Nuovi dati Colon Alain Gelibter Policlinico Umberto I UOC Oncologia «B»

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1 Nuovi dati Colon Alain Gelibter Policlinico Umberto I UOC Oncologia «B» Roma, 7 Ottobre 2017

2 NEOADJUVANT FOLFOX 4 VERSUS FOLFOX 4 PLUS CETUXIMAB VERSUS IMMEDIATE SURGERY FOR HIGH- RISK STAGE II AND III COLON CANCERS: A PHASE II MULTICENTRE RANDOMISED CONTROLLED TRIAL (PRODIGE 22) KAROUI Mehdi, RULLIER Anne, MARIETTE Christophe, MAILLARD Emilie, BARDIER Armelle, POIZAT Flora, LUCIANI Alain, SARRAN Anthony, LEGOUX Jean-Louis, DE CHAISEMARTIN Cécile, LECAILLE Cédric, BOUCHE Olivier, MAUVAIS François, BRUNETTI Francesco, PRUDHOMME Michel, SEITZ Jean-François, LEPAGE Côme, TAIEB Julien 1

3 However recurrence rates at 3 years (95%CI) IDEA (2017) PETACC8 (2014) pt1-t3, N1 Capox 3m 15% ( ) - pt4/ or N2 Folfox 6m 35.3% ( ) Folfox + Cetuximab 6m 43.1% ( ) Reasons for this relative failure - Delayed start of chemotherapy BACKGROUND AND RATIONALE (2) Qian Shi et al., ASCO 2017; Taieb J et al., Lancet Oncol Growth factors stimulation / immunosuppression induced by surgery esmo.org Van der Bij G et al., Ann Surg 2009;249

4 Multicenter randomized phase II trial PRODIGE 22 STUDY DESIGN SURGERY FOLFOX (12 cycles) Stage III ou II (investig) High risk T3 T4 N2 R FOLFOX (4 cycles) SURGERY FOLFOX (8 cycles) RAS WT FOLFOX + Cetuximab (4 cycles) SURGERY FOLFOX + Cetuximab (8 cycles) Challenge: to make decisions on small numbers, dropping of cetuximab arm based upon lack of TRG from 13 pts. Morbidity the same as in the surgery only arm: IDMC decision esmo.org

5 Interim analysis 120 patients Folfox (n = 13) Folfox-Cetuximab (n = 13) Surgery (n = 13) TRG Severe morbidity (Dindo > 3) 1 (7.7%) 2 (15.3%) 2 (15.3%) Folfox-Cetuximab (3) : TRG 1 = 0 Surgery (52) Protocol deviation (1) Colectomy (51) Folfox preop (52) Surgery (49) Colectomy (48) ITT population Metastatic disease (1) PT related complication (1) Disease progression under CT (1) Unresectable PT (1) esmo.org

6 PRODIGE 22 ENDPOINTS (1) Primary endpoint: Tumor response (Ryan simplified Tumor Regression Grade) double central independent and blinded review esmo.org

7 PRODIGE 22 ENDPOINTS (2) Secondary outcome measures - Chemotherapy toxicity - Primary tumor (PT) complications under chemotherapy - Postoperative morbidity - Quality of surgery - Radiological staging - 3 years DFS - Quality of life esmo.org

8 BASELINE CHARACTERISTICS FOLFOX (n = 52) Surgery (n = 52) Total (n = 104) Age (years, median) Males (n, %) 30 (58%) 33 (63%) 63 (60.5%) BMI (kg/m², median) Tumor location (n, %) Right / transverse Left / sigmoid 27 (52%) 25 (48%) 21 (40%) 31 (60%) 48 (46%) 56 (54%) CEA level > 2.5N (n, %) 10 (19%) 10 (19%) 20 (19%) Small numbers and lack of stratification potentially can have Large consequences.

9 FOLFOX PREOP: ADVERSE EVENTS FOLFOX (n = 50) Pts who completed 4 cycles 48 (96%) Pts with grade > 3 AE (n, %) 19 (38%) Pts who discontinued study drug for AE Primary tumor complication 2 (4%) 0 Time to surgery (median, days) 31 (20-62) Grade > 3 AE, n (%) Anemia 1 (2%) Thrombocytopenia 1 (2%) Neutropenia 5 (10%) Diarrhea 2 (4%) Nausea 4 (8%) Fatigue 2 (4%) Fever 2 (4%) Deep venous thrombosis 1 (2%) Acute coronary syndrome 1 (2%)

10 POST-OPERATIVE RESULTS FOLFOX (n = 49) Surgery (n = 51) Total (n = 100 ) PT resection % Mortality 0 1 (2%) 1% Overall morbidity 17 (34.5%) 18 (35%) 35% Severe morbidity (> Dindo III) 4 (8%) 4 (8%) 8% Surgical complications Anastomotic leak % 2% R0 resection 46 (94%) 48 (98%) 94% Complete mesocolic excision 95% 91% 93% esmo.org

11 PATHOLOGICAL RESULTS Stage I II III Surgery (n = 51) 0 20 (39%) 31 (61%) FOLFOX (n = 48) 4 (8%) 25 (52%) 19 (40%) p pt4 and/ or N2 30 (59%) 18 (37.5%) Vascular emboli, lymphatic and/ or perineural invasion 25 (49%) 9 (19%) Number of harvested LN (mean) / / Number of positive LN (mean) 2.5 +/ / Radiological concordance awaited. Up to 40% of patients receiving Oxaliplatin unnecessarily. How many would not have required chemo at all

12 Ryan simplified Tumor Regression Grade PRIMARY ENDPOINT: TUMOR RESPONSE FOLFOX (n = 52) Surgery (n = 52) TRG 1 4 (8%) TRG 2 19 (36%) 4 (8%) TRG 3 25 (48%) 45 (86%) Non available 4 (8%) 3 (6%) Significant tumor regression (TRG 1 + 2) 23 (44%) 4 (8%) <0.001 p esmo.org

13 PRODIGE 22 : CONCLUSION Neoadjuvant FOLFOX chemotherapy (4 cycles) in a perioperative setting in patients with locally advanced colon cancer : - is well tolerated - does not increase surgical morbidity - is not associated with major histological response (TRG1) - is associated with significant tumor regression as compared to upfront surgery (TRG 1+2 : 44% vs. 8% p<0.001) - induces tumor downstaging Failed to meet primary endpoint Phase III studies testing this strategy to see if it significantly impacts esmo.org 3y DFS and 5y OS are now awaited

14 VOLFI: mfolfoxiri + PANITUMUMAB VERSUS FOLFOXIRI AS FIRST-LINE TREATMENT IN PATIENTS WITH RAS WILD-TYPE METASTATIC COLORECTAL CANCER (mcrc): A RANDOMIZED PHASE II TRIAL OF THE AIO (AIO-KRK-0109) M. Geissler (Esslingen, Germany), U. M. Martens (Heilbronn, Germany), J. R. Knorrenschield (Marburg, Germany), J. Greeve (Paderborn, Germany), A. Florschuetz (Dessau, Germany), A. Tannapfel (Bochum, Germany), S. Wessendorf (Esslingen, Germany), P. Büchner-Steudel (Halle, Germany), T. J. Ettrich (Ulm, Germany), S. Kanzler (Schweinfurt, Germany), V. Heinemann (Munich, Germany), S. Held (Leverkusen, Germany), A. Reinacher-Schick (Bochum, Germany) Presented by Michael Geissler at the ESMO congress Slides are property of the author. Permission required for reuse. NCT EudraCT The study was sponsored by AIO-Studien-gGmbH (Berlin, Germany) The study was financially supported by an unrestricted grant from Amgen. esmo.org Abstract 475O

15 RATIONALE FOLFOXIRI is an active and intensive chemotherapeutic regimen in mcrc (Falcone et al. 2007) FOLFOXIRI+bevacizumab (TRIBE, STEAM, OLIVIA) and FOLFOXIRI + anti- EGFR mab (TRIP, MACBETH) resulted in high RR and long OS However, there is no randomized trial demonstrating superiority of FOLFOXIRI plus an anti-egfr or anti-vegf mab compared to FOLFOXIRI alone Therefore, the VOLFI trial compared the FOLFOXIRI Falcone protocol with modified FOLFOXIRI + panitumumab 1 7

16 PHASE II TRIAL DESIGN mcrc Unresectable 1 st -line WT RAS** Age 18yrs ECOG PS 0-1 (n=96) Randomization: 6/2011-1/2017 Strata: R 2:1 mfolfoxiri + panitumumab 6 mg/kg Q2W N=63 Irinotecan 150 mg/m 2 ***, oxaliplatin 85 mg/m 2, LV 200 mg/m 2, 5-FU 3000 mg/m 2 CIV; Planned safety analysis after 10 patients treated in panitumumab arm FOLFOXIRI Q2W N=33 Cohort 1: histologically confirmed and definitively inoperable or unresectable * * 1 cycle FOLFOXIRI prior R was allowed Cohort 2: chance of secondary resection with curative intent (*pretreatment liver/tumor biopsy) **amendment in 11/2013 to include all RAS wild-type only ***Trial started with irinotecan 165 mg/m 2 (n=2), first amendment to 130 mg/m 2 (n=9) and final amendment to 150 mg/m 2 (n=52) Treatment until PD, resectability, or to maximum 12 cycles If resectable: Surgery, then protocol treatment to maximum 12 cycles If CR/PR/SD after 12 cycles: re-induction (same combination) recommended on PD 21 active centers in Germany 1 8

17 HYPOTHESIS AND ENDPOINTS Primary endpoint Objective response rate Secondary endpoints Secondary tumor resection rate Time to relapse Progression free survival (PFS) Overall survival (OS) Pathological response and liver toxicity in resected tumor specimens Toxicity QoL (QLQ-C30) Statistical hypothesis ORR Arm A >75% vs. Arm B 60% N=62 patients arm A RAS wt; 2-sided Fisher exact test, type I <0.05, type II <0.2

18 CONSORT DIAGRAM mfolfoxiri + panitumumab 6 mg/kg Q2W Randomized N = 71 N = 105 FOLFOXIRI Q2W Randomized N = 34 cohort mfolfoxiri + Panitumumab I =definitive non-resectable FOLFOXIRI N % N % N = 4* II=potentially resectable Treated N = 67 Treated N = 34 RAS mutations N = 4 RAS mutations N = 1 Follow up: mean 18.7 months RAS wt ITT: N = 63 RAS wt ITT: N = 33 *Severe violation of inclusion criteria: 2 No valid ICF: 2 20

19 PATIENT CHARACTERISTICS mfolfoxiri + panitumumab N=63 FOLFOXIRI N=33 Gender Female, n(%) Male, n (%) 22 (35) 41 (65) 9 (27) 24 (73) Age (years) mean 56.5 (31-76) 58.2 (32-77) Prior adj. CTx, n (%) 6 (9.5) 3 (9.1) ECOG-PS, n (%) 0 36 (57.1) 20 (60.6) 1 25 (39.7) 11 (33.3) 2 1 (1.6) 1 (3.0) unknown 1 (1.6) 1 (3.0) Previous cycle of FOLFOXIRI (%) Surgery primary cancer, n(%) 28 (44.4) 17 (51.1) Liver limited, n (%) 7 (11.1) 3 (9.1) Total 10.4% 21

20 PATIENT CHARACTERISTICS TUMOR LOCATION mfolfoxiri + panitumumab FOLFOXIRI Total % ITT Left sided, n (%) 53 (84.1) 25 (75.8) 81.3% Rectal cancer, n (%) 24 (38.1) 9 (27.3) 34.4% Right sided, n (%) 10 (15.9) 8 (24.2) 18.7% 22

21 TUMOR CHARACTERISTICS GENOTYPE Genotype analysis n = 76 (79.2% of ITT) mfolfoxiri + panitumumab N=50 genotype analysis FOLFOXIRI N=26 genotype analysis Super wild-type (RAS + all BRAF), n (%) 43 (86.0) 17 (65.4) BRAF mutation, n (%) 7 (14.0) 9 (34.6) MSI, n (%) 1 (2.0) 1 (3.8) Central pathology review using NGS: N=76 (79.2%: technical reasons, no informed consent) 23

22 PRIMARY ENDPOINT: OBJECTIVE RESPONSE RATE 85.7 ORR: Primary endpoint, clearly met 60.6 mfolfoxiri + panitumumab N=63 FOLFOXIRI N=33 % 95%-CI % 95%-CI Odds ratio p ( )

23 EVALUATION OF RESPONSE SUBGROUP ANALYSES Triplet+P (n) Triplet (n) OR BRAF mut BRAF wt Right-sided Left-sided Adj. Chemo Yes Adj. Cx No ECOG ECOG Age Age > Male Favors FOLFOXIRI Favors mfolfoxiri + Panitumumab

24 EVALUATION OF RESPONSE SIDEDNESS + GENOTYPE 90.6 N=78 N=18 OR ( ) P= OR ( ) P= N=60 OR ( ) P= N=16 OR ( ) P=

25 RANDOMIZED TRIALS WITH TRIPLE CHEMOTHERAPY TRIBE STEAM MOMA CHARTA VOLFI n=252 n=93 n=232* n=125 =99 RAS WT Regimen FOLFOXIRI/Bev vs FOLFIRI/Bev FOLFOXIRI/Bev (seq l vs conc t) vs FOLFOX/Bev FOLFOXIRI/Bev Bev ± metroct FOLFOX/Bev ± IRI FOLFOXIRI +/- pan RAS WT Response rate 65% 60% 63% 70% 86% Disease control rate 90% 91% 91% 91% 98% Median PFS, months Median OS, months 29.8 Too early Too early Too early Too early Cremolini et al. Lancet Oncol 2015; Bendell et al. ASCO GI 2016 Falcone et al. ESMO 2016; Schmoll et al. ESMO 2016

26 RANDOMIZED TRIALS WITH TRIPLE CHEMOTHERAPY TRIBE STEAM MOMA CHARTA VOLFI n=252 n=93 n=232* n=125 n=99 RAS WT Regimen FOLFOXIRI/Bev vs FOLFIRI/Bev FOLFOXIRI/Bev (seq l vs conc t) vs FOLFOX/Bev FOLFOXIRI/Bev Bev ± metroct FOLFOX/Bev ± IRI FOLFOXIRI +/- pan RAS WT Response rate 65% 60% 63% 70% 86% Disease control rate 90% 91% 91% 91% 98% Median PFS, months Median OS, months 29.8 Too early Too early Too early Too early Cremolini et al. Lancet Oncol 2015; Bendell et al. ASCO GI 2016 Falcone et al. ESMO 2016; Schmoll et al. ESMO 2016

27 SECONDARY RESECTIONS OF METASTASES mfolfoxiri + panitumumab, (%) FOLFOXIRI (%) P value ITT (n=96) 15 (23.8) 4 (12.1) R0 10 (15.9) 3 (9.1) R1 4 (6.3) 1 (3.0) Cohort 2 (n=31) Secondary resection 14/20 (70%)* 4/11 (36.4%) R0 10/20 (50.0%) 3/11 (27.3%) R1 4 (20.0%) 1/11 (9.1%) *1 patient in Panitumumab arm and belonging to cohort 1 was resected

28 PFS ITT POPULATION INVESTIGATOR DETERMINED Arm mfolfoxiri+ panitumumab + + FOLFOXIRI Censored N (events) PFS (m) median 95% CI FOLFOXIRI 33 (30) mfolfoxiri+ panitumumab 63 (50) P= HR ( ) Results do not include previous FOLFOXIRI cycles before randomization 30

29 TOXICITY - SAEs ***Trial started with irinotecan 165 mg/m 2 (n=2), first amendment to 130 mg/m 2 (n=9) and final amendment to 150 mg/m 2 (n=52) Category mfolfoxiri + panitumumab FOLFOXIRI P N % N % At least one SAE related to treatment At least one SAE with max. grade 3-5 and related to treatment Hematological toxicitiy grade Gastrointestinal toxicity (colitis, diarrhoea, ileus) grade Infections grade G-CSF support

30 Conclusions Primary endpoint was positive: first line treatment with mfolfoxiri + panitumumab resulted in significantly higher ORR compared to FOLFOXIRI. The addition of panitumumab to FOLFOXIRI resulted in high response rates in left and right sided as well as BRAF mutated mcrc. PFS was in the expected range, however, there was no difference in PFS between both arms. OS data are still immature. 32

31 VOLFI (AIO-KRK-0109) DATA PENDING DpR, ETS analyses EORTC QLQ-C30 PFS/OS/TTR in secondary resected patients OS ITT, RAS/BRAF, sidedness Toxicity / AEs Dose reductions, relative dosage, numbers of delivered cycles Pathological response and liver toxicity in resected tumor specimens 33

32 Personal conclusions: EGFR moab s (here: panitumumab) add to improvement of ORR, even with triple chemotherapy and even in unexpected subgroups (right-sided, BRAF mutant) The regimen seems to be tolerable however, more toxicity and quality of life data needed Clinical role a bit unclear R1 rates higher PFS not improved OS pending 34

33 Damien Hirst: Drugs

34 SUMMARY (II) mfolfoxiri + panitumumab has relevant, but manageable hematological and gastrointestinal toxicity and should be used in ECOG 0-1 patients only. Compared to the GONO FOLFOXIRI protocol, the irinotecan dose should be reduced to 150 mg/m 2. The high response rates are of particular interest for symptomatic patients and those with a chance of secondary resections of initially unresectable metastatic sites in left/right as well as BRAF mutated mcrc. 36