Neues aus San Antonio 2017 Therapie des frühen Mammakarzinoms (neo )adjuvant C.A. Hanusch
Topics 1 GS3 05: Survival analysis of the prospectively randomized phase III GeparSepto trial GS3 04: A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane anthracycline chemotherapy, for early HER2 positive breast cancer (the SOLD study). Incidence and management of diarrhea with adjuvant Pertuzumab and Trastuzumab in HER2 positive breast cancer
Topics 2 Pharmacokinetic results of a subcutaneous injection of Trastuzumab into the thigh versus into the abdominal wall in patients with HER2 positive primary breast cancer (BC) treated within the neo /adjuvant GAIN 2 study Efficacy and safety of subcutaneous or intravenous Trastuzumab in patients with HER2 positive early breast cancer after 5 years treatment free follow up: Final analysis from the phase III, open label, randomized HannaH study A phase Ib dose finding study of subcutaneous Pertuzumab in combination with subcutaneous Trastuzumab in healthy male volunteers and female patients with early breast cancer
GS3 05: Survival analysis of the prospectively randomized phase III GeparSepto trial GeparSepto: Überträgt sich die signifikant höhere pcr Rate mit nab-pac in ein besseres DFS?
Schneeweiss A, et al. SABCS 2017 (GS3-05)
Schneeweiss A, et al. SABCS 2017 (GS3-05)
Schneeweiss A, et al. SABCS 2017 (GS3-05)
Schneeweiss A, et al. SABCS 2017 (GS3-05)
Schneeweiss A, et al. SABCS 2017 (GS3-05)
Schneeweiss A, et al. SABCS 2017 (GS3-05)
Fazit pcr Rate gesteigert mit nabpaclitaxel vs. lösl. Paclitaxel als Teil einer sequenziellen Anthracyclin/Taxan basierten Chemotherapie Höhere pcr Rate übersetzt sich in ein signifikant und klinisch relevant verbessertes rezidivfreies Überleben (HR=0.69, log rank p=0.0044) Auch Pat. mit Ki67 <20% bzw. non pcr profitieren bez. DFS von nab Paclitaxel Rate peripherer Neuropathien unter nabpaclitaxel nach Dosisreduktion gesenkt: Grad ¾: 150/ 125 (mg/m2 KOF) 15%/ 8% (nach 464 rekrutierten Pat.)
A randomized phase III study of adjuvant Trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant Taxane Anthracycline chemotherapy, for early HER2 positive breast cancer The Synergism Or Long Duration (SOLD) trial Joensuu H et al. Oral Session General Session 3 Abstract No. GS3 04
SOLD Hypothesis Administration of Trastuzumab concomitantly with a Taxane for a brief time period is not inferior in terms of DFS as compared with the standard treatment*, and may be less cardiotoxic *Standard: Chemotherapy plus 12 months of anti HER2 directed treatment ± endocrine therapy 17 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Design T for 9 wks* Docetaxel (D) 80/100 mg/m 2 F 600 E 75 C 600 iv 3 wkly iv 3 wkly Trastuzumab (T) D D D F E C F E C F E C R D D D F E C F E C F E C In both groups: Locoregional RT given according to the institutional practice Endocrine therapy for a minimum of 5 yrs when cancer ER/PR + ve T for 9 wks* T to complete 1 year of administration** *Wkly iv, or 3 wkly either iv or sc; **14 times 3 weekly, either iv or sc 18 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Patient disposition Category 9 weeks no. (%) 1 year no. (%) Randomized (Jan 2008 to Dec 2014) 1,087 1,089 Included ITT Population* 1,085 1,089 Withdrew consent 0 (0) 0 (0) Had distant metastases at study entry 2 (0) 0 (0) Received study treatment (Safety Population) 1,084 1,089 *ITT, Intention to treat 19 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Key baseline characteristics Characteristic 9-week group (n=1,085) 1-year group (n=1,089) Median age (range) years (range) 56 (23-82) 56 (27-79) Premenopausal 33% 33% Breast tumor diameter 10 mm 12% 14% 11-21 mm 44% 42% 21-50 mm 41% 42% >50 mm 3% 3% Axillary lymph nodes with cancer 0 60% 60% 1-3 30% 29% >3 11% 11% Ductal histological type 92% 92% Estrogen receptor-positive 66% 66% Progesterone receptor-positive 46% 47% 20 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD DFS events and deaths (ITT) Event 9-wk group (n=1,085) n(%) 1-yr group (n=1,089) n (%) Any recurrence or death 140 (13) 105 (10) Distant recurrence 73 (7) 61 (6) Locoregional recurrence 17 (2) 13 (1) Contralateral BC 15 (1) 7 (1) Second cancer 27 (3) 24 (2) Death without cancer 14 (1) 5 (0) Death from any cause 58 (5) 44 (4) Death from BC 34 (3) 33 (3) Death from another cause 24 (2) 11 (1) 21 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Disease free survival 100 90.5%* Chemo: 3 x Doc q3w 3 x FEC q3w, N=2,176 80 88.0%* Non inferiority instead of superiority study design Alive, no recurrence (%) 60 40 HR 1.39 (90% Cl 1.12 1.72) 51 weeks 9 weeks Non inferiority margin 1.385 20 Non inferiority could not be demonstrated 0 Number at risk 0 2 4 6 8 10 Years 1085 1089 1013 1047 707 742 373 394 76 82 0 0 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Hazard Ratio *5 year DFS estimate 22 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Overall survival 95.9%* 94.7%* Proportion alive (%) 51 weeks 9 weeks HR 1.36 (90% Cl 0.98 1.89) Number at risk 1085 1089 1047 1078 761 786 Years 408 421 81 87 0 0 *5 year survival estimate 23 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Distant disease free survival 94.2%* Proportion without distant recurrence (%) HR 1.24 (90% Cl 0.93 1.65) 93.2%* 51 weeks 9 weeks Number at risk 1085 1089 1025 1056 723 760 Years 393 409 80 83 0 0 *5 year DDFS estimate 24 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Predefined subgroup analyses for DFS Subgroup ER status Negative Positive Hazard Ratio (90% Cl) p (interaction) 1.57 (1.14 2.17) 1.28 (0.96 1.69) 0.424 Docetaxel dose 80 mg/m 2 100 mg/m 2 1.66 (1.30 2.11) 0.67 (0.41 1.10) 0.007 Nodes with cancer 0 1 3 3+ Centre accrual Age <100 patients 100 patients <50 yrs 50 yrs 1.31 (0.95 1.80) 1.83 (1.22 2.74) 1.24 (0.82 1.85) 0.460 1.40 (1.06 1.83) 1.37 (0.98 1.93) 0.949 1.08 (0.76 1.53) 1.61 (1.23 2.11) 0.137 25 Stage I II III 1.46 (0.96 2.22) 1.54 (1.12 2.11) 1.21 (0.81 1.79) 0.724 0 0.5 1 1.5 2 2.5 3 Favors 9 weeks Favors 1-year Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD DFS: Docetaxel dose 80 mg/m 2 91.3%* Proportion alive without recurrence (%) HR 1.66 (90% Cl 1.30 2.11) 86.8%* 51 weeks 9 weeks Number at risk 843 835 765 808 545 568 Years 309 317 70 77 0 0 *5 year DFS estimate 26 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD DFS: Docetaxel dose 100 mg/m 2 Proportion alive without recurrence (%) HR 0.71 (90% Cl 0.44 1.14) 87.8%* 92.2%* 51 weeks 9 weeks Number at risk 242 254 228 239 162 174 Years 64 77 5 5 0 0 *5 year DFS estimate 27 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Treatment safety Chemotherapy related toxicity generally similar and expected in the 2 groups 9-week group n (%) 1-year group n (%) Discontinued Chemotherapy 44 (4.1) 51 (4.7) Discontinued Trastuzumab 96 (8.9) -53% for toxicity 217 (19.9) -66% for toxicity Died from treatment-related cause 2 (0.2) 2 (0.2) 28 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Cardiac safety Less cardiac toxicity was observed in the 9 week group Event 9-week group n (%) 1-year group n (%) Any protocol-defined cardiac adverse event* 22 (2.0) 42 (3.9)** Congestive heart failure 21 (1.9) 36 (3.3)*** *Any Gr. 3 or 4 cardiac event; symptomatic cardiac failure; cardiac failure requiring medical management; LVEF decrease >10 percentage points and to a value <50%; LVEF decrease to <45% from any baseline value, ** p=0.012; ***p=0.046 29 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD MeanLVEF stratified by the treatment group 9 weeks LVEF (%) 51 weeks p<0.001 Time after study entry LVEF, Left ventricular ejection fraction 30 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
SOLD Conclusions Non inferiority of 9 weeks of adjuvant Trastuzumab plus Chemotherapy could not be demonstrated as compared to 1 year of Trastuzumab plus Chemotherapy in terms of DFS Patients treated with the 9 week duration had fewer cardiac events and had the LVEF better maintained Docetaxel dosing with Trastuzumab requires further study Chemotherapy plus 1 year of anti HER2 therapy should remain the standard 31 Mod. Joensuu H et al. SABCS 2017, Oral Session General Session 3, Abstract No. GS3 04
Incidence and management of diarrhea with adjuvant Pertuzumab and Trastuzumab in HER2 positive breast cancer Bines J et al. Poster Session 1 Treatment: Adjuvant Therapy Abstract No. P1 13 07
APHINITY Inzidenz der Diarrhoe nach Therapiezyklus Percentage of patients with an event Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy No. at risk Targeted treatment cycle 2,364 2,335 2,329 2,317 2,306 2,302 2,285 2,281 2,265 2,257 2,253 2,241 2,246 2,231 2,233 2,225 2,210 2,211 2,200 2,200 2,193 2,194 2,185 2,190 2,165 2,178 2,151 2,136 2,109 2,169 2,159 2,129 2,051 1,658 2,051 1,700 De Azambuja E et al., SABCS 2017 33 Mod. Bines J et al. SABCS 2017, Poster Session 1 Treatment: Adjuvant Therapy, Abstract No. P1 13 07
APHINITY Inzidenz der Diarrhoe nach Therapiezyklus und Art der Chemotherapie Percentage of patients with an event Pertuzumab + Trastuzumab + Anthracycline Placebo + Trastuzumab + Anthracycline Pertuzumab + Trastuzumab + Non Anthracycline Placebo + Trastuzumab + Non Anthracycline No. at risk Targeted treatment cycle 34 1,834 1,824 528 510 1,813 1,815 514 501 1,798 1,806 506 495 1,783 1,788 500 492 1,764 1,765 499 491 1,755 1,751 496 489 1,751 1,744 493 486 1,741 1,742 490 482 1,721 1,730 487 480 1,713 1,719 485 480 1,708 1,716 483 477 1,703 1,713 480 476 1,689 1,701 474 476 1,677 1,666 1,646 1,608 1,692 1,685 1,659 1,602 Frauenklinik 472 468 Taxisstraße461 441 476 473 469 448 De Azambuja E et al., SABCS 2017 1,312 1,336 345 364 Mod. Bines J et al. SABCS 2017, Poster Session 1 Treatment: Adjuvant Therapy, Abstract No. P1 13 07
APHINITY Inzidenz und Management der Diarrhoe Anthracycline-based chemotherapy Pertuzumab + Trastuzumab n=1,834 Placebo + Trastuzumab n=1,894 Non-Anthracycline-based chemotherapy Pertuzumab + Trastuzumab n=528 Placebo + Trastuzumab n=510 Incidence and severity Total number of patients with at least one event (%) 1,235 (67.3) 772 (40.8) 447 (84.7) 314 (61.6) Total number of events 2,527 1,282 883 508 Total number of patients with at least one NC1-CTCAE grade 3 event (%) 137 (7.5) 59 (3.1) 95 (18.0) 31 (6.1) Total number of NCI-CTCAE grade 3 events 147 60 113 35 Treatment period, total number of patients with at least one event (%) Anthracycline* 296 (16.1) 278 (14.7) HER2-targeted therapy + Taxane¹ 1,006 (54.9) 513 (27.1) 444 (84.1) 301 (59.0) HER2-targeted treatment post-chemotherapy 373 (20.3) 175 (9.2) 55 (10.4) 46 (9.0) De Azambuja E et al., SABCS 2017 All presented data based on the preferred term diarrhea ; *The incidence of diarrhea is based on anthracycline based chemotherapy only as Frauenklinik no Pertuzumab Taxisstraße or Placebo was given concurrently with an Anthracycline. ¹Docetaxel only in the Non Anthracycline groups. 35 Mod. Bines J et al. SABCS 2017, Poster Session 1 Treatment: Adjuvant Therapy, Abstract No. P1 13 07
Safety of adjuvant treatment with Pertuzumab plus Trastuzumab after neoadjuvant Anthracycline based chemotherapy in patients with HER2 positive localized breast cancer: Updated results from the BERENICE study Dang C et al. Poster Session 5 Treatment: Her2 targeted therapy Abstract No. P5 20 04
BERENICE Studie Adjuvantes Trastuzumab/Pertuzumab nach anthrazyklinhaltiger NACT (ddac q2w Pacli q1w vs. FEC q3w Docetaxel q3w, N=397) General AEs (safety population) Overall treatment period n=199 Cohort A (ddac TPH) Adjuvant treatment period n=181 Overall treatment period n=198 Cohort B (FEC DPH) Data are number of patients (%). AE. adverse events; ddac. dose dense Doxorubicin plus Cyclophosphamide; DPH. Docetaxel. Pertuzumab. and Trastuzumab; FEC. Fluorouracil. Frauenklinik Epirubicin. Taxisstraße and Cyclophosphamide; TPH. Paclitaxel, Pertuzumab. and Trastuzumab. Adjuvant treatment period n=190 Any AE 198 (99.5) 171 (94.5) 198 (100.0) 171 (90.0) Grade 3 AE 109 (54.8) 23 (12.7) 126 (63.6) 40 (21.1) Serious AE 54 (27.1) 15 (8.3) 61 (30.8) 17 (8.9) AE leading to P or H discontinuation 19 (9.5) 9 (5.0) 14 (7.1) 11 (5.8) Diarrhea (any grade) 144 (72.4) 26 (14.4) 148 (74.7) 45 (23.7) Diarrhea (grade 3) 6 (3) 0 (0) 22 (11.1) 2 (1.1) 37 Mod. Dang C et al. SABCS 2017, Poster Session 5 Treatment: Her2 targeted therapy, Abstract No. P5 20 04
Take Home Message Die Rate der Diarrhoe unter CTX plus Trastuzumab + Pertuzumab ist im Vgl. zu Trastuzumab erhöht Erhebliche Verbesserung nach Absetzen der CTX APHINITY: Gesteigerte Diarrhoe unter Anthrazyklin freier CTX durch den alleinigen Einsatz von Docetaxel bedingt 38
Pharmacokinetic results of a subcutaneous injection of Trastuzumab into the thigh versus into the abdominal wall in patients with HER2 positive primary breast cancer (BC) treated within the neo /adjuvant GAIN 2 study Möbus V et al. Poster Session 5 Treatment: Her2 targeted therapy Abstract No. P5 20 09
GAIN 2 Studie PK Resultate s.c. Applikation von Trastuzumab N=220 N=2886 Pertuzumab i.v.* Trastuzumab i.v.** 3 weeks Neo /Adjuvant ( 1000 pa ents) R E E E np np np C C C Epirubicin 150 mg/m² q2w nab Paclitaxel 330 mg/m² q2w Cyclophosphamide 2000 mg/m² q2w Pertuzumab i.v.* Trastuzumab i.v.** R Trastuzumab s.c. Abdominal wall Trastuzumab s.c. 600 mg q3w*** Trastuzumab s.c. Thigh Trastuzumab s.c. 600 mg q3w.*** *Pertuzumab i.v. (if HER2 positive and neoadjuvant): Starting dose 840 mg q3w, thereafter 420 mg q3w. **Trastuzumab i.v. (if HER2 positive and neoadjuvant or adjuvant): Starting dose 8 mg/kg BW q3w, thereafter 6 mg/kg BW q3w ***Therapy duration Trastuzumab i.v. and s.c. totally 1 year E E E E C C C C 1 week rest D D D D Epirubicin Starting dose. 90 mg/m² q2w Dose levels (min./max.) Level 3: 38 mg/m² q2w Level + 2: 120 mg/m² q2w Cyclophosphamide Starting dose: 600 mg/m² q2w Dose levels (min./max.) Level 3: 450 mg/m² q2w Level +2: 1200 mg/m² q2w Docetaxel Starting dose: 75 mg/m² q2w Dose levels (min./max.) Level 1: 60 mg/m² q2w Level + 2: 100 mg/m² q2w 40 Mod. Möbus V et al. SABCS 2017, Poster Session 5 Treatment: Her2 targeted therapy, Abstract No. P5 20 09
GAIN 2 Studie PK Resultate s.c. Applikation von Trastuzumab Mean plasma concentration time profile of the s.c. Trastuzumab Thigh Abdw Concentration (ug/ml) Time (days) 41 Mod. Möbus V et al. SABCS 2017, Poster Session 5 Treatment: Her2 targeted therapy, Abstract No. P5 20 09
Take Home Message GAIN 2 Bestätigung der besseren Bioverfügbarkeit und daraus resultierenden Plasmaspiegel nach Applikation von Trastuzumab SC in den Oberschenkel vs. die Bauchdecke Damit Bestätigung der Zulassung von Trastuzumab SC 42
Efficacy and safety of subcutaneous or intravenous Trastuzumab in patients with HER2 positive early breast cancer after 5 years treatment free follow up: Final analysis from the phase III, open label, randomized HannaH study Jackisch C et al., Poster Discussion Novel Drugs / Predicting Response for HER2+ Breast Cancer Abstract No. PD3 11
HannaH Trial Trastuzumab s.c., 5 J FU, finale EFS by tpcr status (ITT population) Analyse Treatment Estimated Probability tpcr 6 year event free rate (95% Cl) HIV 0.83 (0.76, 0.91) H SC 0.82 (0.74, 0.89) H IV / tpcr H SC / tpcr H IV / non tpcr H SC / non tpcr No tpcr 0.57 (0.49, 0.64) 0.54 (0.47, 0.62) No. at risk 94 203 108 186 93 170 105 159 81 143 98 133 76 124 86 116 Months 74 107 79 92 70 99 76 87 51 52 42 44 0 0 0 0 EFS, event free survival; H IV, intravenous Trastuzumab; H SC, subcutaneous Trastuzumab: ITT, intent to treat population: tpcr, total pathologic complete response 44 Mod. Jackisch C et al. SABCS 2017, Poster Discussion Novel Drugs / Predicting Response for HER2+ Breast Cancer, Abstract No. PD3 11
Take Home Message HannaH Überlebensvorteil (EFS/OS) nach pcr bestätigt Konsistente Resultate hinsichtlich der Äquieffektivität von Trastuzumab s.c. vs. i.v. Keine neuen Safety Signale 45
A phase Ib dose finding study of subcutaneous Pertuzumab in combination with subcutaneous Trastuzumab in healthy male volunteers and female patients with early breast cancer Kirschbrown WP et al. Poster Session 5 Treatment: Her2 targeted therapy (presenter: Whitney P) Abstract No. P5 20 07
Take Home Message Pertuzumab s.c. Pertuzumab s.c. ähnliche PK wie Pertuzumab i.v. Kombination von Pertuzumab s.c. und Trastuzumab s.c. ohne beeinträchtigende Wirkung aufeinander Phase 3 Studie mit dualer Blockade s.c. als fixe Dosis in Planung FPI Juni 47
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