Does it matter which chemotherapy regimen you partner with the biologic agents? Yes, it does matter! Axel Grothey
Disclosures Research Funding to MAYO Clinic Genentech Bayer Eisai Pfizer Imclone
Potential Combination Partners Chemotherapy Fluoropyrimidine Bolus 5-FU Infusional 5-FU Capecitabine Irinotecan Oxaliplatin Biologics VEGF inhibitors Bevacizumab Aflibercept EGFR antibodies Cetuximab Panitumumab Multi-kinase inhibitor Regorafenib
VEGF INHIBITORS
p=0.005 p=0.217 p 0.001 p=0.0002 p=0.0023 P<0.001 P<0.001 4.2 P<0.001 Median PFS (months) 5.2 5.1 5.5 5.7 6.2 7.2 8.0 8.5 8.3 9.0 9.2 9.4 9.1 10.6 Summary: PFS in RCTs of BEV 1 st Line IRINO OXALI 12 AVF0780g* (n=104) 1 AVF2107g (n=813) 2 AVF2192g (n=209) 3 NO16966 (n=1,400) 4 AGITG MAX (n=313) 5 ARTIST (n=214) 6 AVEX (n=280) 7 10 8 6 4 2 0 *TTP RCTs = randomized controlled trials 1. Kabbinavar, et al. JCO 2003; 2. Hurwitz, et al. NEJM 2004 3. Kabbinavar, et al. JCO 2005; 4. Saltz, et al. JCO 2008 5. Tebbutt, et al. JCO 2010; 6. Guan, et al. Chin J Cancer 2011 7. Cunningham, et al. ASCO GI 2013
Proportion progression-free 1.0 0.8 Phase III Trial of IFL +/- Bevacizumab in MCRC: PFS HR=0.54, P<0.00001 Median PFS: 6.2 vs 10.6 mo 0.6 0.4 0.2 0 Treatment Group IFL + placebo IFL + bevacizumab 0 10 20 30 Progression-free survival (mo) Hurwitz et al. N Engl J Med 2004
PFS estimate PFS chemotherapy + bevacizumab superiority: primary endpoint 1.0 0.8 HR = 0.83 [97.5% CI 0.72 0.95] (ITT) p = 0.0023 0.6 0.4 0.2 0 8.0 9.4 0 5 10 15 20 25 Months FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events Saltz et al., JCO 2008
PFS estimate PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups 1.0 0.8 0.6 0.4 0.2 7.4 9.3 0 0 5 10 15 20 25 Months 1.0 0.8 0.6 0.4 0.2 8.6 9.4 0 0 5 10 15 20 25 Months XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events XELOX subgroup HR = 0.77 [97.5% CI 0.63 0.94] (ITT) p = 0.0026 FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events FOLFOX subgroup HR = 0.89 [97.5% CI 0.73 1.08] (ITT) p = 0.1871 Saltz et al., JCO 2008
EGFR ANTIBODIES
Outcomes of Phase III First Line Trials with EGFR mabs Trial Significant Fluoropyrimidine Ox mab Iri or EGFR improvement in RR PFS OS CRYSTAL Inf + bolus 5-FU Iri C + + + PRIME Inf + bolus 5-FU Ox P + + - COIN Inf + bolus 5-FU Ox C + + - Capecitabine Ox C - - - NORDIC Bolus 5-FU Ox C - - - Grothey & Lenz, JCO 2011
KRAS WT KRAS mut Tveit et al., J Clin Oncol 2012
Proportion progression free Primrose et al., ASCO 2013, # 3504 Primrose)et)al.,)ASCO)2013,)#)3504) Subgroup No of patients Forest'plot' A randomised clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in KRAS wild-type patients with operable metastases from colorectal cancer The New EPOC study HR (95% CI) Overall 233 1.49 (1.04 2.12) p-value for interaction Poor differentiation at biopsy HR: 1.49 (95% CI: 1.04 2.12) Yes 24 p = 0.030 0.54 (0.19 1.57) 0.052 No 193 1.75 (1.17 2.62) 4 or more mets / poor diff / N2 Yes 131 0.95 (0.61 1.49) 0.005 No 101 2.75 (1.52 5.00) Presentation of disease Arm A Synchronous Arm 113 B (ERBITUX) Cetuximab 0.99 (0.61 1.63) 0.019 Non-synchronous 120 2.34 (1.40 3.92) Backbone treatment OxMdG 155 1.68 (1.06 2.66) 0.226 Time to progression or death (months) IrMdG Number at risk 25 0.59 (0.20 1.70) Arm A 116 89 65 38 23 12 5 2 1 1 0 CAPOX 51 1.49 (0.76 2.93) Arm B 117 87 54 24 15 5 3 2 1 0 0 Progression-free survival of all randomised KRAS wild-type patients 0.1 1.0 10.0 The median PFS was 20.5 months Arm A vs. 14.1 months Arm B Favors Favors Cetuximab ERBITUX Favors no no ERBITUX Cetuximab
COIN : Oxaliplatin/Fluoropyrimidine ± cetuximab Maughan et al., Lancet 2011
Options for combinations: Pros and Cons Beva EGFR pro PFS benefit ph III Large & consistent database Protracted treatment duration critical Panitumumab: ph III OS / PFS with pan RAS WT (High RR in CLM) FOLFOX 1L con NO 16966 trial: benefit in the FOLFOX subgroup? Cetuximab: no phase III Cave: FLOX, Cape/Ox Detriment in resectable CLM
Options for combinations: Pros and Cons Beva EGFR pro PFS benefit ph III Large & consistent database Protracted treatment duration critical Panitumumab: ph III OS / PFS with pan RAS WT (High RR in CLM) FOLFOX 1L con NO 16966 trial: benefit in the FOLFOX subgroup? Cetuximab: no phase III Cave: FLOX, Cape/Ox Detriment in resectable CLM
Options for combinations: Pros and Cons pro con Beva OS benefit ph III (TML with Bev in 1L) FOLFOX 2L EGFR
Options for combinations: Pros and Cons pro con Beva OS benefit ph III (TML in Beva in 1L) FOLFOX 2L EGFR
Options for combinations: Pros and Cons pro con Beva PFS benefit ph III 1L/2L XELOX 1L / 2L EGFR Strongly discouraging data (1L)
Options for combinations: Pros and Cons pro con Beva 3 randomized trials, all with PFS benefit approx. 9 mos. Cape / 5FU EGFR
Options for combinations: Pros and Cons pro con Beva Phase III control arms Phase IV experience no phase III (but IFL...) FOLFIRI 1L EGFR CRYSTAL; FIRE-3: OS benefit Toxicity can affect longterm therapy
Options for combinations: Pros and Cons pro con Beva Phase III control arms Phase IV experience no phase III (but IFL...) FOLFIRI 1L EGFR CRYSTAL, FIRE-3: OS benefit Toxicity can affect longterm therapy
Options for combinations: Pros and Cons pro con VEGF ph III aflibercept:os benefit ph III TML: OS benefit (FOLF)IRI 2L EGFR Panitumumab: PFS benefit, very high ORR Cetuximab: even active in Irinotecan pretreated? no OS benefit
Options for combinations: Pros and Cons pro con VEGF ph III aflibercept: OS benefit ph III TML: OS benefit (FOLF)IRI 2L EGFR Panitumumab: PFS benefit, very high ORR Cetuximab: even active in Irinotecan pretreated? no OS benefit
Options for combinations: Pros and Cons pro con Beva Phase III trial with longest PFS / OS Good tolerability (Role of BEV as add-on unclear) FOLFOXIRI EGFR Phase II data with high RR conversion, symptomatic pts.? Toxicity is a concern
Conclusions There is a large body of evidence demonstrating that the activity of biologic agents, in particular, EGFR mabs is influenced by the chemotherapy backbone Bolus 5-FU and capecitabine problematic There has never been a randomized phase III trial comparing FP +/- EGFR mab Results with oxaliplatin-backbone inconsistent Could depend on concomitant FP Hard to believe that there would be a difference between p-mab and c-mab Pharmacokinetic and pharmacodynamic reasons for these findings need to be investigated