000Charles E Geyer, Jr

15. HER2-Positive Breast Cancer Case StudyCharles E Geyer, Jr09/12/2019 AST/ALT 37/42, Alk Phos 191, TB 0.5Serial follow-up CT scans demonstrated continued improvement10/31/2019 completed paclitaxel and continued trastuzumab and pertuzumab09/11/201911/14/2019

16. HER2-Positive Breast Cancer Case StudyCharles E Geyer, Jr12/09/2019 complained of dizziness for a week so OP MRI ordered01/20/2020 AST/ALT 27/58, Alk Phos 75, TB < 0.2

17. HER2-Positive Breast Cancer Case StudyAssuming restaging scans following completion of WBRT show continuing systemic response to trastuzumab and pertuzumab, what would be your approach to systemic treatment?Continue trastuzumab/pertuzumab until non-CNS progressionConvert to trastuzumab/capecitabineConvert to lapatinib/capecitabineConvert to neratinib/capecitabineConvert to tucatinib/trastuzumab/capecitabineConvert to T-DM1Charles E Geyer, Jr

18. Assuming restaging scans show continuing systemic response to trastuzumab and pertuzumab, following completion of WBRT what would be your approach to treatment?Continue trastuzumab/pertuzumab until non-CNS progressionConvert to trastuzumab/capecitabineConvert to lapatinib/capecitabineConvert to neratinib/capecitabineConvert to tucatinib/trastuzumab/capecitabineConvert to T-DM1https://clinicaltrials.gov/ct2/show/NCT04220203?term=tucatinib&type=Expn&draw=2&rank=1 (Treatment protocol of tucatinib with capecitabine and trastuzumab in patients with unresectable previously treated HER+ breast cancer)HER2-Positive Breast Cancer Case StudyCharles E Geyer, Jr

19. Trastuzumab Deruxtecan (DS-8201) The clinical relevance of these features is under investigation.ADC, antibody-drug conjugate; MOA, mechanism of action.1. Nakada T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 2. Ogitani Y, et al. Clin Cancer Res. 2016;22(20):5097-5108. 3. Trail PA, et al. Pharmacol Ther. 2018;181:126-142. 4. Ogitani Y, et al. Cancer Sci. 2016;107(7):1039-1046.Payload MOA: topoisomerase I inhibitor High potency of payloadTumor-selective cleavable linker High drug to antibody ratio ≈ 8Stable linker-payloadPayload with short systemic half-lifeMembrane-permeable payload A humanized anti-HER2 IgG1 mAb with the same amino acid sequence as trastuzumabA topoisomerase I inhibitor payload, an exatecan derivativeA tetrapeptide-based cleavable linkerTrastuzumab deruxtecan is an ADC composed of 3 components:Humanized anti-HER2 IgG1 mAb1-3Deruxtecan1,2Topoisomerase I Inhibitor payload(DXd)Tetrapeptide-Based Cleavable LinkerModi S, et al. NEJM. 2019 Dec 11

20. DESTINY-Breast01 Study Design:An Open-Label, Multicenter, Phase 2 Study of Trastuzumab DeruxtecanPopulation≥18 years of ageUnresectable and/or metastatic BCHER2-positive (centrally confirmed on archival tissue)Prior T-DM1 Excluded patients with history of significant ILDStable, treated brain metastases were allowedT-DM1Resistant/Refractory(n=249)R1:1:1PK Stage(n=65)PART 16.4 mg/kg(n=22)7.4 mg/kg(n=21)5.4 mg/kg(n=22)PART 2Continuation Stage(n=134)PART 2a5.4 mg/kg(n=130)T-DM1 Intolerant(n=4)PART 2b5.4 mg/kg(n=4)Dose-Finding Stage(n=54)R1:15.4 mg/kg(n=28)6.4 mg/kg(n=26)EndpointsPrimary: confirmed ORR by independent central imaging facility review per RECIST v1.1Secondary: investigator-assessed ORR, DCR, DOR, CBR, PFS, OS, PK and safetyPART 2a5.4 mg/kg(n=130)PART 2b5.4 mg/kg(n=4)5.4 mg/kg(n=22)5.4 mg/kg(n=28)184 patients enrolled at 5.4 mg/kg79 patients (42.9%) are ongoing105 patients (57.1%) discontinued, primarily for progressive disease (28.8%)Data Cutoff: August 1, 2019

21. Best Change in Tumor Size4020-200-40-60-80-100Best % Change From Baseline in the Sum of Diameters of Measurable TumorsBy independent central review.The line at 20% indicates progressive disease; the line at −30% indicates partial response.a Includes all patients who received T-DXd 5.4 mg/kg (intent-to-treat analysis; N=184).Confirmed ORR: 60.9%a(95% CI, 53.4%–68.0%)11 CRsn=168Modi S, et al. NEJM. 2019 Dec 11

22. Patients who received T-DXd 5.4 mg/kg (N=184)Preferred Term, n (%)Grade 1Grade 2Grade 3Grade 4Grade 5Any Grade/ TotalInterstitial lung disease5 (2.7)15 (8.2)1 (0.5)04 (2.2)25 (13.6)Adverse Events of Special Interest: Interstitial Lung DiseaseILD, interstitial lung disease. Among the 25 total events:Median time to investigator-reported onset was 193 days (range, 42-535 days)13 of 20 patients with grade ≥2 ILD received corticosteroids7 patients recovered, 2 were recovering, 12 were either outcome unknown or not followed until resolution, and 4 diedOf the 4 fatal cases, onset was from 63-148 days, 3 received steroids as part of treatment, and death occurred 9-60 days after ILD diagnosisRecommendations: Monitor for symptoms. Hold T-DXd and start steroids as soon as ILD is suspectedDrug related; ILD was determined by the Independent ILD Adjudication Committee based on 44 preferred terms. Modi S, et al. NEJM. 2019 Dec 11

23. Progression-Free and Overall SurvivalPatients who received T-DXd 5.4 mg/kg.CI, confidence interval; NE, not estimable.Progression-Free SurvivalMedian: 16.4 months (95% CI, 12.7-NE)Overall SurvivalMedian: Not reached (95% CI, NE-NE)Censored: 86.4%Events: 13.6%Probability of Progression-Free SurvivalMonths1.00.80.60.40.20.0012345678910111213141520161718191841821741551531351211071039469543817111009431No. at risk:Censored: 68.5%Events: 31.5%Probability of SurvivalMonths1.00.80.60.40.20.00123456789101112131415201617181918418318217917417116716115514713310166362116012984No. at risk:Median follow-up, 11.1 months (range, 0.7-19.9 months)Median PFS in the 24 patients with brain metastases was 18.1 months (95% CI, 6.7-18.1 months)December 20, 2019 - FDA granted accelerated approval for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting

24. NALA: Neratinib with Capecitabine for Previously Treated HER2-Positive Metastatic Breast CancerSaura C et al. Proc ASCO 2019;Abstract 1002.PFS (Co-primary endpoint)OS (Co-primary endpoint)HRp-value0.760.0059Mean OSHRp-valueNeratinib + cape24.0 mo0.880.2086Lapatinib + cape22.2 moTime since randomization (months)PFS probabilityTime since randomization (months)OS probability

25. NALA: Time to Intervention for CNS MetastasesSaura C et al. Proc ASCO 2019;Abstract 1002.InterventionNeratinib + capecitabine(n = 55/307)Lapatinib + capecitabine(n = 75/314)Radiation therapy11%15%Surgery/procedure2%3%Anticancer medication1%1%Time since randomization (months)Cumulative incidence (%)Overall cumulative incidence (Gray’s test): 22.8% vs 29.2%; p = 0.043

26. NCCN Guideline Inclusion of Neratinib for Metastatic HER2-Positive Breast CancerNCCN Clinical Practice Guidelines in Oncology – Breast Cancer. Version 2. 2020. Preferred RegimensPertuzumab + trastuzumab + docetaxel (category 1)Pertuzumab + trastuzumab + paclitaxelOther Recommended RegimensNeratinib + capecitabine (category 2B)Ado-trastuzumab emtansine (T-DM1)Fam-trastuzumab deruxtecan-nxkiTrastuzumab + paclitaxel ± carboplatinTrastuzumab + docetaxel or vinorelbine or capecitabineLapatinib + capecitabineTrastuzumab + lapatinib (without cytotoxic therapy)Trastuzumab + other agents

27. 1. Nordstrom JL, et al. Breast Cancer Res. 2011;13(6):R123. 2. Stavenhagen JB, et al. Cancer Res. 2007;67(18):8882-8890. Margetuximab: Fc-engineered to Activate Immune ResponsesFab: Same specificity and affinitySimilarly disrupts signalingFc engineering:↑ Affinity for activating FcgRIIIA (CD16A)↓ Affinity for inhibitory FcgRIIB (CD32B)Margetuximab1,2Fab:Binds HER2 with high specificityDisrupts signaling that drives cell proliferation and survivalTrastuzumabFc:Wild-type immunoglobulin G1 (IgG1) immune effector domainsBinds and activates immune cellsMargetuximab Binding to FcγR Variants:Receptor TypeReceptorAllelic VariantRelative Fc BindingAffinity Fold-ChangeActivatingCD16A158FLower6.6x ↑158VHigher4.7x ↑CD32A131RLower6.1x ↓131HHigher↔ InhibitoryCD32B232I/TEquivalent8.4x ↓

28. Arm 1Margetuximab (15 mg/kg Q3W) + chemotherapyin 3-week cyclesHER2+ advanced breast cancer≥2 prior anti-HER2 therapies, including pertuzumab1-3 prior treatment linesin metastatic settingPrior brain metastasis ok if treated and stableStudy CP-MGAH22-04 (SOPHIA) Design1,2Stratification:Chemotherapy choicePrior therapies (≤2 vs >2)Metastatic sites (≤2 vs >2)HR=hazard ratio; CBA=central blinded analysis. 1. Rugo HS, et al. J Clin Oncol. 2016;34(suppl 15):TPS630. 2. Clinicaltrials.gov. NCT02492711. www.clinicaltrials.gov/ct2/show/NCT02492711. Accessed April 8, 2019. Investigator’s choice of chemotherapy(capecitabine, eribulin,gemcitabine, or vinorelbine)Sequential Primary EndpointsPFS (by CBA; n=257; HR=0.67; α=0.05; power=90%)OS (n=385; HR=0.75; α=0.05; power=80%)Secondary EndpointsPFS (Investigator assessed)Objective response rate (by CBA) Tertiary/Exploratory EndpointsClinical benefit rate (CBR), duration of response (DoR)Safety profile, antidrug antibodyEffect of CD16A, CD32A, and CD32B on margetuximab efficacyArm 2Trastuzumab (8 mg/kg loading → 6 mg/kg Q3W) + chemotherapy in 3-week cycles1:1 Randomization (N=536)Rugo HS, et al. ASCO 2019

29. PFS Analysis in ITT Population24% Risk Reduction of Disease ProgressionCentral Blinded Analysis (Primary Endpoint)30% Risk Reduction of Disease ProgressionInvestigator Assessed (Secondary Endpoint)PFS analysis was triggered by last randomization on October 10, 2018, after 265 PFS events occurredITT population: N=536. CI=confidence interval.Margetuximab + Chemotherapy (n=266)Trastuzumab + Chemotherapy (n=270)# of events160177Median PFS (95% CI)5.6 months(5.06–6.67)4.2 months(3.98–5.39)HR by stratified Cox model, 0.70 (95% CI, 0.56–0.87)Stratified log-rank P=0.001Margetuximab + Chemotherapy(n=266)Trastuzumab + Chemotherapy (n=270)# of events130135Median PFS (95% CI)5.8 months (5.52–6.97)4.9 months (4.17–5.59)HR by stratified Cox model, 0.76 (95% CI, 0.59–0.98)Stratified log-rank P=0.033Rugo HS, et al. ASCO 2019

30. Planned* Exploratory PFS Analyses by FcR Genotypes (CBA) *Non-alpha allocating, exploratory analysis. †CD32B/TT not included on forest plot because n=9 is too small (5 on margetuximab, 4 on trastuzumab) to make analysis meaningful. Median PFS (95% CI), MonthsHR by Unstratified Cox Model95% CIUnstratified Log-Rank P ValueMargetuximab + ChemotherapyTrastuzumab + ChemotherapyAll patients5.8 (5.52–6.97)4.9 (4.17–5.59)0.78(0.61–0.99)0.044Activating functionCD16A/F carrier (FV or FF), n=4376.9 (5.55–8.15)5.1 (4.14–5.59)0.68(0.52–0.90)0.005CD16A/FF, n=1928.2 (5.52–10.51)5.6 (4.50–8.31)0.69(0.46–1.05)0.080CD16A/FV, n=2456.3 (5.52–7.23)4.3 (4.01–5.59)0.71(0.50–1.01)0.055CD16A/VV, n=694.8 (2.46–5.65)5.6 (2.86–11.04)1.78(0.87–3.62)0.110CD32A/RR, n=1225.7 (4.80–10.55)5.5 (2.76–8.21)0.69(0.41–1.17)0.166CD32A/RH, n=2476.9 (5.55–8.15)5.6 (4.17–6.67)0.74(0.52–1.06)0.102CD32A/HH, n=1375.6 (3.29–8.28)4.1 (2.79–5.59)0.80(0.49–1.30)0.365InhibitoryfunctionCD32B/II†, n=3805.8 (5.55–7.66)5.5 (4.17–5.65)0.85(0.64–1.13)0.265CD32B/IT†, n=1176.0 (4.14–NA)5.5 (2.79–7.16)0.63(0.36–1.10)0.098Margetuximab BetterTrastuzumab BetterMargetuximab benefit appears to be increased in low-affinity CD16A-158F allele carriers

31. Pre-specified Exploratory OS in CD16A-185 F Carriers1Margetuximab + Chemotherapy (n=221)Trastuzumab + Chemotherapy (n=216)# of events103114Median OS(95% CI)23.7 months (18.89–28.32)19.4 months (16.85–22.28)HR by unstratified Cox model, 0.79 (95% CI, 0.61–1.04)Unstratified log-rank P=0.087Median difference of 4.3 monthsCD16A-158F Carriers, FF or FV, n=437 of 506 (86%) genotypedMedian follow-up: 15.6 months1Sep-2019 CutoffRugo H et al. SABCS 2019

32. HER2CLIMB Trial Design https://clinicaltrials.gov/ct2/show/NCT02614794Tucatinib + Trastuzumab + Capecitabine(21-day cycle)Tucatinib 300 mg PO BID + Trastuzumab 6 mg/kg Q3W (loading dose 8 mg/kg C1D1) +Capecitabine 1000 mg/m2 PO BID (Days 1-14)Key Eligibility CriteriaHER2+ metastatic breast cancerPrior treatment with trastuzumab, pertuzumab, and T-DM1ECOG performance status 0 or 1Brain MRI at baselinePreviously treated stable brain metastasesUntreated brain metastases not needing immediate local therapyPreviously treated progressing brain metastases not needing immediate local therapyNo evidence of brain metastasesPlacebo + Trastuzumab + Capecitabine(21-day cycle)Placebo+ Trastuzumab 6 mg/kg Q3W (loading dose 8 mg/kg C1D1) +Capecitabine 1000 mg/m2 PO BID (Days 1-14)N=410N=202*Stratification factors: presence of brain metastases (yes/no), ECOG status (0 or 1), and region (US or Canada or rest of world)R*(2:1)Murthy RK, et al. NEJM 2019 Dec 11

33. Key Baseline Demographics and Disease Characteristics Characteristic, n (%)Total Population, N=612TUC+Tras+Capen=410Pbo+Tras+Capen=202Female407 (99)200 (99)Age (years), median (range)55.0 (22, 80)54.0 (25, 82)ECOG performance status0204 (50)94 (47)1206 (50)108 (54)Stage IV at initial diagnosis143 (35)77 (39)Hormone receptor statusER and/or PR-positive243 (60)127 (63)ER and PR-negative161 (40)75 (37)Prior lines of therapy, median (range)Overall4.0 (2, 14)4.0 (2,17)Metastatic setting3.0 (1, 14)3.0 (1, 13)Presence/history of brain metastases198 (48)93 (46)Treated, stable118 (59.6)55 (59.1)Untreated44 (22.2)22 (23.7)Treated, progressing36 (18.2)16 (17.2)Baseline characteristics were balanced between endpoint populations and treatment armsMurthy RK, et al. NEJM 2019 Dec 11

34. Progression-Free Survival in the Primary Endpoint PopulationPrespecified efficacy boundary for PFS: P=0.05Data cut off: Sep 4, 2019Risk of progression or death was reduced by 46% in the primary endpoint populationOne-year PFS (95% CI): TUC+Tras+Cape33%(27, 40) Pbo+Tras+Cape12% (6, 21)Median PFS (95% CI): 7.8 months(7.5, 9.6) 5.6 months(4.2, 7.1)Events, N=480HR (95% CI)P ValueTUC+Tras+Cape178/3200.54 (0.42, 0.71)<0.00001Pbo+Tras+Cape97/160Median63%33%46%12%Murthy RK, et al. NEJM 2019 Dec 11

35. Progression-Free Survival for Patients with Brain MetastasesEventsN=291HR (95% CI)P ValueTUC+Tras+Cape106/1980.48 (0.34, 0.69)<0.00001Pbo+Tras+Cape51/93Prespecified efficacy boundary for PFSBrainMets (P=0.0080) was met at first interim analysis.Data cut off: Sep 4, 2019Risk of progression or death in patients with brain metastases was reduced by 52% in the total populationOne-year PFS (95% CI): TUC+Tras+Cape25% (17, 34) Pbo+Tras+Cape0%Median PFS (95% CI): 7.6 months (6.2, 9.5) 5.4 months (4.1, 5.7)60%25%34%0%MedianMurthy RK, et al. NEJM 2019 Dec 11

36. Overall Survival in the Total Study PopulationEventsN=612HR (95% CI)P ValueTUC+Tras+Cape130/4100.66 (0.50, 0.88)0.00480Pbo+Tras+Cape85/202Prespecified efficacy boundary for OS (P=0.0074) was met at first interim analysisData cut off: Sep 4, 2019Risk of death was reduced by 34% in the total populationTwo-year OS (95% CI): TUC+Tras+Cape45% (37, 53) Pbo+Tras+Cape27% (16, 39)Median OS (95% CI): 21.9 months(18.3, 31.0) 17.4 months (13.6, 19.9)76%Median45%62%27%Murthy RK, et al. NEJM 2019 Dec 11

37. Checkpoint Inhibitors in Breast Cancer in the Metastatic and Neoadjuvant SettingHarold J. Burstein, MD, PhDDana-Farber Cancer InstituteHarvard Medical Schoolhburstein @ partners.org@drhburstein

38. DisclosuresNone

39. 55 yo woman diagnosed with cT2N0, ER/PR/HER2 negative left breast cancer in June 2017Treated with NACT with T-AC, completed therapy in November 2017Had lumpectomy and SLN biopsy in January 2018: pathology revealed a 1.2 cm residual tumor with 30% cellularity and 1/5 positive SLNReceived adjuvant radiation followed by 6 months of adjuvant capecitabine (completed in 10/2018)In 6/2019, presented with palpable left supraclavicular LN; metastatic workup revealed hilar/mediastinal LAD, and multiple pulmonary nodules, largest 1.5 x 1.1 cmBiopsy of SC LN revealed recurrent ER/PR/HER2 negative breast cancer

40. Tumor sent for PD-L1 testing, and was found to be positive in > 1% in immune cells using VENTANA SP142 antibodyShe started nab-paclitaxel plus atezolizumab in 7/2019; experienced PRIn 11/2019, she was found to have an elevated TSH, and thyroid replacement therapy was institutedIn 12/2019, nab-paclitaxel was discontinued for worsening neuropathyShe continues on atezolizumab monotherapy; imaging continues to reveal PR

41. Nab-paclitaxel plus atezolizumab is FDA approved for which indication?Hormone receptor positive early stage breast cancerTriple-negative early stage breast cancerHormone receptor positive, PD-L1-negative advanced breast cancerPD-L1-positive, advanced, triple-negative breast cancer 

42. Triple-negative breast cancer is more immunogenically active than other forms of breast cancer. True FalseWhat is the most common endocrinopathy associated with checkpoint inhibitors? Primary adrenal insufficiency Secondary adrenal insufficiency Diabetes mellitus Thyroid abnormalities (hyper and/or hypothyroidism)Summary

43. Immunotherapy for TNBCADVANCED STAGE BREAST CANCER

44. Immune Checkpoint Inhibition in TNBC: RationaleTumor Infiltrating LymphocytesNonsynonymous MutationsPD-L1 ExpressionLoi et al, JCO 2013; Mittendorf et al, Cancer Immunol Res 2014; Luen et al, The Breast 2016

45. Checkpoint Inhibition in TNBC: Modest Response Rates with MonotherapyAgentNORRORR (PD-L1+)*Pembrolizumab Single agent (KN-012)Single agent (KN-086-A)Single agent (KN-086-B)321708418.5%4.7%23.0%18.5%4.8%23.0%Atezolizumab Single agent11510.0%13.0%AvelumabSingle agent (JAVELIN)588.6%44.4%*Studies used different antibodies and cutoffs for PD-L1 positivityFactors associated with RR: TILs, PD-L1, fewer lines of therapyNanda et al, JCO 2016; Dirix et al, BCRT 2017; Emens et al, JAMA Onc 2018; Adams et al, Ann Onc 2018 26%6.8%2L+1LObjective Response Rate (%)10%20%30%0%23%4.7%2L+1LPembrolizumab(n = 222)Atezolizumab(n = 115)CRPRCRPRKN-086, Cohort BK-086, Cohort A

46. KEYNOTE-086: Response Rate by Line of Therapy and sTILs with Pembrolizumab MonotherapysTIL levelnRespondersOngoing responses6.4%1.9%Subsequent Line≥5%94<5%536131Combined Cohorts12.6%1.7%≥5%135<5%58171101Front Line39.1%8.7%≥17.5%23<17.5%239252Loi et al. ESMO 2017

47. Response rate:17%8%8%23%35%Voorwerk et al.Nature Medicine 2019:25:920-928Priming the Response to Checkpoint Inhibition in mTNBC: TONIC Trial

48. Co-primary endpoints were PFS and OS in the ITT and PD-L1+ populationsKey secondary efficacy endpoints (ORR and DOR) and safety were also evaluated IMpassion130 study designKey IMpassion130 eligibility criteria:Metastatic or inoperable locally advanced TNBCHistologically documentedNo prior therapy for advanced TNBCPrior chemo in the curative setting, including taxanes, allowed if TFI ≥ 12 moECOG PS 0-1Stratification factors:Prior taxane use (yes vs no)Liver metastases (yes vs no)PD-L1 status on IC (positive [≥ 1%] vs negative [< 1%])Atezo + nab-P arm:Atezolizumab 840 mg IV On days 1 and 15 of 28-day cycle+ nab-paclitaxel 100 mg/m2 IVOn days 1, 8 and 15 of 28-day cyclePlac + nab-P arm:Placebo IV On days 1 and 15 of 28-day cycle+ nab-paclitaxel 100 mg/m2 IVOn days 1, 8 and 15 of 28-day cycleDouble blind; no crossover permittedRECIST v1.1 PD or toxicityR1:1

49. IMpassion 130 PFS/OS in ITT/PD-L1+*Schmid et al, NEJM 2018*Using VENTANA SP142 AssayAtezolizumab + nab-paclitaxelPlacebo + nab-paclitaxel

50. KEYNOTE-355: Pembrolizumab in Combination with Chemotherapy Met Primary Endpoint of PFS as First-Line Treatment for Metastatic Triple-Negative Breast CancerPress Release – February 12, 2020The pivotal Phase 3 KEYNOTE-355 trial investigating pembrolizumab, an anti-PD-1 therapy, in combination with chemotherapy met one of its dual primary endpoints of progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (mTNBC) whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥10). Based on an interim analysis conducted by an independent Data Monitoring Committee (DMC), first-line treatment with pembrolizumab in combination with chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) demonstrated a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy alone in these patients. Based on the recommendation of the DMC, the trial will continue without changes to evaluate the other dual primary endpoint of overall survival (OS). The safety profile of pembrolizumab in this trial was consistent with that observed in previously reported studies; no new safety signals were identified. Data will be Presented at an Upcoming Medical Congress and Discussed with Regulatory Authoritieshttps://investors.merck.com/news/press-release-details/2020/Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Chemotherapy-Met-Primary-Endpoint-of-Progression-Free-Survival-PFS-as-First-Line-Treatment-for-Metastatic-Triple-Negative-Breast-Cancer-mTNBC/default.aspx

51. Immunotherapy for TNBCEARLY STAGE BREAST CANCER

52. GeparNuevo: Neoadjuvant DurvalumabLoibl et al, Ann Oncol 2019:30:1279-88pCR rates:Durvalumab: 53.4%Placebo: 44.2%

53. Neoadjuvant Pembrolizumab: Efficacy Results from the I-SPY2 Adaptively Randomized Platform TrialNanda et al, ASCO 2017, JAMA 2020Estimated pCR rate(95% probability interval)

54. Neoadjuvant Pembrolizumab: Immune-related Adverse Events from the I-SPY2 Adaptively Randomized Platform TrialAdrenal insufficiency 5/6 presented >10 wks after last pembro dose1/6 presented during pembro (5 wks after 1st pembro dose)Rates of primary/secondary AI across studies are 0.8% and 0.6% Nanda et al. JAMA 2020.Pruritus

55. Stratification Factors:Nodal status (+ vs -)Tumor size (T1/T2 vs T3/T4)Carboplatin schedule (Q1W vs Q3W) Key Eligibility CriteriaAge ≥18 yearsNewly diagnosed TNBC of either T1c N1-2 or T2-4 N0-2ECOG PS 0-1Tissue sample for PD-L1 assessmentaNeoadjuvant Treatment 1(cycles 1-4; 12 weeks)Neoadjuvant Treatment 2 (cycles 5-8; 12 weeks)Adjuvant Treatment(cycles 1-9; 27 weeks) Carboplatinb + PaclitaxelcDoxod/Epirubicine+ CyclophosphamidefPembrolizumab 200 mg Q3WPembrolizumab 200 mg Q3WPlaceboPlaceboR 2:1Neoadjuvant PhaseAdjuvant PhaseCarboplatinb + PaclitaxelcDoxod/Epirubicine + CyclophosphamidefSURGERYOutcomesPembro + Carbo/paclitaxel  A/EC pCR 64.8%Placebo + Carbo/paclitaxel  A/EC pCR 51.2%Adrenal insufficiency: 2.7%KEYNOTE-522Schmid et al. SABCS 2019

56. *HER2 negative, ER and PgR negativeearly high-risk (T1cN1; T2N1; T3N0) or locally advanced unilateralbreast cancerNeoTRIP trialFOLLOWUPCarboplatin (AUC2) + nab-paclitaxel (125 mg/m2) weekly for 2 wks every 3; 8 cyCarboplatin (AUC2) + nab-paclitaxel (125 mg/m2) weekly for 2 wks every 3; 8 cy + Atezolizumab day 1 every 3 wks for 8 cyclesRAC/EC/FECfor 4 cyclesAC/EC/FECfor 4 cyclesSSGianni et al SABCS 2019

57. pCR rate and PD-L1 expressionOverall6050403020100No atezoWith atezo43.5% 40.8% 51.9% 48.0% 32.2% 32.3%PD-L1 positivePD-L1 negative

58. Immunotherapy for TNBCTNBC a rational target for checkpoint inhibition based on lessons in other tumors types (mutations, TILs, PD-L1 expression)In mTNBC, nab-paclitaxel + atezolizumab FDA approved as therapyBased on PD-L1 expression by immune cellsMultiple studies suggest adding PD-1/PD-L1 targeted therapy to chemotherapy improves pCR rates in neoadjuvant treatment of TNBCImpact on long-term outcomes still under investigationOverall side effect profile consistent with IO in other cancersAdrenal insufficiency in early stage is a new findingAs with other tumor types, thresholds for PD-L1 testing are debated and still in evolution

59. SummaryMonotherapy responses in mTNBC are modestLine of therapy, PD-L1, TILsAtezolizumab + nab-paclitaxel approved for PD-L1+ advanced TNBCVENTANA SP142, immune cells (concordance among pathologists, antibodies)Addition of pembrolizumab to NACT in TNBC significantly improves pCR rates but with immune-related toxicities