NOVITA IN TEMA DI TERAPIA DEL CARCINOMA DEL COLON-RETTO

Transcription

1 Congresso AIOM Giovani Perugia, 9 luglio 2016 NOVITA IN TEMA DI TERAPIA DEL CARCINOMA DEL COLON-RETTO Carlotta Antoniotti Polo Oncologico Azienda Ospedaliero-Universitaria Pisana Università di Pisa

2 What news for mcrc in ?

3 Breaking news from #1) To Oxa or not to Oxa in neoadjuvant chemoradiotherapy for locally advanced rectal cancer? #2) New evidences about the 1 st -line intensified triplet #3) mcrc: «Does the sideness matter?» #4) HER-2: the new target in mcrc! Also a new predictive marker? #5) A confirmed happy marriage: MSI and immunotherapy

4 Breaking news from #1) To Oxa or not to Oxa in neoadjuvant chemoradiotherapy for locally advanced rectal cancer? STAR-01 trial #2) New evidences about the 1 st -line intensified triplet #3) mcrc: «Does the sideness matter?» #4) HER-2: the new target in mcrc! Also a new predictive marker? #5) A confirmed happy marriage: MSI and immunotherapy

5 Locally advanced rectal cancer: the standard paradigm CRT (or 5x5) Surgery Total Mesorectal Excision Adjuvant CT RT 50.4 Gy + 5-FU or Capecitabine

6 Locally advanced rectal cancer: the standard paradigm CRT (or 5x5) Surgery Total Mesorectal Excision Adjuvant CT RT 50.4 Gy + 5-FU or Capecitabine + OXALIPLATIN?

7 To Oxa or not to Oxa in CRT for LARC? NSABP R04 ACCORD-12 AIO04 PETACC-6 FOWARC STAR-1

8 Primary endpoints NSABP R04 ACCORD-12 AIO04 PETACC-6 FOWARC Time to locoreg failure Pathologic complete response 3ys-DFS 3ys-DFS 3ys-OS STAR-1 OS?

9 STAR-01: study design Aschele et al., ASCO Ann Meet 16

10 STAR-01: primary endpoint OS Statistical hypothesis: H0: 3ys-OS: 75% H1: 3ys-OS: 82% Aschele et al., ASCO Ann Meet 16

11 Primary endpoints NSABP R04 ACCORD 12 AIO04 PETACC-6 FOWARC Time to locoreg failure Pathologic complete response 3ys-DFS 3ys-DFS 3ys-OS OS STAR-1

12 To Oxa or not to Oxa? NOT TO OXA! A relatively small benefit from the addition of oxaliplatin to neoadjuvant CRT is however observed A metanalysis of available studies will be probably performed New approaches to integrate active agents in the treatment strategy for LARC are under investigation

13 New approaches: induction and consolidation CRT (or 5x5) Surgery Total Mesorectal Excision Adjuvant CT CRT (or 5x5) Consolidation CT Surgery Total Mesorectal Excision Induction CT CRT (or 5x5) Surgery Total Mesorectal Excision

14 Breaking news from #1) To Oxa or not to Oxa in neoadjuvant chemoradiotherapy for locally advanced rectal cancer? #2) New evidences about the 1 st -line intensified triplet MACBET and METHEP-2 trials #3) mcrc: «Does the sideness matter?» #4) HER-2: the new target in mcrc! Also a new predictive marker? #5) A confirmed happy marriage: MSI and immunotherapy

15 Modulation of «chemo-intensity» in mcrc

16 Modulation of chemo-intensity in mcrc with bev

17 Modulation of chemo-intensity in mcrc with anti-egfrs

18 Arm B Arm A Macbeth trial: study design Phase II randomized non-comparative trial mcrc pts: Unresectable disease Previously untreated for mts disease RAS and BRAF wt* R 1:1 mfolfoxiri + cetuximab up to 8 cycles mfolfoxiri + cetuximab up to 8 cycles cetuximab until PD bevacizumab until PD INDUCTION MAINTENANCE Primary endpoint: 10months-PFR *centrally assessed: KRAS 12,13,61 wt until Oct 2013, then RAS and BRAF wt administered biweekly. Stratification factor: center Antoniotti et al., ASCO Ann Meet 2016

19 Modified FOLFOXIRI schedule mfolfoxiri + cet Cetuximab 500 mg/sqm irinotecan 130 mg/sqm oxaliplatin 85 mg/sqm L-LV 200 mg/sqm 5FU continuous infusion 2400 mg/sqm 48h 1 hour 1 hour 2 hours 48 hours Classic FOLFOXIRI irinotecan 165 mg/sqm oxaliplatin 85 mg/sqm L-LV 200 mg/sqm 5FU continuous infusion 3200 mg/sqm 48h 1 hour 2 hours 48 hours

20 Toxicity Profile Safety population G3/4 adverse events, % patients Arm A N = 59 Arm B N = 57 Overall N = 116 Nausea 1.7% 0% 0.9% Vomiting 3.4% 1.0% 2.6% Diarrhea 20.3% 15.8% 18.1% Stomatitis 6.8% 5.3% 6.0% Neutropenia 28.8% 33.3% 31.0% Febrile neutropenia 3.4% 1.8% 2.6% Neurotoxicity 6.7% 0% 3.5% Asthenia 10.1% 8.8% 9.5% Skin rash 18.6% 12.3% 15.5% Venous Thrombosis 1.7% 3.5% 2.6% Arterial Thrombosis 1.7% 0% 0.9%

21 Primary endpoint: 10m-PFR mitt population Arm A N = 59 Arm B N = 57 N pts observed at 10 months N pts progression-free at 10 months if at least 33 pts out of 53 per arm will be alive and progression-free at 10 months. Median follow-up: 25.5 months

22 Secondary endpoint: Response rate (mitt) Arm A Arm B Overall Best Response, % N = 59 N = 57 N = 116 Complete Response 5% 4% 4% Partial Response 63% 72% 67% Response Rate 67.8% 75.4% 71.6% Stable Disease 24% 14% 19% Disease Control Rate 92% 89% 91% Progressive Disease 3% 4% 3% Not Assessed 5% 7% 6% Out of 109 pts evaluable for RECIST response, RR and DCR were 76% and 96%, respectively.

23 Secondary endpoint: Resection of Metastases (mitt) Arm A N = 59 Arm B N = 57 All N = 117 R0/R1/R2 surgery 45.8% 29.8% 37.9% R0 secondary surgery 32.2% 22.8% 27.6% Liver-only subgroup N = 28 N = 24 R0/R1/R2 surgery 71.4% 58.3% 65.4% R0 secondary surgery 53.6% 45.8% 50.0%

24 Prodige-14 (Methep-2): study design Pts with potentially resectable LLD* *Unresectable liver mets for technical (<30% residual liver) or oncological reasons (>5 bilobar lesions) Primary endpoint: R0/R1 resection rate H0: R0/R1 resection rate with BiCT = 50% H1: R0/R1 resection rate with TriCT = 70% 2sided-alpha error: 0.05; beta-error: 0.10 Ychou et al., ASCO Ann Meet 16

25 Prodige-14 (Methep-2): primary endpoint R0/R1 resection rate p=0.06 Ychou et al., ASCO Ann Meet 16

26 Prodige-14 (Methep-2): secondary endpoint OS Ychou et al., ASCO Ann Meet 16

27 Intensified first-line regimens in mcrc? Reassuring safety results with triplet plus anti-egfr (with a modified schedule of FOLFOXIRI) Impressive activity results translate into consistent rates of conversion to resectability The intensification of the chemotherapy backbone may be of special interest when secondary resection is a pursuable objective

28 Breaking news from #1) To Oxa or not to Oxa in neoadjuvant chemoradiotherapy for locally advanced rectal cancer? #2) New evidences about the 1 st -line intensified triplet #3) mcrc: «Does the sideness matter?» #4) HER-2: the new target in mcrc! Also a new predictive marker? #5) A confirmed happy marriage: MSI and immunotherapy

29 Right vs left colon

30 Right vs left: prognostic! Venook et al., ASCO 2016

31 Right versus Left: subgroup analysis of CO.17 in KRAS wt Right-sided tumors Left-sided tumors p for interaction=0.002 Higher incidence of other RAS and BRAF mutations Brulé et al., Eur J Can 2015

32 Right vs left: subgroup analysis of CALGB80405 in KRAS wt Left-sided tumors Right-sided tumors p for interaction=0.005 Venook et al., ASCO 16

33 Right versus Left: subgroup analysis of FIRE-3 in RAS wt OS FOLFIRI+cetuximab FOLFIRI+bevacizumab Heinemann et al., ASCO 14

34 Our recent experience Patients with RAS and BRAF wt mcrc clearly evaluable for anti-egfr efficacy* N=75 Right-sided tumors N=14 Left-sided tumors N=61 *anti-egfr monotherapy or cetuximab + irinotecan in irinotecan-refractory pts Moretto et al., Oncologist 2016

35 RECIST Response Best Response Right-sided primary Left-sided primary Evaluable for response N = 13 N = 59 p n (%) n (%) Complete Response 0 (0) 0 (0) Partial Response 0 (0) 24 (40.7) Response Rate 0% 41% Stable Disease 2 (15.4) 23 (39.0) Progressive Disease 11 (84.6) 12 (20.3) Disease Control Rate 15% 80% < Moretto et al., Oncologist 2016

36 Progression-free survival Right-sided primary (N=14), median PFS : 2.3 months Left-sided primary (N=61), median PFS : 6.6 months HR: 3.97 [95%CI: ] P< Moretto et al., Oncologist 2016

37 Right vs left: predictive? Primary tumor location may become a driver in our therapeutic decision-making, but results from randomized studies in well selected pts are awaited. Available data from retrospective series suggest a larger benefit from anti-egfr for left-sided than right-sided tumors.

38 Breaking news from #1) To Oxa or not to Oxa in neoadjuvant chemoradiotherapy for locally advanced rectal cancer? #2) New evidences about the 1 st -line intensified triplet #3) mcrc: «Does the sideness matter?» #4) HER-2: the new target in mcrc! Also a new predictive marker? HERACLES and MyPathway trials #5) A confirmed happy marriage: MSI and immunotherapy

39 HERACLES trial 27 HER-2 +, KRAS wt mcrc pts progressed after fluoropyr, oxaliplatin, irinotecan and an anti-egfr moab Trastuzumab + Lapatinib PD Phase II, primary endpoint: ORR (Recist 1.1) H0: ORR: 10% H1: ORR> 30% a: 0.05; b:0.15 At least 6 responders out of 27 pts Sartore Bianchi et al, Lancet Oncology 16

40 Clinically relevant and durable responses Sartore Bianchi et al, Lancet Oncology 16

41 My Pathway HER-2 BRAF Hedgehog EGFR Overexpression or mutation V600E or other mutations SMO-activ mut PTCH-1 loss Activating mut Trastuzumab + pertuzumab Vemurafenib Vismodegib Erlotinib Hurwitz et al, ASCO GI 16

42 ORR in HER-2+ mcrc ORR: 5/13 DCR: 10/13 Hurwitz et al, ASCO GI 16

43 The beginning of the story: HER-2 as a mechanisms of resistance to anti-egfr moabs Bertotti et al, Cancer Discov 11

44 MD Anderson experience Cohort 1 RAS wt pts screened for advanced lines protocols, previously treated with anti-egfr N=114 HER-2 ampl N=14 HER-2 non ampl N=110 14/114 = 12% in RAS wt 14/97 = 14% in RAS and BRAF wt

45 MD Anderson experience Cohort 1 Cohort 2 RAS wt pts screened for advanced lines protocols, previously treated with anti-egfr N=114 HER-2 ampl N=37 HER-2 non ampl N=62 HER-2 ampl N=14 HER-2 non ampl N=110 PFS during anti-egfr PFS during anti-egfr

46 MD Anderson experience Cohort 1 Cohort 2 RAS wt pts screened for advanced lines protocols, previously treated with anti-egfr N=114 HER-2 ampl N=37 HER-2 non ampl N=62 HER-2 ampl N=14 HER-2 non ampl N=110 PFS during first-line without anti-egfr PFS during first-line without anti-egfr

47 HER-2: precision medicine in mcrc HER-2 testing should be implemented in the daily clinical practice (according to Valtorta et al., Mod Path 15). HER-2 is a promising target a positive predictive marker (an example of precision medicine in mcrc), a potential negative predictive marker with regard to anti-egfrs, supported by a solid biologic background

48 Breaking news from #1) To Oxa or not to Oxa in neoadjuvant chemoradiotherapy for locally advanced rectal cancer? #2) New evidences about the 1 st -line intensified triplet #3) mcrc: «Does the sideness matter?» #4) HER-2: the new target in mcrc! Also a new predictive marker? #5) A confirmed happy marriage: MSI and immunotherapy PEMBRO and NIVO+/-IPI

49 New CRC molecular subgroups Guinney et al, Nature Med 2015

50 Pembrolizumab in MSI mcrc: updated results Type of response MSI (n=28) MSS (n=25) Complete Response 11% 0% Partial Response 46% 0% Objective Response Rate 57% 0% Disease Control Rate 89% 16% Le et al, ASCO 2016

51 Checkmate-142: ORR in MSI-H ORR, n (%) (95% exact CI) Nivolumab 3 mg/kg (n = 47) a 12 (25.5) (15.4, 38.1) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 27) a 9 (33.3) (18.6, 50.9) Complete response 0 0 Partial response 12 (25.5) 9 (33.3) Stable disease 14 (29.8) 14 (51.9) Progressive disease 17 (36.2) 3 (11.1) Unable to determine 4 (8.5) 0 Median time to response, mo (range) 2.12 ( ) 2.73 ( ) Median duration of response, mo (range) NE (0.0 b 15.2 b ) NE (NE NE) a Patients with 12 weeks of follow-up b Includes censored observations CR = complete response; NE = not estimable; PR = partial response Overman et al, ASCO 2016

52 Toxicity profile in MSI-H Event, n (%) Nivolumab 3 mg/kg (n = 70) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 30) Any grade Grade 3 4 Any grade Grade 3 4 Any event 41 (58.6) a 10 (14.3) 25 (83.3) 8 (26.7) Fatigue 13 (18.6) 1 (1.4) 6 (20.0) 0 Diarrhea 10 (14.3) 1 (1.4) 13 (43.3) 0 Pruritus 8 (11.4) 0 5 (16.7) 1 (3.3) Nausea 5 (7.1) 0 6 (20.0) 0 Pyrexia 3 (4.3) 0 7 (23.3) 0 Any event leading to discontinuation a One Grade 5 event of sudden death 4 (5.7) 2 (2.9) 4 (13.3) 4 (13.3) Overman et al, ASCO 2016

53 MSI and anti-pd1: a happy marriage The blockade of PD-1 has a strong biological rationale in the subset of MSIhigh mcrc patients. The anti-pd1 therapy (pembrolizumab alone and nivolumab+/-ipilimumab), shows promising preliminary activity and safety data. Waiting for data from larger ongoing phase II and III trials. Immunotherapy in mcrc is a planet to be discovered.

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