What is the Next Goal for HER2 Targeted Therapy?

Transcription

1 What is the Next Goal for HER2 Targeted Therapy? Hope S. Rugo, MD Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Family Comprehensive Cancer Center

2 MBC : metastatic breast cancer; MoAb : monoclonal antibody Milestones of HER2/anti-HER2 therapies in BC EGFR discovery Cohen neu oncogene discovery Weinberg Her2 cloned Ullrich and Coussens EGFR MoAb inhibited growth Mendelsohn Her2/neu amplification correlates with shorter survival Slamon Her2 amplification in breast cancer Aaronson FDA approves trastuzumab alone for 2nd line and in with paclitaxel for 1st line MBC FDA approves trastuzumab in adjuvant setting FDA approves lapatinib + capecitabine for MBC FDA approves lapatinib + letrozole for MBC FDA approves pertuzumab + trastuzumab + docetaxel for MBC FDA approves trastuzumab emtansine for MBC Accelerated approval of pertuzumab/ trastzumab as neoadjuvant therapy

3 Outline Where are we now? Focus on advanced disease Biomarkers Determining resistance and sensitivity Prediction of benefit? Less is more? What can we learn from neoadjuvant trials? Hormone receptor positive disease Tackling CNS mets New therapies under investigation

4 Metastatic Disease First-Line Therapy: Recent Data Cleopatra Addition of pertuzumab to taxane/trastuzumab Marianne Is T-DM1 equivalent to taxane trastuzumab? Does adding pertuzumab to T-DM1 improve outcome? Other agents MA.31: is lapatinib superior to trastuzumab? NEfERT-T: is neratinib superior to trastuzumab? Bolero-1: Does adding everolimus improve outcome?

5 Cleopatra: Study Design and Patients Double-blind, placebo controlled phase III trial Docetaxel 75 mg/m 2 escalated to 100 as tolerated, about 6 cycles Trastuzumab and pertuzumab/placebo q 3 weeks Primary endpoint Independently assessed PFS 808 patients with treatment naïve centrally confirmed HER2+ MBC Adjuvant therapy 53% no prior chemo 10% prior trastuzumab 49% ER+, 24% received endocrine therapy Baselga J et al NEJM 2012: 366;

6 1st-line Pertuzumab + Trastuzumab (CLEOPATRA) Progression-free survival (inv assessed) Overall survival Median FU 50 mo. (0-70) PFS: HR HR vs 0.55 in HR- OS: HR HR vs 0.61 in HR- Pertuzumab+ trastuzumab+docetaxel Placebo+ trastuzumab+docetaxel Hazard ratio P-value ORR % 69.3% PFS months 12.4 months 0.69 < OS months 40.8 months Most common adverse events Grade 3 in the pertuzumab+trastuzumab+docetaxel group: 1 Neutropenia (48.9%), febrile neutropenia (13.8%), leukopenia (12.3%) and diarrhoea (7.9%) 1. Baselga et al. N Engl J Med 2012;366:109; 2. Swain et al. NEJM 2015;724:734. Median follow-up: 30 months. PFS, progression-free survival; OS, overall survival.

7 MARIANNE: Phase III Trial Patients with HER2+ progressive or recurrent locally-advanced breast cancer or previously untreated MBC (n=1092) 30% received prior HER2 targeted therapy Trastuzumab + Taxane (until PD) n=364 T-DM1 + Pertuzumab (until PD) n=364 T-DM1 + Placebo (until PD) n=364 Trastuzumab + Taxane T-DM1 + Placebo T-DM1 + Pertuzumab Hazard ratio P- value ORR 67.9% 59.7% 64.2% NR NR PFS 13.7 m 14.1m 15.2m HR 0.91 HR 0.87 OS NR NR NR HR 0.86 HR 0.82 p=0.31 p=0.14 p NR p NR TH associated with hair loss, more neutropenia, and peripheral neuropathy Pertuzumab increased toxciity, primarily diarrhea TDM associated with more nausea, liver enzyme abnormalities, low platelets Ellis et al, ASCO 2015

8 1 st line Taxane + Lapatinib vs. Taxane + Trastuzumab (NCIC CTG MA.31) HER2+ MBC (N=652) 1 year from completion of adjuvant trastuzumab and/or taxane therapy 1:1 N=326 N=326 Lapatinib Taxanes (either Paclitaxel or Docetaxel Trastuzumab Taxanes (either Paclitaxel or Docetaxel PD PD Lapatinib + Taxane Trastuzumab + Taxane ORR 54% 55% Hazard ratio P-value PFS 9.0 months 11.3 months OS NR NR At the interim analysis, Lapatinib arm had inferior PFS NCIC DSMC recommended disclosure and notification of patients. Toxicity increased in lapatinib arm. Gelmon et al. JCO 2015;

9 NEfERT-T Randomized Trial HER2+ MBC (N=479) 1 year from completion of adjuvant trastuzumab and/or taxane therapy Asymptomatic CNS metastases allowed 1:1 N=242 N=237 Neratinib (240 mg/d) Weekly paclitaxel Trastuzumab Weekly paclitaxel PD PD Lapatinib + Taxane Trastuzumab + Taxane P-value ORR 74.8% 77.6% 0.24 PFS 12.9 months 12.9 months 0.89 All grade diarrhea: 92.5 vs 33.3% 30.4% grade 3/4 diarrhea with neratinib vs 3.8% with paclitaxel Awada et al, Lancet Oncology 2016

10 First Line Everolimus in Combination with Trastuzumab (BOLERO-1) N = 719 Locally Advanced or Metastatic HER2- positive Breast Cancer 2 1 Everolimus (daily) + Trastuzumab Paclitaxel (weekly) Placebo (daily) + Trastuzumab Paclitaxel (weekly) PFS Trastuzumab + everolimus Trastuzumab + placebo Hazard ratio P-value PFS 15 months 14.5 months PFS ER months 13.1 months * Significant toxicity in the everolimus arm 3.6% AE associated mortality Hurvitz SA et al. Lancet Oncology * Prespecified was <

11 Comparison of Patient Populations Limited prior Adjuvant Trastuzumab Therapy MARIANNE (ASCO 2015) CLEOPATRA (NEJM 2015) BOLERO1 (SABCS 2014) MA-31 (ASCO 2012) Chemotherapy Docetaxel/ Paclitaxel Docetaxel Paclitaxel Taxane Anti-HER2 regimens tested T-DM1 or T-DM1 + Pertuzumab Trastuzumab + Pertuzumab (vs Trast) Trastuzumab + Everolimus 10mg (vs Trast) Lapatinib (vs Trast) De novo metastatic Prior adj. trast. (and interval >1y) 55% 53% 50% 43% 31% 11% 10% 18% The results of most of these trials are relevant today only for de novo metastatic patients Adapted from M. Piccart St. Gallen 2015 Presentation

12 Beyond First-Line Prior trastuzumab Emilia: T-DM1 > cape/lap EGF : lapatinib/trastuzumab > lapatinib Bolero-3: addition of everolimus to vinorelbine/trastuzumab LUX breast-1: afatinib or trastuzumab/vinorelbine Prior trastuzumab and lapatinib TH3RESA: T-DM1 vs TPC

13 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Verma et al. N Engl J Med 2012;367:1783.

14 Cardiac dysfunction rare All grades 3.1 vs 1.8% Grade vs 0.2% Common toxicities Low grade fatigue, nausea, diarrhea Unique toxicities Thrombocytopenia 13% grade 3 Modest increase in AST/ALT PFS in pts with CNS mets at baseline (50 v 45 pts) 12.9 vs 26.8 mo P=.0081 (HR.382) Now a standard of care following progression on trastuzumab based therapy

15 TH3RESA: A Phase III Trial of T-DM1 vs TPC HER2-positive (central) advanced BC a (N=602) 2 T-DM1 3.6 mg/kg q3w IV (n=404) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane 1 Treatment of physician s choice (TPC) (n=198) PD T-DM1 (optional crossover) Co-primary endpoints: PFS by investigator; OS Key secondary endpoints: ORR by investigator and safety TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. First patient in: Sep Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive T-DM1 after documented PD. Krop IE et al. Lancet Oncol 2014; 15:

16 Proportion progression-free Proportion surviving TH3RESA Interim Results PFS by investigator assessment First interim OS analysis T-DM1 Physicians choice Observed 21% of targeted events Time (months) T-DM1 Physicians choice Time (months) T-DM1 Physicians choice * Hazard ratio *68.5% chemo + T. 10.3% T + L. 2.7% chemo + L P-value PFS 6.2 months 3.3 months 0.53 < OS (immature) NE 14.9 months (NS) OS: 44 vs 61 events, HR 0.552, p= (14.9 vs NE); Stopping boundary HR<0.363 or P< Krop IE et al. Lancet Oncol 2014; 15:

17 BOLERO-3 Everolimus and Afatinib mtor inhibitor Trastuzumab/vinorelbine + everolimus/placebo Everolimus dose = 5 mg/d PFS 7 vs 5.8 mos Toxicity HR 0.78 ( ); p= Febrile neutropenia:16 v 4% Stomatitis:13 v 1% Fatigue: 12 v 4% SAE: 42 v 20% LUX Breast 1 Oral dual kinase TKI Vinorelbine + trastuzumab or afatinib PFS 5.55 vs 5.49 mo OS 28.6 vs 20.5 mo Closed early due to IDMC recommendation Unfavorable risk/benefit for afatinib/vinorelbine André F et al. Lancet Oncol 2014; 15: ; Pagani O et al. SABCS Abtr: P

18 Clinical Pathway HER2+ MBC: 2015

19 Treatment Algorithm For Patients With HER2+ MBC in 2014/2015 First Line: Taxane + Trastuzumab + Pertuzumab Second Line: TDM-1 Add endocrine therapy as maintenance? Third, Fourth, Fifth, Sixth Line: Capecitabine + lapatinib or trastuzumab Vinorelbine + trastuzumab Lapatinib + trastuzumab Gemcitabine +/- platinum + trastuzumab Other chemotherapy + trastuzumab

20 Can We Predict Benefit and Resistance from HER2 Targeted Therapy?

21 CLEOPATRA Biomarker Analysis: Phase III Placebo-Controlled Study of Pertuzumab Biomarker results: focus on PIK3CA PIK3CA mutation associated with poorer prognosis in placebo arm: 5.2- month reduction in median PFS (8.6 vs months) PIK3CA mutation associated with poorer prognosis in pertuzumab arm: 9.3- month reduction in median PFS (12.5 vs months) PIK3CA status Placebo arm Median PFS Pertuzumab arm Median PFS HR (95%CI) Mutated 8.6 months 12.5 month 0.64 ( ) Wildtype 13.8 months 21.8 months 0.67 ( ) Predictive ability Predictive ability Prognostic ability Prognostic ability Mutations in PIK3CA were not associated with resistance to pertuzumab, because patients derived similar additional benefit independent of PIK3CA mutational status. Similar data seen in other trials of HER2 targeted therapy, and in trials of therapy targeted to PI3K and mtor in HR+ disease Baselga et al.,jco 2014

22 NeoSphere Biomarker Analyses HER2 expression (H-score) associated with sensitivity to pertuzumab PI3K mutations in exon 9 linked to lack of sensitivity to HER2-directed Mab s (prognosis) Intrinsic differences between HER2+ tumors based on hormone receptor status No predictive role for truncated forms of the HER2 receptor including p95 HER2 So far, no analysis has provided clinically useful assays for patient and/or regimen selection in addition or alternative to the conventional assessment of HER2 by IHC or FISH

23 Additional Biomarker Analyses NeoALTTO 80/355 (23%) had a PIK3CA mutation Mutation associated with lower pcr rate (prognosis) 21% vs 34% in WT (p.03) Lower pcr rate seen across treatment arms, and in both ER- and + disease Prognostic effect seen: Meta-analysis of neoadjuvant trastuzumab trials (GBG) Emilia control arm (lapatinib/capecitabine) Gianni et al; Loible et al

24 Randomized Trials: Trastuzumab versus Control Study N Biomarker Results FinHER Loi et al NSABP B-31 Pogue-Geile et al NCCTG 9831 Perez et al 157 mpik3ca has no effect on benefit from trastuzumab 672 mpik3ca has no effect on benefit from trastuzumab 1802 PTEN loss or low has no effect on benefit from trastuzumab

25 Frequency of Mutations: FinHER Sherene Loi et al. JNCI J Natl Cancer Inst 2013;105:

26 NSABP B-31: The Search for BioMarkers ncounter platform 1,578 blocks with 49 gene expression data to generate PAM50 instrinsic subtypes 741 (47%) were HER2-enriched Six PIK3CA hotspot mutations by mass spec in random subset (n-671) 166 (24.7%) had PIK3CA mutations No difference in HRs for DFS HER2-E vs other subtypes mpik3ca vs wild-type Katherine L. Pogue-Geile et al. JCO 2015;33:

27 Katherine L. Pogue-Geile et al. JCO 2015;33: HER2-E Other subtypes

28 Progression free survival probability Progression free survival probability Bolero 1 and 2: Correlation of PFS and PI3K pathway activity Patients with hyperactive PI3K pathway (low PTEN or known PIK3CA or AKT1 E17K mutation) benefited from everolimus, whereas those without PI3K activation did not. Consistent results in both studies Pooled analysis: KM curve by treatment in the PI3K non-activated group Pooled analysis: KM curve by treatment in the PI3K activated group PBO nonactivated EVE nonactivated P-value = 0.28 PBO activated EVE activated P-value = PI3K pathway normal (55.9% in combined population) Populati Treatme Event Median PFS N HR (95% CI) on nt s mo BOL-1 PBO (0.72- EVE ) BOL-3 PBO (0.8 - EVE ) BOL-1 + PBO ( BOL-3 EVE ) Abbreviations: EVE, everolimus; PBO, placebo. Time, months Slamon et al, ASCO 2014 Time, months PI3K pathway hyperactive (44.1% in combined population) Populati Treatme Event Median PFS N HR (95% CI) on nt s mo PBO (0.44- BOL-1 EVE ) PBO ( BOL-3 EVE ) PBO BOL ( BOL-3 EVE ) 8

29 Other Directions? Why don t these signaling biomarkers identify nonresponders to trastuzumab? Recent data suggests that the clinical activity of trastuzumab is not mediated by inhibition of HER2 signaling but through immunologic targeting What about immunologic markers? Polymorphisms of the FC receptor Confer different affinities for IgG binding, conflicting results Quantification of TILs: early - prognostic not predictive? Immunologic gene expression NOAH, NeoSphere, CALGB demonstrated higher pcr rates with increased immunologic signaling activity or gene expression signatures of immune activation

30 CALGB 40601: Neoadjuvant Trastuzumab, Lapatinib or Both 265/295 (90%) for predictive factor analysis 78/144 (54%) for matched pre/post comparison pcr 70% in HER2-E vs 35% in luminal A or B HR+ (156) Lisa A. Carey et al. JCO 2016;34: HR- (109)

31 CALGB 40601: Additional Associations pcr strongly associated with immune cell signatures 5 immune signatures all significantly associated with increased pcr In MV analysis, IgG, 11 gene proliferation and p53 mutation signatures had independent significance Tumors become more luminal and normal-like with treatment (small numbers); higher pcr rate in HER2E vs not Carey et al, JCO % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% P< % IgG Signature 39% 31% 66% 53% 40% 62% 39% High (n=109) 50% 24% 25% 17% Overall THL TH TL

32 N9831 Genomic Analysis 1282 tumor samples Illumina 24K DASL whole transcriptome technology to quantify mrna Network and pathway analysis to identify key processes associated with RFS 6 biological pathways associated with increased RFS (HR<1.0) in the trastuzumab-containing Arms B/C Cytokine-cytokine receptor interaction, T-cell receptor signaling in CD8+ T-cells, INF-gamma pathway, TNF receptor signaling pathway, Cell surface interaction at the vascular endothelium, Class 1 PI3K signaling events 4 of these pathways linked to immunological functions Perez EA, et al. JCO 2015

33 Immune-enrichment Predicts Response to Trastuzumab Immune Enriched Tumors Immune Not Enriched Tumors Arm A: Chemotherapy Arms B/C: Chemo + Trastuzumab Perez EA, et al. JCO 2015

34 HER2 Somatic Mutations in Breast Cancer Average mutation rate:1.6% Sensitivity to TKIs in vitro Ron Bose et al. Cancer Discovery 2013;3:

35 Clinical Response HER2 L755S mutation: activating mutation in the TKI binding site of the HER2 kinase domain Partial response x 11 months to neratinib Noa Ben-Baruch; J Natl Compr Canc Netw 2015;13:

36 Should we Treat Hormone Receptor Positive Disease Differently?

37 Differential Effect of HER2 Targeted Therapy in Hormone Receptor Positive Disease? pcr rates are lower in ER positive disease Impact of trastuzumab significant in both ER+ and negative disease in adjuvant and metastatic settings Does the degree of ER expression, and HER2 amplification affect response to adjuvant trastuzumab? HERA trial results 3037 (59.6%) patient samples analyzed at a median FU of 8 years 615 (12.1%) with transcript levels of ESR1 and HER2 Loi et al, JAMA Oncology 2016

38 Results FISH/HER2 copy numbers significantly higher in ER neg compared to ER pos disease DFS: Less impact of trastuzumab in ER+/HER2 low FISH ratio (>2 to <5) Higher ESR1 levels may correlate with less benefit from trastuzumab

39 Neratinib as Extended Adjuvant Therapy: The ExteNET Trial Her2+ breast cancer Prior adjuvant trastuzumab/ chemotherapy LN+/- or residual invasive disease after neoadjuvant rx ER/PR +/- R Neratinib x 1 year 240 mg/d N=2840 Placebo x 1 year 24% node negative, 47% 1-3+ nodes; 57% HR+ Summary of changes: 3 sponsors from 2009 to 2011 Study population decreased from 3850 to nd sponsor: Change to stage 2-3; LN+ and <1 year from trastuzumab, endpoint idfs 3 rd sponsor: FU truncated to 2 years for all patients Now extended to 5 years Primary endpoint: invasive DFS (idfs) Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, OS, safety Other: Biomarkers, QOL Stratification: nodes 0, 1-3+, vs 4+, ER/PR status, concurrent vs sequential trastuzumab Median time from trastuzumab N vs P: 4.4 ( ) vs 4.6 ( ) months Chan et al, Lancet Oncology 2016

40 Disease-free survival (%) Primary Endpoint: Invasive DFS (ITT) No. at risk Neratinib Placebo P-value = HR (95% CI) = 0.67 ( ) Months after randomization % 95.6% Neratinib Placebo Hormone receptor-positive tumors (n=1631; HR=0.51, 95% CI ; p=0.001) Hormone receptor-negative tumors (n=1209; HR=0.93, 95% CI ; p=0.735) % 91.6% 2.3% absolute difference 2.5% 3 year difference in centrally confirmed HER2+ disease Safety 95% diarrhea 39.9% grade 3/4 Diarrhea prophylaxis Intensive operamide prophylaxis reduced grade 3 diarrhea to 17% in one study Ongoing studies evaluating this effect Chan et al, Lancet Oncology 2016

41 Disease-free survival (%) 3-year idfs analysis: Hormone receptor-positive & centrally confirmed HER2+ No. at risk Neratinib Placebo % 94.7% Two-sided *P-value <0.001 HR (95% CI) = 0.43 ( ) Months after randomization % 89.9% % 88.0% Neratinib Placebo % 86.3% Absolute difference: 6.5% Increases to 7.7% in HR+, completing adjuvant trastuzumab< one year before study Chan et al, SABCS 2015 * p value descriptive

42 Less is More: Reducing Intensity of Therapy

43 EBC Adjuvant Trastuzumab Trials HERA (ex-usa) 1 BCIRG 006 (global) 2 IHC/FISH N = 5102 Observation 1 year 2 years FISH N = year 1 year NCCTG N9831 (USA) 3 NSABP B-31 (USA) 3 IHC/FISH N = year IHC/FISH N = year 1 year Chemotherapy +/- radiotherapy Doxorubicin + cyclophosphamide IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation. Docetaxel Docetaxel + carboplatin Trastuzumab Paclitaxel 1. Gianni L, et al. Lancet Oncol 2011; 12: ; 2. Slamon D, et al. N Engl J Med 2011; 365: ; 3. Perez EA, et al. J Clin Oncol 2011; 29:

44 Trastuzumab Improves DFS and OS Study HERA 1 4 CT+/ RT H vs. CT+/ RT NCCTG N9831/ NSABP B AC TH H vs. AC T BCIRG CT, chemotherapy; DFS, disease-free survival; H, trastuzumab; HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, taxane. DFS OS Follow-up (years) N HR p value HR p value < < < < < < < < < AC TH H vs. AC T 0.64 < < TCH vs. AC T Piccart-Gebhart MJ, et al; N Engl J Med 2005; 353: ; 2. Smith I, et al. Lancet 2007; 369:29-36; 3. Gianni L, et al; Lancet Oncol 2011; 12: ; 4. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 5. Romond EH, et al. N Engl J Med 2005; 353: ; 6. Perez EA, et al. J Clin Oncol 2011; 29: ; 7. Romond EH, et al. SABCS 2012 (abstract S5-5; oral presentation); 8. Slamon D, et al. N Engl J Med 2011; 365:

45 10 year Follow-up: BCIRG 006 AC/T (1073) AC/TH (1074) TCH (1075) HR PFS 67.9% 74.6% 73% AC/TH v AC/T: 0.72 P< TCH v AC/T: 0.77 P= OS 78.7% 85.9% 83.3% AC/TH v AC/T: 0.63 P< TCH v AC/T: 0.76 P= Toxicity: Less neuropathy, nail changes and myalgia with TCH, but the AC/T regimens used 100 mg/m2 docetaxel Cardiac events: 21 vs 4 grade 3/4 events in AC/TH vs TCH arms Slamon et al, SABCS 2015

46 Adjuvant Paclitaxel and Trastuzumab (APT) (Dana Farber Consortium Trial) HER2+ ER+ or ER- Node Negative < 3 cm N = 410 Median FU 4 years Enroll P T P T P T P T P T P T PACLITAXEL 80 mg/m 2 + TRASTUZUMAB 2 mg/kg x 12 T T T T T T T T T T T T T FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)* P T P T P T P T P T P T 4-year DFS 95% Conf. Interval 98.7% 97.6% to 99.8% Poisson p-value: < distant events out of 12 relapses, 2 CHF events, 6 withdrew due to AEs *Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks Tolaney et al. NEJM 2015

47 ATEMPT Trial Schema Stage I HER2+* ER+ or ER- PS 0-1 Adequate organ fx N=500 R Accrual time: 30 months 3 1 Trastuzumab-DM1 q3weeks X17 N=375 Paclitaxel + Trastuzumab x12 Trastuzumab q3weeks x13 N=125 *HER2-positive defined as IHC 3+ or FISH 2.0; will be confirmed by central HER2 testing prior to study enrollment Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy Adjuvant radiation therapy can be administered concurrently with study treatment. PI: Sara Tolaney, MD, MPH

48 I-SPY2 Adaptive Neoadjuvant Trial: T-DM 1 + Pertuzumab Graduated in all HER2+ Signatures, including HR+ and HR- subsets Arm Estimated pcr Rate (95% PI) All HER2+ TH->AC 0.22 ( ) Prob(>Ctrl) Prob(Ph3) T-DM1+P->AC 0.52 ( ) HR- HER2+ TH->AC 0.33 ( ) T-DM1+P->AC 0.64 ( ) HR+ HER2+ TH->AC 0.17 ( ) T-DM1+P->AC 0.46 ( ) Demichelle et al, AACR 2016 P= pertuzumab; TH = paclitaxel + trastuzumab

49 WSG Neoadjuvant ADAPT 3 arm trial (n=375) T-DM1 x 4; T- DM1/endocrine therapy; trastuzumab/endo crine therapy Association of pcr with early response (low Ki67/cellularity) HER2+/ER+ Herbeck et al, SABCS 2015

50 Additonal Neoadjuvan/Adjuvant Trials Aphinity (n=3806) AC/TH or TCH +/- pertuzumab Kaitlin (n=1750), N+ or HR Randomized to chemo/t/p +/- T-DM1 Neoadjuvant Kristine (n=432) expected at ASCO 2016 TCHP vs TDM-1/pertuzumab x 6 cycles, same HER2 rx post-op Post-neoadjuvant Katherine trial (NSABP B50, n=1484) Residual disease in breast and node Randomized to trastuzumab or TDM-1 for one year

51 Tackling CNS Metastases

52 Studies of Lapatinib+Capecitabine for HER2+ Breast Cancer Brain Metastases Study N Prior chemo Prior RT Response criteria CNS ORR TTP/PFS OS Lin et al CCR 2009* Boccardo et al, ASCO 2008 (LEAP) Sutherland et al, Br J Ca 2010 (LEAP) Metro et al, Ann Oncol 2011 Lin et al, J Neuro-Oncol 2011* 50 81% with >2 T+chemo; PD on lapatinib monotherapy 100% 50% vol NSS, steroids, lack of non- CNS PD 138 Prior T required NR Investigatorassessed on survey 34 82% with >2 chemo for MBC; prior T required 22 Median of 2 prior T-based tx for MBC 13 Prior T required 100% 50% vol, NSS, steroids, lack of non-cns PD 20% 3.6 mo NR 18% Median time on study 2.8 mo 94% RECIST 21% 5.1 mo NR 86% WHO 32% 5.1 mo 27.9 mo NR 38% NR NR Bachelot et al, ASCO 2011* 45 22% with >2 T+chemo (31%: no prior T for MBC) 0% 50% vol, NSS, steroids, lack of non-cns PD 67% 5.5 mo 91% alive at 6 mo L: lapatinib C: capecitabine T: trastuzumab *Prospective trial

53 EMILIA OS in Patients with CNS Mets at Baseline Krop I, et al.

54 Case Series: CNS response with TDM-1 Results: Median brain metastasis free survival 11 mo. PR: 44.4% SD: 22.2% Conclusions: This prospective case series again indicates that systemic therapy offers activity in Her2- positive BM..T-DM1 offers relevant clinical activity; therefore, the role of T-DM1 in BM should be investigated in larger studies. Bartsch et al, J Neurooncol 2014 Pre-T-DM1 Post-T-DM1

55 Neratinib: CNS Metastases in the NEfERT Trial Neratinib + Paclitaxel Trastuzumab + Paclitaxel Hazard ratio P-value Symptomatic or progressive CNS metastases 20 (8.3%) 41 (17.3%) Awada et al, Lancet Oncology yr incidence of 16.3% 31.2% CNS metastases

56 ONT-380 Selective small molecule TKI more selective for HER2 than EGFR Primary toxicity is elevation of transaminases 22 of 68 had evaluable CNS mets Untreated: 8 Progression after prior CNS rx: 14 Treatment ONT T-DM1, cape, T, or C+T Ferrano et al, ASCO 2015

57 New Directions in the Treatment of HER2+ Breast Cancer

58

59 HERMIONE Phase II Trial Miller et al, ASCO 2015

60 Margetuximab: Fc-Optimized anti- HER2 Monoclonal Antibody Margetuximab (MGAH22) Derived from 4D5 with Fc domain engineered to increase binding to isoforms of the activating Fcg receptor CD16A Antiproliferative in cell lines resistant to anti-her2 ab More potent than trastuzumab surrogate in ADCC assays Phase I Well tolerated Partial response Confirmation Ongoing Patients Breast Cancer Patients Parameter Weekly & Q3W Q3W No. of Patients PFS Censored 5 5 Median (wks) (95% CI) (Median) (12.1, 31.1) (6.1, 36.1) Personal communication, Macrogenics

61 New Tyrosine Kinase Inhibitors Poziotinib: Oral pan-her2 TKI, irreversibly blocks signalling Phase II open label study ongoing Epertinib Oral EGFR/HER 2 reversible TKI Possibly less diarrhea, CNS activity Ongoing phase I/II trials ONT-380

62 HER2/neu: Examples of Vaccine Strategies Extracellular Domain (aa 1-652) Trans Membrane Domain (aa ) Intracellular Domain (aa ) ECD TMD ICD I I S A VV G I L GP2-peptide vaccine (aa ) MHC Class I : HLA-A2 Stimulate CD8 T cells K I F G S L A F L G V G S P Y V S R L L G I C L E75-peptide vaccine (aa ) MHC Class I : HLA-A2 & HLA-A3 Stimulate CD8 T cells Courtesy of Beth Mittendorf AE37-peptide vaccine (aa ) MHC Class II : multi-allele Stimulate CD4 T cells

63 Mechanism of Action: Active Specific Immunotherapy HLA-E75 Peptide-TCR complex E75 isolated from HLA in human tumors Induces proliferation of E75-specific T-cell clones Mechanism of synergy ADCC increases CD8 T cell response Broad stimulation of HER2 specific immunity Millions of HER2- targeted CTL clones seek and destroy HER2 expressing cancer cells Increase antigen availability/presentation E75 derived from HER2 endogenous pathway

64 Schema: Ongoing Phase II Trial weeks Neoadjuvant Chemo Surgery Must enroll before 3 rd dose of trastuzumab maintenance therapy weeks Adjuvant Chemo Study Population Primary resected HER2+ breast cancer (upfront surgery) with node positive disease HER2+ breast cancer patients not achieving a pcr after neoadjuvant chemotherapy* HLA-A2/3+ Trastuzumab + E75+GM-CSF^ Trastuzumab + GM-CSF^ Surgery *neoadjuvant chemotherapy regimen must include trastuzumab and at least four cycles (12 weeks) of taxanecontaining therapy ^inoculations to begin with 3 rd dose of trastuzumab maintenance therapy Courtesy of Beth Mittendorf

65 Other Novel Directions HER3 targeted antibody: patritumumab Biosimilars (stay tuned for the HERITAGE results at ASCO 2016) CDK 4/6 inhibitors PI3K/mTOR inhibitors Immunotherapy Androgen receptor inhibitors (e.g. enzalutamide)

66 The Future.. Assume adjuvant/neoadjuvant trials work 92%+ DFS becomes the new benchmark HER2 + disease becomes largely curable Will be mostly be cured in countries where targeted therapy is accessible (biosimilars on the way) Metastatic disease will primarily be seen in the de novo setting Trials will need to be larger and more expensive Remaining questions: Reduce toxicity, tailor therapy for risk Role of ER in selecting therapy Optimal treatment to prevent/treat CNS metastases Who needs what therapy?

67 Thank you!