Sophie Skorupka, Stéphanie Crosetto, Hasnein Cheikh, Juliette Desbonnet AREIPS 2016-2017

Breast Cancer

Key numbers Cancer Incidence France, 2014 USA, 2014 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Cancer Incidence France, 2014 USA, 2014

Key numbers Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY rajouter titre des axes et verifier chiffres de la mortalité http://globocan.iarc.fr/old/FactSheets/cancers/breast-new.asp

Breast anatomy Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY DCIS: Breast profile: A ducts, B lobules, C dilated section of duct to hold milk, D nipple, E fat, F pectoralis major muscle, G chest wall/rib cage Enlargement: A normal duct cells, B ductal cancer cells, C basement membrane, D lumen (center of duct)

Disposition Titre et contenu avec graphique Staging of breast cancer Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Disposition Titre et contenu avec graphique LCIS: Breast profile: A ducts, B lobules, C dilated section of duct to hold milk, D nipple, E fat, F pectoralis major muscle, G chest wall/rib cage Enlargement: A normal lobular cells, B lobular cancer cells, C basement membrane Vascular and lymphatic invasion Breast profile: A blood vessels, B lymphatic channels Enlargement: A normal duct cells, B cancer cells, C basement membrane, D lymphatic channel, E blood vessel, F breast tissue

Disposition Titre et contenu avec graphique Staging of breast cancer Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY No tumor and cancer has spread to the lymph nodes Tumor less than 2 cm and cancer has spread to the lymph nodes Tumor 2 – 5 cm and cancer has not spread to the lymph nodes Tumor 2 – 5 cm and cancer has spread to the lymph nodes Tumor > 5 cm and cancer has not spread to the lymph nodes Disposition Titre et contenu avec graphique LCIS: Breast profile: A ducts, B lobules, C dilated section of duct to hold milk, D nipple, E fat, F pectoralis major muscle, G chest wall/rib cage Enlargement: A normal lobular cells, B lobular cancer cells, C basement membrane Vascular and lymphatic invasion Breast profile: A blood vessels, B lymphatic channels Enlargement: A normal duct cells, B cancer cells, C basement membrane, D lymphatic channel, E blood vessel, F breast tissue

Disposition Titre et contenu avec graphique Staging of breast cancer Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Tumor is less than 2 cm and cancer has spread to 4-9 lymph nodes Tumor larger than 5 cm and cancer clusters found in the lymph nodes Tumor larger than 5 cm and cancer has spread to lymph nodes near the breastbone or underarm Disposition Titre et contenu avec graphique LCIS: Breast profile: A ducts, B lobules, C dilated section of duct to hold milk, D nipple, E fat, F pectoralis major muscle, G chest wall/rib cage Enlargement: A normal lobular cells, B lobular cancer cells, C basement membrane Vascular and lymphatic invasion Breast profile: A blood vessels, B lymphatic channels Enlargement: A normal duct cells, B cancer cells, C basement membrane, D lymphatic channel, E blood vessel, F breast tissue

Metastasis are found in the body Staging of breast cancer Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Metastasis are found in the body LCIS: Breast profile: A ducts, B lobules, C dilated section of duct to hold milk, D nipple, E fat, F pectoralis major muscle, G chest wall/rib cage Enlargement: A normal lobular cells, B lobular cancer cells, C basement membrane Vascular and lymphatic invasion Breast profile: A blood vessels, B lymphatic channels Enlargement: A normal duct cells, B cancer cells, C basement membrane, D lymphatic channel, E blood vessel, F breast tissue

Different prognosis : Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html

Breast Cancer Status HR: Hormone Receptor HER2 Receptor I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY HER2 Receptor HER2 protein receptor: Help control how a healthy breast cell grows, divides and repairs itself 25% breast cancer are HER2 +: tend to grow faster and are more likely to spread and come back Treatment available specifically for HER2 +: Trastuzumab, T-DM1, Pertuzumab, Lapatinib HR: Hormone Receptor Breast cell have receptor for mormones ER+: estrogen receptor + EP+: progesteron receptor + 2/3 of breast cancer are HR+ Treatment for HR+: SERMs, Aromatase inhibitors, ERDs, LHRHs mettre 2/3 en pourcentages?

Diagnosis Breast exam Mammogram Ultrasound MRI Biopsy Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Breast exam Mammogram Ultrasound MRI Biopsy

Breast Cancer Treatment I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Surgery Radiations Chemotherapy Hormonal therapy Targeted therapy Trastuzumab Lapatinib Anti-oestrogen Anti-aromatase ChimioT:  cyclophosphamide administré en intraveineux;  doxorubicine (famille des anthracyclines) administrée en intraveineux ; paclitaxel (famille des taxanes) administré en intraveineux HomonoT: CHEZ LA FEMME NON MÉNOPAUSÉE : Les anti-œstrogènes sont le plus souvent proposés comme premier traitement pour une durée de 5 ans; = tamoxifène Les agonistes de la LH-RH sont envisageables au cas par cas, sur une durée de 3 à 5 ans ; CHEZ LA FEMME MÉNOPAUSÉE : les anti-aromatases sont le plus souvent proposés comme premier traitement pour une durée de 5 ans ou pendant 2 ans, suivi par un traitement par tamoxifène (pour un total de 5 ans de thérapie hormonale). =  létrozole, l'anastrozole et l'exémestane Les anti-oestrogènes peuvent être proposés pendant 2 à 3 ans, suivis d'un inhibiteur de l'aromatase (pour un total de 5 ans de thérapie hormonale) ou, seuls, pendant 5 ans. Thérapie ciblée: Trastuzumab + Lapatinib Institut nationale du cancer Doxorubicin Paclitaxel Cyclophosphamid

Neoadjuvant or Adjuvant? Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Breast Cancer Neoadjuvant therapy Smaller sample size Primary endpoint : pCR (assessed months) Short drug exposure Needs prior safety information Surgery Adjuvant therapy Bigger sample size Primary endpoint : DFS, OS (assessed years) Best setting to assess long-term outcome (DFS, OS) Better safety assessment Bien dire dès maintenant que pCR est un examen Anapat faire apparaître explications après FDA :Guidance for Industry : Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval

Breast Cancer Clinical Trials I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY More than 2000 clinical trials on-going all over the world

Issues in Oncology Clinical Trials Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Phase III trials increase in size, duration and expense  Adaptive Clinical Trials High failure rate (34% Phase II  Phase III) Often result in very small improvements in outcome the failure rate is high: only 34% of phase III oncology drug trials with results announced from 2003 to 2010 achieved statistical significance in their primary end points mettre schéma pourcentage de réussite des différentes phases d’EC Repeated analysis and fixed sample-size inflate probability of type I or type II error

Adaptive Clinical Trials Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY FDA : “An ADAPTIVE DESIGN CLINICAL STUDY is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study” Adaptive randomisation design Sample size re-estimation design Drop-the-loser design Adaptive dose-finding design Adaptive treatment-switching design Hypothesis-adaptive design Adaptive seamless phase II/III Multi-adpative design Seamless phase II / III : combine deux essais cliniques en un seul essai de durée plus longue. -> Evite l’attente entre les deux phases -> réduit les couts car on élimine plus rapidement les bras qui ne donnent pas les résultats escomptés

Traditional Trial vs Adaptive Trial Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Traditional Phase II and III Studies Group A Group B Data analysis Planning phase III Group B Group C Placebo Group Phase II results available Placebo Group End of Phase III Adaptive design – combined Phase II/III Group A Drop Group A Group B Group C Drop C Placebo Group Interim Analysis I Interim Analysis II End of Phase III

Traditional Trial vs Adaptive Trial Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Group A Group B Data analysis Planning phase III Group B Group C Placebo Group Phase II results available Placebo Group End of Phase III Adaptive design – combined Phase II/III Group A Drop Group A Group B Group C Drop C Placebo Group Interim Analysis I Interim Analysis II End of Phase III

Adaptive randomisation Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Drug A Drug B Control Triple negative HER2+ / HR- HER2+ / HR+ expliquer les différents types de biomarqueurs : mettre HER2… rajouter des cadres autour des cases Drop B

Concept of I SPY I-SPY 2 I-SPY 1 I-SPY 3 Find biomarkers Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Biomarkers Phase Screening Phase Confirmatory Phase I-SPY 2 Find biomarkers Validation correlation pCR/RFS Neoadjuvant pCR to predict EFS Neoadjuvant + Adjuvant DFS to predict OS I-SPY 1 I-SPY 3 Accelerated approval Full approval

I-SPY 1 Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and molecular Analysis

I-SPY 1: Objectives I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY I-SPY 1: multicenter neoadjuvant breast cancer study designed to establish standards for collecting molecular and imaging data over the course of care Objectives: Evaluate whether response to therapy – as MRI or pCR – would predict recurrence-free survival (RFS) Defining the relationship of biomarkers to RFS ganglion lymphatiues pCR (pathologic complete response) = no invasive tumor present in either breast or auxillary lymph nodes after neoadjuvant therapy RFS (recurrence free survival) Pathologic Complete Response (pCR) is defined as the absence of invasive cancer in breast and nodes Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657, Journal of Clinical Oncology

FDA Guidance: pCR FDA defined pCR as: avec 13000 patients I-SPY 1 I-SPY 1 Breast Cancer Breast Cancer I-SPY 2 I-SPY 2 I-SPY 3 Accelerated Approval I-SPY 3 Accelerated Approval Limits of I-SPY Conclusion FDA defined pCR as: avec 13000 patients “the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy” “the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy”

Progesterone receptor Biomarkers I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hormone Receptor (HR) MammaPrint Estrogen receptor Progesterone receptor Theses biomarkers are standards biomarkers, accepted and approved by the Food and Drug Administration HER2 Biomarkers will be used to determine patient eligibility and randomization for the trial

Breast Cancer Status HR: Hormone Receptor MP: MammaPrint HER2 Receptor I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY HER2 Receptor HER2 protein receptor: Help control how a healthy breast cell grows, divides and repairs it self 25% breast cancer are HER2 +: tend to grow faster and are more likely to spread and come back Treatment available specifically for HER2 +: Trastuzumab, T-DM1, Pertuzumab, Lapatinib HR: Hormone Receptor Breast cell have receptor for mormones ER+: estrogen receptor + EP+: progesteron receptor + 2/3 of breast cancer are HR+ Treatment for HR+: SERMs, Aromatase inhibitors, ERDs, LHRHs MP: MammaPrint 70 genes signatures which can accurately select early stage breast cancer patients who are highly likely to develop distant metastasis Used to make treatment decisions based on the recurrence risk of early-stage

Only 14 signatures used for I-SPY MammaPrint I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Only 14 signatures used for I-SPY http://www.agendia.com/healthcare-professionals/breast-cancer/mammaprint/

Study treatment and procedures I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 4 cycles anthracyclines -> Surgery OU -> Taxanes -> Surgery Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657, Journal of Clinical Oncology

I-SPY 1 : Results Hazard ratio for RFS of pCR vs no pCR HR+ / HER2- Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hazard ratio for RFS of pCR vs no pCR HR+ / HER2- statistically insignificant result agrandir les schémas, faire en 2 diapos pour que ce soit plus lisible exemple overall : RFS diminue 0,29 fois plus no pCR que pCR Attention ! groupe HR+ / HER2- non significatif (HR=0) donc ce groupe sera exclu de I-SPY2 -> On peut conclure que I-SPY1 montre la capacité de la pCR à prédire les événements définis comme critères primaires lorsque cette pCR est analysée en tenant compte des sous groupe définis dans I-SPY1 (à savoir triple négatif ou HER2+ / HR-). La pCR peut être utilisée comme un indicateur précoce de la RFS.

Hazard ratio for RFS of pCR vs no pCR I-SPY 1 : Results I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hazard ratio for RFS of pCR vs no pCR agrandir les schémas, faire en 2 diapos pour que ce soit plus lisible exemple overall : RFS diminue 0,29 fois plus no pCR que pCR Attention ! groupe HR+ / HER2- non significatif (HR=0) donc ce groupe sera exclu de I-SPY2 -> On peut conclure que I-SPY1 montre la capacité de la pCR à prédire les événements définis comme critères primaires lorsque cette pCR est analysée en tenant compte des sous groupe définis dans I-SPY1 (à savoir triple négatif ou HER2+ / HR-). La pCR peut être utilisée comme un indicateur précoce de la RFS.

Hazard ratio for RFS of pCR vs no pCR I-SPY 1 : Results I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hazard ratio for RFS of pCR vs no pCR agrandir les schémas, faire en 2 diapos pour que ce soit plus lisible exemple overall : RFS diminue 0,29 fois plus no pCR que pCR Attention ! groupe HR+ / HER2- non significatif (HR=0) donc ce groupe sera exclu de I-SPY2 -> On peut conclure que I-SPY1 montre la capacité de la pCR à prédire les événements définis comme critères primaires lorsque cette pCR est analysée en tenant compte des sous groupe définis dans I-SPY1 (à savoir triple négatif ou HER2+ / HR-). La pCR peut être utilisée comme un indicateur précoce de la RFS.

I-SPY 1 I-SPY 2 I-SPY 1 Results from I-SPY 1 Breast Cancer I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Results from I-SPY 1 Tumor subsets defined Subset HR+ / HER2- won’t be studied pCR will be used as an early indicator of RFS I-SPY 2 Find biomarkers Validation correlation pCR/RFS Neoadjuvant pCR to predict EFS I-SPY 1 pCR will be primary endpoint in I-SPY2

I-SPY 2 Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and molecular Analysis

I-SPY 2 : a three tier model Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Il y a un cœur de processus qui permet la prise en charge clinique: ces processus sont intégré dans le modèle des essais cliniques adaptatifs. En vert: les nouvelles structures nécessaire pour supporter le centre en jaune Bleu: ce qui permet au système de fonctionner, cad un consortium compétitif, et des règles édictées par le payeur pour accélérer l’approbation des moélcules Esserman L J. et al 2012 A model for accelerating identification and regulatory approval of effective investigational agents.

I SPY 2 participating organisations Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY

I-SPY 2 Phase II, multicenter, adaptively randomized trial, open label Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Phase II, multicenter, adaptively randomized trial, open label Objectives: Match experimental regimens with responding cancer subtypes Rapidly identify which disease subtypes/signatures are sufficiently responsive to treatment with a given regimen to enable a small, focused and sucessful phase III trial

Inclusion and Exclusion criterias I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Women 18 years old Clinical stage II or III disease and had not received surgical or systemic therapy for this cancer Diameter of tumor had to be at least 2,5 cm (clinical assessment) and 2 cm (imaging) Eastern Cooperative Oncology Group performance status score 0 or 1 (asymptomatic or mild symptomatic) Able to undergo MRI and biopsies Inclusion criterias Exclusion criterias HR + status and low risk according to the 70-gene assay Exclusion criterias HR + and low risk according to the 70-gene assay: more favorable prognosis and benefit of chemotherapy is low. Exposure to novel drug is not justified.

Focus on biomarker signatures = combination of subtypes I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Focus on biomarker signatures = combination of subtypes Berry, D. A. Nat. Rev. Clin. Oncol. 9, 199–207 (2012); published online 8 November 2011

Bayesian Method I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Pre-specified thresholds of efficacy was defined as Bayesian predictive probability of success of 85% or more in a simulated phase 3 trials of neoadjuvant therapy in 300 patients who had undergone randomization in a ratio 1:1 Futility was defined as Bayesian predictive probability of success in a phase 3 trial less than 10% for all 10 biomarker signatures

Adaptive randomization I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Drug A Drug B Control Triple negative HER2+ / HR- HER2+ / HR+ refaire les flèches dans le bon sens Drop B

Randomization updated regarding new data = Adaptive Randomization Clinical Trial Design I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Randomization updated regarding new data = Adaptive Randomization N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Clinical Trial Design I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Novel drugs in combination with standard chemotherapy VS standard therapy alone ADAPT for new patients Randomize HER2 + Paclitaxel 80 mg + trastuzumab ± new drug (12 weekly cycles) Doxorubicin 60 mg + cyclophosphamide 600 mg (4 cycles) Surgery On study HER2 - Paclitaxel 80 mg ± new drug (12 weekly cycles) Doxorubicin 60 mg + cyclophosphamide 600 mg (4 cycles) Surgery Division en deux groupes (HER2 + et HER2-) puisque le marqueur HER2 conditionne la mise sous trastuzumab (SOC si HER2 +) PUIS randomisation : attention, lors de la première randomisation, randomisation « classique » : on ne parle pas de signature génétique. A ce stade, on ne peut pas corréler l’efficacité d’un traitement à un profil génétique particulier. Ce n’est qu’au fur et à mesure de l’avancement de l’essai, en collectant les données des tumeurs opérées qu’on pourra éventuellement associer un médicament (ou combo) à un profil génétique particulier. C’est le principe d’un modèle « Baysien » qui s’enrichie au fur et à mesure de l’avancement de l’essai. Attention, I-SPY2 ne permet que de qualifier une molécule (ou combinaison) pour un essai de Phase III (I-SPY3 dans l’exemple) Biopsy blood MRI MRI MRI MRI Tissue Primary end point = pCR at time of surgery (5 months after initiation of chemotherapy)

240 mg per day for the first 12 weeks Neratinib I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Tyrosine kinase inhibitor (HER2): HER2+ breast cancer Oral route Neratinib: 240 mg per day for the first 12 weeks

Trial Design I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval Limits of I-SPY faire 2 cadres N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Randomization Neratinib + paclitaxel group n = 115 I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Neratinib + paclitaxel group n = 115 Paclitaxel ± trastuzumab group n = 78 ATTENTION BLANC car ANIMATION donc c’est NORMAL N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Only 2 subtypes excluded: Biomarker signatures I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Signatures HR, HER2, MP HER2+ + + + + + - - + + - + - MP+ + - + - - + HR-, HER2+ HR+, HER2+ Pas de corrélation significative pour le groupe HER2- HR+ entre pCR et RFS Exclusion des patients MP- car ils ont risque faible de rechute, et donc il n’y a plus d’intérêt de les soumettre ici au Neratinib qui est très agressif. Only 2 subtypes excluded: HR+ HER2- MP- HR- HER2- MP-

Adverse Events and Toxic Effects I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY More Anemia and gastrointestinal event More early discontinuation for toxic effects

Results I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Predictive probability of success in phase 3 trial = 79% HER2+, HR- results I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Predictive probability of success in phase 3 trial = 79% Neoadjuvant + Adjuvant DFS to predict OS I-SPY 3 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Veliparib I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Poly (ADP-ribose) polymerase (PARP) inhibitor (PARP-1 and 2), BRCA1/2 Mutation Association with Carboplatin The inability of Homologous Recombinaison (= système de reparation de l’AND) to correct double-stranded breaks has been observed in tumors with mutations in the breast cancer-related genes BRCA1 and BRCA2, Usually such double-strand breaks are repaired by homologous recombination (HR), but in cells with defective HR, PARP inhibition can result in chromosomal instability, cell cycle arrest, and subsequent apoptosis. The inability of HR to correct double-stranded breaks has been observed in tumors with mutations in the breast cancer-related genes BRCA1 and BRCA2, which code for proteins essential for normal HR function.  En gros: mécanisme d’action de veliparib: en presence d’une mutation BRCA 1 ou 2, cela provoque une instabilité dans le système de reparation de l’AND, c’est qu’intervient PARP pour la reparation. Donc en inhibant PARP on inhibe la reparation des cellules avec la mutation, donc des cellules cancéreuses, qui vont donc mourir. Veliparib: 50 mg oral routes 2/day for 12 weeks Carboplatin: 6 mg·hr per liter on weeks 1, 4, 7, and 10 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Trial Design I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval Limits of I-SPY N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Randomization Veliparib + Carboplatin group n = 72 I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Veliparib + Carboplatin group n = 72 Paclitaxel + trastuzumab group n = 18 Paclitaxel group n = 44 ATTENTION BLANC car ANIMATION donc c’est NORMAL N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Only HER2+ excluded (for toxicity) Biomarker signatures I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Signatures HR, HER2, MP HER2- + - + + - - - - + - - - HR+, HER2- Triple negative Exclusion des patients HER2+ sur résultats d’études cliniques faites précédemment où ils ont démontré une toxicité plus importante sur les sous groupes HER2+, on avait donc une balance B/R qui n’était plus favorable. C’est pour cela qu’ils ont fait uniquement sur les signatures HER2- Only HER2+ excluded (for toxicity) N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Adverse Events and Toxic Effects I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY More hematologic events More early discontinuation for toxic effects N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Results I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

Triple negative results I-SPY 2 Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Limits of I-SPY Predictive probability of success in phase 3 trial = 88% Neoadjuvant + Adjuvant DFS to predict OS I-SPY 3 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750

I-SPY 2 Breast Cancer AMG 386 +/- Trastuzumab AMG 479 Accelerated Approval I-SPY 3 Limits of I-SPY AMG 386 +/- Trastuzumab AMG 479 MK-2206 +/- Trastuzumab T-DM1 + Pertuzumab Pertuzumab + Trastuzumab Ganetespib Veliparib Neratinib PLX3397 Pembrolizumab Talazoparib + Irinotecan Patritumab +/- Trastuzumab Breast Cancer https://clinicaltrials.gov/ct2/show/record/NCT02032277

I-SPY 2 Breast Cancer T-DM1 + Pertuzumab PLX3397 Accelerated Approval I-SPY 3 Limits of I-SPY T-DM1 + Pertuzumab PLX3397 Talazoparib + Irinotecan Ganetespib Pertuzumab + Trastuzumab Neratinib Breast Cancer Veliparib PROBABILITÉ PASSAGE PHASE II / PHASE III A VOIR ++++ AMG 386 +/- Trastuzumab MK-2206 +/- Trastuzumab Patritumab +/- Trastuzumab Pembrolizumab AMG 479 https://clinicaltrials.gov/ct2/show/record/NCT02032277

Accelerated Approval

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY JAMA, December 21, 2011—Vol 306, No. 23

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY JAMA, December 21, 2011—Vol 306, No. 23

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY JAMA, December 21, 2011—Vol 306, No. 23

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY For products appearing to provide a benefit for: serious or life-threatening illnesses lacking satisfactory treatments subject to the requirement to verify benefit Surrogate endpoint that is reasonably likely to predict clinical benefit : pCR ≈ EMA’s Conditional approval

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY Single large phase 3 trial Accelerated drug approval Biomarker approval With companion diagnostic Full drug approval Biomarker known/ phase2 complete Phase 2 screening trial Investigational agent 3 years Biomarker proposed/phase1 complete Biomarker identified Small confirmatory trial Esserman L J. et al 2012 A model for accelerating identification and regulatory approval of effective investigational agents.

Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 I-SPY 3 Limits of I-SPY FDA may withdraw approval If studies have not been conducted If studies fail to show an increase of survival 10% failed to confirm a benefit or failed to complete confirmatory trial accrual

I-SPY 3 Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and molecular Analysis

I-SPY 3 I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY The I-SPY 3 TRIAL is an international confirmatory trial of successful agents who have graduated from the I-SPY 2 TRIAL I-SPY 3 is designed to confirm the efficacy of new treatments Goal is to accelerate the phase III testing of agents Utilizes parallel approval pathways for FDA and EMA MK-2206 : AKT inhibitor développé par Meck&Co (ou MSD) Neratinib : Puma Biotech Veliparib : AbbVie

Veliparib : Brightness Study I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY A Study Evaluating Safety and Efficacy of the Addition of Veliparib Plus Carboplatin Versus the Addition of Carboplatin to Standard Neoadjuvant Chemotherapy Versus Standard Neoadjuvant Chemotherapy in Subjects With Early Stage Triple Negative Breast Cancer Phase III trial with 3 arms Neoadjuvant therapy Study conducted by AbbVie https://clinicaltrials.gov/ct2/show/record/NCT02032277

Veliparib: Brightness Study I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY * AC : doxorubicin/cyclophosphamide Triple negative Breast Cancer Arm A: Active Comparator Veliparib + Carboplatin + Paclitaxel  followed by AC Arm B: Placebo Comparator Placebo + Carboplatin + Paclitaxel  followed by AC Arm C: Placebo Comparator Placebo + Placebo + Paclitaxel  followed by AC https://clinicaltrials.gov/ct2/show/record/NCT02032277

Veliparib : Brightness Study I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY Primary endpoint Pathological Complete Response (pCR) of breast and axillary tumor Secondary endpoints Event-free Survival (EFS) Overall Survival (OS) Final data collection date for primary outcome measure : March 2016 Estimated study Completion date : December 2026 https://clinicaltrials.gov/ct2/show/record/NCT02032277

Neratinib : Phase III I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY Based on I-SPY 2 results and other clinical data, Phase 3 testing of neoadjuvant neratinib is moving forward in the successor I-SPY 3 program, aimed at generating accelerated approval N Engl J Med. Author manuscript; available in PMC 2017 January 24.

Neratinib : Phase III future design I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY * AC : doxorubicin/cyclophosphamide HER2 + Breast Cancer Arm A Neratinib + Pertuzumab + Trastuzumab + Paclitaxel  followed by AC Arm B Placebo + Pertuzumab + Trastuzumab + Paclitaxel  followed by AC Arm C Neratinib + Placebo + Trastuzumab + Paclitaxel  followed by AC N Engl J Med. Author manuscript; available in PMC 2017 January 24.

Can adaptive trial become the new oncology trial gold standard ? I-SPY 3 I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Limits of I-SPY Reduce Phase III duration Reduce population Reduce cost Can adaptive trial become the new oncology trial gold standard ? Accelerated Approval – Early access to the market Can adaptive trial become the new oncology trial gold standard ?

I-SPY Limits

 Prediction by pCR of an improved survival NeoALTTO Trial Limits of I-SPY Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 HER2 + Breast Cancer Lapatinib alone Lapatinib plus trastuzumab Trastuzumab alone Lapatinib inhibe l'activité tyrosine kinase à la fois des récepteurs ErbB1 et ErbB2 (efficace dans HER 2+) NeoALTTO’s aim : Showing that dual inhibition of HER2 might be a valid approach to treatment of HER2+ breast cancer in the NEOADJUVANT SETTING  Prediction by pCR of an improved survival Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial ; www.thelancet.com Vol379 February18, 2012

NeoALTTO Trial ALTTO Trial Limits of I-SPY Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 The combination of lapatinib and trastuzumab resulted in a significantly higher pCR rate than did trastuzumab or lapatinib alone for both HR+ and HR– tumours Des études ont montré la corrélation entre les endpoints primaires et secondaires (à savoir corrélation entre la pCR et l’event-free survival) -> montre que la pCR peut être prise comme marqueur prédictif de l’event free survival qui sera étudié en ALTTO – Ces études ne vous seront pas présentées ALTTO Trial (adjuvant therapy) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial ; www.thelancet.com Vol379 February18, 2012

ALTTO Trial Primary endpoint : Disease-free survival (DFS) Limits of I-SPY Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 HER2 + Breast Cancer Trastuzumab then Lapatinib Lapatinib plus trastuzumab Trastuzumab alone Disease-free survival event = first occurrence of Invasive breast cancer reccurence at any site A second primary cancer Death from any cause as first event Primary endpoint : Disease-free survival (DFS) Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

Nonsignificant reduction in DFS in HER2-positive tumors ALTTO Trial Limits of I-SPY Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Nonsignificant reduction in DFS in HER2-positive tumors ALTTO Trial FAILED Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

ALTTO Trial Failed Limits of I-SPY Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 ALTTO Phase III trial FAILED to show improvement of DFS  Results of higher pCR don’t lead to improvement of DFS Can we start I-SPY 3 ? Is pCR such a good surrogate marker ? How can we explain those results ?

Different chemotherapy order ALTTO Trial Failed Limits of I-SPY Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 ALTTO Phase III trial FAILED to show improvement of DFS  Results of higher pCR don’t lead to improvement of DFS Low events 2 Different studies NeoALTTO 4years DFS = 75% VS 87% More HR+ status in ALTTO = less sensibility to anti-HER2+ treatment Different population Failed because 2 Differents studies: Même si on faisait 2 études identiques on pourrait avoir des résultats différents Differents populations: (Sachant que dans la Guidance FDA sur la pCR, ils disent bien que dans leur méta analyse, les fois où ils ont eu des mauvais résultat de concordance pCR et EFS ils ont regardé les populations, et c’était des populations très hétérogène. Quand on regarde des études avce population plus homogène on est significatif, car les biomarqueurs sont très importants!! NeoALTTO 4 years DFS = 75% ALTTO 4 years DFS = 87% = Un risque différent, donc une réponse thérapeutic différents aussi + proportion de node - > dans altto donc nodal status devient non prédictif du bénéfice d’un ttt anti her2 + proportion de HR+ > dans altto et eux sont moins sensible au antiher2 NeoALTTO: pCR assess before anthracycline chemotherapy -> exaggerate effect of Lapatinib Ordre de chimioT différents Less evenements (or on détermine la puissance sur le nombre d’évênement et non le nombre de patients) Different chemotherapy order Clin Cancer Res; 21(13); 2911–5. !2015 AACR

Adaptive trials still the future of clinical trials in oncology?

Probability of Success: Traditional Trials Conclusion Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 2006 - 2015 Clinical Development Success Rates 2006-2015

I-SPY 2 50% graduated from I-SPY 2 Breast Cancer T-DM1 + Pertuzumab Conclusion Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 T-DM1 + Pertuzumab PLX3397 Talazoparib + Irinotecan Ganetespib Pertuzumab + Trastuzumab 50% graduated from I-SPY 2 Neratinib Breast Cancer Veliparib PROBABILITÉ PASSAGE PHASE II / PHASE III A VOIR ++++ AMG 386 +/- Trastuzumab MK-2206 +/- Trastuzumab Patritumab +/- Trastuzumab Pembrolizumab AMG 479 https://clinicaltrials.gov/ct2/show/record/NCT02032277

Towards other indications Conclusion Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 BATTLE Trial Biomarker-integrated approaches of targeted therapy for lung cancer elimination Randomisation based on 4 biomarkers Endpoint: eight-week progression-free survival

Conclusion Benefits Disadvantages Conclusion Breast Cancer I-SPY 1 Accelerated Approval I-SPY 3 Benefits Disadvantages

Conclusion Benefits Disadvantages Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Benefits Great efficiencies in terms of resources Accelerated approval Faster clinical development Assessment of a lot of investigational drugs and combinations in the same time Increase chances for patients Flexibility of phase III Increase probability of success phase II to phase III Logistics more complicated (not standard for CRO) Communication and tranparency between stakeholders Enforce rigorous design (population, compliance with FDA pCR guidance +++) Disadvantages Early access

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