Seconda linea di trattamento

XVIII Congresso Nazionale CIPOMO Roma, Giugno 2013 Nuovo paradigma terapeutico nel trattamento del carcinoma mammario HER2+ metastatico: dagli studi alla pratica clinica Seconda linea di trattamento Giorgio Mustacchi, Università di Trieste

HER2-Positive Metastatic Disease: Beyond First Line Lapatinib/Capecitabine Lapatinib/Trastuzumab Trastuzumab/Capecitabine T-DM1

Lapatinib/Capecitabine: Efficacy Result Capecitabine (n = 201) Capecitabine/ Lapatinib (n = 207*) HR P Value Median TTP, wks [1] 18.6 31.3 0.50 <.001 OS, wks [1] 56.6 71.4 0.79.077 ORR, % [2] 13.9 23.7 --.017 Brain mets as site of first progression, n (%) [2] *n = 198 in 2008 study. Exploratory analysis. 13 (6) 4 (2) --.045 1. Cameron D, et al. Oncologist. 2010;15:924-934 2. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.

Cumulative Progression Free (%) Cumulative Progression Free (%) Lapatinib/Capecitabine: TTP 100 TTP With 1 Previous Trastuzumab Regimen 100 TTP With > 1 Previous Trastuzumab Regimen 80 60 Capecitabine Lapatinib/capecitabine 80 60 Capecitabine Lapatinib/capecitabine 40 40 20 20 0 0 20 40 60 80 Wks 0 0 20 40 60 80 Wks Patients with HER2-positive progressive MBC or stage IIIB/IIIC LABC with T4 lesion PD after treatment with regimens that included, but were not limited to, a taxane an anthracycline and trastuzumab Cameron D, et al. Oncologist. 2010;15:924-934.

Probability EGF104900: Lapatinib ± Trastuzumab Progression on anthracycline, taxane, and trastuzumab Patients with progression after 4 wks of lapatinib monotherapy allowed to cross over to receive trastuzumab 1.0 Trastuzumab + lapatinib % RR 0.8 0.6 Lapatinib HR=0.73; p=0.008 40 30 p =.01 24,7 LAPA 0.4 0.2 PSF (weeks) 20 10 p =.46 10,3 6,9 12,4 LAPA/TR AST 0.0 12.0 8.1 0 0 10 20 30 40 weeks 50 60 ORR CBR Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

Trastuzumab Beyond Progression Trial GBG-26 (N = 156) First-line taxane + trastuzumab (n = 111) Trastuzumab alone or with other first-line chemotherapy (n = 42) Taxane + trastuzumab as adjuvant therapy (n = 3) 80 60 p =.012 48,1 54,1 75,3 p =.0068 % 40 27 Cape Cape/Trast 20 0 RR CBR von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.

% Probability Trastuzumab Beyond Progression Trial GBG-26: PSF 1.00 0.8 Trastuzumab + capecitabine (n=78) Capecitabine (n=78) 0.6 0.4 0.2 HR=0,69 (2-sided p=0.034; 1-sided P=0.015) PSF (months) 0.0 5.6 8.2 0 10 20 30 40 months 74 40 15 8 5 3 2 1 1 77 55 29 12 4 3 1 1 1 von Minckwitz G et al, J Clin Oncol 2009

% Probability Trastuzumab Beyond Progression Trial GBG-26: OS 1.00 0.8 0.6 Trastuzumab + capecitabine (n=78) Capecitabine (n=78) HR=0,76 (2-sided p=0.26; 1-sided P=0.013) 0.4 0.2 0.0 20.4* 25.5* 0 10 20 30 40 months 74 66 50 33 21 10 8 3 2 77 68 59 47 27 15 6 1 1 * Median Survival von Minckwitz G et al, J Clin Oncol 2009

T-DM1 activity in HER2 POS & NEG MBC in heavily pretreated patients % RR Prior CHT & AntiHer2 Any 8 (1 19) for M1 7 (1 15) Almost 5 99% of pts 80 60 40 20 0 39,5 HER2 POS 20 HER2 NEG Prior Trastuzumab Prior Lapatinib 19.4 months 6.9 months PSF 7.3 months Krop I, et al. SABCS 2009. Abstract 5090.

Trastuzumab-DM1 Novel Antibody-Drug Conjugate Target expression: HER2 Monoclonal antibody: Trastuzumab Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent DM1 MCC Linker: SMCC Systemically stable T-DM1 Average drug:antibody ratio 3.5:1

T-DM1: mechanism of action Trastuzumab-like activity by binding to HER2 Targeted intracellular delivery of DM1 DM1 is 25 500 fold more potent than taxane in cytotoxic assays Systemic toxicity is limited due to low HER2 expression in normal tissues T-DM1 binds to the HER2 protein on cancer cells Receptor-T-DM1 complex is internalized into cancer cell Potent antimicrotubule agent is released once inside the tumor cell

Single-agent T-DM1 in pretreated HER2-positive MBC patients Phase I TDM3569g 1, 2 (n=52) Dose escalation, q1w and q3w DLT: grade 4 thrombocytopenia T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended Phase II TDM4258g 2 5 (n=112) Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab pretreated (60% lapatinib) and 1 line of chemotherapy for MBC ORR: 34% (centrally confirmed HER2-positive patients) 5 No new safety signals identified Phase II TDM4374g 2 6 (n=112) Pivotal study of T-DM1 (3.6 mg/kg i.v. q3w) in patients pretreated with anthracyclines, taxanes, capecitabine, trastuzumab and lapatinib ORR: 41% (centrally confirmed HER2-positive patients) 5 No new safety signals identified 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010; 6. Krop et al. ESMO 2010

Phase II study of First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC HER2-positive, recurrent locally advanced BC or MBC (n=137) 1:1 T-DM1 3.6 mg/kg Q3W until PD Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m 2 Q3W PD Crossover T-DM1 Primary endpoints: PFS by INV, safety Prior treatment, % Prior (neo)adjuvant trastuzumab Prior (neo)adjuvant taxane Prior (neo)adjuvant anthracycline (Perez EA, et al. ESMO 2010. Abstract LBA3). Trastuzumab + docetaxel (n=70) 27.1 40.0 48.6 T-DM1 (n=67) 17.9 32.8 44.8

First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Adverse Events Adverse Event, n (%) Trastuzumab + Docetaxel (n = 68) T-DM1 (n = 67) Any AE 68 (100) 63 (94.0) Grade 3 AE 51 (75.0) 25 (37.3) Serious AE* 15 (22.1) 13 (19.4) Most common AEs (any grade) on trastuzumab + docetaxel arm Alopecia Neutropenia Diarrhea Most common AEs (any grade) on T-DM1 arm Nausea Fatigue Pyrexia 45 (66.2) 39 (57.4) 31 (45.6) 27 (39.7) 29 (46.2) 14 (20.6) *Resulting in death, life threatening situation, in-patient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, or birth defects. 1 (1.5) 5 (7.5) 7 (10.4) 32 (47.8) 31 (46.3) 24 (35.8) (Perez EA, et al. ESMO 2010. Abstract LBA3)

Proportion Progression Free T-DM1 vs Trastuzumab/Docetaxel : PFS 1.0 0.8 T/D (n = 70) 9.2 T-DM1 (n = 67) 14.2 Median PFS, Mos HR 95% CI 0.594 0.364-0.968 Log-Rank P Value.0353 0.6 0.4 0.2 0 0 2 4 6 8 10 12 14 16 18 20 Mos Patients at Risk, n T/D 70 66 63 53 43 27 12 4 2 2 0 T-DM1 67 60 51 46 42 35 22 15 6 3 0 (Hurvitz S, et al. ESMO 2011. Abstract 500)

1 st Line T-DM1 vs Trastuzumab/Docetaxel: Efficacy Summary % Response Rate 60 54,2 50 40 41,4 47,8 35,5 46,2 44,2 30 20 TrastDoce T-DM1 10 0 Overall Pretreated Untreated (Perez EA, et al. ESMO 2010. Abstract LBA3)

Phase III EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD Primary endpoints: PFS by IRF, OS, Safety Secondary en points: PFS by investigator, ORR, duration of response, time to symptom progression, QoL (FACT B) ClinicalTrials.gov. NCT00829166.

Safety and Selected Side Effects Incidence of Grade 3 AEs T-DM1 arm vs capecitabine + lapatinib arm: 40.8% vs. 57% LVEF <50% and 15-point decrease from baseline 1.7% vs 1.6% Verma S et al. N Engl J Med 2012;367:1783-1791

Percent Proportion progression-free Objective Response Rate and Duration of Response (DOR) in Patients with Measurable Disease ORR DOR 50 Difference: 12.7% (95% CI, 6.0, 19.4) P=0.001 43.6% 1.0 Median, mos (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM1 12.6 (8.4, 20.8) 40 30.8% 0.8 30 0.6 20 0.4 10 0.2 0 120/389 Cap + Lap 173/397 T-DM1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 No. at risk Cap + Lap 120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0 0 0 0 T-DM1 173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0 0 0 0 Verma S et al. N Engl J Med 2012;367:1783-1791

Progression-free Survival, as Assessed by an Independent Review Committee. Verma S et al. N Engl J Med 2012;367:1783-1791

Progression-Free Survival Subgroup Analyses Baseline characteristic Total n Cap + Lap T-DM1 Median, mos Median, mos HR (95% CI) T-DM1 better Cap + Lap better All pts 991 6.4 9.6 0.66 (0.56, 0.78) Age <65 yrs 65 yrs 853 138 6.0 8.1 9.8 7.0 0.62 (0.52, 0.74) 1.06 (0.68, 1.66) ER and PR status ER+ and/or PR+ ER and PR 545 426 7.1 5.6 9.0 10.3 0.72 (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third 118 361 512 5.7 6.8 6.5 10.8 9.6 9.0 0.51 (0.30, 0.85) 0.69 (0.53, 0.91) 0.69 (0.55, 0.86) Hazard ratio 0.2 0.5 1 2 5 HRs were from unstratified analysis. a Defined as any systemic therapy, including endocrine or chemotherapy.

Second Interim Analysis of Overall Survival. Verma S et al. N Engl J Med 2012;367:1783-1791

Patient-Reported Outcomes Time to Symptom Progression The FACT-Breast Trial Outcome Index 1 evaluates Physical Well-Being Functional Well-Being Breast Cancer-Specific Symptoms Symptom progression defined as 5-point decrease from baseline 1 Brady MJ, et al. J Clin Oncol 1997. Time to symptom progression Cap + Lap (n=445) T-DM1 (n=450) Median, mos 4.6 7.1 HR (95% CI) P value 0.80 (0.67, 0.95) 0.0121 Verma S et al. N Engl J Med 2012;367:1783-1791

Ongoing Investigations: HER2-Positive Metastatic Breast Cancer T-DM1 + pertuzumab T-DM1 vs investigator choice Pertuzumab Everolimus

Phase III MARIANNE 1 st Line Study: T-DM1 ± Pertuzumab in HER2+ MBC PD Trastuzumab + Taxane (n = 364) Patients with HER2+, previously untreated MBC (N = 1092) T-DM1 + Pertuzumab (n = 364) T-DM1 + Placebo (n = 364) Primary endpoints: PFS as assessed by IRF, AEs Superiority design with a noninferiority analyses Interim futility analysis: option to drop experimental arm Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR (Perez EA, et al. Abstr LBA3. ESMO 2010) Start recruitment 01/11/2010 End 29/02/2012 (n = 1.095)

TH3RESA: T-DM1 versus investigator choice (3rd line) HER2-positive (Centrally confirmed) LABC or MBC N=795 2:1 randomization T-DM1 q3w Until PD or unmanageable toxicity Treatment of physician s choice Primary endpoints: ORR and OS ORR: Based on n=489 with measurable disease at baseline per IRF Final OS: n=795, 496 events; one OS interim analysis at time of final ORR analysis Secondary endpoints: duration of response, PFS, patient-reported outcomes Stratification: World region, number of prior regimens, presence of visceral disease Key inclusion criteria: Prior anthracycline, taxane, capecitabine, lapatinib, and trastuzumab Progression on at least two regimens of HER2-directed therapy for MBC www.clinicaltrials.gov/ct2/show/nct01419197

Pherexa Trial: Trastuzumab + Capecitabine + Pertuzumab Trial Design HER2-positive MBC 2nd line, progressed on prior trastuzumab & a taxane-base CHT (n=450) 1:1 125 centers, 20 countries Start 26/01/2010 End 02/08/2013 Trastuzumab + capecitabine + placebo Trastuzumab + capecitabine + pertuzumab

mtor Inhibition May Overcome Trastuzumab Resistance Nutrients IGF-1R EGFR/HER2 Increased signaling through IGF-1R LKB1 AMPK PI3K PTEN AKT TSC1 TSC2 RHEB Truncated HER2 Constitutive PI3K/AKT activation Absent or low PTEN Elevated AKT or pakt Growth & proliferation Angiogenesis mtor Cell metabolism mtor inhibitor Downstream inhibition with mtor inhibitor counters these resistance mechanisms Synergy of mtor inhibition and trastuzumab in vitro and in vivo Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496. Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.

RANDOMISATION (2:1) BOLERO-1 (J2301): Phase III 1st Line Paclitaxel + Trastuzumab ± Everolimus [accrual complete] Eligibility Criteria (N=719) HER2-overexpressing, unresectable locally advanced, recurrent, or metastatic breast cancer No prior therapy for locally advanced or recurrent disease except hormonal therapy Everolimus 10.0 mg PO daily Paclitaxel 80 mg/m 2 IV on days 1, 8, 15 Trastuzumab 2 mg/kg a IV on days 1, 8, 15, 22 28-day cycles Placebo PO daily Paclitaxel 80 mg/m 2 IV on days 1, 8, 15 Trastuzumab 2 mg/kg a IV on days 1, 8, 15, 22 PFS (primary) OS ORR Safety PS Biomarkers Stratification by Prior adjuvant or neoadjuvant trastuzumab Visceral metastases Treatment until disease progression or unacceptable toxicity a After a loading dose of 4 mg/kg on day 1, cycle 1 (1 cycle = 28 days) ORR, overall response rate; OS, overall survival; PFS=progression-free survival; PS, performance status Hurvitz et al. J Clin Oncol 30, 2012 (suppl; abstr TPS648).

RANDOMISATION (1:1) BOLERO-3 (W2301): Vinorelbine + Trastuzumab ± Everolimus [accrual complete] Eligibility Criteria (N=530) HER2+ locally advanced or metastatic BC Prior taxane therapy and resistant to trastuzumab Everolimus 5.0 mg po daily Vinorelbine 25 mg/m 2 days 1, 8, 15 Trastuzumab 2 mg/kg b days 1, 8, 15 1 cycle = 21 days Placebo 5.0 mg po daily Vinorelbine 25 mg/m 2 days 1, 8, 15 Trastuzumab 2 mg/kg b days 1, 8, 15 PFS OS ORR CBR Safety PK Biomarkers Stratification by prior lapatinib Treatment until progression or intolerable toxicity a Trastuzumab resistance defined as progression on adjuvant trastuzumab 12 months of last infusion, or progression during or 4 weeks of receiving last dose of trastuzumab for metastatic disease. b After a loading dose of 4 mg/kg on day 1, cycle 1.

Treatment Options for HER2 Pos MBC in 2014 MBC HR + HR 1st Line Lapatinib + AI Trastuzumab + AI Trastuzumab + taxanes + Pertuzumab 2nd Line T-DM1 3rd Line Lapatinib + Trastuzumab Lapatinib + Capecitabine

Treatment Options for HER2 Pos MBC in 201? MBC HR + HR 1st Line Lapatinib + AI Trastuzumab + AI Trastuzumab + taxanes + Pertuzumab T-DM1 + Pertuzumab Trastuzumab +Vin or Pacli + Eve 2nd Line T-DM1 Pertuzumab + Trastuzumab + Capecitabine Trastuzumab + taxanes + Pertuzumab 3rd Line Lapatinib + Trastuzumab Lapatinib + Capecitabine T-DM1

Survival in Metastatic Breast Cancer. A Population Based Analysis 667 700 564 MORE 600 TOOLS, 438 450 500 D 400 A 300 Y 200 S MORE LIFE 100 0 1991-2 1994-5 1997-8 1999-01 Chia SKL et al. ASCO 2003, Abs 22