Terapia sistemica neoadiuvante: in quali tumori? Quali risultati? Dott. Giacomo Pelizzari
Neoadjuvant Treatment A window of opportunity Rational: Historically proposed to enable breast-conserving surgery in stage II-III, in particular for triple negative and HER2-positive EBC
Neoadjuvant Treatment A window of opportunity Rational: Historically proposed to enable breast-conserving surgery in stage II-III, in particular for triple negative and HER2-positive EBC this strategy could fail in reducing the mastectomy rate! Criscitiello C, et al. European Journal of Cancer 97 (2018) 1-6
Neoadjuvant Treatment A window of opportunity Rational: Historically proposed to enable breast-conserving surgery in stage II-III, in particular for triple negative and HER2-positive EBC this strategy could fail in reducing the mastectomy rate! In vivo evaluation of tumor dynamic response as early outcome
Surgery Neoadjuvant Treatment A window of opportunity Rational: Historically proposed to enable breast-conserving surgery in stage II-III, in particular for triple negative and HER2-positive EBC this strategy could fail in reducing the mastectomy rate! In vivo evaluation of tumor dynamic response as early outcome Tailored post-neoadjuvant treatment Neoadjuvant Treatment NO pcr pcr Escalation Strategies De-Escalation Strategies
Pathological complete response Definition and clinical meaning Clinical meaning of pcr: Achievement of pcr at time of surgery is correlated with favourable patient outcome in all breast cancer subtype: prognostic relevance Cortazar P, et al. Lancet 2014
Neoadjuvant Treatment A window of opportunity Rational: Historically proposed to enable breast-conserving surgery in stage II-III, in particular for triple negative and HER2-positive EBC this strategy could fail in reducing the mastectomy rate! In vivo evaluation of tumor dynamic response as early outcome Tailored post-neoadjuvant treatment Ideal scenario for drug development and biomarker discovery shorter follow-ups and smaller sample sizes translational research
Prognostic relevance of pcr Enough for surrogacy? Surrogate endpoint: pcr has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as DFS and OS SURROGACY Incremental gains of pcr should also result in a significant extensions of survival outcomes at trial-level comparison of different treatmets Cortazar P, et al. Lancet 2014
Which is the best candidate for neoadjuvant therapy?
Neoadjuvant chemotherapy Identifying the best candidate Cortazar P, et al. Lancet 2014
Neoadjuvant chemotherapy Identifying the best candidate Cortazar P, et al. Lancet 2014
Neoadjuvant chemotherapy Identifying the best candidate Cortazar P, et al. Lancet 2014
Neoadjuvant chemotherapy Identifying the best candidate The Panel strongly endorsed the use of neoadjuvant therapy for stage II or III, HER2 positive or triple-negative breast cancer as the preferred initial treatment approach, particularly when there is any suggestion that treatment response might enable de- escalation of surgery or radiotherapy Curigliano G, et al, Annals of Oncology 28: 1700 1712, 2017
Neoadjuvant chemotherapy Luminal disease ITT NO CT Ellis, et al, JCO 2017
Recent advances in the neoadjuvant treatment of BC
Escalating strategies We have a plan! + CT (capecitabine, carboplatin) + Bevacizumab + Double HER2-blockage + PARPi + ET + CDK4/6i + Immunotherapy AC T pcr Observation DFS Neoadjuvant Follow-up surgery
HER2+
Escalation Neoadjuvant therapy in HR+/HER2+ Phase II/III clinical trials 45% Double HER2 blockage Harbeck N, et al. The Breast 34 (2017) S99eS103
Escalation Neoadjuvant therapy in HR-/HER2+ Phase II/III clinical trials 70% Double HER2 blockage Harbeck N, et al. The Breast 34 (2017) S99eS103
Neoadjuvant therapy in HER2+ Does Double-blockage improve DFS/EFS? Courtesy of Cortes J. Presented at ESMO 2018
Neoadjuvant therapy in HER2+ Do we need anthracyclines? Schneeweiss A, et al. Annals of Oncology 24: 2278 2284, 2013. Van Ramshorst et al. ASCO 2017
Neoadjuvant therapy in HER2+ Concomitant anthracyclines and anti-her2 therapies? Buzdar et al. Jama Oncol 2018
Neoadjuvant therapy in HER2+ De-escalation chemotherapy? ADAPT HR+ KRISTINE Harbeck N, et al. JCO 2017. Hurvitz S. Lancet Oncol 2017
TNBC
Escalation Neoadjuvant therapy in TNBC Phase II/III clinical trials 50% Harbeck N, et al. The Breast 34 (2017) S99eS103
[1] von Minckwitz, et al. JCO 2010; [2] von Minckwitz, et al. Ann Oncol 2014 [3] von Minckwitz, et al. Lancet Oncology 2014; [4] von Minckwitz, et al. ESMO 2017 1. [5] Loibl S, et al. Annals of Oncol 2018; [6] Sikov W, et al. JCO 2015; [7] Sikov W, et al. SABCS 2015 Escalation Neoadjuvant therapy Platinum salts Ref. Pop. Escalation Neoadjuvant Treatment Pz pcr HR DFS HR OS Gepar IV T 2 cm, 2010 [1,2] or ER, or ER+N+ Gepar VI TNBC 2014 [3,4,5] sub. 4xEC 4xT 4xEC 4xTCape 4xEC 4xT 4xCape 18wPacli/nPLD +Bev 18wPacli/nPLD/Cb1.5AUC +Bev CALGB40603 TNBC 12wPacli 4xddAC ±Bev 2015 [6,7] 12wPacli+4xCb6AUC 4xddAC ±Bev 471 471 479 157 158 212 221 22.3% 19.5% 22.3% ns 0.92 ns 0.97 ns 0.93 ns 0.97 ns 42.7% 53.2%* 0.56* 0.10 ns 41% 54%* 0.84 ns 1.15 ns
Escalation Neoadjuvant therapy Final results of GeparSixto DFS OS Loibl S, et al. Annals of Oncol 2018
Escalation Neoadjuvant therapy in TNBC Platinum salts OR for pcr Poggio et al. Annals of Oncology. 29: 1497 1508, 2018
Escalation Neoadjuvant therapy in TNBC PARP Inhibitors [1] Rugo HS, et al. NEJM 2016; [2] Loibl et al, Lancet Oncol 2018
Escalation Neoadjuvant therapy Clinical trials Ref. Pop. Escalation Neoadjuvant Treatment Pz pcr HR DFS HR OS Gepar IV T 2 cm, 2010 [1,2] or ER, or ER+N+ Gepar VI TNBC 2014 [3,4,5] sub. 4xEC 4xT 4xEC 4xTCape 4xEC 4xT 4xCape 18wPacli/nPLD +Bev 18wPacli/nPLD/Cb1.5AUC +Bev CALGB40603 TNBC 12wPacli 4xddAC ±Bev 2015 [6,7] 12wPacli+4xCb6AUC 4xddAC ±Bev ISPY-2 TNBC 2016 [8] sub. 12wPacli 4xddAC 12wPacli+4xCb6AUC+Veliparib 4xddAC BRIGHTNES S TNBC 12wPacli 4xddAC 12wPacli+Cb 4xddAC 1. 2017 Escalation-NeoAdjuvant [9] 12wPacli+Cb+Veliparib therapy increases pcr from 4xddAC 30-40% to 55% 2. Lack of proven survival benefit. 3. Patient selection (gbrcam?) 471 471 479 157 158 212 221 21 39 158 160 361 22.3% 19.5% 22.3% ns 0.92 ns 0.97 ns 0.93 ns 0.97 ns 42.7% 53.2%* 0.56* 0.10 ns 41% 54%* 0.84 ns 1.15 ns 26% 51%* 31% 57.5%* 53.2%* - - [1] von Minckwitz, et al. JCO 2010; [2] von Minckwitz, et al. Ann Oncol 2014 [3] von Minckwitz, et al. Lancet Oncology 2014; [4] von Minckwitz, et al. ESMO 2017 [5] Loibl S, et al. Annals of Oncol 2018; [6] Sikov W, et al. JCO 2015; [7] Sikov W, et al. SABCS 2015 [8] Rugo HS, et al. NEJM 2016; [9] Loibl et al, Lancet Oncol 2018
Escalation Neoadjuvant therapy in TNBC Parp trapping potency Presented by Litton J at ASCO 2018
Escalation Neoadjuvant therapy in TNBC Parp trapping potency Presented by Litton J at ASCO 2018
Escalation Neoadjuvant therapy in TNBC Parp trapping potency Presented by Litton J at ASCO 2018
Escalation Neoadjuvant therapy in TNBC Carboplatin vs Parp Inhibitors GEPAR-OLA Study Courtesy of Tutt A, at al. Presented at ESMO 2018
Escalation Neoadjuvant therapy Clinical trials Ref. Pop. Escalation Neoadjuvant Treatment Pz pcr HR DFS HR OS Gepar IV T 2 2010 [1,2] cm, or ER, or ER+N+ Gepar VI TNBC 2014 [3,4,5] sub. 4xEC 4xT 4xEC 4xTCape 4xEC 4xT 4xCape 18wPacli/nPLD +Bev 18wPacli/nPLD/Cb1.5AUC +Bev CALGB40603 TNBC 12wPacli 4xddAC ±Bev 2015 [6,7] 12wPacli+4xCb6AUC 4xddAC ±Bev ISPY-2 TNBC 2016 [8] sub. 12wPacli 4xddAC 12wPacli+4xCb6AUC+Veliparib 4xddAC BRIGHTNESS TNBC 12wPacli 4xddAC 2017 [9] 12wPacli+Cb 4xddAC 12wPacli+Cb+Veliparib 4xddAC GeparNuevo 1. Escalation-NeoAdjuvant [10] TNBC 12wNabPacli therapy increases 4xAC pcr from 30-40% to 55% 2. Lack of proven survival 12wNabPacli benefit. ±Durv 4xAC ±Durv 3. Patient selection (gbrcam?) Durvx2w+12wNabPacli±Durv 4xAC ±Durv 471 471 479 157 158 212 221 21 39 158 160 361 22.3% 19.5% 22.3% ns 0.92 ns 0.97 ns 0.93 ns 0.97 ns 42.7% 53.2%* 0.56* 0.10 ns 41% 54%* 0.84 ns 1.15 ns 26% 51%* 31% 57.5%* 53.2%* 44.2% 53.4% 61vs41 % - - [1] von Minckwitz, et al. JCO 2010; [2] von Minckwitz, et al. Ann Oncol 2014 [3] von Minckwitz, et al. Lancet Oncology 2014; [4] von Minckwitz, et al. ESMO 2017 [5] Loibl S, et al. Annals of Oncol 2018; [6] Sikov W, et al. JCO 2015; [7] Sikov W, et al. SABCS 2015 [8] Rugo HS, et al. NEJM 2016; [9] Loibl S, et al. Lancet Oncol 2018; Loibl S, et al. ASCO 2018 - -
Escalating strategies We have a plan! + CT (capecitabine, carboplatin) + Target therapies (PARPi, T-DM1) + ET + CDK4/6i + Immunotherapy AC T RD Adjuvant DFS Neoadjuvant Follow-up surgery
Post-Neoadjuvant therapy CREATE X Masuda N, et al. NEJM 2017
Neoadjuvant CT (at least 4xAnthracycline) Surgery Randomization 1:1 CREATE X Trial Design -HER2 negative -Stage I-IIIB -Age 20-74yr -ECOG 0-1 NO pcr Standard treatment Observation Capecitabine 1250 mg/mq BD d1-14 q21 x6-8 cycles Stratification: ER- vs ER+ Age >50 Taxane use N0 vs N1 vs N2 Fluorouracil use Center End Points & Statistical Analysis: Primary end point: DFS Secondary end point: OS, Safety With a power of the 80%, and a type I error set at 0.05, to see the hypothesized 0.74 hazard for recurrence, second cancer or death, the required sample size was estimated to be 900 patients. Follow-up: 5 years. Prespecified subgroup analysis (TNBC) Masuda N, et al. NEJM 2017
CREATE X Results mfu: 3.9 years All comers: 3-year DFS rate: 82.2% vs 73.9% with Cape 5-year OS rate: 89.2% vs 83.6% with Cape HR for recurrence 0.70 (0.53-0.92; P=0.01) HR for death 0.59 (0.39-0.90; P=0.01) TNBC: 5-year DFS rate: 69.8% vs 56.1% with Cape 5-year OS rate: 78.8% vs 70.3% with Cape HR for recurrence 0.58 (0.39-0.87) HR for death 0.52 (0.30-0.90) Masuda N, et al. NEJM 2017
CREATE X Conclusions Capecitabine showed effectiveness as adjuvant treatment in patients with residual disease after neoadjuvant therapy: Methodological issues Previous trials in the adjuvant setting were negative (FINXX, GEICAM). Statistical enrichment? In the FINXX trial, an exploratory analysis in the TNBC subgroup showed that TX/CEX was more effective than T/CEF. Treatment sequence? In preclinical models, agents such as paclitaxel, cyclophosphamide increase cancer thymidine-phosphorylase concentration. In subgroup analysis the survival benefit was significative only among TNBC patients. Applicability issues Concern about the applicability and safety among non-asian population. Japanase have a 36% lower Cmax and 24% lower AUC than Caucasian. The study dose was 1250mg/mq BD (Tolerability?). Clinical issues Tailored therapies or Clinical Trials are preferred in this setting. Precision medicine? Post-Neoadjuvant Carboplatin? Warnings about Capecitabine use in adjuvant setting. DPYD variants. About 20% pts discontinued, 30% had dose reduction. Off-lable?
Post-Neoadjuvant therapy Ongoing Clinical Trials Ref. Ph Post-NAT Population Ongoing Post-Neoadjuvant Treatment ECOG-ACRIN III TNBC with RD 1 cm 4xCis 75mg/mq q21 4xCb6AUC q21 6xCape 1000mg/mq BID d1-14 q21 A-BRAVE III TNBC with RD Observation Avelumab 10 mg/kg IV q14 x 1 yr SWOG S1418 III TNBC with RD 1 cm or yn+ Observation Pembrolizumab 200 mg q21 x 1yr OlympiA III HER2 BC with gbrcam Placebo Olaparib 300 mg BID x 1yr KATHERINE III HER2+ BC with RD Trastuzumab 6 mg/kg q21 x14 TDM-1 3.6 mg/kg q21 x14 PENELOPE-B III HR+/HER2 BC with RD and CPSEG 3, or 2 if ypn+ CLEE011G2301 III HR+/HER2 BC with RD 1 cm or yn1 2 mm Placebo + ET Palbociclib 125 mg d1-21 q28 x 13 + ET Placebo + ET Ribociclib 600 mg d1-21 q28 x 26 + ET
Dott. Giacomo Pelizzari giacomo.pelizzari@cro.it