Systemic Therapy of HER2-positive Breast Cancer

Systemic Therapy of HER2-positive Breast Cancer Tanja Cufer, MD, PhD University Clinic Golnik, Medical Faculty Ljubljana, Slovenia ESO ESMO Masterclass, Belgrade 2017

Relative Risk HER2-positive Breast Cancer 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Adjuvant trastuzumab trials: Relative risk reduction of death 1 Risk od death 33-59% 0,66 0,67 0,67 0,41 0,59 0,66 HER2-directed therapy in ABC: Survival rates Courtesy of M. Piccart Mendes D, et al. Breast Cancer Res 2015. HER2-directed therapy one of the largest achievements! HER2 is a molecular driver of approx. 20% of BC. EBC: Death reduction risk by approx. 30%. MBC: Doubling of overall survival time.

Adjuvant HER2-directed Therapy

HERA: 1 year or 2 years of Trastuzumab after Cht vs. Observation HR 0.75; Δ 7.0% HR 0.74; Δ 6.0% Piccart M, ASCO 2015, Untch M, et al. Ann Oncol 2008. Goldhirsch A, et al. Lancet 2013.

NCCTG N9831: 1 year Trastuzumab Concurrent or Sequential with Cht vs. Cht alone Perez, et al. Cancer Res 2009.

HR + HR - Trastuzumab in T 2cm N0: Meta-Analysis O Sullivan C, et al. J Clin Oncol 2015. Only 75 pts 1 cm ( T1a/b N0).

Escalation and De-escalation of Adjuvant Anti- HER2 Therapy Adjuvant treatment if no pcr KATHERINE: T-DM1 (on-going) Non-anthracycline-based CT BCIRG 006: TCH regimen (positive) APT: weekly P + H (positive) 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) ANTHRACYCLINE AND TAXANE BASED CHEMOTHERAPY WITH TRASTUZUMAB FOR ONE YEAR CT-free regimen ATEMPT: T-DM1 (on-going) Adoped from Lambertini M, et al. Expert Rev Cancer Ther 2017. Prolonging duration of adjuvant H HERA: H for 2 years (negative) Reducing duration of adjuvant H FinHer: H for 9 weeks (negative) 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 (on-going) SOLD: H for 9 weeks (on-going)

ExteNET: 1 year Neratinib after 1 year of Trastuzumab vs. 1 year Trastuzumab Substantial toxicity (40% G3/4 diarrhea). Chan A, et al. Lancet Oncology 2016. Positive DFS data persist with longer FU (3-year DFS, SABCS 2015). OS data are still pending!

ALTTO: 1 year Trastuzumab plus Lapatinib (concurrent or Sequential) vs. Trastuzumab * Bracketed data in all KM curves represent results of the Primary Analysis ASCO 2014 Δ 3.0% Alvaro Moreno-Aspitia, et at. ASCO 2017, Abstract 502.

ALTTO: 1 year Trastuzumab plus Lapatinib (concurrent ALTTO Updated or Sequential) Results vs. Trastuzumab Alvaro Moreno-Aspitia, et at. ASCO 2017, Abstract 502. Δ 2.0% Δ 4.0%

APHINITY: 1 year Trastuzumab plus Pertuzumab vs. 1 year Trastuzumab plus von Minckwitz G, et al. N Engl J Med 2017. Expected: 89.2% 4yr idfs absolute benefit = 1.7% Number needed to treat: 112

APHINITY: 1 year Trastuzumab plus Pertuzumab vs. 1 year Trastuzumab plus The effect of pertuzumab on idfs was homogenous across all subgroups. No significant interaction for any subgroup, including N status and HR status. von Minckwitz G, et al. N Engl J Med 2017. Δ 3.2% Δ 2.3%

Escalating HER2-directed Adjuvant Therapy Trial HERA Cameron D, et al. Lancet 2017. ExteNET Chan A, et al. Lancet Oncol 2016. ALTTO Piccart-Gebhart M, et al. J Clin Oncol 2016. Moreno-Asptia A et al., ASCO 2017 Abstr 502. APHINITY von Minckwitz G et al., NEJM 2017 Study Design Phase 3 Phase 3 Phase 3 Phase DFS No. of Treatment Arm Absolute values Patients HR (95% CI; p) Longer duration of HER2-directed therapy OS Absolute values HR (95% CI; p) 1,552 CT + trastuzumab 1 yr 10-year DFS: 73.9% 12-year OS: 86.1% 1,553 CT + trastuzumab 2 yrs 10-year DFS: 73.1% 1.02 (0.89-1.17; 0.796) 1,420 CT + trastuzumab 1 yr + 2-years IDFS: 91.6% placebo for another year 1,420 CT + trastuzumab 1 yr + 2-years IDFS: 93.9% neratinib for another 1 yr 0.67 (0.50-0.91; 0.0091) Dual HER2-directed therapy 12-year OS: 83.6% 1.01 (0.84-1.21; 0.916) NR 2,097 CT + trastuzumab 1 year 6-year DFS: 82.0% 6-year OS: 91.0% 2,100 CT + lapatinib 1 year 4-year DFS: 82.0% 1.34 (1.13-1.60; <0.0005) 2,091 CT + trastuzumab -> 6-year DFS: 84.0% lapatinib for 1 year 0.93 (0.81-1.1.08; ns) 2,093 CT + trastuzumab + 6-year DFS: 85.0% lapatinib for 1 year 0.86 (0.74-1.00; ns) 2405 CT + trastuzumab + placebo 3-year idfs:93.2% NR for 1 year 400 CT + trastuzumab + 3-year idfs: 94.1% NR pertuzumab for 1 year 0.81 (0.68-1.00; 0.0045) NR 4-year OS: 93.0% 1.36 (1.09-1.72; 0.007) 6-year OS: 92.0% 0.88 (0.71-1.08; ns) 6-year OS: 93.0% 0.86 (0.70-1.06; ns)

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 OS Absolute Values HR (95% CI; p) Phase 3 1,073 AC -> T 10-year DFS: 67.9% 10-year OS: 78.7% Phase 3 (T1/2 N0) 1,074 AC -> TH -> Trastuzumab for 1 year 1,075 TCH -> Trastuzumab for 1 year 406 Weekly paclitaxel x 12 + trastuzumab for 1 year 10-year DFS: 74.6% 0.72 (0.62-0.85; <0.0001) 10-year DFS: 73.0% 0.65 (0.65-0.90; <0.0011) 7-year idfs: 93.3% 7-year OS: 95.0% 10-year OS: 85.9% 0.63 (0.51-0.79; <0.0001 10-year OS: 83.3% 0.76 (0.62-0.93; <0.0075

De-escalating HER2-directed Adjuvant Therapy FinHER Trial Joensuu H, et al. J Clin Oncol 2009. PHARE Pivot X, et al. Lancet Oncol 2013. HORG Mavroudis D, et al. Ann Oncol 2015. Short-HER Conte PF, et al., ASCO 2017, Abstr 501. Study Design No. of patients Treatment Arm DFS Absolute Values HR (95% CI; p) Shorter duration of adjuvant Trastuzumab Phase 3 116 Docetaxel or vinorelbine x 3 -> FEC x 3 116 Docetaxel or vinorelbine x 3 -> FEC x 3 + trastuzumab for 9 weeks Phase 3 1,690 CT + trastuzumab for 1 year 1,690 CT + trastuzumab for 6 months Phase 3 241 ddfec -> dddocetaxel + trastuzumab for 1 year 240 ddfec -> dddocetaxel + trastuzumab for 6 months Phase 3 627 CT + trastuzumab for 1 year 626 CT + trastuzumab for 9 weeks OS Absolute Values HR (95% CI; p) 5-year distant DFS: 73.0% 5-year OS: 82.3% 5-year distant DFS: 83.3% 0.65 (0.38-1.12; 0.12) 2-year DFS: 93.8% 2-year DFS: 91.1% 1.28 (1.05-1.56; 0.29) 3-year DFS: 95.7% 3-year DFS: 93.3% 1.57 (0.86-2.10; 0.137) 5-year DFS: 87.5.% 5-year DFS: 85.4% 1.15 (0.91-1.46; ns) 5-year OS: 91.3% 0.55 (0.27-1.11; 0,094) NR NR 1.46 (1.06-2.01; 0.03) NR NR 1.45 (0.57-3.67; 0.438 NR NR

SHORT-HER: 9 weeks vs. 1 year Adjuvant Trastuzumab in Combination with Cht Conte PF, et al. ASCO 2017, Abstr 501.

Cardiac Safety of Adjuvant HER2-directed Agents Trial Arm Any CHF (%) Any LVEF drop (%) HERA, de Azambuja, et al. Chemo (2014) Chemo T 1y Chemo T 2y NSABP B-31, Romond, et al. AC P (2012) AC PT NCCTG N9831, Advani, et al. (2016) AC P AC P T AC PT BCIRG 006, Slamon, et al. AC D (2015) 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 10y Chemo T 1y Chemo T + Pertu 1y 0 0.8 0.8 1.2 3.8 0.9 2.6 3.5 0.8 2.0 0.4 1.0 <1.0 1.0 0.3 0.7 0.9 7.2 4.1 NR 12.0 9.6 16.7 23.8 11.2 19.1 9.4 Risk factors for CHF: low LVEF, age, obesity, hypertension. LVEF is mandatory before initiation of trastuzumab and during treatment. 5.0 3.0 5.0 2.8 2.7

Take Home Points 1 year of trastuzumab remains standard in adjuvant therapy of HER2-positive EBC! A dual HER2 blockade with pertuzumab or lapatinib or extended neratinib might be considered in higher risk HER2-positive patients (HR-negative, multiple-node positive), if available. ESMO MCBS pending! Trastuzumab plus paclitaxel seems to be appropriate therapy patients with T1 N0 disease. Shorter duration of trastuzumab may be considered in selected, low risk patients who can not tolerate 12 months of therapy. Additional biomarkers to identify HER2-positive patients suitable for escalation or de-escalation of adjuvant therapy are urgently needed!

HER2-directed Therapy of Advanced Breast Cancer (ABC)

Pivotal Trials of HER2-directed Therapy in Addition to Cht in HER2-positive MBC Trial Slamon, et al. 1 Smith, et al. 2 Marty, et al. 3 Di Leo, et al. 4 (ErbB2+ pts only) Guan, et al. 5 * statistically significant Treatment Trastuzumab + paclitaxel vs. paclitaxel Trastuzumab + docetaxel vs. docetaxel Lapatinib + paclitaxel vs. paclitaxel Lapatinib + paclitaxel vs. Paclitaxel ORR (%) 49 vs. 17* 61 vs. 34* 63 vs. 38* 69 vs. 50* TTP (months) 7.1 vs. 3.0* 11.7 vs. 6.1* 8.5 vs. 5.8* 9.7 vs. 6.5* OS (months) 25.1 vs. 18.0* 31.2 vs. 22.7* 24.0 vs. 19.8* 27.8 vs. 20.5* 1. Slamon, et al. N Engl J Med 2001.; 2. Smith, et al. Anticancer Drugs 2001.; 3. Marty, et al. J Clin Oncol 2005.; 4. Di Leo, et al. J Clin Oncol 2008.; 5. Guan, et al. J Clin Oncol 2013.

Pivotal trials on Add-on HER2-directed Therapy to Endocrine Therapy in HR+/HER2+ MBC Trial TAnDEM 1 EGF 30008 2 electra 3 Treatment arm Anastrozole +/- Trastuzumab Letrozole +/- Lapatinib Letrozole +/- Trastuzumab * Statistically significant difference. No. pts Median PFS / TTP (months) 208 2.4 4.8* 219 3.0 8.2* 92 3.3 14.1* Overall Response Rate (ORR) 7% 20%* 15% 28%* 13% 27%* Overall Survival (months) 1. Kaufman B, et al. J Clin Oncol 2009.; 2. Johnston S, et al. J Clin Oncol 2009.; 3. Huober J, et al. Breast 2012. 23.9 28.5 32.2 33.3 NR

HER2-directed Therapy Beyond Progression Trial GBG-26 1 Treatment arm No. pts PFS Median (months) Median (months) HR (95% CI; p) OS HR (95% CI; p) Capecitabine 78 5.6 20.6 Capecitabine + Trastuzumab 78 8.2 24.9 0.69 (0.48-0.97; 0.034) 0,76 (0.48-1.22; 0.257) Capecitabine 201 4.1 15.3 EGF 100151 2 Capecitabine 8.4 15.6 + 198 0.47 (0.33-0.67; <0.001) 0.78 (0.55-1.12; NS) Lapatinib 1. Von Minckwitz G, et al. 2008.; 2. Cameron D, et al. 2008.

Year 2017: HER2-directed Therapy for ABC All HER2+ Trastuzumab plus Taxanes Trastuzumab plus Vinorelbine (Eribulin, Capecitabine) Lapatinib plus Capecitabine Trastuzumab plus Pertuzumab plus Taxane T-DM1 Trastuzumab plus Lapatinib HER+ /HR+ Trastuzumab plus AI Lapatinib plus AI Tratuzumab plus Pertuzumab plus AI Trastuzumab plus Lapatinib plus AI

First-line HER2-directed Therapy of ABC: Pivotal trials HERNATA (type of Cht) Taxane + Trastuzumab vs. Vinorelbine + Trastuzumab No difference in PFS or OS (Andersson, et al. JCO 2011) MA.31 (type of HER2-directed agent) Taxane + Trastuzumab vs. Taxane + Lapatinib Trastuzumab plus Taxane sign. improvement in PFS, not in OS (Gelmon, et al. JCO 2015.) CLEOPATRA (dual HER2 blockade) Docetaxel + Trastuzumab vs. Docetaxel + Trastuzumab + Pertuzumab Trastuzuab plus Pertuzumab sign. improvement in PFS and OS (Swain, et al. NEJM 2015.) MARIANNE (dual HER2 blockade) Docetaxel/Pacltaxel + Trastuzumab vs. T-DM1 vs. T-DM1 + Pertuzumab T-DM1 or T-DM1 + Pertuzumab no sign. improvement in PFS, OS (Perez, JCO 2017.)

CLEOPATRA: First-line Trastuzumab and Docetaxel +/- Pertuzumab in HER2+ MBC Pertuzumab + trastuzumab+docetaxel Placebo + trastuzumab+docetaxel Hazard P-value ratio 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! Swain S, et al. NEJM 2015.

HER2- directed plus ET in First-line Therapy of HR+/HER2+ ABC: Dual Blockade Trial PERTAIN** Arpino G et al., SABCS 2016. ALTERNATIVE Gradishar WJ et al., ASCO 2017, Abstr 1004. Treatment arm AI + Trastuzumab +/- Pertuzumab** AI + Trastuzumab AI + Lapatinib AI + Trastuzumab + Lapatinib No. pts Median PFS (months) 258 15.8 18.9* 355 5.7 8.3 11.0* * Statistically significant difference, ** Induction Cht with taxane allowed. Gradishar WJ, et al. ASCO 2017, Abstr 1004. Overall Response Rate (ORR) 56% 63% 14% 19% 32%* Dual HER2 blockade might be a reasonable option in HR+/HER2+ patients who are not candidates for Cht. Overall Survival (months) NR NR

Take Home Points: First-line HER2-directed Therapy ABC Trastuzumab plus pertuzumab and taxane represents the standard first-line therapy in 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. One may consider T-DM1 as an effective and tolerable alternative to trastuzumab/taxane combination in the first-line setting, mainly for patients pre-treated with neo-/adjuvant HER2-directed therapy. For highly selected patients with HER2+/HR+ MBC for whom ET is chosen over or after Cht, concomitant ET plus HER2- directed therapy should be offered. Dual HER-2 blockade with trastuzumab plus pertuzumab or lapatinib may be considered.

Optimal Second-Line Therapy of ABC Prior Trastuzumab only EGF 104900 Lapatinib vs. Lapatinib +/- Trastuzumab Lapatinib + Trastuzumab sign. improvement in PFS and OS (Blackwell, et al. JCO 2012.) EMILIA T-DM1 vs. Capecitabine + Lapatinib T-DM1 sign. improvement in PFS and OS (Verna, et al. NEJM 2012.) PHEREXA Capecitabine + Trastuzumab +/- Pertuzumab Trastuzumab plus Pertuzumab no sign. difference in PFS (Urruticoechea, et al. ASCO 2016, Abstract 504.) Prior Trastuzumab and Lapatinib TH3RESA T-DM1 vs. Physician Treatment of Choice (PTC) T-DM1 sign. improvement in PFS and OS (Krop, et al. Lancet Oncol 2014.)

Proportion progression-free Proportion surviving EMILIA: T-DM1 vs. Lapatinib Plus Capecitabine in HER+ MBC Progression-Free Survival by Independent Review 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 1.0 0.8 0.6 0.4 0.2 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Unstratified HR=0.66 (P<0.0001). Verma S, et al. NEJM 2012. 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 T-DM1 13 www.esmo2012.org Overall Survival: Confirmatory Analysis 1.0 0.8 0.6 0.4 0.2 78.4% 85.2% 51.8% 64.7% 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 Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). Lapatinib + capecitabine Median (months) No. of events Cap + Lap 25.1 182 T-DM1 30.9 149 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006 Efficacy stopping boundary P=0.0037 or HR=0.727 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 16 www.esmo2012.org

Take Home Points Patients progressing on HER2-directed therapy should continue it beyond progression. 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. T-DM1 is considered the standard second-line treatment of HER2-positive ABC. Trastuzumab plus Cht, lapatinib plus capecitabine or trastuzumab plus lapatinib remain viable options in pre-treated patients. There are no data supporting dual HER2 blockade beyond progression. Patients with CNS disease benefit from HER2-directed therapy: trastuzumab, trastuzumab plus pertuzumab or T-DM1 are viable treatment options. Intrathecal trastuzumab might be considered in patients with leptomeningeal disease (Zagouri, et al. BCRT 2013).