Temi aperti sui trattamenti adiuvanti: Malattia Her 2+ Alessandra Gennari S.C. Oncologia Medica E.O. Ospedali Galliera Genova

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1 Temi aperti sui trattamenti adiuvanti: Malattia Her 2+ Alessandra Gennari S.C. Oncologia Medica E.O. Ospedali Galliera Genova

2 Anti HER2 Adjuvant Therapy Challenges with Evidence De-escalation of anti HER2 therapy - non inferiority RCTs Combination vs Sequence - Trastuzumab + Lapatinib - Trastuzumab + Pertuzumab - Trastuzumab Neratinib Biosimilars - Equivalence trials

3 Courtesy of PF Conte 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: results of the phase III multicentric Italian Short-HER study PF Conte, G. Bisagni, A. Frassoldati, A. Brandes, E. Anselmi, F. Giotta, M. Aieta, V. Gebbia, A. Musolino, O. Garrone, C. Taverniti, G. Cavazzini, A. Turletti, D. Rubino, A. Ferro, E. Picardo, F. Piacentini, S. Balduzzi, R. D'Amico, V. Guarneri Medical Oncology 2, Istituto Oncologico Veneto IRCCS DiSCOG-University of Padova, Italy On behalf of the Short-HER Study Team

4 Short-HER: Study Design Courtesy of PF Conte Stratification factors: HR status, Nodal status

5 Total planned amount of chemotherapy and trastuzumab in the two treatment arms Courtesy of PF Conte Long Short Presented by: PierFranco Conte, ASCO 2017

6 Short-HER: Disease Free Survival Courtesy of PF Conte Months from randomization Number at risk A long B short A long B short Presented by: PierFranco Conte, ASCO 2017

7 DFS Subgroup analysis Courtesy of PF Conte Events/randomized HR (90% CI) Age <60 years 123/ years 66/ (0.85, 1.54) 1.18 (0.78, 1.76) Stage I 52/509 II 81/549 III 56/ (0.57, 1.44) 0.96 (0.66, 1.38) 1.76 (1.11, 2.80) Ratio of HRs (90%CI) p- value Nodal status N0 73/670 N1 56/385 N2+N3 60/198 Hormone-receptor Negative 71/398 Positive 118/ (0.62, 1.33) 0.93 (0.60, 1.45) 2.07 (1.33, 3.22) 1.20 (0.81, 1.78) 1.12 (0.83, 1.52) Stage III vs I+II Nodal status N2+N3 vs N0+N (1.35, 3.94) < (1.33, 3.83) < Favouring SHORT Favouring LONG Presented by: PierFranco Conte

8 Short-HER: Overall Survival Courtesy of PF Conte Long (N=627) Short (N=626) OS events # y OS % HR (90% CI) 1.06 ( ) Months from randomization Number at risk A long B short A long B short Presented by: PierFranco Conte

9 LVEF change from baseline 64 LVEF% mean over time Courtesy of PF Conte Baseline 3 months 6 months 9 months 12 months 18 months p= A long B short

10 At a median FUp of 5.2 years: Conclusions 5y DFS Long Arm 87.5%, Short Arm 85.4% HR= 1.15 (90% CI ) Courtesy of PF Conte Non inferiority cannot be claimed on the basis of the frequentist approach According to the pre-planned Bayesian analysis, probability that the short treatment is not inferior is 0.78 Significant lower cardiac toxicity for the short treatment (HR 0.32, 95% CI ; p < ) Presented by: PierFranco Conte

11 Anti HER2 Adjuvant Therapy Challenges with Evidence De-escalation of anti HER2 therapy - non inferiority RCTs Combination and Sequence - Trastuzumab + Lapatinib - Trastuzumab + Pertuzumab - Trastuzumab Neratinib Biosimilars - Equivalence trials

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14 Pertuzumab by Nodal Status

15 ExteNET: study design

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24 Anti HER2 Adjuvant Therapy Challenges with Evidence De-escalation of anti HER2 therapy - non inferiority RCTs Combination and Sequence - Trastuzumab + Lapatinib - Trastuzumab + Pertuzumab - Trastuzumab Neratinib Biosimilars - Equivalence trials

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27 EMA Guideline: Requirements and Study Design for Biosimilar and Innovator Clinical Trials Patient Population Clinical Design Biosimilar Sensitive and homogeneous patient population Comparative vs innovator (equivalence studies) Innovator Any Superiority vs standard of care Study Endpoints Safety Immunogenicity Sensitive ORR, pcr Similar safety profile to innovator Similar immunogenicity profile to innovator Efficacy data (OS, PFS) Acceptable risk/benefit profile vs standard of care Acceptable risk/benefit profile vs standard of care Extrapolation Possible Not allowed 27

28 EMA GUIDELINE Extrapolations of Indication Extrapolation of clinical efficacy and safety data to other indications of the reference mab, not specifically studied during the clinical development of the biosimilar mab, is possible based on the overall evidence of comparability provided from the comparability exercise and with adequate justification. 28

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31 Jan Tannock, ESMO Madrid 2017

32 Implications for the clinic New treatment algorithm HR- Higher risk Chemotherapy plus one year trastuzumab/pertuzumab HER2+ EBC Adjuvant HR+ Lower risk Chemotherapy plus one year trastuzumab Risk based: Neratinib x one year Neoadjuvant Chemotherapy plus trastuzumab/pertuzumab No pcr Neratinib x one year

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