First line treatment in metastatic colorectal cancer

Transcription

1 First line treatment in metastatic colorectal cancer Claus-Henning Köhne University Clinic Onkology and Haematology North West German Cancer Center (NWTZ)

2 A non authorised version of ESMO guidelines was presented at WCGIC in June 2015

3 1) Patient 2) Disease heterogeneity go Fit (for intensive Chemotherapy) slow fit no Fit Her2/neu ~5% 3) Treatment aims Resection / Cure Suvival Symptom control

4 Triplet CTx in RAS wt & mut: FOLFIRI vs. FOLFOXIRI Regimen N RR PFS OS Author FOLFIRI % Falcone FOLFOXIRI % JCO 2007 FOLFIRI+Bev % Falcone FOLFOXIRI+Bev % NEJM 2015 FOLFOXIRI more effective than FOLFIRI Unroven role of bevacizumab

5 FOLFOXIRI in molecular subgroups analyses Progression free survival Factor N HR p Experimental better (FOLFOXIRI + Bev) Control Better (FOLFIRI+Bev) Promising regimen for BRAF mut Equally effective for KRAS wt & mut Falcone et al. ASCO 2014

6 Pooled analysis of OS in patients with KRAS wt tumors according to BRAF mutation status OS estimate KRAS wt/braf wt HR (95% CI): ( ); p=0.041 FOLFIRI/FOLFOX4 +cetuximab (n=349): mos 24.8 mo FOLFIRI/FOLFOX4 (n=381): mos 21.1 mo KRAS wt/braf mt HR (95% CI): ( ); p=0.079 FOLFIRI/FOLFOX4 + cetuximab (n=32): mos 14.1 mo FOLFIRI/FOLFOX4 (n=38): mos 9.9 mo Time (months) 2012 年 CSCO 年会北京 Bokemeyer C..Köhne, et al. J Clin Oncol 2010;28(Suppl. 15):Abstract No. 3506

7 Meta-analyses of BRAF mutation as a predictive biomarker of benefit from anti-egfr monoclonal antibody therapy... there are insufficient data to justify the exclusion of anti-egfr mab therapy for patients with RAS WT/BRAF MT mcrc. A Rowland, M M Dias, M D Wiese, G Kichenadasse, R A McKinnon, C S Karapetis and M J Sorich British Journal of Cancer 112, (09 June 2015) C- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients.... Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, Cabiddu M, Iacovelli R, Bossi I, Lonati V, Ghilardi M, de Braud F, Barni S. Eur J Cancer Mar;51(5):

8 CTx + EGFR (?) FOLFOXIRI (?) BRAF mut

9 Randomised trials of EGFR antibodies 1 st line k-ras exon 2 wt only European & Asian experience Trial Therapy ORR PFS (mo) OS (mo) CRYSTAL (n=666) FOLFIRI +/- Cetux 40% vs. 57% 8,4 vs. 9, vs. 23,5 Infusional 5FU Chinese * (n=138) PRIME (n=656) FOLFIRI or FOLFOX +/- Cetux FOLFOX +/- Pani 40% vs. 57% 5,8 vs. 10,2 21,0 vs. 30,9 48% vs. 57% 8,6 vs ,4 vs. 23,8 OPUS (n=197) FOLFOX +/- Cetux 34% vs. 57% 7,2 vs. 8,3 18,5 vs.(22,8) Bolus 5FU Cape COIN (n=729) NORDIC (n=194) XELOX/FOLFOX +/- Cetux FLOX +/- Cetux 57% vs. 64% 8,6 vs.8,6 17,9 vs.17,0 47 vs. 46% 8,7 vs. 7,9 22,0 vs. 21,0 sig. diff; (clinically relevant not statist. Sig); no sig. diff * LLD only

10 Influence of KRAS and RAS mutational status on survival Randomised trials of EGFR antibodies 1 st line Trial Therapy OS (mo) KRAS wt OS (mo) RAS wt OS (mo) RAS mut CTx +EGFR CTx +EGFR CTX +EGFR CRYSTAL (n=666) PRIME (n=656) OPUS (n=197) FOLFIRI /- Cetux * FOLFOX 19, /- Pani * FOLFOX 18,5 (22.8) /- Cetux * Van Cutsem, Ciardiello, Köhne et al. ASCO 2014 Douillard et al. NEJM 2014 Bokemeyer, Köhne et al ASCO 2014

11 RAS wt EGFR therapy prolongs survival (3/4 RCT) by a median of 6-8 months (HR~0.7) over CTx alone

12 Randomised trials of VEGF antibodies in less effective chemotherapy (FU/FA alone or IFL) 1 st line sig. diff;. Sig; no sig. diff # exploratory * rand phase II, 1st Line mcrc Trial Therapy ORR PFS (mo) OS (mo) AGITG (n=313) UK (n=280) AVF2192g (n=209*) Capecitabine +/- Beva Capecitabine +/- Beva (>70y) FU/LV +/- Beva 31% vs. 38% 48% vs. 57% 15% vs. 26% 5.7 vs. 8.5 HR = 0, vs. 9.1 HR = vs. 9.2 HR = 0, vs HR = 0, vs HR = vs HR = 0,855 AVF2107g (n=211)# IFL vs. FU/FA+ Bev 37% vs. 40% 6.7 vs vs.18.3 AVF2107g (n=813) IFL +/- Bev 35% vs. 45% 6.2 vs HR = vs HR = 0.65

13 Progression free survival NO16966 and HORIZON II studies NO HORIZON II Proportion of patients HR aim XELOX/FOLFOX4 + bevacizumab (n=699) XELOX/FOLFOX4 + placebo (n=701) Probability of progression-free survival Cediranib 20 mg (n=502) Placebo (n=358) HR aim Time (months) Time from randomisation (months) Events Median PFS (m) HR (97.5% CI) Bevacizumab 513 (73%) Placebo 547 (78%) 8.0 (0.72, 0.95) P= Events Median PFS (m) HR (95% CI) Cedarinib 412 (82%) (0.73, 0.98) Placebo 308 (86%) 8.2 P= Saltz LB et al. J Clin Oncol 2008;26:

14 NO16966 PFS CTx +/- Bevacizumab : XELOX and FOLFOX subgroups PFS estimate XELOX+placebo XELOX+bevacizumab Months FOLFOX+placebo FOX+bevacizumab FOLFOX+ XELOX FOLFOX Bev XELOX +Bev N Pat PFS mo HR 97.5% CI p-value OS (mo) HR % CI 0.75 to P-value n.s. n.s. Cassidy et al. ASCO 2007; Saltz et al. JCO 2008, Table 1A appendix

15 PFS in Phase III PFS data VEGF TKI or Bevacizumab FOLFOX PTK TKI failure + PTK Beva antibody breakthrough? FOLFOX + Bev HR 0.88 P=0.118 HR 0.89 P= 0.19 CONFIRM I; Hecht et al. JCO 2011 NO16966; Saltz et al. JCO 2008

16 PTK/ZK doesn t work

17 ItaCa, Phase III trial: Efficacy Bevacizumab + FOLFOX / FOLFIRI vs FOLFOX /FOLFIRI Response Rate Bevacizumab + FOLFOX/ FOLFIRI (n=179) FOLFOX / FOLFIRI (n=197) HR P Value 49% 48% p = PFS (mo) p = OS (mo) p= A Passardi, Annals Of Oncology accepted 2015

18 BRITE: Avastin increases survival post first-progression Overall survival estimate Post-progression therapy: No treatment n=253 No Avastin post PD n=531 Avastin post PD n= PD = progressive disease Overall survival (months) Grothey, et al. ASCO 2007

19 Hidden Biases in an Observational Study of Bevacizumab Beyond Progression - Ondansetron beyond progression - Kopetz et al. JCO 2009

20 Overall survival : Bevacizumab beyond PD in mcrc CT (n=410) BEV + CT (n=409) Unstratified a HR: 0.81 (95% CI: ) p= (log-rank test) OS estimate Stratified b HR: 0.83 (95% CI: ) p= (log-rank test) mo 11.2 mo Time (months) Overall survival composite from 1 st and 2 nd line treatment = 12.7 mo 1 st line (CTx+Bev) = 12.7 mo 9.8 mo 2 nd line (CTx ± Bev) 11.2 mo 22.5 mo 1.4 mo 23.9 mo

21 VEGF Inhibition in 2 nd or later line therapy 2 nd line VEGF Last line multi VEGF TKI TML E3200 VELOUR RAISE CORRECT Bev in 1 st line 2 nd line Chemothera py VEGF inhibitor all pts. no pts yes / no All pts. FOLFIRI or FOLFOX all pts (+ EGFR if KRASwt) FOLFOX FOLFIRI FOLFIRI Last line BSC bevacizumab bevacizumab aflibercept Ramucirumab regorafenib OS 11.2 v 9.8 mo HR 0.81 p= v 10.8 mo HR 0.75 p= v 12.1 mo HR 0.82 p= vs mo HR 0.84 P= vs. 5.0 mo HR 0.77 P=0.0052

22 Bevacizumab efficacy in 1 st line (IFL ± Bev) and pooled analysis of 1 st & 2 nd line studies Overall survival HR 95% CI P-value KRAS wt IFL ± Bev N= Pooled analysis N= KRAS mut IFL ± Bev N= Pooled analysis N= Hurwitz et al. The Oncologist 2009 and 2013

23 TML study : Chemo ± bevacizumab continued in 2 nd line Survival difference mainly driven by KRASwt subgroup Overall survival KRAS wt KRAS mut KRAS wt N=314 OS KRAS mut N=297 CTx CTx + Bev HR P-value EGFR antibody 69% 8% Kubicka et al. Ann Oncol 2014

24 CORRECT: BSC +/- Regorafenib Overall survival Grothey et al. Lancet Oncol 2013

25 FIRE 3 results - No survival benefit for VEGF in RAS mutant disease - RAS wt (n=201) RAS mutant (n=188) FOLFIRI + Bevacizumab FOLFIRI + Cetuximab FOLFIRI + Bevacizumab HR/Odds ratio p ORR (95%-CI) 56 % % % PFS (95% CI) 10.2 mo mo OS (95% CI) 25.0 mo mo Similar observations in TML and CORRECT studies. Survival of all pts benefit driven by KRASwt. Stintzing et al. ESMO 2014

26 mcrc a heterogenous disease Data supporting bevacizumab for OS! Data NOT supporting bevacizumab for OS! EGFR therapy prolongs survival (3/4 RCT) by a median of 6-8 months (HR~0.7) over CTx alone

27 Statistical considerations mcrc 1st-line therapy KRAS wildtype Randomize 1:1 FOLFIRI + Cetuximab Cetuximab: 400 mg/m 2 i.v. 120min initial dose 250 mg/m 2 i.v. 60min q 1w FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v min q 2w FOLFIRI q2w: 5-FU: 400 mg/m 2 (i.v. bolus); folinic acid: 400mg/m 2 irinotecan: 180 mg/m 2 5-FU: 2,400 mg/m 2 (i.v. 46h) Primary objective: Overall response rate (ORR) Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%) 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher s exact test at an alpha level of 2.5% all analyzed in the ITT population

28 FIRE 3: KRAS vs. RAS analysis KRAS wt RAS wt RR independend read Cetuximab + CT Bevacizumab + CT P-value Cetuximab + FOLFIRI Bevacizumab + FOLFIRI P-value 67% 56% % 56% PFS 10.0 mo 10.3 mo mo 10.2 mo 0.77

29 PEAK study: Overall survival Panitumumab vs. Bevacizumab in RAS wt mcrc: WT RAS (exon 2,3,4 KRAS/NRAS) mfolfox6 + Panitumumab + (n=88) Bevacizumab + (n=82) Events n (%) Median (95% CI) months 30 (34) 41.3 ( ) 40 (49) 28.9 ( ) Proportion alive (%) HR*=0.63 (95% CI: ) p= Months Schwartzberg L, et al. JCO 2014

30 How do CALGB/SWOG Results fit into the European and Asian Experience? mcrc 1st-line KRAS wild type (codons 12,13) FOLFIRI or FOLFOX Chemo + Cetuximab STRATA: FOLFOX/FOLFIRI Prior adjuvant Prior XRT MD choice Chemo + Bevacizumab N = Endpoint: Overall Survival

31 Overall Survival By Arm (All RAS Wild Type Patients) Lenz et al. ESMO 2014 Arm Chemo + Bev Chemo + Cetux N (Events) 256 (178) 270 (177) Median (95% CI) 31.2 ( ) 32.0 ( ) HR (95% CI) 0.9 ( ) p 0.40

32 Overall Survival by Arm (All RAS Wild Type FOLFOX Patients) Lenz et al. ESMO 2014 Arm N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev Chemo + Cetux 192 (137) 198 (129) 29.0 ( ) ( ) ( ) 0.2

33 Overall Survival RAS wt vs RAS mt* RAS wt RAS mt Arm N (Events) Median (95% CI) HR (95% CI) p N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev Chemo + Cetux 256 (178) 270 (177) 31.2 ( ) 0.9 (0.7, 1.1) 32.0 p=0.40 ( ) 42 (33) 53 (41) 22.3 (15.3, 29.0) 28.7 (20.2, 34.7) 0.74 (0.4, 1.1) p=0.21 Median, months *(NRAS, KRAS exon 3+4 NOT KRAS exon 2)

34 Head to Head Comparison EGFR vs. VEGF inhibition 1st line mcrc in all RAS wt Objective Response rate Progression free survival Overall survival Anti-EGFR Anti-EGFR Anti-EGFR Khattak et al. Clinical Colorectal Cancer 2015

35 mcrc a heterogenous disease Data NOT supporting VEGF to prolong survival in 1 st line FOLFOXIRI RCT are needed EGFR therapy prolongs survival (3/4 RCT) by a mediain of 6-8 months (HR~0.7) over CTx alone Data supporting EGFR > VEGF

36 Magnitude of clinical benefit The ESMO approach EGFR all RAS wt EGFR KRAS wt VEGF in all lines

37 Clinical condition of the patient No fit BSC RASwt FU/FA +/- VEGF Carefully dosed Doublet + EGFR Slow FIT RASmut FU/FA Carefully dosed Doublet Go FIT

38 Clinical condition of the patient Go FIT Aim -> resection/cure Most active but still tolerable CTx RAS wt RAS mut BRAF mut Aim -> OS /symptom control Tolerable/acceptable CTx RAS wt RAS mut BRAF mut Triplet/Doublet +EGFR Triplet or Doublet Triplet or Doublet Doublet*+EGFR Doublet*+VEGF Triplet Triplet* or Doublet*/ # +/- VEGF? Triplet* or Doublet* +/-EGFR or +/-VEGF? If responding continue Tx until resectable consider changing from FOLFIRI to FOLFOX or vice versa If responding continue Tx for ~6mo consider pause and reintroduction of regimen * In case of adjuvant pre-tx probably no oxaliplatin, # consider also FU/LV+VEGF

39