Does it matter which chemotherapy regimen you partner with the biologic agents?

Transcription

1 Does it matter which chemotherapy regimen you partner with the biologic agents? Yes, it does matter! Axel Grothey

2 Disclosures Research Funding to MAYO Clinic Genentech Bayer Eisai Pfizer Imclone

3 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

4 VEGF INHIBITORS

5 p=0.005 p=0.217 p p= p= P<0.001 P< P<0.001 Median PFS (months) 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) *TTP RCTs = randomized controlled trials 1. Kabbinavar, et al. JCO 2003; 2. Hurwitz, et al. NEJM Kabbinavar, et al. JCO 2005; 4. Saltz, et al. JCO Tebbutt, et al. JCO 2010; 6. Guan, et al. Chin J Cancer Cunningham, et al. ASCO GI 2013

6 Proportion progression-free Phase III Trial of IFL +/- Bevacizumab in MCRC: PFS HR=0.54, P< Median PFS: 6.2 vs 10.6 mo Treatment Group IFL + placebo IFL + bevacizumab Progression-free survival (mo) Hurwitz et al. N Engl J Med 2004

7 PFS estimate PFS chemotherapy + bevacizumab superiority: primary endpoint HR = 0.83 [97.5% CI ] (ITT) p = Months FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events Saltz et al., JCO 2008

8 PFS estimate PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups Months Months XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events XELOX subgroup HR = 0.77 [97.5% CI ] (ITT) p = FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events FOLFOX subgroup HR = 0.89 [97.5% CI ] (ITT) p = Saltz et al., JCO 2008

9 EGFR ANTIBODIES

10 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

11 KRAS WT KRAS mut Tveit et al., J Clin Oncol 2012

12 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 ( ) p-value for interaction Poor differentiation at biopsy HR: 1.49 (95% CI: ) Yes 24 p = ( ) No ( ) 4 or more mets / poor diff / N2 Yes ( ) No ( ) Presentation of disease Arm A Synchronous Arm 113 B (ERBITUX) Cetuximab 0.99 ( ) Non-synchronous ( ) Backbone treatment OxMdG ( ) Time to progression or death (months) IrMdG Number at risk ( ) Arm A CAPOX ( ) Arm B Progression-free survival of all randomised KRAS wild-type patients The median PFS was 20.5 months Arm A vs months Arm B Favors Favors Cetuximab ERBITUX Favors no no ERBITUX Cetuximab

13 COIN : Oxaliplatin/Fluoropyrimidine ± cetuximab Maughan et al., Lancet 2011

14 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 trial: benefit in the FOLFOX subgroup? Cetuximab: no phase III Cave: FLOX, Cape/Ox Detriment in resectable CLM

15 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 trial: benefit in the FOLFOX subgroup? Cetuximab: no phase III Cave: FLOX, Cape/Ox Detriment in resectable CLM

16 Options for combinations: Pros and Cons pro con Beva OS benefit ph III (TML with Bev in 1L) FOLFOX 2L EGFR

17 Options for combinations: Pros and Cons pro con Beva OS benefit ph III (TML in Beva in 1L) FOLFOX 2L EGFR

18 Options for combinations: Pros and Cons pro con Beva PFS benefit ph III 1L/2L XELOX 1L / 2L EGFR Strongly discouraging data (1L)

19 Options for combinations: Pros and Cons pro con Beva 3 randomized trials, all with PFS benefit approx. 9 mos. Cape / 5FU EGFR

20 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

21 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

22 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

23 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

24 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

25 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