Biosimilares: una aportación inagotable? Dr. Antonio Llombart Cussac Jefe de Servicio de Oncología Hospital Arnau de Vilanova ( Valencia, España)

Biosimilares: una aportación inagotable? Dr. Antonio Llombart Cussac Jefe de Servicio de Oncología Hospital Arnau de Vilanova ( Valencia, España)

El concepto de Biosimilar Producto proteico Gran tamaño Actividad ligada a diferentes procesos de estructura Requiere proceso de fabricación biológica La estructura molecular nunca será idéntica Pero el resultado clínico debe ser indiferenciable Complejidad Tecnología Seguridad Eficacia

Un juego mental Recuerdas la marca del televisor de la habitación de tu hotel esta noche? Sabes decirme el último taxi en el que te has subido? Tienes en mente la imagen ecográfica de tu último embarazo?

Un juego mental - televisores GRUNDIG T818/16 1983 PHILIPS LED Serie 3008 2015

Un juego mental - transporte Renault 12 1983 Toyota Prius 2015

Un juego mental tecnología sanitaria SIEMENS SL1 1986 GE Voluson S8 2016

Historia de los Anticuerpos Monoclonales 1980 - Primera sintesis de AcMo 1989 - Primer estudio en humanos 1991 - Primer AcMo humanizado 1992 - Fase I Trastuzumab 1994 - Primer AcMo aprobado por FDA 1998 - FDA Trastuzumab Georges Köhler y César Milstein (Premios Novel Medicina 1984)

Actualización de las sumisiones y aprobaciones a la EMA en Mayo 2017 Rituximab: Two biosimilars (BS) have been approved by EMA in 2017 Three other have had a positive opinion from CHMP Trastuzumab: four applications Bevacizumab: two applications Pegfilgrastim: two applications

New gamblers on board

Thursday April 21th 2019 PFIZER S TRASTUZUMAB KILLS PATIENTS

Pasos y Peso de los requisitos EMA para el desarrollo y aprobación de Biosimilares

Los timings a la Opinión positiva por la EMA son similares para Originales y Biosimilares

2017 - Escenario Biosimilares en Oncologia Biosimilars limited to G-CSF and Erythropoietin s Relative molecular complexity PK/PD studies in healthy volunteers Simple Clinical objectives (Hg levels, neutrophils recovery) Both agents are supportive therapies Introduced in Europe since 2008, high penetration based on local national guidelines

El Ejemplo del Biosimilar Trastuzumab Estudios Fase 3: Población seleccionada Biosimilar Company HER2+ EBC HER2+ MBC ABP 980 Amgen Neoadjuvant + adjuvant n=827 BCD-022 Biocad 1 st line n=126 CT-P6 Celltrion Neoadjuvant + adjuvant n=562 1 st line n=475 MYL-1401O Mylan/Biocon 1 st line n=600 PF-05280014 Pfizer Neoadjuvant n=226 1 st line n=690 SB3 Merck/ Samsung Bioepis Neoadjuvant n=806

Paclitaxel/Trastuzumab vs. P/Biosimilar CT-P6 Phase III First Line MBC HER2[+] HER2+ MBC N=475 R 1:1 Im YH, J Clin Oncol 31, 2013 (suppl; abstr 629). N=244 CT-P6 + paclitaxel q3w N=231 Herceptin + paclitaxel q3w Inclusion Criteria: MBC with measurable lesions Her 2 + IHC or FISH centrally confirmed No prior trastuzumab and/or chemo Tx in metastatic setting > 12 months since prior adjuvant or neoadjuvant trastuzumab and/or chemo ECOG 0 or 1 Exclusion Criteria: Prior chemo for MBC CNS metastases Baseline LVEF 50% or history of CHF

Primary Objective: ORR CT-P6 + Paclitaxel (n = 244) ITRC Trastuzumab + Pac (n = 231) CT-P6 + Paclitaxel (n = 244) Investigator Trastuzumab + Pac (n = 231) Complete response 9 (3.7%) 4 (1.7%) 12 (4.9%) 6 (2.6%) Partial response 129 (52.9%) 139 (60.2%) 146 (59.8%) 152 (65.8%) Stable disease 49 (20.1%) 38 (16.5%) 61 (25.0%) 56 (24.2%) Overall response rate 138 (56.6%) 143 (61.9%) 158 (64.8%) 158 (68.4%) Difference, % [95% CI] 5.4 [-14.3, 3.6] 3.6 [-12.6, 5.4] Difference, % (95% CI %) ITRC FAS 5.4 (-14.3, 3.6) ITRC PPS 5.0 (-14.1, 4.1) Investigator FAS 3.6 (-12.6, 5.4) Investigator PPS 3.2 (-12.3, 5.9) Favors Trastuzumab -15-10 -5 0 5 10 15 FAS, Full analysis set; PPS, per protocol patients set Difference in proportion of complete response or partial response Confidence interval estimated using the exact method. Im YH, et al. J Clin Oncol. 2013;31(suppl): Abstract 629. Favors CT-P6

Secondary Objective: Time to Progression Time to progression in the responder group by independent review committee (full analysis set, 1 year data) 1.0 Probability 0.8 0.6 0.4 P =.0978 0.2 0.0 CT-P6 + Paclitaxel Trastuzumab + Paclitaxel 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Months Safety: CT-P6 was well tolerated with a safety profile comparable to trastuzumab (Herceptin) Im YH, et al. J Clin Oncol. 2013;31(suppl): Abstract 629.

HERITAGE : MYL-1401o Safety and Efficacy study in HER2+ MBC Rugo HS, et al. JAMA 2017, 317(1): 37-47

HERITAGE : MYL-1401o Primary and Secondary Efficacy Endpoints ORR by arm PFS Kaplan Meier Rugo HS, et al. JAMA 2017, 317(1): 37-47

HERITAGE : MYL-1401o Safety profile No significant differences between the two groups with regard to the type, incidence or severity of SAEs Immunogenicity profile was low, similar between the 2 products. Similar cardiac safety Rugo HS, et al. JAMA 2017, 317(1): 37-47

Trastuzumab BS: Is First Line Metastatic Disease the Optimal Scenario To Observe Differences? Trastuzumab is approved in early and metastatic HER2-positive Breast Cancer with dramatic impact in survival in both populations ORR in metastatic disease do not seems a robust surrogate marker of DFS and mostly OS Clinicians may have doubts about extrapolation to early disease It is reasonable to look for a different HER2[+] population to test trastuzumab BS in an earlier scenario with an stronger objective

Neoadjuvant Therapy for Early Stage HER2[+]: Optimal Scenario for New Agents Pathological Complete Response (pcr) to Neoadjuvant therapy is a trustable surrogate marker of DFS and OS in HER2[+] BC patients Both FDA and EMA had accepted neoadjuvant trials with pcr as primary endpoint for early registration Cortazar et al. Lancet 2014

Registration study: A Phase III (non-inferiority) Herceptin SC vs IV Neoadjuvant HER2+ EBC Herceptin SC CM II-III HER2[+] (N=596) R 1:1 Herceptin IV Cirugía Follow up: 24 months DFS, OS Herceptin SC Fixed dose 600 mg (5 ml aprox 5 minutes) Herceptin IV 8 mg/kg loding dose; 6 mg/kg maintenance Docetaxel 75 mg/m 2 FEC 500/75/500 1 year (18 cycles) Herceptin Safety, Objective Response pcr Safety, DFS, OS Fc Primary objective Non-inferiority SC vs. IV: Fc: C min Herceptin before Cycle 8 (pre-surgery) Efficacy: Breast pcr

HannaH: Efficacy Parameter Primary endpoint Herceptin IV n=263 Herceptin SC n=260 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%) Non-inferiority of SC vs. IV demonstrated: lower bound of 95% CI greater than pre-specified non-inferiority margin of 12.5% Secondary endpoints tpcr (pcr in breast and axilla),* n (%) Difference in tpcr rates, SC IV (95% CI) 90 (34.2%) 102 (39.2%) 5.0% ( 3.5; 13.5) Overall response rate, n (%) 231 (88.8%) 225 (87.2%) Ismael G, et al. Lancet Oncol 2012

Pivot X, et al. Clin Ther 2016; 38:1665-1673. Phase I Clinical Trial: SB3 vs EU and US Originator Trastuzumab

Randomized, Double-blind,Parallel-Group, Multicenter Study In Women With HER2+ EBC - LABC Primary Endpoint Breast pcr (bpcr) Secondary Endpoints Total pcr (tpcr) ORR EFS Other Assessments Safety immunogenicity Pharmacokinetics Pivot X, et al. ASCO 2017

Efficacy- bpcr and tpcr Rate SB3 vs Originator Trastuzumab Per-Protocol set: All randomized subjects who completed 8 cycles of neoadjuvant therapy and surgery. Used as the primary analysis set Pivot X, et al. ASCO 2017 Pivot X, et al. ASCO 2017

Efficacy- EFS & OS (ESMO 2017) SB3 vs originator Trastuzumab 1 year EFS and OS rates: EFS: 92.2% in SB3 vs. 91.6% in TRZ. OS: 99.8% in SB3 vs. 98.9% in TRZ. SB3 was well tolerated with a comparable safety profile during neoadjuvant-adjuvant treatment period. The 1 year safety and immunogenicity where equal Pivot X, et al. ESMO 2017 Pivot X et al. ESMO 2017. 153PD

ABP 980 vs trastuzumab reference product in EBC: Phase 3 study design ( LILAC ) Study population HER2+ invasive breast cancer Histologically confirmed, measurable disease ( 2.0 cm) No prior treatment Planning for surgical resection of breast tumour and sentinel node or axillary lymph node resection Planning neoadjuvant chemotherapy No distant metastases S C R E E N I N G E N R O L L E D Epirubicin + cyclophosphamide Q3W for 4 cycles (n=808)* R A N D O M I S A T I O N ABP 980 Q3W for 4 cycles + paclitaxel Trastuzumab Q3W for 4 cycles + paclitaxel S U R G E R Y S U R G E R Y ABP 980 Q3W for up to 1 year ABP 980 Q3W for up to 1 year Trastuzumab Q3W for up to 1 year Neoadjuvant phase Surgery Adjuvant phase E N D O F S T U D Y pcr assessment; primary analysis End of study Stebbing J, et al. Abstract 510, ASCO 2017

Results Pathologic Complete Response* Local Review von Minckwitz et al. ESMO 2017, Poster discussion 151 PD

Results Historical Results of Trastuzumab Studies Reference Treatment N pcr rate (95% CI) a Untch 2011 Trastuzumab 217 0.39 (0.32, 0.46) Dawood 2007 Trastuzumab 40 0.55 (0.38, 0.71) Mittendorf 2009 Trastuzumab 142 0.51 (0.42, 0.59) Untch 2010 Trastuzumab 426 0.40 (0.35, 0.45) Holmes 2011 Trastuzumab 33 0.55 (0.36, 0.72) Guarneri 2012 Trastuzumab 36 0.25 (0.12, 0.42) Bayraktar 2012 Trastuzumab 235 0.58 (0.52, 0.65) Roche 2012 Trastuzumab 298 0.41 (0.35, 0.46) Untch 2012 Trastuzumab 307 0.45 (0.39, 0.50) Buzdar 2007 Trastuzumab 45 0.60 (0.44, 0.74) Gianni 2010 Trastuzumab 117 0.38 (0.30, 0.48) EBC Study 20120283 Trastuzumab ABP 980 338 358 0.1 0.3 0.5 0.7 pcr rate 0.41 (0.35, 0.46) 0.48 (0.43, 0.53) von Minckwitz et al. ESMO 2017, Poster discussion 151 PD

Results: Summary of Adverse Events and any Cardiac event in the Neoadjuvant Phase AE category, n (%) ABP 980 (n=364) Timepoint, n/n1 (%) Trastuzumab (n=361) Any treatment-emergent AE 292 (80.2) 287 (79.5) Any grade 3 treatment-emergent AE 54 (14.8) 51 (14.1) Any fatal treatment-emergent AE 1 (0.3) 0 (0.0) *3 (0.8%) and 2 patients (0.6%) experienced serious AEs that were considered by the investigator to be related to IP Incidence of LVEF Decline by 10% and to <50% ABP 980 (n=364) Trastuzumab (n=361) Visit 9* 1/345 (0.3) 2/344 (0.6) End of neoadjuvant phase 0/5 (0.0) 1/5 (20.0) Overall 1/350 (0.3) 3/348 (0.9) von Minckwitz et al. ESMO 2017, Poster discussion 151 PD

Conclusiones Biosimilars of Trastuzumab trials have shown that The efficacy objectives achieve predefined goals. Any of the phase III studies identifies a single significant difference or trend in terms of safety or immunogenicity There is no evidence of increased cardiotoxicity All these results support clinical equivalence between trastuzumab biosimilars and the original product

ABP 215: Bevacizumab Biosimilar candidate Analytical Similarity Analytical similarity demonstrated for more than 100 attributes/assays

Clinical Pharmacology PK Similarity

Clinical Head-to-Head Bevacizumab vs. ABP 215 Comparison in Advanced NSCLC

Oportunidad de los Biosimilares en Oncologia BS provide reliable data on the therapeutic equivalency to originators Oncologist have good experience on prior biosimilars, well integrated in clinical practice There is an increasing number of new agents with great impact on patients health - Incorporating innovative therapies is mandatory There is an understood on reducing costs Great credibility among physicians on pharma companies with large experience in oncology

Riesgos de los Biosimilares en Oncologia There is a great need on information and education Important focus on preclinical (analytical) understanding it should be communicated by trustable people The robust Clinical trial should be performed in the best scenario Medical Oncologist (ESMO & national societies) must be integrated on the discussion process - guidelines

Biosimilares en Oncologia Los BS son una herramienta de gestión sanitaria; pero no representan una innovación terapéutica Su objetivo en oncología es facilitar/acelerar la innovación clínica, definida como la introducción precoz de nuevas terapias disruptivas El oncólogo y el farmacéutico hospitalario deben ser parte del proceso de decisión. Se debe definir y gestionar bien tanto la extrapolación como la intercambiabilidad Las vías subcutáneas de trastuzumab y rituximab han supuesto una disminución importante de la carga laboral de estos fármacos. El análisis debe incluir este factor tanto para profesionales como pacientes

Finalidad: Encontrar el equilibrio entre los distintos objetivos Definir poblaciones para la introducción de los BS Consenso entre profesionales sanitarios (oncólogos, farmacéuticos), gestores y pacientes El objetivo económico no debe ser el prioritario Ideal: Consenso autonómico

Un ejemplo para Trastuzumab Biosimilar para toda paciente con enfermedad metastática por encima de primera línea Rango regional / autonómico preferible al hospitalario Ventajas: Ausencia de perdida de oportunidad para críticos (sin impacto en SG) Representa el 10 15% del uso de trastuzumab Las pacientes previamente han beneficiado de los mejores tratamientos (pertuzumab, TDM1, lapatinib, herceptin) - Compromiso social No somete a la institución al retorno a via IV en escenarios de monoterapia Equidad entre ciudadanos e instituciones