Analyses des sous groupes. Prof. X Pivot Strasbourg France

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1 Analyses des sous groupes Prof. X Pivot Strasbourg France

2 Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial Stefan Aebi, Shari Gelber, Stewart J Anderson, István Láng, André Robidoux, Miguel Martín, Johan W R Nortier, Alexander H G Paterson, Mothaffar F Rimawi, José Manuel Baena Cañada, Beat Thürlimann, Elizabeth Murray, Eleftherios P Mamounas, Charles E Geyer Jr, Karen N Price, Alan S Coates, Richard D Gelber, Priya Rastogi, Norman Wolmark, Irene L Wapnir, on behalf of the CALOR investigators* Lancet Oncol 214; 15: Articles Disease-free survival (%) A Disease-free survival in all patients 6 2 Number at risk Chemotherapy No chemotherapy C Chemotherapy No chemotherapy Chemotherapy 85 No chemotherapy Events % (95% CI 56 79) 57% (95% CI 44 67) HR (95% CI) p value 59 ( 35 99) Overall survival (%) HR (95% CI) Oestrogen-receptor status of ILRR (positive vs negative) 77 ( ) 37 Location of ILRR Breast Reference group NA Mastectomy scar or chest wall 84 ( ) 59 Lymph nodes 1 18 ( ) 69 Previous chemotherapy (yes vs no) 99 ( ) 97 p value Interval from primary surgery (in years, continuous) 9 ( 85 96) 21 Treatment (chemotherapy vs no chemotherapy) 49 ( 29 84) 98 HR=hazard ratio. NA=not applicable. Table 2: Multivariable proportional hazards regression model of disease-free survival models, 18 and all yielded non-significant results. All analyses are by intention to treat, and all reported p values are two-sided. Data as of Oct 16, 212, were used for the efficacy analyses. We used SAS version 9.2 for this analysis. This study is registered with ClinicalTrials.gov, number NCT At a median follow-up of 4 9 years (IQR ) disease-free survival was significantly improved in the adjuvant chemotherapy group compared with the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56 79) in the chemotherapy group compared with 57% (44 67) in the no chemotherapy group (HR 59 [95% CI 35 99]; p= 46). Role of the funding source IBCSG and NSABP were responsible for the design of the study. IBCSG coordinated the collection and management of the data, medical review, and data analysis. The reporting of the results was done jointly. Members of the trial steering committee (appendix) reviewed the manuscript and were responsible for the decision to submit for publication. SG and SJA had access to the raw data. The corresponding author (SA) had full access to all the data in the study and had final responsibility to submit for publication. The interaction between treatment group and expression of oestrogen receptor was statistically significant (p interaction = 46). patien negati propo endoc treatm group p= 3 group group tumou respec expres negati Proge 16 (22 19 (29 with HER2 were p Che physic teristic prima regim At a (4 6 y 5 y diseas adjuva chemo surviv group group

3 no chemotherapy (HR 32 [95% CI 14 73]; 5-year disease-free survival was 67% (95% CI 44 82) in the overall survival according to oe ILRR also show that overall su A Disease-free survival in all patients B Overall survival in all patients Chemotherapy for isolated locoregional recurrence 6 of breast cancer (CALOR): a randomised trial Stefan Aebi, Shari Gelber, Stewart J Anderson, István Láng, André Robidoux, Miguel Martín, Johan W R Nortier, Alexander H 2 G Paterson, Chemotherapy 85 Mothaffar F Rimawi, José Manuel Baena Cañada, Beat Thürlimann, Elizabeth Murray, Eleftherios P Mamounas, Charles E Geyer No Jr, chemotherapy Karen N Price, 77 Alan S Coates, Richard D Gelber, Priya Rastogi, Norman Wolmark, Irene L Wapnir, on behalf of the CALOR investigators* Number at risk Chemotherapy No chemotherapy Lancet Oncol 214; 15: Disease-free survival (%) Chemotherapy No chemotherapy Events % (95% CI 56 79) 57% (95% CI 44 67) Overall survival (%) HR (95% CI) p value 59 ( 35 99) 46 Chemotherapy 85 No chemotherapy D 9 21 C Disease-free survival in patients with oestrogen-receptor-negative ILRR D Overall survival in patients wit Disease-free survival (%) A Disease-free survival in all patients 6 2 Number at risk Chemotherapy No chemotherapy C Chemotherapy No chemotherapy Chemotherapy 85 No chemotherapy Events % (95% CI 56 79) 57% (95% CI 44 67) HR (95% CI) p value 59 ( 35 99) 46 Adjuvant chemotherapy for local relapse breast cancer X Pivot Lancet Oncol. 214 Feb;15(2): Overall survival (%) Disease-free survival (%) 6 2 Number at risk Chemotherapy No chemotherapy Disease-free survival (%) 6 2 Number at risk Chemotherapy No chemotherapy Chemotherapy 29 No chemotherapy Events % (95% CI 44 82) 35% (95% CI 18 53) E Disease-free survival in patients with oestrogen-receptor-positive ILRR Events HR (95% CI) 32 ( 14 73) Chemotherapy 29 No chemotherapy % (95% CI 53 81) 69% (95% CI 53 81) D 5 11 F Overall survival in patients wit Chemotherapy No chemotherapy Years from randomisation Years from HR (95% CI) 94 ( ) Chemotherapy No chemotherapy Overall survival (%) Overall survival (%) Figure 2: Kaplan-Meier curves of disease-free survival and overall survival according to assigned treatment group Disease-free survival (A) and overall survival (B) in all patients; patients with oestrogen-receptor-negative ILRR (C and D); and pa positive ILRR (E and F). 5-year disease-free survival or 5-year overall survival are presented, as applicable, on each graph. HR=haza recurrence D 4 1

4 The trick of Heterogeneity «To derive conclusions from overall results only rather than to take subgroup analysis into account when an interaction is observed has its pros and cons» «Reporting of an overall result in the presence of a significant interaction is debatable; therefore, reporting of the findings and their interpretations for both subgroups separately might be a valuable alternative» X Pivot et al. Adjuvant chemotherapy for local relapse breast cancer Lancet Oncol. 214 Feb;15(2):125-6.

5 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in With Human Epidermal Growth Factor Receptor 2 Positive Metastatic Breast Cancer Xavier Pivot, Alexey Manikhas, Bogdan Żurawski, Ewa Chmielowska, Boguslawa Karaszewska, Rozenn Allerton, Stephen Chan, Alessandra Fabi, Paolo Bidoli, Stefania Gori, Eva Ciruelos, Magdolna Dank, Lajos Hornyak, Sara Margolin, Arnd Nusch, Roma Parikh, Fareha Nagi, Michelle DeSilvio, Sergio Santillana, Ramona F. Swaby, and Vladimir Semiglazov A Progression-Free Survival (%) No. at risk Lap + Cap Tras + Cap Lap + Cap Tras + Cap Events, n PFS, months (95% CI) First quartile Median Third quartile Hazard ratio (95% Cl) Stratified log-rank P Lap + Cap (n = 271) 16 (59%) 3.9 (2.8 to 5.4) 6.6 (5.7 to 8.1) 12.2 (9. to 13.8) 1.3 (1.4 to 1.64).21 Tras + Cap (n = 269) 134 (5%) 5.5 (4.8 to 5.6) 8.1 (6.1 to 8.9) 18.2 (12. to 25.1) Time Since Random Assignment (months) A Progression-Free Survival (%) No. at risk Lap + Cap Tras + Cap Lap + Cap Tras + Cap Time Since Random Assignment (months) Events, n PFS, months (95% CI) First quartile Median Third quartile 57 (55%) 3. (2.8 to 5.5) 6.3 (5.6 to 8.1) 13.7 (8.3 to 19.4) 48 (44%) 5.6 (3.8 to 7.1) 1.9 (8.3 to 15.) 25.1 (15. to 27.4) Hazard ratio (95% Cl) 1.7 (1.15 to 2.5) Lap + Cap (n = 14) Tras + Cap (n = 11) B Progression-Free Survival (%) No. at risk Lap + Cap Tras + Cap Lap + Cap Tras + Cap Lap + Cap (n = 167) Tras + Cap (n = 159) Events, n PFS, months (95% CI) First quartile Median Third quartile 13 (62%) 4.1 (2.8 to 5.5) 6.6 (5.7 to 8.3) 11.2 (8.8 to 13.7) 86 (54%) 5.4 (4.3 to 5.5) 6.1 (5.7 to 8.) 11.2 (8.7 to 18.2) Hazard ratio (95% Cl) 1.13 (.85 to 1.5) Time Since Random Assignment (months) «A heterogeneity between treatment effect was observed for PFS and prior trastuzumab treatment (P.8) or prior metastatic therapy (P.6)»

6 EGF149: Study design HER2 (FISH+/IHC3+) metastatic breast cancer Progression on Anthracycline Taxane Trastuzumab Progression on most recent trastuzumab regimen for MBC R A N D O M I S E Lapatinib (oral) 15 mg QD (n=148) Crossover allowed to lapatinib + trastuzumab if progression after at least 4 weeks on therapy Lapatinib (oral) mg QD + trastuzumab (IV) 4 mg/kg loading dose, then 2 mg/kg weekly (n=148) Primary endpoint: Progression-free survival Secondary endpoints: Overall survival Overall response rate Clinical benefit rate Tumour assessment occurred at 4, 8, 12, 16 weeks, and then every 8 weeks Independent review of Response Evaluation Criteria in Solid Tumors (RECIST) data was performed Blackwell KL et al. J Clin Oncol. 21;28:

7 Blackwell KL et al. J Clin Oncol. 212;3: EGF149: Overall survival in the ITT population Died n (%) Median P-value Lapatinib (n=145) 113 (78%) 9.5 months Lapatinib + trastuzumab (n=146) % 15 (72%) 14 months.26 HR:.74 (95% CI.57,.97) Survival (%) 7% 6-month OS 56% 41% 12-month OS at risk L L+T Time from randomisation (months)

8 Number at Risk Median OS, mos EGF149: Overall survival by hormone receptor status HR-positive Lap+Tras Lap Lap+Tras N=71 Lap N= OS HR (95% CI).84 ( ) Cumulative Proportion Alive HR-negative Lap+Tras Lap Time from Randomization (Months) Median OS, mos CI=confidence interval; HR=hazard ratio; Lap=laptinib; OS=overall survival; Tras=trastuzumab EUROPEAN MEDICINES AGENCY. Assessment report - Tyverb Junho 213. Disponível em: Lap+Tras Lap Lap+Tras N=75 Lap N= OS HR (95% CI).62 (.42-.9)

9 The new england journal of medicine Original Article Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer Gunter von Minckwitz, M.D., Marion Procter, Ph.D., Evandro de Azambuja, M.D., Dimitrios Zardavas, M.D., Mark Benyunes, M.D., Giuseppe Viale, M.D., Thomas Suter, M.D., Amal Arahmani, Ph.D., Nathalie Rouchet, M.Sc., Emma Clark, M.Sc., Adam Knott, Ph.D., Istvan Lang, M.D., Christelle Levy, M.D., Denise A. Yardley, M.D., Jose Bines, M.D., Richard D. Gelber, Ph.D., Martine Piccart, M.D., and Jose Baselga, M.D., for the APHINITY Steering Committee and Investigators* DOI: 1.156/NEJMoa A Intention-to-Treat Population Invasive Disease free Survival Rate (%) No. at Risk Pertuzumab Placebo 6 2 Stratified hazard ratio,.81 (95% CI,.66 1.) P= Pertuzumab, 171 events Placebo, 21 events Months B Population with Node-Negative Disease Invasive Disease free Survival Rate (%) No. at Risk Pertuzumab Placebo 6 2 Unstratified hazard ratio, 1.13 (95% CI, ) P= Pertuzumab, 32 events Placebo, 29 events C Population with Node-Positive Disease Invasive Disease free Survival Rate (%) No. at Risk Pertuzumab Placebo 6 Months Unstratified hazard ratio,.77 (95% CI,.62.96) P= Pertuzumab, 139 events Placebo, 181 events Months

10 The new england journal of medicine 1. Original Article Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer Gunter von Minckwitz, M.D., Marion Procter, Ph.D., Evandro de Azambuja, M.D., Dimitrios Zardavas, M.D., Mark Benyunes, M.D., Giuseppe Viale, M.D., Thomas Suter, M.D., Amal Arahmani, Ph.D., Nathalie Rouchet, M.Sc., Emma Clark, M.Sc., Adam Knott, Ph.D., Istvan Lang, M.D., Christelle Levy, M.D., Denise A. Yardley, M.D., Jose Bines, M.D., Richard D. Gelber, Ph.D., Martine Piccart, M.D., and Jose Baselga, M.D., for the APHINITY Steering Committee and Investigators* 1 year 2 years 99.7% 99.5% 99.1% 99.% 3 years 98.4% 97.5% 4 years 96.7% 96.2% Proportion event-free Pertuzumab Herceptin (n = 897) Placebo Herceptin (n = 92) Events, n (%) 32 (3.6) 29 (3.2) Unstratified HR (95% CI) 1.13 (.68, 1.86) p value.6436 Median FU, months 48.3 N No. of patients at risk Time (months) Hazard ratios were estimated by Cox regression.

11 The new england journal of medicine Proportion event-free Original Article Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer Gunter von Minckwitz, M.D., Marion Procter, Ph.D., Evandro de Azambuja, M.D., Dimitrios Zardavas, M.D., Mark Benyunes, M.D., Giuseppe Viale, M.D., Thomas Suter, M.D., Amal Arahmani, Ph.D., Nathalie Rouchet, M.Sc., Emma Clark, M.Sc., Adam Knott, Ph.D., Istvan Lang, M.D., Christelle Levy, M.D., Denise A. Yardley, M.D., Jose Bines, M.D., Richard D. Gelber, Ph.D., Martine Piccart, M.D., and Jose Baselga, M.D., for the APHINITY Steering Committee and Investigators* Pertuzumab Herceptin (n = 153) Placebo Herceptin (n = 152) Events, n (%) 139 (9.2) 181 (12.1) Unstratified HR (95% CI).77 (.62,.96) p value.188 Median FU, months 1 year 98.1% 98.2% No. of patients at risk years 94.9% 93.7% Time (months) 3 years Hazard ratios were estimated by Cox regression. von Minckwitz G, et al. N Engl J Med % 9.2% N+ 4 years 89.9% 86.7%

12 Editorial Page 1 of 4 Why the results of adjuvant pertuzumab in HER2-positive early breast cancer has been received as a mitigate success? Xavier Pivot 1,2, David G. Cox 1,2, Joseph Gligorov 3,4 Chin Clin Oncol 217. doi: /cco «Subgroup analyses are not always deleterious, or lead to invalid statistical conclusions. Some situations require adequate subgroup evaluation in order to adjust the validity of the overall conclusion, particularly when factors are known to influence outcome.»

13 Study 31: study schema (planned N=112) Locally advanced or mbc 3 prior chemotherapies ( 2 for advanced disease) Prior anthracycline and taxane in (neo)adjuvant setting or for locally advanced/metastatic disease VOLUME 33 NUMBER 6 FEBRUARY Eribulin mesilate 1.4mg/m 2,* 2 5 min IV Day 1 and 8, q21 days Randomisation 1:1 Capecitabine 1,25mg/m 2 PO BID Days 1 14, q21 days JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Co-primary endpoints OS and PFS Secondary endpoints Quality of life ORR DOR 1-, 2- and 3-year survival Tumour-related symptom assessments Safety parameters Population PK (eribulin arm only) Peter A. Kaufman, Norris Cotton Cancer Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Peter A. Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, Edith A. Perez, Galina Velikova, Martin S. Olivo, Yi He, Corina E. Dutcus, and Javier Cortes 13 13

14 VOLUME 33 NUMBER 6 FEBRUARY JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Peter A. Kaufman, Norris Cotton Cancer Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Peter A. Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, Edith A. Perez, Galina Velikova, Martin S. Olivo, Yi He, Corina E. Dutcus, and Javier Cortes A B S T R A C T Co-primary efficacy endpoints were OS and PFS Alpha=.5 split in.4 (OS) +.1 (PFS) 2 interim analyses + 1 final (OBF spending) for OS (Final Analysis at 95 deaths) Nominal alpha at the final analysis=.372

15 VOLUME 33 NUMBER 6 FEBRUARY JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Peter A. Kaufman, Norris Cotton Cancer Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Peter A. Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, Edith A. Perez, Galina Velikova, Martin S. Olivo, Yi He, Corina E. Dutcus, and Javier Cortes A B S T R A C T Stratified Log rank and Cox Model Overall survival was not significant N=112 (554 vs 548) Hazard ratio=.88 95% CI: p=.56 > alpha=.372

16 Overall survival by HER2 status Events/n Median (months) Subgroup Eribulin Cape HR (95% CI) Eribulin Cape Overall 446/ /548 HER2 status Positive * 73/86 73/ (.77, 1.3).965 (.688, 1.355) Negative 296/ /3.838 (.715,.983) Unknown 77/93 7/ (.71, 1.375) ITT population * 19/83 (23%) and 7/86 (8%) of HER2-positive patients in the capecitabine and eribulin treatment arms, respectively did not receive anti-her2 therapy prior to study, but received it afterwards. 16

17 Study 31 - OS: Lack of significance? OS analysis adjusted for previous treatment (presence or absence trastuzumab) exhibits statistical significance P=.325 <.372 If OS is shown to be NOT Significant in the Overall Population for the main analysis Claim for OS in a subgroup is not valid! Claim for OS gain based on additional analysis is not valid! Multiplicity issue: it is well known that the risk of error is inflated, >5%

18 Overall Survival endpoints & Homogeneous tested population «In the future, large randomised studies in metastatic breast cancer should include a statistical plan that is able to provide conclusions about overall survival and the population should be restricted to a group of patients that unquestionably require chemotherapy alone» X Pivot. Classic cytotoxic drugs: a narrow path for regulatory approval Lancet Oncol February 217, S (17)388-8

19 Annals of Oncology 27: , 216 doi:1.193/annonc/mdw23 Published online 13 May 216 Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy X. Pivot 1 *, F. Marmé 2, R. Koenigsberg 3,4, M. Guo 5, E. Berrak 6 & A. Wolfer 7 Survival probability Eribulin (n = 946, [events = 844]) Median 15. months Comparator (n = 698, [events = 621]) Median 12.6 months Hazard ratio (95% Cl):.85 (.76,.94).2.1. P = Time (months) Number of patients at risk: Eribulin Comparator Events/n Median (months) Subgroup Eribulin Comparator HR (95% CI) Eribulin/Comp P value Overall 844/ / (.76,.94) 15./ HER2 status Positive Negative Unknown ER status Positive Negative Unknown Triple negative Yes No Site of disease 136/15 97/14 59/ / /133 82/97 484/ /1 285/ /237 75/83 48/6 179/ / / / (.57, 1.) 13.5/ (.74,.96) 15.1/ (.73, 1.32) 16.5/ (.75, 1.) 15.7/ (.59,.86) 12.9/9.4 < (.7, 1.57) 17.1/ (.57,.9).86 (.76,.97) 12.4/ /14..17