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

0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

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)

0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

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

Implications for the clinic New treatment algorithm