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Sophie Skorupka, Stéphanie Crosetto, Hasnein Cheikh, Juliette Desbonnet AREIPS 2016-2017 Breast Cancer Key numbers Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Cancer Incidence France, 2014 USA, 2014 3 Key numbers Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval 120 100 80 60 40 20 0 1980 1985 1990 1995 2000 2005 2010 France USA http://globocan.iarc.fr/old/FactSheets/cancers/breast-new.asp Limits of I-SPY Evolution of mortality Age-standardised rate per 100 000 Age-standardised rate per 100 000 Evolution of incidence I-SPY 3 25 20 15 10 5 0 1975 1980 1985 1990 1995 2000 2005 2010 France USA 4 Breast anatomy Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 5 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 6 Staging of breast cancer Breast Cancer I-SPY 1 I-SPY 2 No tumor and cancer has spread to the lymph nodes Accelerated Approval I-SPY 3 Limits of I-SPY Tumor 2 – 5 cm and cancer has spread to the lymph nodes Tumor > 5 cm and Tumor less than 2 cm et contenu avec Disposition Titre cancer has not spread and cancer has spread to the lymph nodes to the lymph nodes graphique Tumor 2 – 5 cm and cancer has not spread to the lymph nodes 7 Staging of breast cancer Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 • 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 Limits of I-SPY Disposition Titre et contenu avec • Tumor larger than 5 cm and cancer graphique has spread to lymph nodes near the breastbone or underarm 8 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 9 Different prognosis : Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 5-year survival rate 99 93 Survival Rate 72 22 0-I II III IV Breast Cancer Stages https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html 10 Breast Cancer Status Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 HER2 Receptor HR: Hormone Receptor HER2 protein receptor: Help control how a healthy breast cell grows, divides and repairs itself Breast cell have receptor for mormones ER+: estrogen receptor + EP+: progesteron receptor + 25% breast cancer are HER2 +: tend to grow faster and are more likely to spread and come back 2/3 of breast cancer are HR+ Treatment available specifically for HER2 +: Trastuzumab, T-DM1, Pertuzumab, Lapatinib Treatment for HR+: SERMs, Aromatase inhibitors, ERDs, LHRHs Limits of I-SPY 11 Diagnosis Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Breast exam Mammogram Ultrasound MRI Biopsy 12 Breast Cancer Treatment Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Targeted therapy Hormonal therapy Chemotherapy I-SPY 3 Limits of I-SPY Trastuzumab Lapatinib Anti-oestrogen Anti-aromatase Doxorubicin Paclitaxel Cyclophosphamid Radiations Surgery 13 Neoadjuvant or Adjuvant? Breast Cancer Breast Cancer I-SPY 1 I-SPY 2 Neoadjuvant therapy Accelerated Approval Surgery • Smaller sample size • Primary endpoint : pCR (assessed months) • Short drug exposure • Needs prior safety information I-SPY 3 Limits of I-SPY Adjuvant therapy • Bigger sample size • Primary endpoint : DFS, OS (assessed years) • Best setting to assess long-term outcome (DFS, OS) • Better safety assessment 14 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 Breast Cancer 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 15 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 High failure rate (34% Phase II Phase III) Adaptive Clinical Trials Often result in very small improvements in outcome Repeated analysis and fixed sample-size inflate probability of type I or type II error 16 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 • Adaptive treatment-switching design • Sample size re-estimation design • Hypothesis-adaptive design • Drop-the-loser design • Adaptive seamless phase II/III • Adaptive dose-finding design • Multi-adpative design 17 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 Phase II results available Placebo Group 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 18 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 Phase II results available Placebo Group 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 19 Adaptive randomisation Breast Cancer Triple negative I-SPY 1 I-SPY 2 Drug A Accelerated Approval Drug B I-SPY 3 Limits of I-SPY Control HER2+ / HRHER2+ / HR+ Drop B 20 Concept of I SPY Breast Cancer I-SPY 1 Biomarkers Phase • Find biomarkers • Validation correlation pCR/RFS I-SPY 1 I-SPY 2 Accelerated Approval Screening Phase I-SPY 2 • Neoadjuvant • pCR to predict EFS I-SPY 3 Limits of I-SPY Confirmatory Phase • Neoadjuvant + Adjuvant • DFS to predict OS I-SPY 3 Accelerated approval Full approval 21 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 Pathologic Complete Response (pCR) is defined as the absence of invasive cancer in breast and nodes 23 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 Breast Cancer I-SPY 1 I-SPY 2 Accelerated I-SPY Approval 3 Accelerated I-SPY Approval 3 Limits Conclusion of I-SPY 24 Biomarkers Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hormone Receptor (HR) Estrogen receptor MammaPrint Progesterone receptor HER2 Biomarkers will be used to determine patient eligibility and randomization for the trial 25 Breast Cancer Status Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 HER2 Receptor HR: Hormone Receptor MP: MammaPrint HER2 protein receptor: Help control how a healthy breast cell grows, divides and repairs it self Breast cell have receptor for mormones ER+: estrogen receptor + EP+: progesteron receptor + 25% breast cancer are HER2 +: tend to grow faster and are more likely to spread and come back 70 genes signatures which can accurately select early stage breast cancer patients who are highly likely to develop distant metastasis 2/3 of breast cancer are HR+ Treatment available specifically for HER2 +: Trastuzumab, T-DM1, Pertuzumab, Lapatinib Treatment for HR+: SERMs, Aromatase inhibitors, ERDs, LHRHs Limits of I-SPY Used to make treatment decisions based on the recurrence risk of earlystage 26 MammaPrint Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Only 14 signatures used for I-SPY 27 http://www.agendia.com/healthcare-professionals/breast-cancer/mammaprint/ Study treatment and procedures Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 28 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 I-SPY 1 : Results Breast Cancer I-SPY 1 Hazard ratio for RFS of pCR vs no pCR I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY HR+ / HER2statistically insignificant result 30 I-SPY 1 : Results Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hazard ratio for RFS of pCR vs no pCR 31 I-SPY 1 : Results Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Hazard ratio for RFS of pCR vs no pCR 32 I-SPY 1 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval 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 • Find biomarkers • Validation correlation pCR/RFS I-SPY 3 Limits of I-SPY I-SPY 2 • Neoadjuvant • pCR to predict EFS I-SPY 1 pCR will be primary endpoint in I-SPY2 33 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 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 35 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 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY I-SPY 2 Breast Cancer I-SPY 1 I-SPY 2 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 37 Inclusion and Exclusion criterias Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Inclusion criterias 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 Exclusion criterias o HR + status and low risk according to the 70-gene assay 38 Biomarker signatures Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Focus on biomarker signatures = combination of subtypes 39 Berry, D. A. Nat. Rev. Clin. Oncol. 9, 199–207 (2012); published online 8 November 2011 Bayesian Method Breast Cancer I-SPY 1 I-SPY 2 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 40 Adaptive randomization Breast Cancer Triple negative I-SPY 1 I-SPY 2 Drug A Accelerated Approval Drug B I-SPY 3 Limits of I-SPY Control HER2+ / HRHER2+ / HR+ Drop B 41 Clinical Trial Design Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Randomization updated regarding new data = Adaptive Randomization 42 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Clinical Trial Design Breast Cancer I-SPY 2 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 Paclitaxel 80 mg ± new drug (12 weekly cycles) Doxorubicin 60 mg + cyclophosphamide 600 mg (4 cycles) Surgery On study HER2 Biopsy blood MRI MRI MRI MRI Tissue Primary end point = pCR at time of surgery (5 months after initiation of chemotherapy) 43 Neratinib Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval Tyrosine kinase inhibitor (HER2): HER2+ breast cancer Oral route I-SPY 3 Limits of I-SPY Neratinib: 240 mg per day for the first 12 weeks 44 Trial Design Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 45 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Randomization Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Neratinib + paclitaxel group n = 115 Paclitaxel ± trastuzumab group n = 78 46 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Biomarker signatures Breast Cancer I-SPY 1 I-SPY 2 Signatures Accelerated Approval I-SPY 3 Limits of I-SPY HR, HER2, MP HER2+ +++ ++- -++ -+- MP+ +++ +-+ -++ --+ HR-, HER2+ -++ -+- HR+, HER2+ +++ ++- Only 2 subtypes excluded: • HR+ HER2- MP• HR- HER2- MP47 Adverse Events and Toxic Effects Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY More Anemia and gastrointestinal event More early discontinuation for toxic effects 48 Results Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 49 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 HER2+, HR- results Breast Cancer I-SPY 1 I-SPY 2 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 50 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Veliparib Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Poly (ADP-ribose) polymerase (PARP) inhibitor (PARP-1 and 2), BRCA1/2 Mutation Association with Carboplatin Limits of I-SPY Veliparib: 50 mg oral routes 2/day for 12 weeks Carboplatin: 6 mg·hr per liter on weeks 1, 4, 7, and 10 51 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Trial Design Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 52 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Randomization Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Veliparib + Carboplatin group n = 72 Paclitaxel + trastuzumab group n = 18 Paclitaxel group n = 44 53 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Biomarker signatures Breast Cancer I-SPY 2 I-SPY 1 Signatures Accelerated Approval I-SPY 3 Limits of I-SPY HR, HER2, MP HER2- +-+ +-- HR+, HER2- +-+ +-- Triple negative --- --+ --- Only HER2+ excluded (for toxicity) 54 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Adverse Events and Toxic Effects Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY More hematologic events More early discontinuation for toxic effects 55 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Results Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 56 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 Triple negative results Breast Cancer I-SPY 1 I-SPY 2 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 57 N Engl J Med 2016;375:11-22. DOI: 10.1056/NEJMoa1513750 I-SPY 2 Breast Cancer I-SPY 2 I-SPY 1 PLX3397 Accelerated Approval T-DM1 + Pertuzumab I-SPY 3 Limits of I-SPY Talazoparib + Irinotecan Pertuzumab + Trastuzumab Ganetespib Breast Cancer Neratinib Veliparib AMG 386 +/Trastuzumab MK-2206 +/Trastuzumab Patritumab +/Trastuzumab AMG 479 Pembrolizumab 58 https://clinicaltrials.gov/ct2/show/record/NCT02032277 I-SPY 2 Breast Cancer I-SPY 2 I-SPY 1 PLX3397 Accelerated Approval T-DM1 + Pertuzumab I-SPY 3 Limits of I-SPY Talazoparib + Irinotecan Pertuzumab + Trastuzumab Ganetespib Breast Cancer Neratinib Veliparib AMG 386 +/Trastuzumab MK-2206 +/Trastuzumab Patritumab +/Trastuzumab AMG 479 Pembrolizumab 59 https://clinicaltrials.gov/ct2/show/record/NCT02032277 Accelerated Approval Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 61 JAMA, December 21, 2011—Vol 306, No. 23 Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 62 JAMA, December 21, 2011—Vol 306, No. 23 Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 63 JAMA, December 21, 2011—Vol 306, No. 23 Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval 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 64 Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY number of indications granted accelerated approval 20 18 16 14 12 10 8 6 4 2 0 65 https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm Pathway for accelerated approval Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Single large phase 3 trial Biomarker proposed/phase1 complete Biomarker identified 3 years Full drug approval With companion diagnostic Phase 2 screening trial Accelerated drug approval Biomarker approval Investigational agent Small confirmatory trial 66 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 Accelerated Approval 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 67 I-SPY 3 Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and molecular Analysis I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 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 69 Veliparib : Brightness Study Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 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 70 https://clinicaltrials.gov/ct2/show/record/NCT02032277 Veliparib: Brightness Study Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY * AC : doxorubicin/cyclophosphamide Triple negative Breast Cancer Arm A: Active Comparator Arm B: Placebo Comparator Arm C: Placebo Comparator Veliparib + Carboplatin + Paclitaxel Placebo + Carboplatin + Paclitaxel Placebo + Placebo + Paclitaxel followed by AC followed by AC followed by AC 71 https://clinicaltrials.gov/ct2/show/record/NCT02032277 Veliparib : Brightness Study Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 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 72 https://clinicaltrials.gov/ct2/show/record/NCT02032277 Neratinib : Phase III Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 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 73 N Engl J Med. Author manuscript; available in PMC 2017 January 24. Neratinib : Phase III future design Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY * AC : doxorubicin/cyclophosphamide HER2 + Breast Cancer Arm A Arm B Arm C Neratinib + Pertuzumab + Trastuzumab + Paclitaxel Placebo + Pertuzumab + Trastuzumab + Paclitaxel Neratinib + Placebo + Trastuzumab + Paclitaxel followed by AC followed by AC followed by AC 74 N Engl J Med. Author manuscript; available in PMC 2017 January 24. I-SPY 3 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Reduce Phase III duration Reduce population Reduce cost Accelerated Approval – Early access to the market Can adaptive trial become the new oncology trial gold standard ? 75 I-SPY Limits NeoALTTO Trial Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY HER2 + Breast Cancer Lapatinib alone Lapatinib plus trastuzumab Trastuzumab alone 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 77 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 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 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 ALTTO Trial (adjuvant therapy) 78 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 Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY HER2 + Breast Cancer Trastuzumab then Lapatinib Lapatinib plus trastuzumab Trastuzumab alone Primary endpoint : Disease-free survival (DFS) 79 Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting ALTTO Trial Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY Nonsignificant reduction in DFS in HER2-positive tumors ALTTO Trial FAILED 80 Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting ALTTO Trial Failed Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 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 ? 81 ALTTO Trial Failed Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Limits of I-SPY 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 Different population - - Different chemotherapy order NeoALTTO 4years DFS = 75% VS 87% More HR+ status in ALTTO = less sensibility to antiHER2+ treatment 82 Clin Cancer Res; 21(13); 2911–5. !2015 AACR Adaptive trials still the future of clinical trials in oncology? Probability of Success: Traditional Trials Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Conclusion 2006 - 2015 Clinical Development Success Rates 2006-2015 84 I-SPY 2 Breast Cancer I-SPY 1 I-SPY 2 PLX3397 Accelerated Approval T-DM1 + Pertuzumab I-SPY 3 Talazoparib + Irinotecan Ganetespib 50% graduated from I-SPY 2 Breast Cancer Neratinib Conclusion Pertuzumab + Trastuzumab Veliparib AMG 386 +/Trastuzumab MK-2206 +/Trastuzumab Patritumab +/Trastuzumab AMG 479 Pembrolizumab 85 https://clinicaltrials.gov/ct2/show/record/NCT02032277 Towards other indications Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Conclusion BATTLE Trial Biomarker-integrated approaches of targeted therapy for lung cancer elimination Randomisation based on 4 biomarkers Endpoint: eight-week progression-free survival 86 Conclusion Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Conclusion Benefits Disadvantages 87 Conclusion Breast Cancer I-SPY 1 I-SPY 2 Accelerated Approval I-SPY 3 Conclusion Benefits Great efficiencies in terms of resources Disadvantages • Logistics more complicated (not standard for CRO) • Communication and tranparency between stakeholders • Enforce rigorous design (population, compliance with FDA pCR guidance +++) Early access 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 88 Thank you for your attention