Deze presentatie is bedoeld voor het ontbijtsymposium tijdens de V&VN oncologiedagen en zijn gemaakt door I.O Baas.

Deze presentatie is bedoeld voor het ontbijtsymposium tijdens de V&VN oncologiedagen en zijn gemaakt door I.O Baas. Het ontbijtsymposium zal staan in het teken van de ontwikkelingen binnen HER2- positieve ziekte en wordt mede vormgegeven door de SIG Immuno-/targeted therapy en mede mogelijk gemaakt door Roche Nederland BV. Deze slide is enkel ter begeleiding van de clearance en niet voor presentatie bedoeld 1

RECENTE ONTWIKKELINGEN BINNEN DE BEHANDELING VAN HET GEMETASTASEERD HER2+ MAMMACARCINOOM dr. I.O.Baas, internist oncoloog Meander Medisch Centrum, Amersfoort

HER2 neu receptor Human Epidermal Growthfactor Receptor 2. Familie van 4 verschillende receptoren. Receptor in de celmembraan. Geamplificeerd in 15 20 % mammacarcinoom. Biologisch gedrag anders dan HER2-mammacarcinoom. 3

Gemiddelde overleving: HER2-positief 3 jaar HER2-negatief 6 7 jaar Slamon DJ et al. Science 1987;235:177 82

Trastuzumab (Herceptin) (2001) Gehumaniseerd anti-her2 monoklonaal antilichaam. Hoge affiniteit en specificiteit. 95% humaan, 5% muis: Minder immunogeen.

Landmark studie Slamon. NEJM 2001;344:783

anti-her2 targeting 1980 1998 2006 2007 2012 2013 2013 Recent improvements Discovery HER2 Trastuzmab 1st line Trastuzmab adjuvant Lapatinib 2nd line Pertuzumab 1st line T-DM1 2nd line Pertuzumab neo-adjuvant Modi. ASCO 2014 Annual Meeting

Toepasbaar in de kliniek anno 2014 Trastuzumab. Intraveneus. Subcutaan. Lapatinib. Pertuzumab. Trastuzumab-emtansine (T-DM1).

Pertuzumab Trastuzumab Lapatinib

Trastuzumab-emtansine (T-DM1) Antilichaam conjugaat. Bindt aan HER2- receptor zoals trastuzumab. Intracellulaire afgifte emtansine.

Adjuvant setting (en ook toepasbaar in gemetastaseerde setting)

Trastuzumab subcutaan Fixed dose 600 mg. Behandelduur 5 minuten i.p.v. 90 minuten. Geen i.v. toegang nodig. Gelijke toxiciteit en effectiviteit. Prijs nog gelijk. Toekomst? Trastuzumab in thuissetting (alleen in studieverband met een device Homerus).

Gemetastaseerde setting

Recente toepassingen in therapie

CLEOPATRA: Study design Placebo + trastuzumab (n = 406) PD Patients with HER2- positive mbc centrally confirmed (N = 808) R 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab (n = 402) PD Docetaxel* 6 cycles recommended Randomisation: Stratified by geographic region and prior treatment status ([neo]adjuvant chemotherapy received or not) Dosing: Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance q3w Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance q3w Docetaxel: 75 mg/m 2, escalating to 100 mg/m 2 if tolerated q3w *<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion PD, progressive disease Baselga J, et al. N Engl J Med 2012; 366:109 119.

CLEOPATRA: A global study Finland Mexico Canada USA Guatemala Costa Rica Ecuador Brazil UK Germany Latvia Poland France Croatia Spain Italy Macedonia Russian Federation South Korea Japan China Hong Kong Thailand Philippines Singapore Argentina Feb 2008: First patient in Jul 2010: Last patient in Baselga J, et al. N Engl J Med 2012; 366:109 119. 2008 2010 808 patients 212 investigators

CLEOPATRA: Significantly prolonged PFS with the pertuzumab-based regimen PFS (%) 100 90 80 70 60 50 40 30 20 10 0 Pertuzumab + trastuzumab + docetaxel: median 18.5 months Δ 6.1 months 12.4 18.5 Placebo + trastuzumab + docetaxel: median 12.4 months HR 0.62; 95% CI = 0.51, 0.75 p < 0.001 0 5 10 15 20 25 30 35 40 Time (months) n at risk 402 345 267 139 83 32 10 0 0 406 311 209 93 42 17 7 0 0 CI, confidence interval; HR, hazard ratio Baselga J, et al. N Engl J Med 2012; 366:109 119.

OS (%) Final OS Analysis Median follow-up 50 months (range 0 70 months) n at risk Ptz + T + D Pla + T + D 100 90 80 70 60 50 40 30 20 10 0 HR 0.68 95% CI = 0.56, 0.84 p = 0.0002 0 10 20 30 40 50 60 70 402 406 371 350 Time (months) ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 318 289 268 230 226 179 104 91 Ptz + T + D Pla + T + D Δ 15.7 40.8 months months 56.5 months Swain S, et al. Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Oral presentation at the 39th European Society for Medical Oncology (ESMO) congress, Madrid, Spain, 2014 (Abstract 350O_PR). 28 23 1 0

CLEOPATRA: No increase in incidence of LVSD with the addition of pertuzumab LVSD, n (%) Placebo, trastuzumab and docetaxel (n = 397) Pertuzumab, trastuzumab and docetaxel (n = 407) All grades 33 (8.3) 18 (4.4) Grade 2 15 (3.8) 10 (2.5) Grade 3* 11 (2.8) 5 (1.2) Symptomatic LVSD a 7 (1.8) 4 (1.0) * All symptomatic LVSD events (n = 11) were reported as LVSD grade 3. However, there were five patients with grade 3 LVSD (placebo arm, n = 4; pertuzumab arm, n = 1) that was not deemed to be symptomatic by the investigator Assessment of NCI-CTCAE grade was missing for one patient Data cut-off: May 2011 LVSD, left ventricular systolic dysfunction Swain SM, et al. Oncologist 2013; 18:257 264. Swain SM, et al. Oncologist 2013; 18:257 264.

CLEOPATRA conclusions Important OS gain (15,7 months). Preferred option in first line treatment. No increase in cardiac toxicity. 90% trastuzumab naive. 55% chemotherapy naive. No prior anti-her2 for MBC allowed. Prior endocrine treatment for MBC allowed. Baselga. NEJM 2012; 366: 109 Swain. Lancet Oncol 2013; 14: 461/ Swain S, et al. Final overall survival analysis from the CLEOPATRA study. Oral presentation at the 39th European Society for Medical Oncology (ESMO) congress, Madrid, Spain, 2014 (Abstract 350O_PR).

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 Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Verma. NEJM 2012;367:1783

EMILIA progression-free survival Median (mos) No. events Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.65 (95% CI, 0.55, 0.77) P<0.0001 Verma. NEJM 2012;367:1783

EMILIA overall survival Median (mos) No. events Cap + Lap 25.1 182 T-DM1 30.9 149 HR=0.68 (95% CI, 0.55, 0.85) P<0.0001 Verma. NEJM 2012;367:1783

EMILIA conclusions Five months overall survival benefit. Comparator arm was not approved in the Netherlands. Mixed study population: 12% first line 36% second line 52% third line or higher ±15% no trastuzumab for MBC Viable treatment option in second/third line. Verma. NEJM 2012;367:1783

TH3RESA study design Krop. Lancet Oncol 2014;15:689

TH3RESA progression-free survival Krop. Lancet Oncol 2014;15:689

TH3RESA conclusions Similar PFS benefit as Emilia (3 months). OS results not yet mature. True third line and above. Krop. Lancet Oncol 2014;15:689

Conclusies / Take home message Adjuvant setting: Trastuzumab subcutaan. Thuistoediening, wordt op dit moment onderzocht in de Homerus studie. Gemetastaseerde setting: 1 e lijn docetaxel, trastuzumab en pertuzumab. OS voordeel 15,7 maanden. Opties daarna: Trastuzumab beyond progression Plaats pertuzumab? Trastuzumab-emtansine/T-DM1 Lapatinib 28

Toekomst Combinatie: Andere cytostatica met pertuzumab/trastuzumab. T-DM1 + pertuzumab 1e Lijn: Marianne studie. Nieuwe middelen: anti-pd(l)1 HER1-4 blockade chemotherapie + antihormonale therapie en anti-her therapie

Trastuzumab Pertuzumab Trastuzumab-emtansine/T-DM1

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