Management Strategies for HER2 Posi4ve Metasta4c Breast Cancer

Transcription

1 Management Strategies for HER2 Posi4ve Metasta4c Breast Cancer Karen A Gelmon MD FRCPC Professor Medicine University of Bri4sh Columbia Medical Oncologist, BC Cancer Agency Head, Division of Medical Oncology, UBC

2 COI Boards Susan G Komen Scien4fic Advisory Board OICR Scien4fic Advisory Board Breast Interna4onal Group Execu4ve Board Pharmaceu4cal Company Associa4ons Advisory Boards AstraZeneca, Roche, Novar4s, Pfizer, Oncotheryon, Nanostring, Merck Research Funding Pfizer, AstraZeneca, Novar4s, BMS

3 Our priori4es within cancer control Support the Patient Journey Facilitate Prevention / Early Detection Encourage Research Promote Optimal Performance Cancer Preven*on & Healthy Lifestyle Cancer Screening Cancer Treatment, Care Delivery and Follow Up Quality of Life: Survivorship Through End of Life Well Being C U R E Improve Information & Access

4 HER2+ Disease: Major Clinical Advances Trastuzumab Approved 2002 Three Large Adjuvant Trials Reported Lapa*nib Approved Preopera4ve Trials of Dual Blockade Pertuzumab Approved For MBC 2013 Pertuzumab Approved For neoadj in US 1998 First Preopera4ve Trials Reported Paving The Way For Use in Early Stage Disease Ini4al Trials of T-DM1, Nera4nib T-DM1 Approved Development of DUAL BLOCKADE as a strategy to increase impact

5 Milestones in the Management of HER2-posi4ve Advanced Breast Cancer Abbrevia4ons: Ana, anastrozole; Cape, capecitabine; CT, chemotherapy; Doc, docetaxel; Lap, lapa4nib; Let, letrozole; OS, overall survival; Pac, paclitaxel; Pert, pertuzumab; T-DM1, trastuzumab emtansine; Tras, trastuzumab. 5

6 Hazard Rate of Relapse (HRR) by subtype Cohort 1 ( ) vs Cohort 2 ( ) N= 7178 (3589 in each cohort) Cossef et al, JCO 2015

7 HER2 Posi4ve MBC The problem Despite high response rates, almost all pa4ents eventually develop progressive disease Can we improve up-front therapy and increase survival? Combined signal blockade Can we avoid current issues CNS disease Resistance Toxicity Are there pa4ents who are cured and can stop therapy? Are there very responsive pa4ents who can be treated with simple therapy

8 Mul4-target Strategies in HER2 Therapy An4 HER2 plus chemotherapy An4 HER2 plus hormone therapy An4 HER2 plus an4 angiogeneic agents Dual HER 2 blockade HER2 plus an mtor inhibitor Novel new HER2 agents Other targets such as Hsp-90, PI3K agents, CDK4/6 agents, checkpoint inhibitors, etc Vaccines

9 Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and Have Synergis4c Ac4vity HER2 receptor Trastuzumab Subdomain IV of HER2 Trastuzumab suppresses HER2 ac*vity Flags cells for destruc*on by the immune system Dimerisa4on domain of HER2 9

10 Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and Have Synergis4c Ac4vity Trastuzumab HER2 receptor Pertuzumab Dimerisa4on domain of HER2 Subdomain IV of HER2 Trastuzumab suppresses HER2 ac*vity Flags cells for destruc*on by the immune system Pertuzumab inhibits HER2 heterodimeriza*on Suppresses mul*ple HER signaling pathways Flags cells for destruc*on by the immune system 10

11 BO17929 Pertuzuamb and Trastuzumab in HER2 Posi4ve Advanced Cancer Progressing on Trastuzumab 1. Gelmon KA, et al. J Clin Oncol. 2008;26(May 20 suppl): Abstract Baselga J, et al J Clin Oncol, Baselga et al Cancer Res 2009, Cortes et al JCO 2012

12 CLEOPATRA Study Design HER2-positive MBC centrally confirmed (N = 808) 1:1 n = 406 Placebo + trastuzumab Docetaxel* 6 cycles Pertuzumab + trastuzumab PD PD n = 402 Docetaxel* 6 cycles Randomization stratified by geographic region and neo/adjuvant chemotherapy Study dosing q3w: Pertuzumab/placebo: 840 mg loading 420 mg maintenance Trastuzumab: 8 mg/kg loading 6 mg/kg maintenance Docetaxel: 75 mg/m mg/m 2 escalation if tolerated * < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at inves4gator discre4on. HER2, human epidermal growth factor receptor 2; MBC, metasta4c breast cancer; PD, progressive disease. Baselga J, et al. N Engl J Med 2012; 366:

13 Progression Free Survival Inves&gator-Assessed PFS (%) Ptz + T + D: median 18.7 months Pla + T + D: median 12.4 months Time (months) Δ 6.3 months HR % CI = 0.58, 0.80 p < n at risk Ptz + T + D Pla + T + D ITT popula4on. Stra4fied by geographic region and neo/adjuvant chemotherapy. 13

14 Final Overall Survival Analysis Median follow-up 50 months (range 0 70 months) OS (%) n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) months Δ 15.7 months Ptz + T + D Pla + T + D 56.5 months ITT popula4on. Stra4fied by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab

15 CLEOPATRA: Toxicity and PFS in Pa4ents with Prior Trastuzumab Diarrhea 20% increase in all grades to 67%, 8% grade 3 Febrile neutropenia Grade 3: 14 vs 7.6% Rash All grades: 34 vs 24% Baselga et al, 2011; Swain et al, 2015

16 Pertuzumab: Key Clinical Ques4ons Is the use of pertuzumab standard in the first-line sefng? YES What chemotherapy partners are acceptable? For now, docetaxel and paclitaxel (less evidence) Velvet trial (vinorelbine) What about the pa4ent who missed out on firstline pertuzumab? Probably reasonable, but label is currently restricted to the first line secng Should pertuzumab be given beyond progression on P? NO, but a quesgon to test in clinical trial(s)

17 Con4nued HER2 Blockade Aser Progression on Trastuzumab Improves Outcome Author Agents N TTP PFS OS Von Minckwitz, et al Capecitabine + trastuzumab vs capecitabine months vs 5.6 months, P =.03 NR 25.5 months vs 20.4 months P =.257 Geyer, et al Capecitabine + lapa*nib vs capecitabine months vs 4.4 months, P< months vs 4.1 months, P< months vs 16 months P =.206 Blackwell, et al Lapa*nib + trastuzumab vs lapa*nib 291 NR 11.1 weeks vs 8.1 weeks, P = months vs 9.5 months, P =.026 TTP, time to progression Blackwell K, et al. J Clin Oncol. 2012:30(21): Cameron D, et al. Oncologist. 2010:15(9): Geyer CE, et al. N Engl J Med. 2006;355(26): Von Minckwitz G, et al. J Clin Oncol. 2009:27(12):

18 T-DM1 and Pertuzumab Mechanisms of Ac4on T-DM1 HER3 Antibody: Trastuzumab HER2 HER2 HRG Cytotoxic: DM1 PI3K Stable linker: MCC p85 Lysosome Pertuzumab p110 HER3 HER2 HRG PI3K p85 p110 DM1 Survival Prolifera*on Nucleus Nucleus Nucleus An4body-drug conjugate Induces cell death by inhibi4ng microtubule polymeriza4on 1 Inhibits HER2 signaling 2 Ac4vates ADCC 2 Inhibits HER2 shedding 2 HER2/HER3 dimeriza4on inhibitor Inhibits ligand-dependent HER2 dimeriza4on and signaling 3 Ac4vates ADCC 4 1. Lewis Phillips, Cancer Res 2008; 2. Junttila, Breast Cancer Res Treat 2010; 3. Baselga, Nature Rev Cancer 2009; 4. Scheuer, Cancer Res 2009.

19 HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) First line setting Phase II Randomized Open Label Study 1:1 Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m 2 q3w (n=70) T-DM1 3.6 mg/kg q3w IV (n=67) PD a PD a Crossover to T-DM1 (optional) Stra4fica4on factors: World region, prior adjuvant trastuzumab therapy, disease-free interval Primary end points: PFS by inves4gator assessment, and safety Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover Key secondary end points: OS, ORR, DOR, CBR, and QOL Demographics imbalanced: 29 vs 34 % stage IV at diagnosis, 27 vs 18% exposed to prior trastuzumab, 40 vs 33% exposed to prior taxanes a Patients were treated until PD or unacceptable toxicity. b This was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred. Hurvitz et al, JCO 2013

20 EMILIA Study Design 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD 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, NEJM 2012

21 Progression-Free Survival by Independent Review Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001).

22 Overall Survival: Confirmatory Analysis Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

23 ORR and DOR in Pa4ents with Measurable Disease Patients, % Objective response rate (ORR) Difference: 12.7% (95% CI, 6.0, 19.4) P= % 120/389 Cap + Lap 43.6 % 173/397 T- DM1 1.0 Proportion progressionfree No. at risk Cap + Lap T-DM1 Duration of response (DOR) Median, months (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) Time (months)

24 Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Asian patients Cap + Lap (n=86 ; 17%) Neutropenia Hypokalemia Fatigue Nausea Mucosal inflammation Thrombocytopenia Increased AST Increased ALT Anemia ALT, alanine aminotransferase; AST, aspartate aminotransferase. Updated with package insert, trastuzumab emtansine T-DM1 (n=94; 19%) Grade > 3 thrombocytopenia 1.3% 45.1%

25 Differen4al Toxicity in Asian Pa4ents? Median number of regimens for MBC: 3 (range 1-8)

26 Management of Toxicity Transaminase eleva4on Self-limited Persistent throughout course of therapy Generally does not require specific management Thrombocytopenia No need to check mid-cycle labs Hold and consider dose reduc4on for grade 3+ toxicity (<75K) on day of treatment start.

27 Exposure to TDM1 and Survival in EMILIA Highest quar*le lowest quar*le Wang J et al, Clin Pharmacol Ther, 2014

28 TH3RESA: A Phase III Trial of T-DM1 vs TPC HER2-posi*ve (central) advanced BC a (N=600) 2 T-DM1 3.6 mg/kg q3w IV (n=404) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapa*nib, and a taxane 1 Treatment of physician s choice (TPC) b (n=198) PD T-DM1 c (optional crossover) Stra*fica*on factors: World region, number of prior regimens for advanced BC, d presence of visceral disease Co-primary endpoints: PFS by inves4gator and OS Key secondary endpoints: ORR by inves4gator and safety a Advanced BC includes MBC and unresectable locally advanced/recurrent BC. b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combina4on of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. c First pa4ent in: Sep Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow pa4ents in the TPC arm to receive T-DM1 aser documented PD. d Excluding single-agent hormonal therapy. BC, breast cancer; IV, intravenous; ORR, objec4ve response rate; PD, progressive disease; q3w, every 3 weeks. Krop Lancet Oncology

29 OS: Analysis s*ll early 44 vs 61 events, HR 0.552, p= (14.9 vs NE) Stopping boundary HR<0.363 or P< Less toxic than standard op*ons More costly PFS benefit of 3 months Including in comparison with trastuzumab beyond progression

30 Response to subsequent therapy aser T-DM1 Maximum decrease in tumor diameter (%) Pa4ents had median of 7 prior lines of therapy prior to T-DM1 Median 4me on post-tdm1 therapy was 5.5 months Olson E M et al. Ann Oncol 2012;23:93-97

31 Are there alterna&ves to chemotherapy/pertuzumab in the first line and to TDM1 in the second line?

32 Randomized Controlled Trial Comparing Taxane-Based Chemotherapy with Lapa4nib or Trastuzumab as First-Line Therapy for Women with HER2+ Metasta4c Breast Cancer: MA.31 Pa*ent Popula*on HER2+ MBC Newly diagnosed or ajer failure of adjuvant therapy No CNS mets confirmed by MRI/CT Stra*fica*on Factors Prior (neo)adjuvant HER2 targeted therapy Prior (neo)adjuvant taxane chemo Taxane on study Liver metastases Randomize Lapa*nib + taxane* x 24 weeks Trastuzumab + taxane* x 24 weeks Lapa*nib un*l PD *Pacitaxel 80 mg/m 2 q wk on a 4-wk schedule or docetaxel 75 mg/m 2 q 3 wk at inves*gator s discre*on. radiological assessment, including head CT/MRI Trastuzumab un*l PD Primary objec*ve: PFS (NI followed by superiority) Secondary objec*ves: OS, 4me to/incidence of CNS mets at first PD, ORR, CBR, safety, biomarkers, QoL, health economics, pharmacogene4cs Gelmon et al, JCO 2014

33 Progression Free Survival Centrally-confirmed HER2+ Analysis Median PFS TTAX/T= 13.7 months Median PFS LTAX/L = 9.0 months HR = 1.48 (95% CI = ), P = TTAX/T LTAX/L # TTAX/T # LTAX/L Gelmon et al, ASCO 2012

34 MARIANNE Study Design HER2-posi*ve (central) LABC a or MBC No prior chemotherapy for LABC/ MBC >6 months from prior neo-/adjuvant vinca alkaloid or taxane chemotherapy N = 1095 Trastuzumab + docetaxel (8 mg/kg LD then 6 mg/kg or 75 mg/m 2 q3w) OR Trastuzumab + paclitaxel (4 mg/kg LD then 2 mg/kg + 80 mg/m 2 qw) T-DM1 + placebo b (3.6 mg/kg mg LD then 420 mg q3w) T-DM1 + pertuzumab (3.6 mg/kg mg LD then 420 mg q3w) Stra*fica*on factors: World region, Prior neo-/adjuvant therapy (if Yes: prior trastuzumab/lapa4nib), Visceral disease Primary end point: PFS by independent review facility (IRF), non-inferiority and superiority assessed Key secondary end points: OS, PFS by inves4gator, ORR, Safety, Pa4ent-reported outcomes LD, Loading dose. a Locally progressive or recurrent and not amenable to resection with curative intent; b Pertuzumab placebo.

35 Overall Survival (First Interim Analysis) Survival (%) No. at Risk HT T-DM1 T-DM1+P Time (mo.) HT T-DM1 T- DM1+P Median OS NR NR NR (mo.) Events (no.) Stra*fied HR (97.5% CI) vs HT 0.86 ( ) 0.82 ( ) HT T-DM1 T-DM1+P NR, not reached.

36 Randomized Phase II Study of T-DM1 + capecitabine in HER2- posi4ve MBC pa4ents progressing aser trastuzumab-based therapy (TRAX HER2) Cohorts 1 and 2 1,2 HER2-posi4ve MBC progressing aser trastuzumab T-DM1 Cohort 3 3 T-DM1 plus capecitabine Primary objec4ves efficacy (response rate + stabilisa4on of disease = CBR) 3. Baselga et al. Cancer Res. 2009;69(Suppl): Abstract Completed accrual in Spring 2016 MBC, metasta4c breast cancer; CBR, clinical benefit rate

37 HER2 targeted therapy adds modestly to endocrine therapy Addi4on of HER2-directed therapy improves PFS but not OS Endocrine therapy + HER2-directed therapy can be considered for select 1 st line pts with MBC (e.g. asymptoma4c, low burden disease, pts at increased risk of toxicity from chemotherapy)? No data on later lines

38 HER2 targeted therapy adds modestly to endocrine therapy Anastrozole vs Anastrozole + Trastuzumab Kaufman et al, JCO 2008 Letrozole vs Letrozole + Lapa4nib Johnston et al, JCO 2009

39 Treatment Approach For Pa4ent Presen4ng With HER2+ MBC in 2016 First Line: Taxane + Trastuzumab + Pertuzumab Second Line: TDM-1 Third, Fourth, Fifth, Sixth Line: Capecitabine + Lapatinib or Trastuzumab Vinorelbine + Trastuzumab Lapatinib + Trastuzumab Pertuzumab + Trastuzumab (?? if no prior Pertuzumab) Other chemotherapy + Trastuzumab?Everolimus/Trastuzumab/vinorelbine/ Endocrine Therapy + Trastuzumab Neratinib plus? capecitabine Clinical trial of new agents including immune modulators

40 CNS Disease Common 25 35% of metasta4c HER2 posi4ve cases Solitary mets removal and RT Whole brain, Stereotac4c RT Restaging if only brain mets con4nue systemic therapy, if progressive systemic disease change therapy Issue of op4mal treatment for HER2+ with brain mets Con4nued trastuzumab - Dawood Capecitabine plus lapa4nib? Or trastuzumab + cap? CEREBEL study Sugges4on of response with other agents including TDM1 ONT 380 -TKI with increased brain ac4ity

41 Progression-free survival (PFS) and (B) overall survival (OS) in the intent-to-treat popula4on in CEREBEL Study. Xavier Pivot et al. JCO doi: /jco by American Society of Clinical Oncology

42 EMILIA OS in Pa4ents with CNS Mets at Baseline Krop I, et al. Abstract P SABCS,2013

43 Case Series: CNS response with TDM-1 Results: Median brain metastasis free survival 11 mo. PR: 44.4% SD: 22.2% Conclusions: This prospec4ve case series again indicates that systemic therapy offers ac4vity in Her2-posi4ve BM T-DM1 offers relevant clinical ac4vity; therefore, the role of T-DM1 in BM should be inves4gated in larger studies. Bartsch et al, J Neurooncol 2014 Pre-T-DM1 Post-T-DM1

44 New HER2-directed agents Class HER2-targeted TKI HER2-targeted liposome Trifunc4onal an4body HER2 vaccine/ Checkpoint inhibitors PI3-kinase inhibitors/ mtor CDK 4/6 inhibitors Example(s) Nera4nib, afa4nib, ONT 380 (ARRY-380) MM-302 Ertumaxomab AE37 GDC-0032, BYL-719 everolimus Palbo, Abemaciclib

45 Simultaneous blockade of the HER2 pathway HER2 HER3 VEGF an4her2 + mtor inhib. AKT PI3K PTEN RAS RAF Cell membrane mtor MEK p27 Cyclin D Cyclin E MAPK Nucleus CDK 4/6 CDK 2 G1 S

46 BOLERO-3: Study Design N = 572* Locally advanced or metasta4c HER2 + breast cancer Prior taxane required TRAS resistance Adjuvant: progression on or within 12 months of TRAS Metasta4c: progression within 4 weeks of TRAS Measurable disease only Randomize 1:1 Stra4fica4on by prior lapa4nib use (yes/no) Everolimus (5 mg PO daily) + Vinorelbine (25 mg/m 2 weekly) + TRAS (2 mg/kg week ) (n = 284) Placebo (PO daily) + Vinorelbine (25 mg/m 2 weekly) + TRAS (2 mg/kg weekly*) (n = 285) Therapy un*l PD or intolerable toxicity Endpoints: Primary: PFS Secondary: OS, ORR, 4me to deteriora4on of ECOG PS, safety, DoR, CBR, and QoL * Actual enrollment was 569. Following a 4-mg/kg loading dose on day 1, cycle 1 (1 cycle = every 21 days). Abbrevia4ons: CBR, clinical benefit rate; DoR, Dura4on of response; ECOG, Eastern Coopera4ve Oncology Group; HER2, human epidermal growth factor receptor 2; ORR, overall response rate; OS overall survival; PD, progressive disease; PFS, progressive-free survival; PO, oral; PS, performance status; QoL, quality of life. h p:// 46 O Regan R, et al. ASCO 2013; Abstract 505. Not for distribu4on. Andre et al, Lancet Oncol 2014

47 BOLERO-3: Primary Endpoint Progression-Free Survival by Local Assessment Probability, % Hazard ratio = 0.78; 95% CI [0.65, 0.95] Log-rank P value =.0067 Median PFS Everolimus: 7.00 months; 95% CI [6.74, 8.18] Placebo: 5.78 months; 95% CI [5.49, 6.90] Censoring times Everolimus (n/n = 196/284) Placebo (n/n = 219/285) Time, weeks Number of Pa*ents S*ll at Risk Everolimus Placebo Abbrevia4ons: CI, confidence interval. 47 O Regan R, et al. ASCO 2013; Abstract 505. Not for distribu4on. Andre et al, Lancet Oncol 2014

48 BOLERO-1/TRIO 019: Study Design N = 719 Locally advanced or metastatic HER2+ breast cancer No prior therapy for advanced or metastatic disease (except endocrine therapy) Prior (neo)adjuvant trastuzumab and/or chemotherapy allowed 1 Measurable disease or presence of bone lesions (lytic or mixed) Randomized 2:1 Stratification factors: Prior neo/adjuvant TRAS Visceral metastases Everolimus (10 mg PO daily) + w Paclitaxel + Trastuzumab Placebo + w Paclitaxel + Trastuzumab Endpoints Primary: PFS (investigator-assessed) Overall population and HR - subpopulation Secondary: OS, ORR, CBR, Time to response, Safety, Duration of response

49 BOLERO-1/TRIO 019: PFS Full Popula4on (Inves4gator-assessment) Hurwitz S et al, SABCS 2014

50 Simultaneous blockade of HER2 and PI3K Trials combining an4her2 drugs and PI3K pathway inhibitors, including alpelisib (NCT ), taselisib (NCT ) and pic4lisib (NCT ) are underway In a phase 1b trial, the combina4on of buparlisib and trastuzumab was well tolerated and showed some ac4vity (ORR of 17%, 58% SD 6 weeks) in pa4ents with trastuzumab-pretreated HER2-posi4ve breast cancer 1 1 Saura C et al. Clin Cancer Res 2014;20:

51 Burstein H et al, J Clin Oncol 28:1301, 2010

52 A Randomized Phase II Trial of Nera4nib vs Lapa4nib /Capecitabine in HER2+ MBC Mar&n M et al, European Journal of Cancer, 49: 3763, 2013

53 A Study of Nera4nib Plus Capecitabine Versus Lapa4nib Plus Capecitabine in Pa4ents With HER2+ Metasta4c Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metasta4c Sefng NALA study(nala) Phase 3, double-blind trial in HER2+ metastatic BC patients with two or more lines of prior therapy N=600 Randomiza4on is stra4fied based on geographical regions. R A N D O M I Z E Neratinib 240 mg/day Capecitabine 1,500 mg/m 2 per day Lapatinib 1,250 mg/day Capecitabine 2,000 mg/m 2 per day

54 Presented by: Miguel Mar4n LoRusso P et al, AACR 2015

55 HERMIONE Study Schema NCT

56 Simultaneous blockade of the HER2 pathway HER2 HER3 VEGF PI3K RAS Cell membrane an4her2 + CDK 4/6 inhib. AKT PTEN RAF mtor MEK p27 Cyclin D Cyclin E MAPK Nucleus CDK 4/6 CDK 2 G1 S Studies of Palbociclib and Abemaciclib In metasta4c HER2 posi4ve cancer

57 Immune signature predicts benefit of adjuvant trastuzumab in N9831 Not immune signature enriched Immune signature enriched Interac4on term P <.001 Perez E et al. JCO :701

58 Immune System as a Target Tumour Infiltra4ng Lymphocytes TILs have been shown to be prognos4c and predic4ve in HER2 posi4ve breast cancers Be er prognosis and response NeoAn4gens Increased muta4onal load appears to be associated with a response to immune modula4ng agents PDL1 and PD 1 inhibitors Checkpoint inhibitors responses in HER2 cancers

59

60 CCTG - IND 229 Trial Schema HER2+ MBC Must have had prior trastuzumab and pertuzumab Durvalumab q3w un4l PD Trastuzumab q3w x 6 Dose ranging phase to establish RP2D RP2D / Expansion cohort 10 pa4ents (at least 6 with paired biopsies pre and post treatment ) This is a mul4centre phase 1bexpansion study of durvalumab given to pa4ents with advanced/ recurrent HER-2 posi4ve metasta4c breast cancer (MBC) who are receiving treatment with trastuzumab. Following an ini4al dose-ranging phase to establish RP2D, a cohort expansion will involve paired biopsies. PI : Stephen Chia 60

61 Vaccines Several pep4de-based vaccines derived from the extracellular domain of HER2 under clinical test A randomized phase II trial of E75 showed a non-sta4s4cally significant increase in 5-y DFS in early breast cancer (90% vs 80%, p=0.08) 1 A phase III with E75 currently ongoing (NCT ) Dendri4c cell vaccines and vaccine/ trastuzumab combina4ons also under test

62 This is how most cancers are structured but we have not been able to see this un4l now A single tumor biopsy may not represent the complete molecular landscape of disease

63 Heterogeneous HER2 amplifica4on may be associated with reduced sensi4vity to HER2- directed therapy HER2-targeted Rx Gene4cally heterogeneous for HER2 Blue=HER2+ Red= HER2- Selec4on for HER2-nega4ve tumor cells 1. Wolff, A.C., et al. J Clin Oncol, Viale et al. Modern Pathology 2013

64 Summary Incredible progress in HER2 treatment 1 st line pertuzumab/trastuzumab/taxane 2 nd line TDM-1 Evidence of con4nued targe4ng of HER2 in advanced disease Improved survival in newer studies With increased dual therapy in early disease this may not be seen we will need new strategies in MBC We need to understand Resistance CNS disease Tumour heterogenieity Who needs aggressive treatment vs who will be well with trastuzumab/ct alone

65 Challenges Op4mal therapy strategies need to be tailored to the individual pa4ent Dura4on of therapy. Do we need to treat persons forever or can they have drug holidays? Delivering the therapy is our societal challenge

66 Even clear signs can be misleading