Colorectal Cancer: Critical review

Transcription

1 AIOM POST-ASCO 2018 Updates and Review from Chicago Milano, June 15-16, 2018 Colorectal Cancer: Critical review Alfredo Falcone, MD Department of Oncology and Translational Medicine University of Pisa and Azienda Ospedaliero Universitaria Pisana PISA- ITALY

2 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

3 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

4 Colon adiuvante: 3 vs 6 mesi As an Oncologist: What am I going to do? Educational Session Presented By Weijing Sun at 2018 ASCO Annual Meeting

5 Circulating tumor DNA as a prognostic marker in stage III colon cancer: DFS 4-10 wks after surgery After adjuvant CT Jeanne Tie et al. abst. #3516 (poster discussion)

6 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

7 Oxaliplatin-based RT in Rectal Cancer Historic Oxaliplatin-based XRT studies Presented By Cathy Eng at 2018 ASCO Annual Meeting

8 PETACC-6 Slide 7 Presented By Hans-Joachim Schmoll at 2018 ASCO Annual Meeting

9 PETACC-6 Overall survival (ITT) Presented By Hans-Joachim Schmoll at 2018 ASCO Annual Meeting

10 FOWARC Disease Free Survival Presented By Yanhong Deng at 2018 ASCO Annual Meeting

11 FOWARC Overall survival Presented By Yanhong Deng at 2018 ASCO Annual Meeting

12 ADORE Study design and Rationale Presented By Yong Sang Hong at 2018 ASCO Annual Meeting

13 ADORE Disease-free survival, ITT population Presented By Yong Sang Hong at 2018 ASCO Annual Meeting

14 ADORE Slide 16 Presented By Yong Sang Hong at 2018 ASCO Annual Meeting

15 TAKE HOME MESSAGES: MALATTIA LOCALIZZATA Nel colon III stadio 3 mesi di CAPOX adiuvante si può fare se basso rischio, ma più strategico definire più accuratamente il rischio! Nel retto II-III stadio l aggiunta dell oxali alla RT + fluoropirimidina neoadiuvante non migliora DFS e OS Nel retto II-III stadio patologico dopo CT+RT considerare FOLFOX adiuvante x 8 cicli (o XELOX)

16 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

17 Slide 4 Presented By Filippo Pietrantonio at 2018 ASCO Annual Meeting

18 Slide 11 Presented By Filippo Pietrantonio at 2018 ASCO Annual Meeting

19 Anti-EGFR maintenance trials ongoing 600 RAS and BRAF wt mcrc pts R 1:1 FOLFIRI + cetuximab x 8 cycles FOLFIRI + cetuximab x 8 cycles FOLFIRI + cetuximab until PD cetuximab until PD Phase III trial ERMES Primary endpoint: PFS for non-inferiority

20 PD PD Anti-EGFR maintenance trials ongoing 280 pts SD or better after 3 mos of FOLFOX + panitumumab in RAS wt mcrc R 1:1 FUFA + panitumumab FUFA FOLFOX + panitumuma b until PD or unacceptabl e toxicity Phase II trial PANAMA Primary endpoint: PFS Sponsor: AIO Cooperative Group USC trial 450 RAS wt mcrc pts R 1:1 FOLFOX + panitumumab x 6 cycles FOLFOX + panitumumab x 6 cycles FUFA + panitumumab Capecitabine Phase III trial Primary endpoint: PFS Sponsor: Amgen

21 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

22 Study Design Phase II, non comparative, study Target accrual: 27 pts mcrc pts RAS and BRAF wt FOLFIRI/ FOLFOXIRI + Cetuximab PD FOLFOX/XELOX / FOLFOXIRI + Bevacizumab PD Irinotecan + Cetuximab At least a RECIST 1.1 partial response 1st-line PFS 6 months PD to 1 st -line cetuximab within 4 weeks after the last cetuximab administration Time between the end of 1 st -line therapy and the start of 3 rd -line 4 months Study treatment: Irinotecan 180 mg/sqm iv Cetuximab 500 mg/sqm iv

23 Patients RAS status on ctdna Objective Response #1 Wild-type Confirmed PR #2 KRAS G12D PD #3 Wild-type Confirmed PR #4 Wild-type PD #5 Wild-type SD #6 KRAS G12D PD #7 Wild-type SD #9 Wild-type Confirmed PR #10 Wild-type Unconfirmed PR #11 Wild-type PD #12 KRAS G12D PD #13 KRAS G12V PD #15 NRAS Q61L SD Predictive Role of ctdna RAS mutations were found in liquid biopsies collected at the rechallenge baseline in 12 (48%) out of 25 evaluable patients No BRAF or PI3KCA mutations were found Patients RAS status on ctdna Objective Response #16 Wild-type SD #17 KRAS G12V/ PD Q61H #18 KRAS G12V PD #19 Wild-type Confirmed PR #21 KRAS G12D SD #22 KRAS G12V SD #23 KRAS G12V PD #24 KRAS G12D Unconfirme d PR #25 KRAS G12D SD #26 Wild-type SD #27 Wild-type PD #28 Wild-type SD No RAS mutations were detected in samples from patients who achieved a confirmed PR

24 Parseghian et al, ASCO Ann Meeting 2018; abst #3511 How do RAS and EGFR mut alleles decay? Discovery Set N=135 pts RAS/BRAF/EGFR wt treated with anti-egfrs Validation Set N=267 pts RAS/BRAF/EGFR wt treated with anti-egfrs RAS and EGFR mutations testing on ctdna [Guardant360 ] Exponential decay: median estimated t/2: 4-5 months

25 Liquid biopsy: potential applications Use of liquid biopsy for treatment strategy in various stages of cancer EARLY DETECTION Diagnosis of cancer or pre-cancer earlier through screening. LOCALIZED DISEASE Prognostication; Detection of residual disease and treatment personalization in macroscopically resected patients. METASTATIC DISEASE Molecular profiling and replacement of tumor tissue analyses; Prognostication. REFRACTORY DISEASE Monitoring response and tracking resistance; Identification of mechanisms of acquired resistance. adapted from Wan et al, Nature Rev 2017; adapted from Heitzer et al, Precision Oncology 2017

26 Plasma HER-2 copy number to predict response in HERACLES Slide 17 ctdna NGS assay GUARDANT360 Presented By Giulia Siravegna at 2018 ASCO Annual Meeting

27 Detection of gene fusions in plasma Slide 6 ctdna NGS assay GUARDANT360 Presented By Katherine Clifton at 2018 ASCO Annual Meeting

28 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

29 265 pts with isolated perioteneal mets and Peritoneal Cancer Index (PCI) < 25 Unicancer Prodige 7 trial design Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting

30 Primary Enpoint: OS Overall survival (ITT) Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting

31 Overall Survival in PCI subgroup Overall survival and PCI Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting

32 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

33 mfolfoxiri+pani in VOLFI trial: RECIST RR mfolfoxiri +pan N=63 FOLFOXIRI N=33 OR p Response Rate 87.3% 60.6% Left-sided tumors Right-sided tumors RAS/BRAF wt BRAF mut N=53 N= % 68.0% N=10 N=8 70.0% 37.5% N=43 N= % 64.7% N=7 N=9 85.7% 22.2% Geissler et al, ASCO Ann Meeting 2018; abstr #3508

34 To improve tumor shrinkage: TRIPLETE study by G.O.N.O. Phase III random mfolfox6+pani (up to max 12 cycles) 5-FU/LV +Pani RAS and BRAF wt mcrc pts 1st line unresectable R PD mfolfoxiri+pani (up to max 12 cycles) 5-FU/LV +Pani Stratification factors: PS 0-1 vs 2; primary tumor location (right vs left or rectum); previous adjuvant chemotherapy; liver-only metastases. INDUCTION MAINTENANCE Primary endpoint: Response Rate Target accrual: 432 pts

35 OUTLINE MALATTIA LOCALIZZATA Colon Retto MALATTIA METASTATICA Mantenimento dopo I linea anti-egfr Rechallange anti-egfr e biopsia liquida HIPEC FOLFOXIRI+anti-EGFR Sequenza Regorafenib/anti-EGFR Immunoterapia nei MSS

36 TAKE HOME MESSAGES: MALATTIA METASTATICA Considerare dopo induzione con comboct+anti-egfr mantenimento con anti-egfr+5fu/lv (in attesa di nuovi dati) Rechallange con anti-egfr da considerare nella pratica clinica in alcuni casi, ma previa rivalutazione di RAS La biopsia liquida sarà uno strumento importante nel management dal carcinoma del colon-retto Chirugia su mets peritoneali SI, ma HIPEC? FOLFOXIRI+anti-EGFR, sequenza Rego/anti-EGFR ed immunotx nei MSS: aspettiamo i risultati di nuovi studi

37 Grazie per l attenzione! alfredo.falcone@med.unipi.it