2018.4.6 GBCC Satellite symposium Current and Future perspectives of HER2+ BC Jee Hyun Kim, M.D., Ph.D. Seoul National University Bundang Hospital Seoul National University College of Medicine
Disclaimer All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription.
Current status OVERVIEW OF ANTI-HER2 TREATMENT IN EBC
` Slamon DJ et al, science 1987;235:177-182
Trastuzumab: An anti-her2 antibody A humanised IgG1, anti-her2 monoclonal antibody that binds with high affinity and specificity to subdomain IV, a juxta-membrane region of the HER2 extracellular domain 1 Trastuzumab inhibits HER2 intracellular signalling, thereby inhibiting the proliferation of human tumour cells that overexpress HER2 1 Trastuzumab is a potent mediator of ADCC 1 Abrogation of HER2-mediated intracellular signalling by trastuzumab 3 HER2 Trastuzumab HERCEPTIN 1. EMA. Herceptin SmPC. October 2016; 2. FDA. Herceptin PI. March 2016; 3. http://www.herceptin.com/hcp/treatment/moa
Survival probability Survival probability Taxane + trastuzumab significantly improved OS vs taxane alone in HER2-positive mbc H0648g 1 M77001 2 1.0 H + CT (n = 235) CT (n = 234) 1.0 H + T (n = 92) T (n = 94) 0.8 0.6 RR (95% CI) = 0.80 (0.64 1.00) p = 0.0462 0.8 0.6 p = 0.0325 0.4 0.4 0.2 0 0 20.3 25.1 5 15 25 35 45 Time (months) 0.2 0 22.7 31.2 0 5 10 15 20 25 30 35 40 45 50 Time (months) 1. Slamon DJ, et al. NEJM 2001;344:783 792; 2. Marty M, et al. J Clin Oncol 2005;23:4265 4274; 3. Jackisch C. Oncologist 2006;11 Suppl 1:34 41.
Four adjuvant trastuzumab trials in HER2 positive EBC Extensive clinical programme involving >13 000 patients Study N Treatment arms HERA 1 5102 BCIRG 006 2 3222 CT* ± RT observation CT* ± RT trastuzumab 1 year CT* ± RT trastuzumab 2 years AC docetaxel AC docetaxel + trastuzumab trastuzumab Docetaxel + carboplatin + trastuzumab trastuzumab Median FU (years) Cross-over 11 52% 10.3 3.1% NCCTG N9831 3 3505 NSABP B-31 3 2101 Arm A: AC paclitaxel Arm B: AC paclitaxel trastuzumab 8.4 Arm C: AC paclitaxel + trastuzumab trastuzumab AC paclitaxel AC paclitaxel + trastuzumab trastuzumab 8.4 20% 1. Goldhirsch Lancet Oncol 2013;82:1021. 2. Slamon Cancer Res 2016;763. Perez J Clin Oncol 2014;32:3744-52.
DFS event-free (%) 100 80 60 Joint analysis: DFS at 8.4 years after randomization 40% reduction in risk of DFS event with trastuzumab after 8.4 years AC PH AC P 81.4% 76.8% 73.7% 11.5% 69.5% 64.9% 62.2% 40 20 0 No. at risk N Events AC PH 2028 473 AC P 2018 680 HR: 0.60 (95% CI: 0.53 0.68); p < 0.001 0 2 4 6 8 10 Years from randomisation 2028 1959 1848 1747 1675 1611 1514 1293 910 619 350 2018 1887 1689 1529 1423 1329 1232 1027 705 449 255 HR, hazard ratio Romond EH, et al. SABCS 2012 (Abstract S5-5) Perez EA, et al. J Clin Oncol 2014; 32:3744 3752.
Survival (%) 100 80 60 Joint analysis: OS at 8.4 years after randomization Addition of trastuzumab was associated with a 37% relative risk reduction after 8.4 years follow-up AC P 93.2% 90.3% 89.8% 84.3% 87.0% 79.4% AC PH = 2.9% = 5.5% = 7.6% = 8.8% 84.0% 75.2% 8.8% 40 20 0 0 2 4 6 8 10 Years from randomisation No. at risk N Events AC PH 2028 286 AC P 2018 418 HR: 0.63 (95% CI = 0.54, 0.73); p < 0.001 2028 1995 1959 1897 1843 1785 1709 1506 1085 735 439 2018 1962 1883 1806 1730 1640 1534 1336 944 604 353 Romond EH, et al. SABCS 2012 (Abstract S5-5); Perez EA, et al. J Clin Oncol 2014; 32:3744 3752.
Survival (%) Joint analysis: Magnitude of OS benefit consistent irrespective of HR status HR-positive HR-negative 100 80 60 AC P AC PH 86% 77.1% AC PH AC P 81.6% 73% 40 20 No. at risk N Events AC PH 1110 137 AC P 1105 206 HR: 0.61 (95% CI = 0.49 0.76); p < 0.0001 HR: 0.64 (95% CI = 0.52 0.79); p < 0.0001 0 0 2 4 6 8 10 0 2 4 6 8 10 Years from randomisation 1110 1002 263 1105 925 204 Romond EH, et al. SABCS 2012 (Abstract S5-5); Perez EA, et al. J Clin Oncol 2014; 32:3744 3752. N Events AC PH 917 149 AC P 911 212 917 782 176 911 713 148
Alive and disease-free (%) NCCTG N9831: DFS for sequential vs. concurrent trastuzumab Non-significant* DFS benefit for concurrent treatment 100 80 84.5% 80.1% AC PH AC P H 60 40 No. at risk 20 0 0 1 2 3 4 5 6 949 954 n Events HR 95% CI p value* 949 139 0.77 0.53 1.11 0.022 954 174 837 830 790 766 742 707 691 654 576 519 334 288 Years from randomisation * Significant p value predefined as p = 0.00116 Perez EA, et al. J Clin Oncol 2011; 29:4491 4497.
Trastuzumab significantly improved OS in patients with HER2-positive EBC after long-term follow-up HERA: H vs. observation 1 11 years median follow-up a BCIRG 006: H in combination with different chemotherapy regimens 2,3 10.3 years median follow-up Time (years) Trastuzumab IV approval in HER2-positive ebc The HERA, BCIRG 006 and NCCTG N9831/NSABP B-31 studies led to the approval of Trastuzumab IV in the adjuvant setting (EU 2006; US - 2008) 4,5 1. Jackisch C, et al. SABCS 2015 (Abstract PD5-01);. 2. Slamon D, et al. SABCS 2015 (Abstract S5-04); 3. Slamon D, et al. NEJM 2011; 365:1273 1283 (Suppl data);4. EMA. Herceptin SmPC. October 2016; 5. FDA. Herceptin PI. March 2016.
pcr* (%) EFS (%) Neoadjuvant and adjuvant Herceptin therapy improved pcr and EFS in after long-term follow-up NOAH 1,2 50 p = 0.0007 40 43% 30 20 22% 10 0 With Without Herceptin Herceptin 38% p = 0.001 With Herceptin 19% 100 90 80 70 60 50 40 30 20 Chemotherapy plus Herceptin (n = 117) Chemotherapy plus Herceptin Chemotherapy HR (95% CI) = 0.64, 0.44 0.93 log-rank p value = 0.016 Chemotherapy (n = 118) 10 Events 49 (42%) 62 (53%) 5-year EFS (%, 58 (48 66) 43 (34 52) 0 95% CI) Without 0 12 24 36 48 60 72 84 Herceptin Number at risk Mont Chemotherapy plus 117 110 88 77 hs 66 56 43 24 bpcr tpcr Herceptin 118 98 69 55 49 39 28 14 Chemotherapy Trastuzumab IV approval in HER2-positive ebc The NOAH study led to the approval of Herceptin IV in the neoadjuvant-adjuvant setting in the EU (2012) 3 1. Gianni L, et al. Lancet 2010;375:377 384; 2. Gianni L, et al. Lancet Oncol 2014;15:640 647; 3. EMA. Herceptin SmPC. October 2016.
Trastuzumab revolutionized treatment for patients with HER2-positive BC 2,227,799 patients treated ~16,830 trial BC patients 1 1. PSUR (PBRER) trastuzumab, 25th Sep. 2015 to 24th Sep. 2016, F. Hoffmann-La Roche Ltd, Report Number 1072735
Still, there are unmet needs BCIRG 006 Disease free survival Biomarker! Needs more (effective) therapy Less (toxic) therapy Slamon D,et al. Cancer Res 2016;76
Escalation strategy BEYOND TRASTUZUMAB
Increase duration of trastuzumab Goldhirsch Lancet Oncol 2013;82:1021.
Adding different agent -neratinib ExteNET study design HER2+ BC Prior adjuvant trastuzumab & chemotherapy LN + or residual invasive disease after NACT (N = 2840 ) R Stratification factors HR status: HR+ vs HR- LN status : 0 vs 1-3 vs 4 Adjuvant trastuzumab: sequential vs concurrent Neratinib x 1 year 240mg/day Placebo x 1 year F O L L O W - U P 2y idfs 5y idfs OS Chan et al, Lancet Oncol 2016;17:367-377
Adjuvant neratinib : 5 year analysis HR 0.73 (95% CI 0.57-0.92); p = 0.0083 Martine M et al, Lancet Oncol 2017;18:1688-1700
Adjuvant neratinib : ExteNET results HR (+) 1 HR (-) Martine et al, Lancet Oncol 2017;18:1688-1700
ExteNET : summary Adjuvant neratinib after 1 year of trastuzumab increased idfs in HR+ HER2+ BC High rates of diarrhea: G2 32%, G3 40% Intensive anti-diarrheal prophylaxis needed Adjuvant neratinib approved by US FDA in 2017 More questions than answers Why only in HR(+)? Neratinib use after neoadjuvant therapy or after pertuzumab? (non clinical trial evidence) Biomarker?
Adding different agent -lapatinib NeoALTTO Baselga J, et al, Lancet 2012;379:633-40-
Adding different agent -lapatinib ALTTO: Safety analysis AE leading to discontinuation AE leading to dose reduction AE leading to dose interruptions / delays TL T-L L T 481 (23%) 413 (20%) 945 (46%) 261 (13%) 275 (13%) 668 (32%) 317 (15%) 448 (22%) 821 (40%) 171 (8%) 81 (4%) 419 (20%) Moreno-Aspitia A et al, ASCO 2017
Adding different agent : pertuzumab 1. Swain S, et al. N Engl J Med 2015;372:724-34 2. Schneeweiss A, et al. Ann Oncol 2013;24:2278-2284, 3.Gianni L, et al. Lancet Oncol 2012: 13:25-32,
Adding different agent -pertuzumab S U R G E R Y APHINITY (BO25126): Phase III adjuvant study Central confirmation of HER2 status (N = 4805 ) R Randomisation and treatment within 8 weeks of surgery Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy * Standard anthracycline or non-anthracycline (TCH) regimens were allowed F O L L O W - U P 10 Y E A R S von Minckwitz G, et al. N Engl J Med 2017 clinicaltrials.gov/ct2/show/nct01358877.
APHINITY : endpoints and statistical assumptions Endpoints Primary IDFS (excluding second primary non-breast cancer tumors): Time from randomization until the date of the first occurrence of one of the following events: - Ipsilateral invasive breast tumor recurrence - Ipsilateral local-regional invasive breast cancer recurrence - Distant recurrence - Contralateral invasive breast cancer - Death attributable to any cause including breast cancer, non-breast cancer, or unknown cause Secondary IDFS: as per STEEP definition (including second non-primary BC tumors) DFS OS RFI DRFI Safety Cardiac safety (primary safety endpoint) HRQoL Statistical assumption: HR=0.75 Expected 3-year IDFS rate placebo vs pertuzumab: 89.2% vs 91.8% 379 events and 4,800 patients required for 870% power and αof 5%
Stratification factors by treatment Nodal status, n (%) 0 positive nodes and T 1 cm* 0 positive nodes and T >1 cm* 1 3 positive nodes 4 positive nodes Adjuvant chemotherapy regimen (randomized), n (%) Anthracycline-containing regimen Non-anthracycline-containing regimen Hormone receptor status (central), n (%) Negative (ER- and PR-negative) Positive (ER- and/or PR-positive) Protocol version, n (%) Protocol A Protocol Amendment B Pertuzumab n = 2400 90 (3.8) 807 (33.6) 907 (37.8) 596 (24.8) 1865 (77.7) 535 (22.3) 864 (36.0) 1536 (64.0) 1828 (76.2) 572 (23.8) Placebo n = 2404 84 (3.5) 818 (34.0) 900 (37.4) 602 (25.0) 1877 (78.1) 527 (21.9) 858 (35.7) 1546 (64.3) 1827 (76.0) 577 (24.0) Tumour size (cm), n (%) <2 2 <5 5 978 (40.8) 1275 (53.1) 147 (6.1) 948 (39.4) 1283 (53.3) 174 (7.2)
Proportion event-free Invasive disease free survival 1.0 0.9 0.8 1 year 98.6% 98.8% 2 years 96.4% 95.7% 3 years 94.1% 93.2% 4 years 92.3% 90.6% 0.7 0.6 0.5 0.0 Pertuzumab (n = 2400) Placebo (n = 2404) HR 0.81; 95% CI 0.66 1.00; p = 0.0446 0 6 12 18 24 30 36 42 48 Time (months) No. of patients at risk 2400 2309 2275 2236 2199 2153 2101 1687 879 2404 2335 2312 2274 2215 2168 2108 1674 866 All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription
Proportion eventfree IDFS results: Lymph node-positive subgroup 1.0 0.8 1 year 2 years 98.1% 94.9% 98.2% 93.7% 3 years 4 years 92.0% 89.9% 90.2% 86.7% 0.6 0.4 0.2 Unstratified HR 0.77; 95% CI 0.62 0.96; p = 0.0188 0.0 0 6 12 18 24 30 36 42 48 Time (months) No. of patients at risk 1503 1444 1419 1387 1358 1327 1283 912 423 1502 1453 1439 1408 1359 1319 1264 882 405 All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription
Proportion event-free IDFS results: HR-negative subgroup 1.0 0.8 1 year 2 years 98.1% 97.9% 96.2% 93.7% 3 years 4 years 92.8% 91.0% 91.2% 88.7% 0.6 0.4 0.2 Unstratified HR 0.76; 95% CI 0.56 1.04; p = 0.085 0.0 0 6 12 18 24 30 36 42 48 Time (months) No. of patients at risk 864 836 821 813 797 774 755 600 314 858 827 811 793 771 758 730 569 302 All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription
Patients, % Most common AEs Pertuzumab n = 2364 Placebo n = 2405 All grade Grade 3 All grade Grade 3 Diarrhoea 71.2 9.8 45.2 3.7 Nausea 69.0 2.4 65.5 2.5 Fatigue 48.8 3.9 44.3 2.5 Arthralgia 28.7 0.9 32.5 1.1 Myalgia 26.0 0.9 29.5 1.3 Stomatitis 28.4 2.0 24.0 1.0 Anaemia 27.8 6.9 23.3 4.7 Dysgeusia 26.0 0.1 21.5 <0.1 Rash 25.8 0.4 20.3 0.2 Decreased appetite 23.9 0.8 19.9 0.4 Mucosal inflammation 23.4 1.7 18.4 0.7 Epistaxis 18.2 <0.1 13.6 0.0 Oedema peripheral 17.1 0 20.1 0.2 Pruritus 14.0 0.1 9.0 <0.1
Cardiac toxicity Primary cardiac, n (%) Heart failure NYHA III/IV + LVEF drop Recovered according to LVEF Cardiac death* Pertuzumab n = 2364 17 (0.7) 15 (0.6) 7 2 (0.08) Pertuzumab vs. placebo (95% CI) Placebo n = 2405 0.4 (0.0, 0.8) 8 (0.3) 6 (0.2) 4 2 (0.08) Secondary cardiac** Identified from LVEF assessments Identified by CAB 64 (2.7) 50 (2.1) 14 (0.6) -0.1 (-1.0, 0.9) 67 (2.8) 47 (2.0) 20 (0.8) Note: one death due to heart failure occurred in the Trastuzumab arm All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription
De-escalation strategy LESS IS MORE
Adjuvant Paclitaxel and Trastuzumab for nodenegative HER2 positive breast cancer S U R G E Tumor 3cm Node negative HER2 positive BC (N = 406 ) Weekly paclitaxel 80mg/m 2 + trastuzumab 4mg/kg D1 2mg/kg for 12 weeks Trastuzumab 2mg/kg weekly or 6mg/kg every 3 weeks for 40 weeks R Y Tolaney SM et al. N Engl J Med 2015;372:134-141.
Disease-free and recurrence-free survival, APT 3yr idfs: 98.7% DFS events at 7 years Any recurrence or death Local/Regional recurrence N 23 (5.7%) 5 (1.2%) Ipsilateral axilla 3 Ipsilateral breast 2 New contralateral primary breast cancer 6 (1.5%) HER2+ 1 HER2-3 Her2 unknown 2 Distant recurrence 4 (1.0%) Non breast cancer related death 8 (2.0%) Tolaney SM et al. N Engl J Med 2015;372:134-141, Tolaney ASCO 2017.
Docetaxel/cyclophosphamide/Trastuzumab for early stage HER2+ BC Stage 1-2 HER2+ BC (N = 493) Docetaxel Cyclophosphamide Trastuzumab Trastuzumab F O L L O W - U P 2y idfs 2 year DFS: 97.8% (95% CI: 94.2-99.2) 2 year OS; 99.5% (95% CI: 96.2-99.9) Excellent outcome in both TOP2A amplified & nonamplified patients Jones SE et al, Lancet Oncol 2013.
ATEMPT trial Stage 1 HER2+ BC ER+ or ER- PS 0-1 Adequate organ fx (N = 500 ) R T-DM1 q 3 weeks x 17 Paclitaxel + Trastuzumab x 12 Trastuzumab q 3 weeks x 13 F O L L O W - U P DFS All the contents in the presentation is owned by the speaker and does not necessarily represent the views and opinions of Roche Korea. It may contain therapies currently under clinical development for the purpose of scientific discussion and the company does not recommend any off-label uses. Physicians should refer to the approved PI before prescription
SOLD PHARE Short-HER Hellenic Group Persephone HERA Duration of trastuzumab Chemo Backbone Duration N DFS HR PHARE 1 Investigator choice 6 mos 1690 84.9% (48m) 1.28 (1.05-1.56) 12 mos 1690 87.8% Short-HER 2 TH#3-FEC#3 9 weeks 626 85.4% 1.15 (0.91-1.46) AC/FEC#4-TH#4-H 12 mos 627 87.5% SOLD 3 TH#3-FEC#3 9 wks 1085 88.0% (5y) 1.39 TH#3-FEC#3-H 12 mos 1089 90.5% Hellenic ddfec-t 6 vs 12 group 4 months 481 93.3% vs 95.7% (3yr) 1.57 (0.86-2.10) Persephone 5 Investigator choice 6 vs 12 months 4000 1. Pivot X, et al, Lancet Oncol 2013;14:741-8 2. NCT00629278. 3. SABCS 2017. 4. Mavroudis D, e al. Ann Oncol 2015. 5. NCT00712140
Results: SOLD trial Joensuu H, et al. SABCS 2017
Subset analyses : SOLD trial Joensuu H, et al. SABCS 2017
Duration of trastuzumab 12 months of adjuvant trastuzumab : standard Selected group of patients may benefit from shorter duration Low disease burden HR positive Cardiac risk factors
Surgery Randomised, open-label, Phase III, non-inferiority study to compare the pharmacokinetics, efficacy and safety of Herceptin SC and IV in HER2-positive early breast cancer Herceptin SC HER2-positive early breast cancer (N=596) R 1:1 Herceptin IV Follow-up: 5 years 2 Herceptin SC Fixed dose of 600 mg (5 ml over 5 minutes) Herceptin IV 8 mg/kg loading dose; 6 mg/kg maintenance dose Docetaxel 75 mg/m 2 FEC 500/75/500 1 year (18 cycles) Herceptin Safety, tumour response pcr Safety, EFS, OS Pharmacokinetics Primary endpoint Show non-inferiority of SC vs. IV based on co-primary endpoints Pharmacokinetics: observed Herceptin C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pcr in the breast EFS, event-free survival; FEC, 5-fluorouracil+epirubicin+cyclophosphamide; IV, intravenous; pcr, pathological complete response; OS, overall survival; SC, subcutaneous 1. Ismael G, et al. Lancet Oncol 2012; 2. http://clinicaltrials.gov/ct2/show/nct00950300
Estimated probability HannaH: Similar EFS rates seen with Herceptin SC and IV (ITT population) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 EFS rates 3 years after randomisation: Herceptin SC: 76% Herceptin IV: 73% (HR 0.95; 95% CI = 0.69; 1.30) 0.1 0.0 Randomised treatment Herceptin IV Herceptin SC N at risk Herceptin IV Herceptin SC 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Months 297 288 277 264 254 238 225 215 206 181 118 19 4 0 294 287 271 264 255 246 231 220 210 168 97 17 3 0 24 months treatment-free follow-up CI, confidence interval; EFS, event-free survival; HR, hazard ratio; ITT, intent-to-treat; IV, intravenous; SC, subcutaneous Jackisch C, et al. St. Gallen 2015 (Poster P201)
Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years treatment-free follow-up: Final analysis from the phase III, open-label, randomized HannaH study Overview The HannaH study has shown that Herceptin SC has a comparable safety and efficacy profile to that of Herceptin IV in HER2-positive ebc 1 This long-term follow-up analysis evaluates whether the benefit seen with Herceptin SC continues after treatment stops, as is the case with Herceptin IV, and also the potential relationship between tpcr and long-term outcomes The overall safety profile of Herceptin SC after long-term follow-up is also evaluated Results Baseline characteristics including nodal status, hormone receptor status, tumour size and whether the disease was locally advanced were balanced across both arms Overall rates of any grade, Grade 3 or cardiac AEs were similar in the two study arms More serious AEs were observed with H SC than H IV (21.9% vs. 15.1%) Data in context 6-year EFS Rate, (95% CI) 6-year EFS by tpcr status* Rate, (95% CI) 6-year OS Rate, (95% CI) H SC n = 294 0.65 (0.59 0.70) tpcr 0.82 (0.74 0.89) 0.83 (0.76 0.91) no tpcr 0.54 (0.47 0.62) 0.57 (0.49 0.64) n = 294 0.84 (0.79 0.88) Comparable efficacy was observed across all subgroups Hazard ratio H IV (95% CI) n = 297 0.65 (0.60 0.71) 0.98 (0.74 1.29) n = 297 0.84 (0.79 0.88) 0.94 (0.61 1.45) The non-inferiority of Herceptin SC compared with IV was confirmed after long-term follow-up, with no new safety signals being reported The results also add to the evidence that there is a positive association between tpcr and more favourable long-term outcomes 2 in HER2-positive ebc 3 A notable proportion of patients experience disease recurrence despite neoadjuvant therapy, and so more advanced treatment options are still needed Herceptin SC is being investigated in combination with PERJETA SC as part of the breast cancer development programme (Phase Ib data presented at SABCS P5-20-07) Jackisch C, et al. Abstract PD3-11 * Efficacy per-protocol population 1. Ismael G, et al. Lancet Oncol 2012; 2. Cortazar P, et al. Lancet 2014 3. Gianni L, et al. Lancet Oncol 2016
HER2 positive BC: from the most deadly disease to most treatable form of breast cancer 2013 2013 Adjuvant 2017 Pertuzumab Adjuvant Neratinib Trastuzumab SC T-DM1 for MBC Neoadjuvant Pertuzumab 1998 1987 Discovery of HER2 2006 Trastuzumab for MBC firstline 2007 Lapatinib for ABC Trastuzumab For EBC adjuvant 2012 Pertuzumab for MBC
Preoperative/Adjuvant therapy regimens for HER2-positive BC, NCCN guideline 2018 Preferred regimens: AC followed by T + trastuzumab AC followed by T + trastuzumab + pertuzumab Paclitaxel + trastuzumab TCH TCH + pertuzumab Useful in certain circumstances Docetaxel + cyclophosphamide + trastuzumab Other recommended regimens AC followed by docetaxel + trastuzumab AC followed by docetaxel + trastuzumab + pertuzumab
Patients cannot benefit from the treatment they did not receive! Indication Korea Japan Thailand Hong Kong Taiwan Singapore Philippines Indonesia Malaysia China T_DM1 MBC; Monotherapy Reimburs ement Reimburs ement None None None None None None None None Pertuzu mab HER-2 (+) MBC Treatment in Combination with trastuzumab & docetaxel Reimburs ement Reimburs ement Reimbur sement Reimburse ment None None None None None None Neo adjuvant None not identifi ed None None None None None None None None MBC Reimburs ement Reimburs ement None Reimburse ment Reimbu rsement None None Reimburse ment None Reimbu rsement Trastuz umab Neoadjuvant Reimburs ement Reimburs ement Reimbur sement Reimburse ment Reimbu Reimburs rsement ement Reimburse ment None Reimbur sement Reimbu rsement Adjuvant Reimburs ement Reimburs ement Reimbur sement Reimburse ment Reimbu Reimburs rsement ement Reimburse ment None Reimbur sement Reimbu rsement
Biomarkers to predict response to anti- HER2 therapy HER2 mrna expression, FISH ratio, protein expression, HER2 CTC, HER2 ECD PIK3CA mutation ER positivity Intrinsic subtypes TILs Immune signatures
Biomarkers to predict response to anti- HER2 therapy HER2 : Higher pcr PIK3CA mutation: Lower pcr ER positivity: Lower pcr HER2 enriched subtype: Higher pcr Currently there are no reliable biomarker to predict benefit from anti-her2 treatment in the adjuvant setting! Please visit overcoming resistance to HER2-directed therapies presentation by Dr. Ian Krop
Using response to neoadjuvant therapy as biomarker pcr is predictive of EFS and DRFS : I-SPY2 TRIAL EFS HR-HER2+ DRFS Yee D, et al. San Antonio Breast Cancer Symposium, Dec 5-9, 2017
Neoadjuvant trials as platform of testing novel escalation/de-escalation strategy Experimental therapy De-escalation pcr Neoadjuvant therapy Non-pCR Standard therapy Experimental therapy - escalation Please visit plenary session 1 by Dr. Eric Winer Standard therapy
What next? Escalation Combination with CDKi Combination with IO Combination with mtor inhibitor/pi3k inhibitor De-escalation Biologics only Combination with endocrine therapy We need robust biomarker to select therapy!
Ongoing clinical Trials of Anti-HER2 S. Parakh et al. Cancer Treatment Reviews 59(2017) 1-21
Ongoing clinical Trials of Immune Checkpoints Inhibitors in HER2+ BC Please visit overcoming resistance to HER2-directed therapies presentation! Prof SB.Kim L. De la Cruz-Merino et al. International Review of Cell and Molecular Biology 331 (2017) 1-53
Kaitlin : study schema Curative surgery HER2 positive LN positive or >2cm (n=1846) R FEC AC EC FEC AC EC T-DM1 + Pertuzumab Taxane + Trastuzumab + pertuzumab IDFS IDFS in LN(+)
Katherine : study schema Preoperative therapy Taxane ± Anthracycline (n=1484) Residual tumor T-DM1 Trastuzumab 3 year IDFS
Summary One year of trastuzumab standard adjuvant treatment in ebc Extended neratinib reduce recurrence in HR+HER2+ higher risk BC Pertuzumab improves DFS but only in Node positive BC Many escalation and de-escalation strategies are ongoing to improve efficacy/reduce toxicity of adjuvant treatment HER2+ EBC Biomarker to identify those who need more/less therapy is eagerly awaited
Hur!