HER2: Target sempre più importante ed aggredibile

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1 Passato, Presente e Futuro: Evoluzione Diagnosi e Cura del Carcinoma della Mammella Cagliari, 4-5 luglio 2014 HER2: Target sempre più importante ed aggredibile Carlo Barone Oncologia Medica Università Cattolica del S. Cuore

2 Slide 2

3 HER2+ MBC: Key Treatment Options Trastuzumab Pertuzumab Ado-trastuzumab emtansine (T-DM1) Everolimus Lapatinib Tras beyond progression Dual blockade Combination therapy Chemotherapy Anti-oestrogen mtor inhibitors Subcutaneous Trastuzumab

4 Clinical Pathway: HER2 positive MBC, 2007 Clinical Pathway: HER2 Positive MBC,<br />2007

5 Paradigm Shift: Continuing Trastuzumab after Progression? Paradigm Shift: Continuing Trastuzumab After Progression?

6 Slide 10

7 Observational Hermine Study: Efficacy of Tras after Progression in Clinical Practice Extra JM et al, The Oncologist 2010

8 COMPLETE: Trastuzumab o Lapatinib until PD HER2-positive MBC 1st-line therapy Prior (neo)adjuvant chemotherapy and Trastuzumab were allowed (n=636) R 24 weeks Trastuzumab +Taxane, continuation of Trastuzumab until PD (n=318) 24 weeks Lapatinib +Taxane, continuation of Lapatinib until PD (n=318) Interim Analysis of NCIC CTG MA.31/GSK EGF Gelmon K et al. Abstract LBA671 ASCO 2012

9 COMPLETE: Trastuzumab o Lapatinib until PD Primary Endpoint Lapatinib arm Trastuzumab arm HR Median PFS 8.8 months 11.4 months HR=1.33, 95% CI , p=0.01) Median PFS (HER2+ centrally confirmed 9.0 months 13.7 months HR=1.48, 95% CI , p=0.003 Secondary Endpoint Lapatinib arm Trastuzumab arm HR OS: immature but trend vs Trastuzumab HR=1.25, 95% CI , p=0.32 Safety Lapatinib arm Trastuzumab arm Diarrhea 80% 35% Rash 55% 35% SAEs (n) Gelmon K et al. Abstract LBA671 ASCO 2012

10 Preclinical Synergy Of Lapatinib + Trastuzumab In HER2+ Tumor Xenografts Presented By Shanu Modi at 2014 ASCO Annual Meeting

11 Pivotal EGF Phase III Study: Dual HER2 Blockade in MBC Patients with HER2+ (FISH/IHC3+) MBC and progression on anthracycline, taxane, and trastuzumab Lapatinib 1500 mg/day PO (n = 148) Lapatinib 1000 mg/day PO + Trastuzumab 4 mg/kg 2 mg/kg IV wkly (n = 148) Primary endpoint: PFS Secondary endpoints: OS, ORR, clinical benefit Patients with progression after 4 wks of lapatinib monotherapy allowed to cross over to receive trastuzumab Blackwell KL, et al. J Clin Oncol. 2010;28:

12 Lapatinib + Trastuzumab dual therapy is superior to Lapatinib monotherapy <br />Lapatinib + Trastuzumab dual therapy is superior to Lapatinib monotherapy

13 EGF Phase III Study of Dual HER2 Blockade in MBC: OS OS (%) % 80% 6-mo OS 41% 56% 12-mo OS L + T (n = 146) L (n = 145) Median OS, mos HR (95% CI) 0.74 ( ) Stratified log-rank P value % of patients in the L arm crossed over to L + T Pts at risk, n L 1000/T L Mos From Randomization Blackwell KL, et al. J Clin Oncol. 2012;30:

14 Clinical Pathway: HER2 positive MBC, 2009 Clinical Pathway: HER2 Positive MBC,<br />2009

15 Phase III CLEOPATRA Study: Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC Stratified by geographic region and previous (neo)adjuvant chemotherapy Primary endpoint: PFS (independently assessed) Secondary endpoints: PFS (investigator assessment), ORR, OS, Safety Women with previously untreated, HER2- positive locally recurrent/metastatic breast cancer (N = 808) Trastuzumab 6 mg/kg q3w* + Docetaxel mg/m 2 q3w + Pertuzumab 420 mg q3w (n = 402) Trastuzumab 6 mg/kg q3w* + Docetaxel mg/m 2 q3w + Placebo q3w (n = 406) Treatment until disease progression or unacceptable toxicity *Trastuzumab 8-mg/kg loading dose. Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptable toxicity or PD. Pertuzumab 840-mg loading dose. Baselga J, et al. N Engl J Med. 2012;366:

16 CLEOPATRA: Significant improvement in PFS and OS with Pertuzumab CLEOPATRA: Significant improvement in PFS and OS with Pertuzumab

17 Phase II Study: Paclitaxel + Trastuzumab + Pertuzumab for HER2+ MBC Slide 19

18 Progression-Free Survival Med FU of 15 mo Progression-Free Survival<br />Med FU of 15 mo

19 Clinical Pathway: HER2 positive MBC, 2012 Clinical Pathway: HER2 Positive MBC,<br />2012

20 Ado Trastuzumab Emtansine (T-DM1) Ado Trastuzumab Emtansine <br />(T-DM1)

21 Phase III EMILIA Study: T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC EMILIA Study Design

22 EMILIA Study of T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC: PFS (IRC) Progression-Free Survival <br />by Independent Review

23 EMILIA Study of T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC: OS Slide 26

24 TH3RESA Study Schema TH3RESA Study Schema

25 TH3RESA Study: PFS by Investigator Assessment PFS by Investigator Assessment

26 TH3RESA Study: First OS Analysis First Interim OS Analysis

27 Clinical Pathway: HER2 positive MBC, 2013 Clinical Pathway: HER2 Positive MBC, <br />2013

28 Phase III BOLERO-3: Trastuzumab and Vinorelbine ± Everolimus in HER2+ BC Multicenter, randomized, double-blind study Anticipated recruitment (N = 572) Women 18 yrs old HER2+ advanced BC Progression during trastuzumab treatment Everolimus 5 mg/day + Vinorelbine 25 mg/m 2 IV on Days 1, 8, 15 + Trastuzumab 2 mg/kg IV* on Days 1, 8, 15 Placebo daily + Vinorelbine 25 mg/m 2 IV on Days 1, 8, 15 + Trastuzumab 2 mg/kg IV* on Days 1, 8, 15 Primary Endpoint PFS Secondary Endpoints OS ORR Clinical benefit rate Toxicity Patients were stratified by previous lapatinib use ( 6 wks of treatment) Granulocyte colony stimulating factor support allowed following febrile neutropenia *After a loading dose of 4 mg/kg on Day 1, Cycle 1; 1 cycle = 21 days. ClinicalTrials.gov. NCT

29 Trastuzumab/Vinorelbine ± Everolimus in HER2+ BC (BOLERO-3): PFS PFS (%) Median PFS Everolimus: 7.00 mos Placebo: 5.78 mos HR: 0.78 (95% CI: ; log-rank P =.0067) Censoring Times Everolimus (n/n = 196/284) Placebo (n/n = 219/285) Wks O Regan R, et al. ASCO Abstract 505.

30 Cross-Talk Between Signal Transduction and Endocrine Pathways Cross-Talk Between Signal <br />Transduction and Endocrine Pathways

31 Clinical Evidence for Co-Targeting Growth Factor Receptors in ER+ MBC Slide 33

32 Phase III, Randomized, Double-Blind Controlled Trial: Study Design Phase III, Randomized, Double-Blind Controlled Trial: Study Design

33 HER2+ Population: Improved PFS; No OS Benefit HER2+ Population:<br />Improved PFS Survival; No OS Benefit <br />

34 Current 2014 Guideline Current 2014 Guideline

35 Neoadjuvant therapy confirms the value of Dual Bockade and Combination Therapy and less favourable outcome of HR +ve pts Study Phase CT Main Results GeparQuinto III EC TXT pcr: higher Tras than with Lap NeoALTTO III TXL pcr: higher with Tras+Lap HR ve better than HR +ve NeoSphere III TXT FEC pcr: higher with Per+Tras HR ve better than HR +ve Tryphaena II FEC TXT TC Low rate of LVSD with Tras+Per HR ve better than HR +ve TRIO-US II TXT+CBDCA pcr: higher with Lap+Tras o Tras HR ve better than HR +ve CHERLOB II TXL FEC pcr: higher with Tras+Lap

36 Summary of HER2+ MBC: What Do We Know Summary of HER2+ MBC:<br />What Do We Know

37 Summary of HER2+ MBC: What Do We Need to Know What Do We Need to Know

38 Development of a subcutaneous formulation of trastuzumab Subcutaneous administration of trastuzumab has been made possible by the use of recombinant human hyaluronidase as an excipient Subcutaneous administration of large volumes is restricted by the structure and physiology of the subcutaneous layer Contains a matrix of hyaluronan fibres and collagen fibres, which limits subcutaneous administration to <1 ml Hyaluronan is broken down by the naturally occurring enzyme, hyaluronidase, on a daily basis Recombinant human hyaluronidase (rhuph20) causes temporary and local degradation of hyaluronan Results in a temporary increase in the local subcutaneous dispersion area, enabling large volumes of fluids to be administered After subcutaneous administration, skin returns to normal Haller MF. Pharm Tech 2007; 10:

39 BP22023: Phase I dose finding/dose confirmation of trastuzumab SC " Open-label, 2-part, phase I/Ib dose-finding and dose confirmation study " Conducted at 2 centers in New Zealand and 1 in Australia " Patient population " 24 healthy male volunteers and 42 female patients with HER2-positive breast cancer Primary objective " To select the dose of trastuzumab SC that results in comparable exposure to trastuzumab IV at 6 mg/kg in healthy male volunteers and in patients with HER2-positive EBC " Evaluated by analyzing the area under the serum concentration time curve (AUC) Secondary objective " To assess the safety and tolerability of IV and SC trastuzumab in healthy male volunteers and patients with HER2-positive EBC Wynne C, et al. J Clin Pharmacol. 2013;53:

40 Exposure to trastuzumab comparable for 8 mg/kg SC vs. 6 mg/kg IV in pts with HER2-positive EBC 250 Mean trastuzumab concentration (µg/ml) mg/kg IV 8 mg/kg SC Mean (± SD) trastuzumab concentration-time profile in all cohorts. C trough for 600 mg trastuzumab subcutaneous predicted to be comparable or higher than trastuzumab IV from Cycle 1 onwards Nominal time (h) Graphical elaboration Wynne C, et al. J Clin Pharmacol. 2013;53: Wynne C.., et al. ESMO 2010 Poster n. 218 Available at - Last accessed on September 2013

41 Hannah: Randomised, open-label, Phase III, noninferiority study to compare PK, efficacy and safety of Tras SC and IV in HER2-positive EBC trastuzumab SC HER2- positive EBC (N=596) R 1:1 trastuzumab IV Surgery Follow-up: 60 mo* (24 mo for EFS, OS) trastuzumab SC Fixed dose of 600 mg (5 ml over 5 minutes) trastuzumab IV 8 mg/kg loading dose; 6 mg/kg maintenance dose Docetaxel 75 mg/m 2 FEC 500/75/500 1 year (18 cycles) trastuzumab Safety, tumour response pcr Safety, EFS, OS PK Primary endpoint Show non-inferiority of SC vs. IV based on co-primary endpoints PK: observed trastuzumab C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pcr) in the breast Graphical elaboration from text data pcr, pathological complete response EFS, event-free survival; OS, overall survival Ismael G, et al. Lancet Oncol. 2012;13: * Clinicaltrial.gov NCT

42 HannaH: Non-inferiority margins for coprimary endpoints Pharmacokinetic co-primary endpoint: " Observed C trough at pre-dose Cycle 8 " Prespecified non-inferiority margin for geometric mean ratio SC vs. IV: 0.8 Efficacy co-primary endpoint: " Pathological complete response in the breast " Pre-specified non-inferiority margin for pcr rate difference SC-IV: -12.5% Ismael G, et al. Lancet Oncol 2012; 13:

43 HannaH: First co-primary endpoint met (pharmacokinetics) trastuzumab IV n=235 trastuzumab SC n=234 Primary endpoint: Observed C trough pre-dose Cycle 8 Geometric mean (µg/ml) Geometric mean ratio (GMR) SC vs. IV (90% CI) 1.33 (1.24; 1.44) Non-inferiority of SC vs. IV demonstrated: lower bound of 90% CI greater than prespecified non-inferiority margin for geometric mean ratio SC vs. IV of 0.8 Pharmacokinetic per protocol population Ismael G, et al. Lancet Oncol 2012; 13:

44 HannaH: Second co-primary endpoint met (efficacy) trastuzumab IV n=263 trastuzumab SC n=260 Primary endpoint pcr in the breast, * n (%) 107 (40.7%) 118 (45.4%) Difference in pcr rates, SC-IV (95% CI)* 4.7% (-4.0%; 13.4%) Graphical elaboration from text data Non-inferiority of SC vs. IV demonstrated: lower bound of 95% CI greater than pre-specified non-inferiority margin for pcr rate difference SC IV: -12.5% *Efficacy per protocol population; pathological tumour response was assessed locally pcr defined as absence of invasive neoplastic cells in the breast Residual ductal carcinoma in situ (DCIS) is acceptable for pcr Ismael G, et al. Lancet Oncol 2012; 13:

45 HannaH: Neither body weight nor C trough concentration correlated with pcr Summary of pathological complete response by body weight quartiles Weight Quartiles at Baseline (Kg) trastuzumab IV n=263 n Responders No (%) trastuzumab SC n=260 n Responders No (%) < (37%) (54%) 58, < (43%) (44%) 67, < (41%) (46%) (41%) (40%) N represents number of patients within subgroup Melichar B., et al. ESMO 2012 Poster n. 254P Available at - Last accessed on July 2013

46 HannaH: Conclusions HannaH demonstrated that comparable drug exposure and efficacy can be achieved for trastuzumab SC and IV Efficacy is robust and consistent across subgroups and analysis populations pcr rate is not correlated with body weight or trastuzumab C trough level trastuzumab C trough levels are higher in SC, but exposure (AUC) is comparable between IV and SC, and peak exposure (C max ) is lower for SC Overall, the safety profiles of the trastuzumab SC and IV formulations are comparable, and consistent with the known safety profile of trastuzumab The overall safety profile, combined with the totality of the applied analyses, suggest that there are no safety concerns (in particular in patients <51 kg) with the use of a fixed 600 mg dose of trastuzumab SC compared with standard IV treatment trastuzumab SC 600 mg fixed dose administered q3w in less than 5 minutes provides a valid treatment alternative to the q3w IV regimen 1. Ismael G, et al. Lancet Oncol. 2012;13: Jackisch C., et al. ESMO 2012 Poster n. 271P Available at - Last accessed on July 2013

47 PrefHer: A global, randomised, two-cohort crossover preference study Cross-over period SID cohort SID every 3 weeks x 4 IV every 3 weeks x 4 Arm A HER2-positive primary invasive breast adenocarcinoma (N = 248) R 1:1 Herceptin Remaining Herceptin to complete 18 cycles in total PINT1 Arm B IV every 3 weeks x 4 SID every 3 weeks x 4 PINT2 Cross-over period Handheld syringe cohort Arm A SC handheld syringe every 3 weeks x 4 IV every 3 weeks x 4 HER2-positive primary invasive breast adenocarcinoma (N = 240) R 1:1 Herceptin Remaining Herceptin SC to complete 18 cycles in total PINT1 Arm B IV every 3 weeks x 4 SC handheld syringe every 3 weeks x 4 PINT2 Includes optional TaM sub-study in both cohorts * Remaining Herceptin administered by IV infusion unless patients participated in SID self-administration IV, intravenous; PINT, Patient Interview; R, randomised; SC, subcutaneous; SID, single-use injection device; TaM, time-and-motion Pivot X, et al. Lancet Oncol 2013

48 PrefHer: A global, randomised, two-cohort crossover preference study Cross-over period SID cohort SID every 3 weeks x 4 IV every 3 weeks x 4 Arm A HER2-positive primary invasive breast adenocarcinoma (N = 248) R 1:1 Herceptin Remaining Herceptin to complete 18 cycles in total Randomisation was stratified by de novo vs Arm B IV SID PINT1 every 3 weeks x 4 every 3 weeks x 4 PINT2 non-de novo Herceptin, to balance the sequence groups for Cross-over period the proportion of patients with pre-study Herceptin IV SC handheld syringe IV Handheld syringe cohort every 3 treatment weeks x 4 every 3 weeks x 4 Arm A HER2-positive primary invasive breast adenocarcinoma (N = 240) R 1:1 Herceptin Remaining Herceptin SC to complete 18 cycles in total PINT1 Arm B IV every 3 weeks x 4 SC handheld syringe every 3 weeks x 4 PINT2 Includes optional TaM sub-study in both cohorts * Remaining Herceptin administered by IV infusion unless patients participated in SID self-administration IV, intravenous; PINT, Patient Interview; R, randomised; SC, subcutaneous; SID, single-use injection device; TaM, time-and-motion Pivot X, et al. Lancet Oncol 2013

49 Pts preferred Herceptin SC over IV irrespective of whether received Trastuzumab prior to enrollment IV SC Nopreference Overall n = % Single-use injection device cohort n = % n = % De novo Herceptin Non De novo Herceptin Hand-held syringe cohort n = % n = % n = % SC preferred (exact binomial): Overall = 86.1% (95% CI 81.0% to 90.3%) IV, intravenous; SC, subcutaneous Pivot X, et al. SABCS 2013 (Abstract P )

50 PrefHer conclusions In PrefHer, patients very strongly preferred Herceptin SC using the SID or handheld syringe, mainly because it saved them time, caused them less pain/ discomfort and was more convenient than IV administration There was a high preference for Herceptin SC irrespective of whether patients received Herceptin IV prior to study enrolment There was a high level of healthcare professional satisfaction with Herceptin SC Herceptin SC was well tolerated and no new safety signals were identified compared to the known profile of Herceptin IV in early breast cancer The overall safety profile of 4 cycles of Herceptin SC and 4 cycles of Herceptin IV observed during the cross-over period of the hand-held syringe cohort in the PrefHer study was consistent with that reported in the SID cohort Consistent results from both cohorts of PrefHer, combined with data from the HannaH study, demonstrate that the Herceptin SC formulation is a valid, well tolerated and preferred option for patients and healthcare professionals, regardless of SC delivery method (SID or hand-held syringe) IV, intravenous; SC, subcutaneous; SID, single-use injection device Pivot X, et al. Lancet Oncol 2013 Pivot X, et al. SABCS 2013 (Abstract P )

51 The Schearly Study Prospective, two cohort, non randomized, multicenter, open label study, to assess the safety and molecular biomarkers of trastuzumab injected subcutaneously ( vial or SID) in patients with early and locally advanced HER 2 positive breast cancer Investigators Meeting 30 ottobre Milano

52 Design: Treatment in the (Neo)Adjuvant Setting Cohort A: 120 pts ebc (neo)adjuvant N = 240* Cohort B: 120 pts 4 cycles Anthracyclinecontaining chemotherapy 4 cycles Anthracyclinecontaining chemotherapy 4 cycles Trastuzumab SC + taxane 4 cycles Trastuzumab SC + taxane 14 cycles Trastuzumab SC ± RT ± OT 14 cycles Trastuzumab SC ± RT ± OT 2-year Follow up 18 cycles of trastuzumab SC, 3-weekly regimen Cohort A: fixed dose of trastuzumab SC 600 mg Injection in upper thigh within up to 5 minutes, in hospital using a handheld hypodermic syringe [SC syringe] Cohort B: fixed dose of trastuzumab SC 600 mg Injection in upper thigh within up to 5 minutes, in hospital using singleuse injection device [SID] *Adjuvant or Neoadjuvant :pragmatic selection according to physician choice

53 Objectives Primary Objectives: Collect safety data for trastuzumab SC Collect tolerability data for trastuzumab SC Secondary Objectives: Efficacy: Disease-free survival (DFS), overall survival (OS) In the Neo-adjuvant setting activity of two sequential drug regimens, assessed as the incidence of pathological Complete response in breast and nodes ( pcr;ypt0-is ypn0) Obtain information on patient overall satisfaction with the handling of trastuzumab SC using the single-use injection device HCP satisfaction Investigators Meeting 30 ottobre Milano

54 Progetto di valutazione dell impatto/beneficio organizzativo-gestionale della formulazione sc Sono state individuate, alla luce delle attuali modalità di gestione di Trastuzumab, le possibili aree di impatto della nuova formulazione sotto-cute. In base alle possibili aree di impatto è stata effettuata la raccolta dei dati sul campo presso le Unità Operative di Oncologia. Il confronto tra i dati raccolti sul campo e le caratteristiche della nuova formulazione dei due farmaci ha consentito di quantificare gli impatti in termini tecnico organizzativi. Analisi delle attuali modalità di gestione dei farmaci Identificazione dei possibili impatti della nuova formulazione (sottocute) Raccolta dati e informazioni sul campo sulle attuali modalità di gestione dei farmaci (formulazione endovena) Quantificazione degli impatti della nuova formulazione dei farmaci (sottocute) Fonte dati: RCP ed informazione generali Fonte dati: Unità Operative coinvolte

55 Impatto positivo della formulazione sottocute sulle attività a rischio clinico Su 33 aree di rischio complessive la formulazione sotto cute porta alla eliminazione di 25 attività e relativi rischi (eliminazione del 78 % delle attività a rischio). In particolare vi è una ricaduta sui rischi legati alla somministrazione endovena, alla fase di prescrizione (calcolo dosaggio), alla fase di allestimento delle sacche da infusione. Vengono inoltre a mancare i possibili effetti avversi da infusione (es. stravaso, occlusioni dell accesso venoso, infezioni, ecc.). Permangono peraltro i rischi associati ad attività nelle quali la modifica della formulazione non può avere impatti di rischio (es. errata identificazione del paziente).

56 Quantificazione dell impatto della formulazione sottocute Impegno tempo del paziente - 22% (- 4,5 h per 18 somministrazioni) Impegno tempo del personale infermieristico: gestione pz - 45% (-1,3 FTE) Impegno tempo per allestimento farmaco - 80% (Giornaliero tra Farmacia e Scarti farmaco Sicurezza paziente: IR da FMEA - 100% - 78 % (25 attività a rischio eliminate) Reparto) 0% 0% 0% 0% 0% 22 % 45% 80% 78% 100% 100% 100% 100% 100%