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 HER2positieve 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
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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.
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Gemiddelde overleving:
Slamon DJ et al. Science 1987;235:177–82
HER2-positief
3 jaar
HER2-negatief
6–7 jaar
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 adjuvant Trastuzmab 1st line
Modi. ASCO 2014 Annual Meeting
Pertuzumab 1st line Lapatinib 2nd line
Pertuzumab neo-adjuvant T-DM1 2nd line
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 HER2receptor 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) Patients with HER2positive mBC centrally confirmed (N = 808)
PD
Docetaxel*
≥6 cycles recommended
1:1 R Pertuzumab + trastuzumab (n = 402) 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/m2, escalating to 100 mg/m2 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.
PD
CLEOPATRA: A global study
Finland Canada UK Germany France
Poland
Croatia
Spain
USA
Russian Federation
Latvia
Italy
South Korea
Macedonia
Japan
China Hong Kong
Mexico
Thailand Philippines
Guatemala Costa Rica Ecuador
Singapore Brazil
Argentina
Feb 2008: First patient in 2008
Jul 2010: Last patient in 2010
808 patients 212 investigators Baselga J, et al. N Engl J Med 2012; 366:109–119.
CLEOPATRA: Significantly prolonged PFS with the pertuzumab-based regimen
PFS (%)
Pertuzumab + trastuzumab + docetaxel: median 18.5 months
100 90 80 70 60 50 40 30 20 10 0
Placebo + trastuzumab + docetaxel: median 12.4 months
HR 0.62; 95% CI = 0.51, 0.75 p < 0.001
12.4 0
n at risk 402 406
Δ 6.1 months
5
10
15
345 311
267 209
139 93
CI, confidence interval; HR, hazard ratio Baselga J, et al. N Engl J Med 2012; 366:109–119.
18.5
20 25 Time (months) 83 42
32 17
30
35
40
10 7
0 0
0 0
Final OS Analysis Median follow-up 50 months (range 0–70 months)
100
Ptz + T + D
90
Pla + T + D
80 70 60 50 40 30 HR 0.68 95% CI = 0.56, 0.84 p = 0.0002
OS (%)
20
10
40.8 months
Δ 15.7 months
56.5 months
0
0
10
20
Ptz + T + D
402
371
318
Pla + T + D
406
350
289
n at risk
30 Time (months)
40
50
60
70
268
226
104
28
1
230
179
91
23
0
ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 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).
CLEOPATRA: No increase in incidence of LVSD with the addition of pertuzumab 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 LVSDa
7 (1.8)
4 (1.0)
LVSD, n (%)
* 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) • •
Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx
T-DM1 3.6 mg/kg q3w IV
PD
1:1
Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w
+ Lapatinib
PD
1250 mg/day orally qd
• 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: • 1e lijn docetaxel, trastuzumab en pertuzumab. – OS voordeel 15,7 maanden.
• Opties daarna: – – – –
Trastuzumab beyond progression Plaats pertuzumab? Trastuzumab-emtansine/T-DM1 Lapatinib
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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
Wat is de beste opstelling?
