Systemic Therapy of HER2-positive Breast Cancer Tanja Cufer, MD, PhD University Clinic Golnik, Medical Faculty Ljubljana, Slovenia ESO ESMO Masterclass, Belgrade 2018
HER2-positive Breast Cancer Adjuvant trastuzumab trials: Relative risk reduction of death HER2-directed therapy in ABC: Survival rates Relative Risk 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 Risk od death 33-59% 0.66 0.67 0.67 0.41 0.59 0.66 Analysis Year Expected: 5-year Survival (%) Expected: Mean Per-Patient Survival (Months) 1995 9.1 26.6 2000 10.9 28.7 2005 14.2 32.6 2010 18.2 37.3 2015 34.0 50.8 Roth J, et al. ESMO 2017. Courtesy of M. Piccart HER2-directed therapy is the largest achievements in medical treatment of breast cancer, during the last decade! HER2 is a molecular driver of approx. 20% of BC. EBC: Uniform efficacy, 30 40 % improvement in DFS and OS. MBC: Doubling of overall survival time.
Adjuvant HER2-directed Therapy
Adjuvant Trastuzumab: Pivotal Phase 3 Trials Trial HERA Piccart-Gebhart M, et al. NEJM 2015 Cameron D, et al. Lancet 2017. NCCTG N9831 and NSABP-B31 Perez EA, et al. J Clin Oncol 2014. BCIRG 006 Slamon DJ, et al. SABCS 2015. FNCLCC-PACS 04 Spielmann M, et al. J Clin Oncol 2011. Study Design Phase 3 Phase 3 Phase 3 Phase 3 No. of Patients Treatment Arm DFS Absolute values HR (95% CI; p) OS Absolute values HR (95% CI; p) 1,698 Observation 11-year DFS: 63.0% 12-year OS: 72.9% 1,703 Sequential trastuzumab 1 yr 11-year DFS: 69.3% 0.76 (0.68-0.86; <0.0001) 12-year OS: 79.4% 0.74 (0.64-0.86; <0.0001) 1,701 Sequential trastuzumab 2 yrs 11-year DFS: 68.5% 0.77 (0.69-0.87; <0.0001) 12-year OS: 79.5% 0.72 (0.62-0.83; <0.0001) 2,018 CT 8-year DFS: 62.0% 8-year OS: 75.2% 2,028 CT + 8-year DFS: 73.7% 8-year OS: 84.0% trastuzumab 1 yr 0.60 (0.53-0.68; <0.001 0.63 (0.54-0.73; <0.001) 1,073 AC -> T 10-year DFS: 67.9% 10-year OS: 78.7% 1,074 AC -> TH -> trastuzumab 1 yr 10-year DFS: 74.6% 0.72 (0.62-0.85; <0.0001) 10-year OS: 85.9% 0.63 (0.62-0.79; <0.0001) 1,075 TCH -> trastuzumab 1 yr 10-year DFS: 73.0% 0.77 (0.65-0.90; 0.0011) 10-year OS: 83.3% 0.76 (0.62-0.93; 0.0075) 260 Observation 3-year DFS: 77.9% 3-year OS: 96.0% 268 Sequential trastuzumab 1 yr 3-year DFS: 80.9% 0.86 ( 0.61-1.22; 0.41) 3-year OS: 95.0% 1.27 (0.68-2.38; NS)
Trastuzumab is Effective Regardless Nodal and/or HR Status: HERA Trial Subgroup (no. patients) HR (95% CI) Nodal status Not assessed (neoadjuvant chemotherapy) (372) 0.66 (0.43, 1.00) Negative (1099) 0.59 (0.39, 0.91) 1 3 positive nodes (976) 0.61 (0.43, 0.87) 4 positive nodes (953) 0.64 (0.49, 0.83) Hormone receptor status ER negative + PgR negative (1627) 0.63 (0.50, 0.78) ER negative + PgR positive (172) 0.77 (0.34, 1.74) ER positive + PgR negative (460) 0.82 (0.50, 1.34) ER positive + PgR positive (984) 0.63 (0.43, 0.93) All patients (3401) 0.64 (0.54, 0.76) 0.0 0.5 1.0 1.5 Favours trastuzumab HR Favours observation Untch, et al. Ann Oncol 2008.
Concurrent Trastuzumab Performs Better than Sequential: NCCTG N9831Trial Perez, et al. Cancer Res 2009.
Benefit of Trastuzumab in Small 2cm N0 Disease: Meta-Analysis HR + HR - Only smal number (n=75) pts with T1a/b ( 1 cm) included! O Sullivan C, et al. J Clin Oncol 2015 Trastuzumab is recommended for patients with T1c (> 1cm) tumors, while its role in tumors 1 cm is still debatable.
No Benefit of Trastuzumab in HER2-low Disease: NSABP B-47 Trial (HER2 IHC 1+/2+ and ISH-negative) Fehrenbacher L, et al. SBCS 2017. There is no benefit of adjuvant trastuzumab in HER2-negative disease.
Cardiac Safety of 1 year Adjuvant HER2-directed Therapy Trial Arm Any CHF (%) Any LVEF drop (%) HERA, de Azambuja, et al. (2014) Chemo 0 0.9 Chemo T 1y 0.8 7.2 NSABP B-31, Romond, et al. (2012) AC P 1.2 NR AC PT 3.8 12.0 NCCTG N9831, Advani, et al. (2016) AC P AC P T AC PT 0.9 2.6 3.5 9.6 16.7 23.8 BCIRG 006, Slamon, et al. (2015) AC D AC DT DCarboT APT, Tolaney, et al. (2015) PT 0.5 3.2 ALLTO, Piccart M, et al. (2016) APHINITY, von Von Minckwitz, et al. (2017) Chemo T 1y Chemo T Lapa 1y Chemo T + Lapa 1y Chemo T 1y Chemo T + Pertuz 1y 0.8 2.0 0.4 1.0 <1.0 1.0 0.3 0.7 Risk factors for CHF: low LVEF, age, obesity, hypertension. LVEF is mandatory before initiation of trastuzumab and during treatment. 11.2 19.1 9.4 5.0 3.0 5.0 2.8 2.7
Escalation and De-escalation of Adjuvant Anti-HER2 Therapy Adjuvant treatment if no pcr KATHERINE: T-DM1 (on-going) Escalating targeted agents BETH: H + Bevacizumab (negative) ExteNET: H -> neratinib (positive) ALTTO: H -> L or H+L (negative) APHINITY: H + pertuzumab (positive) KAITLIN: T-DM1 + pertuzumab (on-going) Prolonging duration of adjuvant H HERA: H for 2 years (negative) ANTHRACYCLINE AND TAXANE BASED CHEMOTHERAPY WITH TRASTUZUMAB FOR ONE YEAR Non-anthracycline-based CT BCIRG 006: TCH regimen (positive) APT: weekly P + H (positive) CT-free regimen ATEMPT: T-DM1 (on-going) Reducing duration of adjuvant H PHARE: H for 6 months (negative) HORG trial: H for 6 months (negative) SHORT-HER: H for 3 months (negative) PERSEPHONE: H for 6 months (positive) SOLD: H for 9 weeks (on-going) Adoped from Lambertini M, et al. Expert Rev Cancer Ther 2017.
ExteNET: 1 year Neratinib after 1 year of Trastuzumab vs 1 year Trastuzumab alone 5yr DFS absolute benefit = 2.5% Subsets HR idfs Node-negative 0.83 (ns) 1 3+ nodes 0.75 (ns) 4+ nodes 0.67* ER+ 0.60* ER- 0.95 (ns) Positive DFS data persist with longer FU (5-year DFS, Martin M, Lancet Oncol 2017). OS data are still pending! Substantial toxicity (40% G3/4 diarrhea) Diarrhea prophylaxis key! Chan A, et al. Lancet Oncology 2016.
APHINITY: 1 year Trastuzumab plus Pertuzumab vs 1 year Trastuzumab plus Placebo Expected: 89.2% 4yr idfs absolute benefit = 1.7% Number needed to treat: 112 Statistically significant, but is it clinically meaningful? von Minckwitz G, et al. N Engl J Med 2017.
APHINITY: 1 year Trastuzumab plus Pertuzumab vs 1 year Trastuzumab plus Placebo Node-positive Subgroup Δ 3.2% HR-negative Subgroup Δ 2.3% 2.3% von Minckwitz G et al. N Engl J Med 2017.
De-escalating HER2-directed Adjuvant Therapy Trial BCIRG 006 Slamon DJ, et al. SABCS, 2015. APT Tolaney SM, et al. N Engl J Med 2015; ASCO 2017, Abstr 511 Study Design No. of patients Treatment Arm DFS Absolute Values HR (95% CI; p) Non-anthracycline- based Cht Phase 3 1,073 AC -> T 10-year DFS: 67.9% 1,074 AC -> TH -> 10-year DFS: Trastuzumab 74.6% for 1 year 0.72 (0.62-0.85; <0.0001) 1,075 TCH -> 10-year DFS: Trastuzumab 73.0% for 1 year 0.65 (0.65-0.90; <0.0011) Phase 2 (T1/2 N0) 406 Weekly paclitaxel x 12 + Trastuzumab for 1 year 7-year idfs: 93.3% OS Absolute Values HR (95% CI; p) 10-year OS: 78.7% 10-year OS: 85.9% 0.63 (0.51-0.79; <0.0001) No significant difference in DFS or OS between Trastuzumab arm; hiowever, trails was not powered to detect equivalence. 10-year OS: 83.3% 0.76 (0.62-0.93; <0.0075) 7-year OS: 95.0%
De-escalating HER2-directed Adjuvant Therapy Trial PHARE Phase 3 Pivot X, et al. Lancet Oncol 2013. HORG Phase 3 Mavroudis D, et al. Ann Oncol 2015. Short-HER Phase 3 Conte PF, et al., ASCO 2017, Abstr 501. PERSEPHONE Phase 3 Earl H, et al. ASCO 2018, Abstr 506 No. of patients Treatment Arm DFS Absolute Values HR (95% CI; p) OS Absolute Values HR (95% CI; p) Shorter duration of adjuvant Trastuzumab 1690 CT + trastuzumab for 1 year 2-year DFS: 93.8% NR 5.7% Cardiac Events Shorter vs Longer Trastuzumab 1690 CT + trastuzumab for 6 months 2-year DFS: 91.1% 1.28 (1.05-1.56; 0.29) NR 1.46 (1.06-2.01; 0.03) 1.9% 241 ddfec -> dddocetaxel + 3-year DFS: 95.7% NR 2 cases trastuzumab for 1 year 240 ddfec -> dddocetaxel + 3-year DFS: 93.3% NR 0 cases trastuzumab for 6 months 1.57 (0.86-2.10; 0.137) 1.45 (0.57-3.67; 0.438 627 CT + trastuzumab for 1 year 5-year DFS: 87.5.% NR 16% 626 CT + trastuzumab for 9 weeks 5-year DFS: 85.4% NR 6% 1.15 (0.91-1.46; ns) 2045 CT + trastuzumab for 1 year 4-year DFS: 89.8% NR 12% 2043 CT + trastuzumab for 6 months 4-year DFS: 89.4% 1.07 (0.93-1.24; 0.01) NR 9%
PERSEPHONE and SHORT-HER Subgroups Analysis PERSEPHONE: Subgroups for which 12 m might be superior SHORT-HER: Subgroups for which 6 m might be non-inferior ER- Stage I, II Taxane N0-1 Neoadjuvant Cht Concomitant T Earl H, et al ASCO 2018, Abstr 506; Conte PF, et al. ASCO 2017, Abstr 501. Shorter trastuzumab treatment duration might be equally effective in low stage, ER + disease. However, in all other scenarios 1 year of trastzumab remains the gold standard!
Take Home Messages: Adjuvant HER2-directed Therapy 1 year of trastuzumab remains standard in adjuvant therapy of HER2- positive EBC. A dual HER2 blockade with pertuzumab or extended neratinib might be considered in specific populations, higher risk HER2-positive patients, i.e. patients multiple-node positive disease or ER+ disease, respectively. Shorter duration of trastuzumab may be considered in selected, low risk patients who can not tolerate 12 months of therapy. Anthracycline based Cht followed by taxane with concurrent trastuzumab or TCH are proposed regimens. Trastuzumab plus paclitaxel seems to be appropriate therapy patients with T1/2 N0, disease. Additional biomarkers to identify HER2-positive patients suitable for escalation or de-escalation of adjuvant therapy are urgently needed.
HER2- directed Therapy for Advanced Breast Cancer (ABC)
Cardoso F, et al The Breast 2011.
HER2+ Advanced Breast Cancer: Currents Standards of Care in 2018 First line Second line* Later lines**.... Pertuzumab Lapatinib Pertuzumab Lapatinib Trastuzumab Trastuzumab TDM1 Taxane Vinorelbine Capecitabine Superior to trastuzumab + docetaxel (CLEOPATRA) Superior to capecitabine + lapatinib (EMILIA) or to physicians choice (TH3RESA) Superior to lapatinib plus capecitabine (MA.31) Trastuzumab Capecitabine Trastuzumab Superior to lapatinib alone (EGF 104900) If patients relapse 12 mos start as first line; ** Combination of trstuzumab plus either capecitabine, eribulin, gemciatbine, platinum agents or metronomic Cht might be used as well as per ABC3! Adopted from Piccart M, SABC Symposium 2017; Cardoso F, et al. Ann Oncol 2016.
CLEOPATRA: First-line Trastuzumab and Docetaxel +/- Pertuzumab in HER2+ MBC Swain S, et al. NEJM 2015. Pertuzumab + trastuzumab+docetaxel Placebo + trastuzumab+docetaxel Hazard ratio P-value ORR 1 80.2% 69.3% 0.0001 PFS 2 18.7 months 12.4 months 0.68 <0.0001 OS 2 56.5 months 40.8 months 0.66 0.0001 Long term cardiac safety maintained, with favorable LVEF and CHF in experimental arm!
EMILIA: T-DM1 vs Lapatinib Plus Capecitabine in HER+ MBC Proportion progression-free 1.0 0.8 0.6 0.4 0.2 Progression-Free Survival by Independent Review Median (months) No. of events Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77) P<0.0001 Proportion surviving Overall Survival: Confirmatory Analysis Median (months) No. of events Cap + Lap 25.1 182 T-DM1 30.9 149 1.0 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006 85.2% Efficacy stopping boundary P=0.0037 or HR=0.727 0.8 78.4% 64.7% 0.6 51.8% 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (months) No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 No. at risk: Time (months) Cap + Lap 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 Unstratified HR=0.66 (P<0.0001). 13 16 www.esmo2012.org Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). www.esmo2012.org T-DM1 Lapatinib + capecitabine Hazard ratio P-value PFS 9.6 months 4.6 months 0.65 <0.001 OS 30.9 months 25.1 months 0.68 <0.001 Verma S, et al. NEJM 2012.
HER2+ Advanced Breast Cancer: Standards of Care for Triple Positive Disease in 2018 First line Second line Later lines.... Pertuzumab Lapatinib Lapatinib Trastuzumab Trastuzumab Trastuzumab Trastuzumab Endocrine Therapy TDM1 Endocrine Therapy Vinorelbine Superior to lapatinib alone (EGF 104900) Superior to trastuzumab + ET (PERTAIN); Induction Cht in 57% Superior to lapatinib or trastuzumab + ET (ALTERNATIVE) Trials comparing HER2 plus ET vs HER2 plus Cht in ABC are ongoing (Detect V, CHEVENDO, PERNETTA, ) Despite absence of EBD, HER2 plus ET might be considered as maintenance therapy as per ABC3. Adopted from Piccart M, SABC Symposium 2017. Cardoso F, et al. Ann Oncol 2016.
HER2- directed plus ET in First-line Therapy of HR+/HER2+, Triple positive MBC Trial Treatment arm No. pts Median PFS (months) Overall Response Rate (ORR) Overall Survival (months) First-line setting PERTAIN* AI + Trastuzumab 258 15.8 56% NR Arpino G et al., SABCS 2016. +/- Pertuzumab** 18.9* 63% Second-line setting ALTERNATIVE AI + Trastuzumab 355 5.7 14% NR Gradishar WJ et al., ASCO 2017, Abstr 1004. AI + Lapatinib AI + Trastuzumab + Lapatinib 8.3 11.0* 19% 32%* * PERTAIN: Induction Cht in 57%. Dual HER2 blockade plus ET performs better than mono HER2 plus ET; however; therefore, it is a reasonable option in selected HR+/HER2+ patients, used as induction or as maintenance therapy. Gradishar WJ, et al. ASCO 2017, Abstr 1004.
Treatment of CNS Metastases in HER2+ MBC
Trastuzumab Improves Survival in Patients with CNS Disease: Retrospective Analysis Kirsch DG, et al. JCO 2005
CEREBEL: Capecitabine plus Lapatinib or Trastuzumab in HER2+ MBC without CNS mets Early closure! Lapatinib + capecitabine (N=251) Trastuzumab + capecitabine (N=250) OS (ITT population) OR (95% CI) P-value CNS at first site of relapse, n (%) 8 (3) 12 (5) 0.65 (0.26-1.63) 0.360 Incidence of CNS progression at any time, n (%) 17 (7) 15 (6) 1.14 (0.52-2.51) 0.8646 Time to first CNS progression, median (range) 5.7 (2-27) 4.4 (2-27) - - Low number of brain metastses Trastuzumab + capecitabine better OS Survival (%) Lap + Cap (N=271) Tras + Cap (N=269) Median OS, months 22.7 27.3 Hazard ratio (95% CI) 1.34 (0.95,1.90) Stratifiedlog-rank p-value 0.095 Pivot X, et al. J Clin Oncol 2015. Subjects at risk Lap + Cap Tras + Cap Time from randomisation (months) 271 194 129 79 48 27 7 269 207 140 97 61 29 6 1
Efficacy of Pertuzumab + Trastuzumab and of T-DM1 in CNS metastases Post-hoc Analyses of CLEOPATRA, EMILIA Median time to progression, CNS as first site of progression Progression-free probability (%) 100 90 80 70 60 50 40 30 20 10 0 11.9 15.0 Pertuzumab, trastuzumab, docetaxel Trastuzumab, docetaxel, placebo HR 0.58 95% CI 0.39, 0.85 p = 0.0049 0 5 10 15 20 25 30 35 40 Time (months) 45 No. PHTat risk 55 54 42 27 17 10 6 1 0 0 HT 51 45 28 16 6 4 3 0 0 0 Patients without prior chemotherapy or biologic therapy for HER2-positive MBC were included; patients with evidence of CNS metastases were excluded Swain S, et al. Ann Oncol 2014. Krop I, et al. Ann Oncol 2015.
Novel Treatment Strategies for HER2+ Breast Cancer in Clinical Research New HER2-directed Agents New anti-her TKIs (tucatinib, poziotinib) Antibody Drug Conjugates (ADCs) New anti-her Antibodies Bi-specific Antibodies New Combinations Anti-HER2 + mtor Inhibitors Anti-HER2 + PI3K Inhibitors Anti-HER2 + CDK 4/6 Inhibitors Anti-HER2 + PD-1/PD-L1 Inhibitors New predictive markers for better tailoring of HER2-directed therapy are urgently needed! So far, we only have additional prognostic markers (HER2 mrna, PIK3CA, TIL), while HER2 status remains the only predictive biomarker, after decades of research in HER2+ breast cancer! At least we should take into consideration that triple positive breast cancer is a distinctive subtype!
Take Home Messages: HER2-directed Therapy of ABC Trastuzumab plus pertuzumab plus taxane represents the standard firstline therapy for ABC pts, not receiving previous HER2-directed therapy. When pertuzumab is not given (available) trastuzumab plus taxane or vinorelbine should be given in first-line setting! T-DM1 represents the standard second-line therapy in ABC pts receiving previous HER2-directed therapy. T-DM1 can be considered as alternative to trastuzumab/taxane combination in the first-line setting, mainly for patients with short DFI (< 12 mos) after neo-/adjuvant HER2-directed therapy. For later lines of therapy trastuzumab plus Cht, lapatinib plus capecitabine or trastuzumab plus lapatinib remain viable options.
Take Home Messages: HER2-directed Therapy of ABC For selected triple positive, especially elderly patients with a low burden of disease, a combination of ET and dual HER2-directed therapy with trastuzumab plus pertuzumab in first-line or with trastuzumab plus lapatinib in second-line can be considered, as upfront or as maintenance therapy. Optimal duration of HER2-directed therapy in ABC patients achieving CR is not yet known. Stopping HER-2 therapy might considered if re-challenge is available in case of progression. Patients with CNS disease benefit from HER2-directed therapy: trastuzumab plus capecitabine, trastuzumab plus pertuzumab plus taxane or T-DM1 are viable options. Intrathecal trastuzumab might be considered in patients with leptomeningeal disease (Zagouri, et al. BCRT 2013.).