La strategia terapeutica per il trattamento del carcinoma del colon-retto metastatico

Transcription

1 VI Corso Nazionale Eventi Formativi AIOM-SIAPEC Roma,15 Giugno 2016 La strategia terapeutica per il trattamento del carcinoma del colon-retto metastatico Francesco Di Costanzo Direttore SC Oncologia Medica Azienda Ospedaliero Universitaria Careggi Firenze

2 ITALY 2015 Incidence: 52,000 Mortality:19,202

3 The Goal of Palliative Therapy

4 Colorectal Cancer: ~20 Years after meta-analysis 1992 P r o b a b i l i t y o f CALGB/S WOG Old & New Drugs 5FU+FA Irinotecan Oxaliplatin Anti-EGFR Anti-VEGF Regorafenib (Aflibercept) O S J Clin Oncol, 1992

5 Improved use of medical treatment *Compared with irinotecan use in 1998 and normalized by yearly patient volume Kopetz S et al, J Clin Oncol 2009

6 La resezione delle metastasi epatiche nei centri specializzati migliora la sopravvivenza a lungo termine olandmark analysis della sopravvivenza dei pazienti vivi a 12 mesi dalla diagnosi (70% della popolazione iniziale) Pazienti resecati Pazienti non resecati OS mediana (mesi) OS a 5 anni 65,3 55% 26,7 19,5% HR 0,35 La resezione delle metastasi epatiche incrementa sensibilmente la sopravvivenza a lungo termine e offre reali possibilità di cura Kopetz S et al. J.Clin.Onc. 2009;27:

7 Although OS Continues to Improve, PFS Has Been Mostly Stable With First-line Therapy in the Chemobiologic Era

8 Although OS Continues to Improve, PFS Has Been Mostly Stable With First-line Therapy in the Chemobiologic Era

9 Tools for Treatment Selection

10 Percentuale di pazienti (%) Accesso alle linee successive alla 1a a linea 2a linea 3a linea 4a linea Coorte US (n=4877) Registro tedesco FIRE-3 (n=592) Italy (Observer) 1. Abrams TA, et al. J Natl Cancer Inst 2014;106:djt Modest D, et al. J Clin Oncol 2015 [epub ahead of print]

11

12

13 Example of Decision Matrix Presented By Axel Grothey at 2016 ASCO Annual Meeting

14

15

16

17 RAS and BRAF distribution in mcrc Fakih et al, J Clin Oncol 15

18 Prevalence of Mutations* KRAS EXON 1 EXON 2 EXON 3 EXON % (440/1096) 4.5% (29/638) 5.8% (36/620) NRAS EXON 1 EXON 2 EXON 3 EXON % (22/637) 4.4% (28/636) 0.0% (0/629) *The KRAS exon 2 data is from the overall population. The remaining data are within the wild-type KRAS exon 2 subset and based on samples that yielded a result. Douillard et al., NEJM 2013

19 BRAF Mutation in CRC- 1st and 2nd Line Phase III Studies

20 TRIBE: benefit of more intensive treatment for patients with BRAF-mutated mcrc OS estimate FOLFOXIRI + bevacizumab (n=16) FOLFIRI + bevacizumab (n=12) HR=0.55 (95% CI: ) FOLFOXIRI + bevacizumab FOLFIRI + bevacizumab Overall trial mos (months) HR= Time (months) Treatment with a chemotherapy triplet plus bevacizumab may be an appropriate treatment for patients with BRAF mutations Loupakis, et al. ASCO Abstract 3519

21 FIRE-3: OS in BRAF mutant FOLFIRI + cetuximab (N=23): mos 12.3 FOLFIRI + bevacizumab (N=25): mos 13.7 Stintzing S, ASCO GI 2014

22 There is no role for biological therapy in the neoadjuvant therapy in resectable metastatic CRC

23 No Role for anti-egfr in resectable metastatic KRAS-WT CRC

24 No proven role for bevacizumab in resectable metastatic CRC

25 Both Anti-EGFR and Angiogenesis Inhibitors improve the outcome of metastatic CRC

26 Anti-EGFR Therapy in the 1st Line Treatment of MCRC

27 Anti-EGFR Therapy in the 2nd Line Treatment of MCRC

28 Anti-EGFR Therapy in MCRC: Chemotherapy- Refractory Disease

29 Anti-EGFR Therapy in MCRC

30 Bevacizumab Improves Clinical Outcome When Added to 1st Line Combination Therapies

31 Anti-Angiogenic Strategies Result in Limited Improvements When Combined with 2nd Line Chemotherapy

32 Metastatic Colorectal Cancer Is there an optimal sequence for biological therapy (Ras WT)?

33 Phase II Phase III Head-to-head trials of targeted agents in 1st line treatment of mcrc 1º endpoint FIRE-3 1 Patients with untreated KRAS 12/13 wt mcrc N=592 R Cetuximab + FOLFIRI Bevacizumab + FOLFIRI ORR CALGB ,3 Patients with untreated KRAS 12/13 wt mcrc N=1177 (after trial modification) Efficacy data expected Q1/Q R Cetuximab + FOLFOX/FOLFIRI Bevacizumab + FOLFOX/FOLFIRI Bevacizumab + cetuximab + FOLFOX/FOLFIRI* *Arm closed to accrual as of 09/10/2009 OS PEAK 4,5 Patients with untreated KRAS 12/13 wt mcrc N=285 R Panitumumab + mfolfox6 Bevacizumab + mfolfox6 PFS 1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506); 2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611); 3. NCT ; 4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446); 5. Schwartzberg LS, et al. ASCO 2013 (Abstract No. 3631)

34 Head to Head trials in RAS wt RR PFS OS CET/PAN BEV CET/PAN BEV CET/PAN BEV FIRE-3 N=400 RR 1 endpoint CALGB N=526 OS 1 endpoint PEAK N=170 PFS 1 endpoint 65% 59% P=0.18 HR=0.97 HR=0.70, P=.006 NEGATIVE NEGATIVE POSITIVE 69% 54% P<0.01 HR=1.10 HR=0.90 POS/NEG NEGATIVE NEGATIVE 64% 61% NA NA POSITIVE POS/NEG Adapted from Stintzing et al., ESMO 2014 Lenz et al, ESMO 2014 Schwartzberg et al, JCO 2014

35 FIRE-3 STUDY R FOLFIRI + Cetuximab FOLFIRI + Bevacizumab FOLFIRI Cetuximab FOLFIRI Bevacizumab p ORR, % 95% CI 65% % 60% % 57.9 to to Primary Endpoint not met! Heinemann V. et al Lancet Oncol Sep;15(10):

36 Lenz HJ, ESMO 2014 CALGB trial: overall survival by arm All RAS Wild Type Patients

37 PEAK STUDY R FOLFOX + Panitumumab FOLFOX + Bevacizumab FOLFOX Panitumumab FOLFOX Bevacizumab % % Primary Endpoint exploratory Schwartzberg L.S. et al. J Clin Oncol Jul 20;32(21):

38 A CLINICALLY MEANINGFUL DIFFERENCE IN OS: POSSIBLE EXPLANATIONS? Choice and duration of 2nd line therapy Change in tumor biology during 1st line therapy OS Depth of response

39 Depth of response correlates with overall survival OS ETS DpR (smallest tumor size) Time under treatment Correlation index Cetuximab + FOLFIRI Bevacizumab + FOLFIRI PFS -0.53, p< , p< OS -0.38, p< , p< adapted from Mansmann et al, ASCO GI 2013 abstract #427

40 ETS predicts longer PFS and OS PFS OS Petrelli et al., Eur J Canc 15

41 A CLINICALLY MEANINGFUL DIFFERENCE IN OS: POSSIBLE EXPLANATIONS? Choice and duration of 2nd line therapy Change in tumor biology during 1st line therapy OS Depth of response

42 Titel der Präsentation und Name des Redners

43 HER2 AMPLIFICATION IS A DRIVER OF RESISTANCE TO CETUXIMAB IN MCRC PATIENT-DERIVED XENOGRAFTS (XENOPATIENTS) Presented By Salvatore Siena at 2015 ASCO Annual Meeting

44 ESTIMATED NUMBERS OF HER2+ MCRCS AND OTHER MALIGNANCIES WITH ACTIONABLE MOLECULAR TARGETS Presented By Salvatore Siena at 2015 ASCO Annual Meeting

45 HERACLES CONSORT DIAGRAM Presented By Salvatore Siena at 2015 ASCO Annual Meeting

46 REPRESENTATIVE CE-CT SCANS OF 2 RESPONDERS Presented By Salvatore Siena at 2015 ASCO Annual Meeting

47 POTENTIAL EXPLANATORY FACTORS Presented By Kimmie Ng at 2016 ASCO Annual Meeting

48 SLIDE 29

49 NOT EXACTLY A NEW STORY. Presented By Kimmie Ng at 2016 ASCO Annual Meeting

50 80405: SIDEDNESS IS PROGNOSTIC<BR />PROGRESSION FREE SURVIVAL (PFS) Presented By Alan Venook at 2016 ASCO Annual Meeting

51 80405: SIDEDNESS IS PROGNOSTIC<BR /> OVERALL SURVIVAL (OS) Presented By Alan Venook at 2016 ASCO Annual Meeting

52 MEDIAN OS BY SIDEDNESS:<BR />80405 AND FIRE-3* Presented By Alan Venook at 2016 ASCO Annual Meeting

53 OVERALL SURVIVAL BY SIDEDNESS AND BIOLOGIC Presented By Alan Venook at 2016 ASCO Annual Meeting

54 PFS BY TREATMENT GROUP AND LOCATION OF <BR />PRIMARY TUMOR (RIGHT VS LEFT)

55 LEE ET AL: MAJOR FINDINGS Presented By Kimmie Ng at 2016 ASCO Annual Meeting

56 NIVOLUMAB ± IPILIMUMAB IN TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER WITH AND WITHOUT HIGH MICROSATELLITE INSTABILITY: <BR />CHECKMATE 142 INTERIM RESULTS Presented By Michael Overman at 2016 ASCO Annual Meeting

57 INVESTIGATOR-ASSESSED BEST OVERALL RESPONSE IN <BR />PATIENTS WITH MSI-H RECEIVING NIVOLUMAB MONOTHERAPY Presented By Michael Overman at 2016 ASCO Annual Meeting

58 INVESTIGATOR-ASSESSED PFS IN PATIENTS WITH MSI-H<BR />NIVOLUMAB ± IPILIMUMAB IN METASTATIC CRC Presented By Michael Overman at 2016 ASCO Annual Meeting

59 CONCLUSIONS<BR />NIVOLUMAB ± IPILIMUMAB IN METASTATIC CRC Presented By Michael Overman at 2016 ASCO Annual Meeting

60 NIVOLUMAB ± IPILIMUMAB IN TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER WITH AND WITHOUT HIGH MICROSATELLITE INSTABILITY: <BR />CHECKMATE 142 INTERIM RESULTS Presented By Michael Overman at 2016 ASCO Annual Meeting

61 SUMMARY Presented By Johanna Bendell at 2016 ASCO Annual Meeting

62 Conclusioni Selezionare i pazienti su base clinica e molecolare, considerare sempre che il trattamento ha finalità palliative. Avere sempre una strategia a lunga scadenza. La scelta dei possibili trattamenti deve essere basata sempre su dati clinici scientifici. Discutere sempre le decisioni terapeutiche per avere sempre più pareri. Partecipare attivamente ai trial clinici.