Rethinking neoadjuvant therapy: neoadjuvant therapy as a platform for drug development in HER2 positive breast cancer

Transcription

1 GBCC luncheon symposium Rethinking neoadjuvant therapy: neoadjuvant therapy as a platform for drug development in HER2 positive breast cancer Seoul National University Bundang Hospital Seoul National University College of Medicine Jee Hyun Kim, M.D., Ph.D.

2 Contents Overview of neoadjuvant systemic therapy in BC pcr to neoadjuvant therapy as clinical trial endpoint in BC Neoadjuvant therapy in HER2 positive BC Neoadjuvant anti-her2 therapy : history Pertuzumab in neoadjuvant therapy Current practice and recommendations Summary

3 Neoadjuvant (preoperative) systemic therapy in breast cancer Most achieve clinical response, with rare disease progression during chemotherapy Results in surgical downstaging, leading to more breast conservation DFS and OS are similar between neoadjuvant and adjuvant therapy Dose not interfere with post-chemotherapy surgery or radiotherapy Chapter 54. Preoperative Chemotherapy for operable breast cancer Diseases of the Breast, Fifth edition

4 NSABP B-18 T1-3, N0-1, M0 Operable breast cancer (n=1,523) AC #4 Op Op AC#4 Fisher B, et al. J Clin Oncol 1998;16:

5 NSABP B-18 Breast conservation rate: 68% (pre) vs. 60% (post) 27% scheduled for mastectomy achieved BCS after PST Fisher B, et al. J Clin Oncol 1998;16:

6 Overall & Disease-Free Survival Rastogi et al, J Clin Oncol 2008;6:

7 DFS and OS according to pcr OS HR 0.32 (n <0.0001) at 16 yr follow up in patients with pcr Fisher B, et al. J Clin Oncol 1998;16: Rastogi et al, J Clin Oncol 2008;6:

8 Neoadjuvant (preoperative) systemic therapy in breast cancer Most achieve clinical response, with rare disease progression during chemotherapy Results in surgical downstaging, leading to more breast conservation DFS and OS are similar between adjuvant and adjuvant therapy Dose not interfere with post-chemotherapy surgery or radiotherapy pcr may be surrogate marker of improved DFS and OS Platform for new drug development Chapter 54. Preoperative Chemotherapy for operable breast cancer Diseases of the breast, Fifth edition

9 Criteria for study endpoints in clinical trials Measurable / interpretable Sensitive Clinically relevant with respect to the disease condition and population studied

10 OS- Gold standard in oncology clinical trials SHARP trial in advanced HCC BIG 1-98 trial in early breast cancer Llovet et al, N Engl J Med. 2008;359: Regan MM et al, Lancet Oncol 2011;12:1101-8

11 Adjuvant trials in breast cancer Statistical power for survival end points depend on the number of events 5,000 10,000 patients needed Great expense, lengthy follow-up periods Many subtype-focused trials are now required Large adjuvant trials are no longer sustainable in breast cancer

12 Preoperative trials Earlier documentation of response to therapy Smaller size, shorter follow up Identification of predictive biomarkers Candidate for neoadjuvant therapy R Standard therapy novel targe ted therapy Standard therapy Chemotherapy Novel targeted therapy Chemotherapy Surgery ~2 weeks Biopsy PD biomarker circulating tumor cell.. Imaging biomarker 4-6 weeks

13 Endpoint Hierarchy True clinical efficacy measure Validated surrogate endpoint (Rare) Surrogate endpoint reasonably likely to predict clinical benefit None of the above: A correlate that is solely a measure of biological activity

14 Surrogate validation: requires meta-analysis Sargent DJ, et al. J Clin Oncol 2005;23:

15 US FDA funded meta-analysis of 12 randomized neoadjuvant trials including 11,955 patients Trial N Trial N AGO1 668 NOAH 334 ECTO 1355 TECHNO 217 EORTC 10994/BIG GeparDuo 907 GeparQuattro 1495 GeparTrio 2072 GeparTrio -pilot 285 NSABP B NSABP B PREPARE 733 Cortazar P et al, Lancet 2014;384:

16 Which pcr definition is best associated with long term outcome? % 18% 13% pcr EFS HR OS HR ypt0 ypt0/isypn0 ypt0ypn0 Cortazar P et al, Lancet 2014;384:

17 Pathological complete response and longterm clinical benefit in breast cancer EFS*: interval from randomization to the earliest occurrence of disease progression resulting in inoperability, locoregional recurrence (after neoadjuvant therapy), distant metastases, or death from any cause Cortazar P et al, Lancet 2014;384:

18 Association strongest in aggressive tumors Association between pcr and long term outcomes strongest in; TNBC (EFS: HR 0.24, OS 0.16), HER2+/HR- (EFS HR 0.15 OS 0.08) who received trastuzumab

19 HR for EFS Trial-level correlation between treatment effect on pcr and event-free survival or overall survival Odds ratio for pcr

20 Trial-level correlation between treatment effect on pathological complete response and eventfree survival or overall survival Little association between increases in frequency of pcr and EFS (R 2 = 0.03, 95% CI ) and OS (R 2 = 0.24, )

21 Why? The heterogeneity of the patient population Inclusion of HR (+) disease : low pcr with good prognosis pcr to chemotherapy (not endocrine therapy) for HR (+) disease : cannot be appropriate endpoint for HR (+) disease The overall low pcr rates in the CTNeoBC trials Larger difference in pcr needed to improve EFS In NOAH, pcr : 38% vs 19% 3 year EFS : 71% vs 56% The lack of targeted therapies except for the NOAH trial EFS/OS can be affected by adjuvant treatment (endocrine treatment, trastuzumab)

22 Is pcr appropriate surrogate marker in neoadjuvant chemotherapy? Yes, at patient level No, at trial level (maybe, for HER2+, TNBC subtype) Randomized trials of targeted agents in more homogeneous tumor subtypes, with larger differences in pcr rates between treatment arms, may demonstrate a relationship between pcr and longterm outcome at a trial level.

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24 The accelerated approval regulations of FDA The FDA may grant accelerated approval... upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

25 PREOPERATIVE SYSTEMIC THERAPY FOR HER2+ BC

26 NOAH trial design AT AT AT T T T T CMF CMF CMF H H H H H H H H H H Gianni L et al, Lancet 2010; 375:

27 NOAH trial results Pathologic response 50 38% HR = 0.59, p=0.013 HR=0.59, p= y EFS: 71% vs 56% % bpcr With trastuzumab tpcr Without trastuzumab

28 The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumor responses.

29 Four receptors in the HER family Yarden Y & Sliwkowski MX. Nat Rev Mol Cell Biol 2001; HER4 HER3 HER2 2: Subdomain I HER1/EGFR Subdomain II (dimerization domain) Subdomain III Subdomain IV Receptors are able to form homo- and heterodimers Yarden Y & Sliwkowski MX. Nat Rev Mol Cell Biol 2001; 2:

30 HER2-containing dimers induce potent mitogenic signalling resulting in cell survival and proliferation Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER Signalling activity Most common and most potent oncogenic dimer in HER2-positive breast cancer Tzahar E, et al. Mol Cell Biol 1996; 16: ; Citri A, et al. Exp Cell Res 2003; 284:54 65.

31 HER2:HER3 dimerization initiates multiple signalling pathways, including increased tumor cell proliferation Receptor dimerisation leads to the activation of the PI3K/Akt and Ras/MEK/MAPK pathways, resulting in the expression of genes that support proliferation, survival and migration, and that antagonise apoptosis HER3 HER2 Ligand-activated HER2 heterodimer RAS SOS GRB2 PDK1 PIP RAF MEK ERK mtor AKT Survival Proliferation Cell cycle control Apoptosis 1. Yarden Y & Sliwkowski MX. Nat Rev Mol Cell Biol 2001; 2: ; 2. Baselga J & Swain SM. Nat Rev Cancer 2009; 9:

32 Pertuzumab is the first in a new class of HER2 dimerization inhibitors Key HER signalling pathways that mediate cancer cell proliferation and survival are inhibited by pertuzumab blockade of HER2 dimerisation 1 4 In addition, pertuzumab can activate antibody-dependent cellular cytotoxicity 5 HER1, 3, 4 Pertuzumab HER2 1. Agus DB, et al. Cancer Cell 2002; 2: ; 2. Hughes JB, et al. Mol Cancer Ther 2009; 8: ; 3. Baselga J. Cancer Cell 2002; 2:93 95; 4. Franklin MC, et al. Cancer Cell 2004; 5: ; 5. Scheuer W, et al. Cancer Res 2009; 69:

33 Pertuzumab and trastuzumab (or T-DM1) bind to different domains on HER2 and have complementary mechanisms of action HER1, 3, 4 Pertuzumab HER2 Trastuzumab Pertuzumab binds to subdomain II and inhibits ligand-dependent signalling 1 Trastuzumab binds to subdomain IV and inhibits ligand-independent intracellular signalling 2 The pertuzumab trastuzumab combination offers a more comprehensive HER2 blockade 3,4 The same MOA principles apply to pertuzumab T-DM1 combination 5 1. Franklin MC, et al. Cancer Cell 2004; 5: ; 2. Junttila TT, et al. Cancer Cell 2009; 15: ; 3. Nahta R, et al. Cancer Res 2004; 64: ; 4. Scheuer W, et al. Cancer Res 2009; 69: ; 5. Fields C, et al. AACR Abstract 5607.

34 Mean tumour volume (mm 3 ) ± SEM Pertuzumab plus trastuzumab demonstrates a more comprehensive block of HER2 signaling compared to monotherapy alone KPL-4 breast cancer xenograft model Vehicle control Pertuzumab (30*/15 mg/kg/wk ip) Trastuzumab (30*/15 mg/kg/wk ip) Pertuzumab (30*/15 mg/kg/wk ip) + trastuzumab (30*/15 mg/kg/wk ip) * Loading dose ip, intraperitoneal; SEM, standard error of the mean Treatment period (days) Adapted from Scheuer W, et al. Cancer Res 2009; 69:

35 Mean tumour volume (mm 3 ) ± SEM Pertuzumab and trastuzumab combination is effective following progression on trastuzumab KPL-4 breast cancer xenograft model Vehicle control Trastuzumab (30*/15 mg/kg/wk ip) Trastuzumab (30*/15 mg/kg/wk ip) with addition of pertuzumab (30*/15 mg/kg/wk ip) at Day * Loading dose ip, intraperitoneal; SEM, standard error of the mean Treatment period (days) Adapted from Scheuer W, et al. Cancer Res 2009; 69:

36 CLEOPATRA: Phase III trial of trastuzumab plus docetaxel with or without pertuzumab n = 406 Placebo + trastuzumab Patients with HER2-positive MBC centrally confirmed (N = 808) 1:1 R Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab n = 402 Docetaxel* 6 cycles recommended *<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator s discretion Randomisation was stratified by geographic region and prior treatment status ([neo]adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Docetaxel: 75 mg/m 2, escalating to 100 mg/m 2 if tolerated Baselga J, et al. N Engl J Med 2012; 366: PD, progressive disease; R, randomised

37 Investigator-assessed PFS (%) CLEOPATRA: P + H + T increased median PFS* by 6.3 months vs. H + T alone n at risk PHT HT MONTHS Δ 6.3 months MONTHS Time (months) PHT: 284 events; median 18.7 months HT: 320 events; median 12.4 months HR % CI = 0.58, 0.80 p < Swain SM, et al. ESMO 2014 (Abstract 350O_PR) 2. Swain et al. Lancet Oncol 2013;14:

38 Overall survival (%) CLEOPATRA: Patients lived 15.7 months longer when treated with P + H + T vs. H + T alone in final OS analysis n at risk PHT HT PHT: 168 events; median 56.5 months HT: 221 events; median 40.8 months Time (months) Δ 15.7 months HR % CI = 0.56, 0.84 p < Data cut-off: February 2014 CI, confidence interval; H, trastuzumab; HR, hazard ratio; P, pertuzumab; T, docetaxel N Engl J Med 2015;372:724-34

39 CLEOPATRA: Adverse events (all grades) 25% incidence or 5% difference between arms Adverse event, n (%) HT (n = 397) PHT (n = 407) Diarrhoea 184 (46.3) 272 (66.8) Alopecia 240 (60.5) 248 (60.9) Neutropenia 197 (49.6) 215 (52.8) Nausea 165 (41.6) 172 (42.3) Fatigue 146 (36.8) 153 (37.6) Rash 96 (24.2) 137 (33.7) Decreased appetite 105 (26.4) 119 (29.2) Mucosal inflammation 79 (19.9) 113 (27.8) Asthenia 120 (30.2) 106 (26.0) Peripheral oedema 119 (30.0) 94 (23.1) Constipation 99 (24.9) 61 (15.0) Febrile neutropenia 30 (7.6) 56 (13.8) Dry skin 17 (4.3) 43 (10.6) Data cut-off: May 2011 Orange, 5% lower in HT arm; blue, 5% lower in PHT arm H, trastuzumab; P, pertuzumab; T, docetaxel Adapted from Baselga J, et al. N Engl J Med 2012; 366:

40 CLEOPATRA:Grade 3 adverse events (incidence 2%) Adverse event, n (%) HT (n = 397) PHT (n = 407) Neutropenia 182 (45.8) 199 (48.9) Febrile neutropenia 30 (7.6) 56 (13.8) Leucopenia 58 (14.6) 50 (12.3) Diarrhoea 20 (5.0) 32 (7.9) Peripheral neuropathy 7 (1.8) 11 (2.7) Anaemia 14 (3.5) 10 (2.5) Asthenia 6 (1.5) 10 (2.5) Fatigue 13 (3.3) 9 (2.2) Granulocytopenia 9 (2.3) 6 (1.5) LVSD 11 (2.8) 5 (1.2) Dyspnoea 8 (2.0) 4 (1.0) Data cut-off: May 2011 Orange, 2% lower in HT arm; blue, 2% lower in PHT arm H, trastuzumab; P, pertuzumab; T, docetaxel Adapted from Baselga J, et al. N Engl J Med 2012; 366:

41 Events (n) CLEOPATRA: Events of febrile neutropenia and accompanying therapy in Asia vs. RoW HT RoW PHT RoW HT Asia PHT Asia 0 Febrile neutropenia Hospitalisation G-CSF treatment Subsequent G-CSF prophylaxis Docetaxel dose reduction Concomitant mucositis/diarrhoea Data cut-off: May 2011 All events of febrile neutropenia are presented including multiple events in the same patient G-CSF, granulocyte colony-stimulating factor; RoW, rest of the world Adapted from Baselga J, et al. ASCO 2012 (Abstract 597; poster presentation).

42 Combination strategies in neoadjuvant systemic therapy in HER2 positive disease - NEOSPHERE HER2+ LABC and large stage Ⅱ breast cancer (n=417) Trastuzumab + docetaxel q3w x 4 Trastuzumab+ pertuzumab +docetaxel q3w x 4 Trastuzumab+ pertuzumab q3w x 4 Pertuzumab +docetaxel q3w x 4 Surgery Surgery Surgery Surgery FEC q3w x 3 trastuzumab q3w until Week 52 FEC q3w x 3 trastuzumab q3w until Week 52 Docetaxel + trastuzumab Q3w x 4 FEC q3w x 3 trastuzumab q3w until Week 52 Endpoints: pathological CR FEC q3w x 3 trastuzumab q3w until Week 52

43 pcr, % 95% CI NeoSphere: Pertuzumab and trastuzumab plus docetaxel significantly increased the pcr rate vs. other arms p = p = p = H, trastuzumab; P, pertuzumab; pcr, pathological complete response; T, docetaxel n = 107 n = 107 n = 107 n = 96 Arm A Arm B Arm C Arm D HT PHT PH PT Giani L, et al. Lancet Oncol 2012; 13: 25 32

44 Giani L, et al. Lancet Oncol 2012; 13: 25 32

45 TRYPHAENA: A Phase II study of pertuzumab and trastuzumab in the neoadjuvant setting All three arms are experimental Cycles A FEC Docetaxel Pertuzumab + trastuzumab S U HER2-positive EBC (N = 225) B FEC Docetaxel Pertuzumab + trastuzumab R G E Trastuzumab to complete 1 year C Docetaxel Pertuzumab + trastuzumab R Y Carboplatin FEC, 5-fluorouracil, epirubicin, cyclophosphamide Primary endpoint: Cardiac safety Symptomatic LVSD (grade 3) LVEF declines ( 10 percentage points and below 50%) Schneeweiss A, et al. Ann Oncol 2013;24:

46 Cardiac events during neoadjuvant treatment Symptomatic LVSD (grade 3),n (%) FEC+H+P x3 T+H+P x3 n = 72 FEC x3 T+H+P x3 n = 75 TCH+P x6 n = 76 0 (0.0) 2 (2.7) 0 (0.0) LVSD (all grades), n (%) 4 (5.6) 3 (4.0) 2 (2.6) LVEF decline 10% points and below 50%, n (%) 4 (5.6) 4 (5.3) 3 (3.9) Schneeweiss A, et al. Ann Oncol 2013;24:

47 Pathologic complete response (%) Pathologic complete response ypt0/is ypt0 ypn FEC+H+P x3 T+H+P x3 (n = 73) FEC x3 T+H+P x3 (n = 75) TCH+P x6 (n = 77) Schneeweiss A, et al. Ann Oncol 2013;24:

48 Patients with pathological complete response (%) TRYPHAENA: pcr rate stratified by HR ER/PR ER and/ or PR+ FEC + PH x3 PHT x3 ER/PR ER and/ or PR+ FEC x3 PHT x3 ER/PR ER and/ or PR+ PHTC x6 C, carboplatin; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; pcr, pathological complete response (defined as ypt0/is); T, docetaxel Schneeweiss A, et al. Ann Oncol 2013;24:

49 Breast-conserving surgery in patients for whom mastectomy was planned FEC+H+P x3 T+H+P x3 n = 46 FEC x3 T+H+P x3 n = 36 TCH+P x6 n = 37 Achieved, n (%) [95% CI] 10 (21.7) [ ] 6 (16.7) [ ] 10 (27.0) [ ] Not achieved, n (%) 36 (78.3) 30 (83.3) 27 (73.0) Patients in the intent-to-treat population with T2 3 tumors for whom mastectomy was planned Schneeweiss A, et al. Ann Oncol 2013;24:

50 Patterns of response after neoadjuvant therapy Bossuyt V, et al. Ann Oncol 2015;26:

51 Grade 3 adverse events excluding cardiac events during neoadjuvant treatment Adverse event, n (%) FEC+H+P x3 T+H+P x3 n = 72 FEC x3 T+H+P x3 n = 75 TCH+P x6 n = 76 Neutropenia 34 (47.2) 32 (42.7) 35 (46.1) Febrile neutropenia 13 (18.1) 7 (9.3) 13 (17.1) Leukopenia 14 (19.4) 9 (12.0) 9 (11.8) Diarrhea 3 (4.2) 4 (5.3) 9 (11.8) Anemia 1 (1.4) 2 (2.7) 13 (17.1) Thrombocytopenia 0 (0.0) 0 (0.0) 9 (11.8) Vomiting 0 (0.0) 2 (2.7) 4 (5.3) Fatigue 0 (0.0) 0 (0.0) 3 (3.9) Alanine aminotransferase 0 (0.0) 0 (0.0) 3 (3.9) Drug hypersensitivity 2 (2.8) 0 (0.0) 2 (2.6)

52 The accelerated approval regulations of FDA The FDA may grant accelerated approval... upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

53 Accelerated approval of neoadjuvant pertuzumab Effect on surrogate endpoint that is reasonably likely to predict clinical benefit NEOSPHERE ; Doubling pcr in pertuzumab containing arm TRYPHAENA; high pcr rates were observed in all 3 pertuzumab-containing treatment arms. CLEOPATRA trial in first-line, HER2-positive MBC Confirmatory adjuvant trial (APHINITY) near completion standard chemotherapy and trastuzumab plus one year of pertuzumab to chemotherapy and trastuzumab alone fully accrued with more than 4,800 patients at the time of accelerated approval The first DFS results from this trial anticipated in late 2016

54 Association of pcr to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis Cohort studies and RCTs: stage Ⅰ-Ⅲ, HER2 + BC, neoadjuvant therapy, pcr and EFS-type outcome reported 2614 publications 38 studies

55 Association of pcr to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes: A Meta-Analysis JAMA Oncol 2016

56 Recommendations for neoadjuvant chemotherapy for breast cancer Absolute Locally advanced BC Inflammatory BC Relative T2-T3 tumors with goal of breast conservation therapy Alternative to adjuvant therapy Improve cosmesis, decrease morbidity and extent of axillary surgery, increase feasibility of SNB in formerly node-positive disease

57 Preoperative/Adjuvant therapy regimens for HER2- positive disease, NCCN guideline Preferred regimens AC followed by T +trastuzumab pertuzumab TCH pertuzumab Other regimens AC followed by docetaxel + trastuzumab pertuzumab Docetaxel + cyclophosphamide + trastuzumab FEC followed by docetaxel + trastuzumab + pertuzumab FEC followed by paclitaxel + trastuzumab + pertuzumab Paclitaxel + trastuzumab Pertuzumab + trastuzumab + docetaxel followed by FEC Pertuzumab + trastuzumab + paclitaxel followed by FEC

58 Summary Neoadjuvant systemic therapy provides Similar outcome as adjuvant therapy Increased chance of breast conservation Platform for new drug development in accelerated fashion Neoadjuvant systemic therapy in HER2 positive BC Combination of chemotherapy and double anti-her2 treatment results in significant improvement in pcr Neoadjuvant taxane + trastuzumab + pertuzumab are preferred standard option in HER2 positive BC Biomarker studies to select patients who can benefit from double vs single anti-her2 treatment, as well as personalized strategy to select best anti-her2 treatment option, are needed