Alessandra Gennari S.C. Oncologia Medica E.O. Ospedali Galliera Genova
Temi aperti sui
trattamenti adiuvanti:
Malattia Her 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
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
Courtesy of PF Conte
Short-HER: Study Design
Stratification factors: HR status, Nodal status
Courtesy of PF Conte
Total planned amount of chemotherapy and trastuzumab in the two treatment arms
Long Short
Presented by: PierFranco Conte, ASCO 2017
Courtesy of PF Conte
Short-HER: Disease Free Survival
0.000.250.500.751.00
626 601 576 554 476 351 233 120 46
B short
627 608 592 566 482 374 239 132 43
A long Number at risk
0 12 24 36 48 60 72 84 96
Months from randomization
A long B short
Presented by: PierFranco Conte, ASCO 2017
Courtesy of PF Conte
Presented by: PierFranco Conte
DFS – Subgroup analysis
Age
<60 years 123/802
≥60 years 66/451
Stage
I 52/509 II 81/549 III 56/191
Nodal status
N0 73/670 N1 56/385 N2+N3 60/198
Hormone-receptor
Negative 71/398 Positive 118/855
1.14 (0.85, 1.54) 1.18 (0.78, 1.76)
0.91 (0.57, 1.44) 0.96 (0.66, 1.38) 1.76 (1.11, 2.80)
0.91 (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)
HR (90% CI) Events/randomized
1
.5 .75 1 1.5 2.5 3.5
Favouring SHORT Favouring LONG
Ratio of HRs (90%CI)
p- value Stage
III vs I+II
2.30
(1.35, 3.94) <
0.001 Nodal status
N2+N3 vs N0+N1
2.25
(1.33, 3.83) < 0.001
Courtesy of PF Conte
Short-HER: Overall Survival
Presented by: PierFranco Conte
Long (N=627)
Short (N=626)
OS events # 37 38
5y OS % 95.1 95.0
HR (90% CI)
1.06 (0.73-1.55)
0.000.250.500.751.00
626 610 602 591 516 389 258 129 50 B short
627 615 612 601 519 408 268 149 50 A long
Number at risk
0 12 24 36 48 60 72 84 96
Months from randomization
A long B short
Courtesy of PF Conte
LVEF change from baseline
50 52 54 56 58 60 62 64
Baseline 3 months 6 months 9 months 12 months 18 months
A long B short
LVEF% mean over time
p= 0.023
Courtesy of PF Conte
Conclusions
• At a median FUp of 5.2 years:
5y DFS Long Arm 87.5%, Short Arm 85.4%
HR= 1.15 (90% CI 0.91-1.46)
• 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 0.21-0.50; p < 0.0001)
Presented by: PierFranco Conte
Courtesy of PF Conte
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
Pertuzumab by Nodal Status
ExteNET: study design
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
27
Biosimilar Innovator
Patient Population Sensitive and
homogeneous patient population
Any
Clinical Design Comparative vs innovator (equivalence studies)
Superiority vs standard of care
Study Endpoints Sensitive ORR, pCR
Efficacy data (OS, PFS)
Safety Similar safety profile to innovator
Acceptable risk/benefit profile vs standard of care Immunogenicity Similar immunogenicity
profile to innovator
Acceptable risk/benefit profile vs standard of care
Extrapolation Possible Not allowed
EMA Guideline: Requirements and Study Design for
Biosimilar and Innovator Clinical Trials
EMA GUIDELINE
Extrapolations of Indication
28
‘’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.’’
Jan Tannock, ESMO Madrid 2017
HER2+
EBC
Adjuvant
Neoadjuvant Chemotherapy plus
trastuzumab/pertuzumab No pCR Neratinib x one year
HR-
HR+
Higher risk
Lower risk
Chemotherapy plus one year trastuzumab/pertuzumab
Chemotherapy plus one year trastuzumab
Risk based:
Neratinib x one year