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Gene Profiling in Clinical Oncology - Slide 5 - R. Labianca - What do we do today to chose “targeted agents” in metastatic CRC treatment? Is k-ras mutation enough? What about b-raf? And how to decide between EGFR inhibitions and angiogenesis inhibitio
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Gene Profiling in Clinical Oncology - Slide 5 - R. Labianca - What do we do today to chose “targeted agents” in metastatic CRC treatment? Is k-ras mutation enough? What about b-raf? And how to decide between EGFR inhibitions and angiogenesis inhibitio

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  • Hurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646.
  • sample size refres to IIT population. Check demographics etc to see if all are PP
  • Moreover this post hoc change raises some multiplicity concerns too. With 3 arms there is a multiplicity of hypothesis test leading to a alpha risk inflation. To be confirmatory, the trial must control this inflation by using a signification level adjustment (Bonferroni, etc.). In the reported analysis, no such a method was performed. So given the post hos change of hypothesis and the multiplicity concern these results are only exploratory, not confirmatory. The present conclusion is a little bit stronger given these restrictions. For the calculation of the sample size, the underlying incidence (in the control group) is missing. The sample size calculation presented here is for 2 groups, I guess that in the protocol a sample size calculation for 3 arms was performed initially Is this trial registered into a clinical trial register (if yes what are the change in the protocol compared with the description put in the register) In the abstract the trial was described as a phase II/III trial, here it’s a phase III only The methodology of this trial seems like meta analysis or others? One more point may be that the number of patients enrolled is not so large which may make people challenge the results.
  • Difference between arms in KRAS wt only Belt at point 0.5, thus small difference in medians but compelling Hazard Ratio
  • Difference between arms in KRAS mt only Cetuximab addition to FOLFOX in KRASmt more or less implausible, suggesting better PFS for treatment without cetuximab
  • This slide shows the randomized studies that directly compare FOLFOX + cetuximab vs. FOLFIRI plus cetuximab with results that mostly favor FOLFOX + cetuximab. Unfortunately for CELIM and CALGB 80203 results are not available for the subgroup with KRAS wt tumors

Gene Profiling in Clinical Oncology - Slide 5 - R. Labianca - What do we do today to chose “targeted agents” in metastatic CRC treatment? Is k-ras mutation enough? What about b-raf? And how to decide between EGFR inhibitions and angiogenesis inhibitio Gene Profiling in Clinical Oncology - Slide 5 - R. Labianca - What do we do today to chose “targeted agents” in metastatic CRC treatment? Is k-ras mutation enough? What about b-raf? And how to decide between EGFR inhibitions and angiogenesis inhibitio Presentation Transcript

  • Where do we stand in colorectal cancer? METASTATIC DISEASE ROBERTO LABIANCA Department of Oncology and Hematology Ospedali Riuniti Bergamo, Italy
  • Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Best supportive care (BSC) Panitumumab median overall survival
  • Treatment paradigms for mCRC
    • Some patients with stage IV disease can be cured by an interdisciplinary approach
    • FOLFOX = XELOX = FOLFIRI (XELIRI: toxicity problems)
    • Most patients tolerate a chemotherapy doublet
    • The addition of biologics to chemotherapy, or triplets (in dedicated centers), has improved outcomes
    • We are in the early era of individualized therapy based on molecular predictive factors
  • ANTI-ANGIOGENESIS Focus on bevacizumab
  • Phase III Trial IFL +/- Bevacizumab in mCRC: Efficacy Hurwitz et al. N Engl J Med 2004 IFL+ Placebo (n=411) IFL+ Bevacizumab (n=402) P Value OS (mo) 15.6 20.3 0.00004 PFS (mo) 6.2 10.6 <0.00001 RR (%) 35 45 0.0036
  • XELOX/FOLFOX +/- Bevacizumab: PFS (NO16966) 0 5 10 15 20 25 Months PFS estimate HR = 0.83 [97.5% CI 0.72–0.95] (ITT) p = 0.0023 9.4 8.0 1.0 0.8 0.6 0.4 0.2 0 Saltz et al., JCO 2008 FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events
  • MACRO - Study Design Progression R Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Bevacizumab until progression N=480 N=239 N=241 Capecitabine Oxaliplatin Bevacizumab x6 cycles q3w Capecitabine Oxaliplatin Bevacizumab until progression
  • Summary of efficacy *Odds Ratio XELOX-BEV (N=239) s/a BEV (N=241) HR (CI 95%) PFS median Events % 10.4 (9.3-11.9) 67% 9.7 (8.5-10.6) 72% 1.11 (0.89–1.37) OS median Events % 23.4 (20.0-26.0) 55% 21.7 (18.3-25.1) 54% 1.04 (0.81–1.32) Confirmed OR % 46% 49% 0.89 (0.62-1.27)*
  • BRiTE: Patient Outcome Based on Treatment Post 1st PD BBP (n=642) No BBP (n=531) No Post-PD Treatment (n=253) Grothey et al. JCO 2008 # of deaths (%) 168 (66%) 306 (58%) 260 (41%) Median OS (mo) 12.6 19.9 31.8 1yr OS rate (%) 52.5 77.3 87.7 OS after 1st PD (mo) 3.6 9.5 19.2
  • AIO 0504 / Roche ML18147 Multinational European Trial Any-OX + BEV Any-IRI + BEV Any-IRI + BEV Any-IRI Any-OX Any-OX + BEV R R N = 820 Primary EP: OS Accrual completed May 31, 2010
  • SWOG/NCCTG S600/iBET - Revised – Re-activated October 15, 2009 (FOLFOX or XELOX or OPTIMOX) + BEV (FOLF) IRI + BEV (FOLF) IRI + C225 R KRAS wt N = 620 Primary EP: PFS (HR 1.3, 5 -> 6.5 mos for BEV arm) Secondary EP: OS (HR 1.3, 12 -> 15.6 mos in BEV arm)
  • Bevacizumab demonstrates OS benefits regardless of mutation status* or P53 expression Ince et al. JNCI 2005 * K-Ras, b-raf or P53 0.2 0.5 1 2 5 (0.45–1.10) (0.15–0.70) 0.70 0.32 26.35 25.07 99 47 17.45 16.26 92 28 191 75 P53 overexpression Positive Negative (0.30–0.95) (0.32–1.42) 0.54 0.67 27.7 NR 76 35 21.72 16.36 63 31 139 66 P53 mutation status Mutant Wild-type (0.37–1.20) (0.34–0.82) 0.67 0.57 19.91 27.7 51 68 13.6 21.72 37 57 88 125 K-Ras and b-raf mutation status Mutant Wild-type (0.01–1.06) (0.34–0.82) 0.11 0.53 15.93 26.35 7 120 7.95 17.45 3 97 10 217 b-raf mutation status Mutant Wild-type (0.37–1.31) (0.34–0.99) 0.69 0.58 19.91 27.7 44 85 13.6 17.64 34 67 78 152 K-Ras mutation status Mutant Wild-type (0.39–0.85) 0.57 26.35 147 17.45 120 267 All subjects HR (95% CI) HR Median (months) n Median (months) n Total n Biomarker Bevacizumab + IFL Placebo + IFL
  • Patients with previously untreated, not resectable metastatic colorectal cancer N = 255 CAPIRI + Avastin (128) R A N D O M I Z A T I O N CAPOX + Avastin (127) Primary endpoint 6-month PFS rate. Secondary endpoints OS, PFS, toxicity and secondary resection of liver/lung metastases. Objective: To assess the effect of KRAS status on outcome in patients undergoing treatment with bevacizumab + CapOx/mCapIri
  • AIO 0604: PFS and OS according to KRAS status Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD) PFS estimate 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 50 Time (months) 9.3 10.8 WT (n=100) MT (n=42) p=0.32 21.0 28.0 p=0.19 WT (n=100) MT (n=42) OS estimate 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 50 Time (months) PFS OS
  • HORIZON III: phase III study of cediranib versus bevacizumab Experimental arm: mFOLFOX6 + cediranib (n=709) Active comparator arm: mFOLFOX6 + bevacizumab (n=713) Schmoll, et al. ESMO 2010 (Abstract 580O)
    • Primary endpoint
      • PFS (non-inferiority)
    • Secondary endpoints
      • OS, ORR, safety, tolerability, QoL
    Previously untreated mCRC (n=1,422) R
  • HORIZON III: progression-free survival Schmoll, et al. ESMO 2010 (Abstract 580O) 709 591 454 296 132 59 22 10 7 713 601 472 319 140 64 22 12 4 0 PFS estimate 0 0.2 0.4 0.6 0.8 1.0 6 12 18 24 mFOLFOX6 + cediranib mFOLFOX6 + bevacizumab Time (months) 9.9 10.3 3 9 15 21 Non-inferiority assessment: HR=0.75 (95% CI 0.97–1.25); p=0.1190 ) required boundary of <1.2 not reached
  • HORIZON III: overall survival Schmoll, et al. ESMO 2010 (Abstract 580O) Time (months) 0 OS estimate 0 0.2 0.4 0.6 0.8 1.0 3 6 9 12 15 21 27 33 18 24 30 709 713 660 612 559 414 241 93 28 4 147 60 14 666 618 561 389 225 77 29 2 139 58 5 21.3 22.8 mFOLFOX6 + cediranib HR=0.94 p=0. 5459 mFOLFOX6 + bevacizumab
  • TARGETING EGFR Focus on cetuximab and panitumumab
  • CRYSTAL trial: FOLFIRI +/- Cetuximab: PFS ITT population, independent review Months PFS estimate 1.0 8.9 mo 8.0 mo FOLFIRI FOLFIRI + Cetuximab Van Cutsem et al. NEJM 2009 HR = 0.851 P = 0.0479 RR 46.9% 38.7% P = 0.0038 0.8 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0 2 4 6 8 10 12 14 16 18 20 Subjects at risk FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1 Cetuximab + FOLFIRI 599 499 392 298 196 103 58 29 12 5 1
  • CRYSTAL - KRAS wild-type mCRC (N=348): PFS 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 4 6 8 10 12 14 16 18 Months Progression-free survival estimate Cetuximab + FOLFIRI FOLFIRI FOLFIRI + Cetuximab: 9.9 mos FOLFIRI: 8.7 mos HR=0.68, p=0.017 1-yr PFS rate 25% vs 43% Van Cutsem et al. NEJM 2009
  • OPUS – FOLFOX +/- Cetuximab in first-line mCRC: PFS – KRAS wild-type 0.5 1.0 0.4 0.3 0.2 0.1 0.0 0.6 0.7 0.8 0.9 8 0 2 4 6 10 12 Months mPFS Cetuximab + FOLFOX: 7.7 mos FOLFOX: 7.2 mos HR=0.57; p=0.016 FOLFOX (N=73) Cetuximab + FOLFOX (N=61) Progression-free survival estimate Bokemeyer et al. JCO 2008
  • OPUS – FOLFOX +/- Cetuximab in first-line mCRC: PFS – KRAS mutant 0.5 1.0 0.4 0.3 0.2 0.1 0.0 0.6 0.7 0.8 0.9 8 0 2 4 6 10 12 Months Progression-free survival estimate mPFS Cetuximab + FOLFOX: 5.5 mos FOLFOX: 8.6 mos HR=1.83; p=0.019 Bokemeyer et al. JCO 2008 FOLFOX (N=47) Cetuximab + FOLFOX (N=52)
  • PRIME: FOLFOX +/- P-mab PFS by KRAS Mutation Status
    • WT KRAS
    MT KRAS Douillard, et al. ECCO-ESMO 2009 Events n (%) Median (95% CI) months Panitumumab + FOLFOX 199 (61) 9.6 (9.2–11.1) FOLFOX 215 (65) 8.0 (7.5–9.3) HR = 0.80 (95% CI: 0.66–0.97) P-value = 0.02 Events n (%) Median (95% CI) months Panitumumab + FOLFOX 167 (76) 7.3 (6.3 – 8.0) FOLFOX 157 (72) 8.8 (7.7 – 9.4) HR = 1.29 (95% CI: 1.04 – 1.62) P-value = 0.02
  • COIN (cetuximab): First-line Study
    • Primary endpoints:
      • OS in patients with K-ras wild-type tumours
    • Secondary endpoints include:
      • OS in K- ras mutant; “all” wild-type (K- ras , N- ras , B- raf ); “any” mutant, ITT
      • PFS
      • Response rate
      • Quality of life
      • Health economic evaluation
    Continuous* XELOX or FOLFOX Arm A R First-line mCRC (n= 2445) Arm B Continuous XELOX or FOLFOX + cetuximab Arm C Intermittent** XELOX or FOLFOX *Treatment until disease progression or unacceptable toxicity **Stop and Go treatment (12 wks then restart at progression) MRC-sponsored study supported by Merck (109 UK/Irish Hospitals)
      • 65% XELOX; 35% FOLFOX (patient/physician choice)
    Maughan, et al. ECCO-ESMO 2009
  • COIN study: KRAS WT PFS 1.00 0.75 0.50 0.25 0 Survival probability Time (months) No. at risk Arm A Arm B 0 6 12 18 24 30 36 42 367 361 245 249 92 103 41 42 18 22 11 9 6 6 1 0 Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) HR point estimate = 0.959 95% CI 0.84–1.09 p=0.60 Maughan, et al. ECCO-ESMO 2009 Arm A Arm B Diff. Median PFS, months 8.6 8.6 +0.07
  • Conclusions
    • In this negative study, subgroup analyses suggest that there may be a benefit for cetuximab in combination with oxaliplatin chemotherapy in patients with
      • KRAS wildtype tumours,
      • Limited metastatic disease (0/1 metastatic sites),
      • Used in combination with infusional 5FU and oxaliplatin
    • The differential benefit for choice of fluoropyrimidine and distribution of disease requires validation from other datasets
    • Strong prognostic effect of KRAS, BRAF and NRAS mutation status independent of the use of cetuximab
  • EGFR antibodies in first-line therapy: outcome in KRAS wild-type mCRC 1. Van Cutsem, et al. ASCO GI 2010 2. Maughan , et al. ESMO 2009 3. Siena, et al. ASCO GI 2010 Cetuximab Panitumumab CRYSTAL 1 (N=666) COIN 2 (N=729) PRIME 3 (N=656) Chemotherapy FOLFIRI XELOX/FOLFOX FOLFOX OS, months HR p value 23.5 vs 20.0 0.80 0.0093 17.0 vs 17.9 1.04 0.68 23.9 vs 19.7 0.83 0.072 PFS, months HR p value 9.9 vs 8.4 0.70 0.0012 8.6 vs 8.6 0.96 0.60 9.6 vs 8.0 0.80 0.02 ORR (%) p value 57 vs 40 <0.0001 64 vs 57 0.049 55 vs 48 0.068
  • EGFR antibodies vs BSC as salvage therapy: outcome in KRAS wild-type mCRC n.s. = not significant 1. Karapetis, et al. NEJM 2008 2. Amado, et al. JCO 2008 *Patients on BSC could cross over to panitumumab + BSC upon PD Cetuximab Panitumumab CO.17 1 (N=225) CONSORT 2 (N=243) OS, months HR p value 9.5 vs 4.8 0.55 <0.001 8.1 vs 7.6* 0.99 n.s. PFS, months HR p value 3.7 vs 1.9 0.40 <0 .001 2.8 vs 1.7 0.45 <0.0001 ORR (%) p value 13 vs 0 <0.0001 17 vs 0 <0.0001
  • CRYSTAL trial update: outcome in KRAS wild-type/ BRAF mutated mCRC a Stratified log-rank test; b Cochran-Mantel-Haenszel test Van Cutsem et al, ASCO GI 2010 KRAS wt/ BRAF wt (n=566) KRAS wt/ BRAF mt (n=59) FOLFIRI   (n= 289) FOLFIRI + Cetuximab (n= 277) FOLFIRI   (n=33) FOLFIRI + Cetuximab (n=26) mOS (mo) 21.6 25.1 10.3 14.1 HR [95% CI] p-value a 0.83 [0.687–1.004] 0.0549 0.91 [0.507–1.624] 0.7440 mPFS (mo) 8.8 10.9 5.6 8.0 HR [95% CI] p-value a 0.68 [0.533–0.864] 0.0016 0.93 [0.425–2.056] 0.8656 RR (%) [95% CI] 42.6 [36.8–48.5] 61.0 [55.0–66.8] 15.2 [5.1–31.9] 19.2 [6.6–39.4] p-value b <0.0001 0.9136
  • CALGB/SWOG 80405: Phase III First-line Therapy of mCRC – KRAS wild-type! Bevacizumab Cetuximab Cetux + Bev FOLFOX FOLFIRI “ Dealer’s Choice”
    • Primary endpoint: OS
    As of May 2010 1758/2843 >90% FOLFOX
  • The results: NORDIC ( n = 566)
    • RR PFS OS TOX
    • FLOX 41 7.9 20.4
    • FLOX CET 49 8.3 19.7 more
    • maintenance 47 7.3 20.3
    • no better outcome in the K-RAS wt population !!!
  • Panitumumab for mCRC Patients with KRAS Wild-type Tumors
    • Present indication: Panitumumab as monotherapy for the treatment of patients with EGFR+ mCRC KRAS wt after failure of fluoropyrimidine, oxaliplatin and irinotecan
    • BSC ± Panitumumab (Amado, JCO 2008)
  • Panitumumab 1 st line (PRIME )
    • PRIME is the first prospective phase 3 study to demonstrate the utility of KRAS as a predictive biomarker
    • In patients with KRAS wt tumors, panitumumab significantly improved PFS when added to FOLFOX chemotherapy for first-line treatment of mCRC (median 9.6 vs 8.0; HR=0,80, p=0,02)
    • Response rate was improved in patients with KRAS wt tumors , although no significantly
    • In patients with KRAS mutant tumors, outcomes were inferior for those receiving panitumumab + FOLFOX vs FOLFOX alone (mechanism unknown)
    • Panitumumab was well-tolerated when administered with FOLFOX
      • AE profile was as expected for an anti-EGFR antibody
      • Grade 3/4 panitumumab-related infusione reaction were rare (n=2/259)
    • Interim overall survival was improved in patients with KRAS wt tumors. Long-term follow-up is ongoing and will be presented at a later congress
    Douillard JY, et al. Eur J Cancer 2009;7(3suppl):10LBA, oral presentation
    • This is the first prospective phase 3 study in second-line mCRC to demonstrate the utility of KRAS as a predictive biomarker for an anti-EGFR therapy
    • Panitumumab administered in combination with FOLFIRI significantly prolonged PFS compared with FOLFIRI alone in the second-line treatment of patients with KRAS wild-type mCRC (median PFS 5.9 vs 3.9; HR=0.73; p=0.004)
    • Response rate was significantly improved in patients with wt KRAS tumors with panitumumab with FOLFIRI (35% vs 10%)
    • Although no statistically significant difference in OS was detected, the absolute difference in median OS was 2 months in favor of the panitumumab arm
    • No inferior outcome was detected in patients with KRAS mutant tumors when panitumumab was added to FOLFIRI
    • Panitumumab was well-tolerated when administered with FOLFIRI
      • AE profile was as expected for an anti-EGFR antibody
      • Grade 3 / 4 panitumumab-related infusione reaction were rare (n=2)
    Panitumumab in 2 nd line Peeters M, et al. Eur J Cancer 2009;7(3suppl):14LBA, oral presentation
  • Panitumumab in cetuximab-refractory KRAS WT mCRC: summary
    • Panitumumab has no efficacy in patients with cetuximab-resistant KRAS WT mCRC
      • ORR 0 % (Primary Endpoint)
      • best response was stable disease (45%)
      • median OS: 2.1 months
    Wadlow, et al. ASCO GI 2011 (Abstract 428) Cetuximab-refractory patients with KRAS WT mCRC (n=20) Panitumumab (6mg/kg q2w) until PD, toxicity, death or study withdrawal
  • One possible reason for oxaliplatin and anti-EGFR negative outcomes
    • Src is acutely and chronically activated by oxaliplatin
    • EGFR can be activated by Src in the absence of ligand binding
    • EGFR resistance in vitro is mediated by Src
    Kopetz, et al Cancer Res 2009, Liu et al Cancer Res 2007 Oxaliplatin Src activity Signal Transduction R R Y Y Src Kopetz GI ESMO 2010
  • Is Irinotecan a better partner for cetuximab than oxali ?
    • IRINOTECAN
    • III line ++ BOND (MLE)
    • II line ++ EPIC
    • I line +++ CRYSTAL
    • No detrimental effect mut
    • OXALIPLATIN
    • III line no data
    • II line - little data
    • I line ++ OPUS
    • + COIN
    • - NORDIC
    • Adjuvant - NO146
    • Detrimental effect in mut
    Very solid shaky
  • Bevacizumab vs EGFR Antibodies in Advanced CRC - Simplified Agent Strength Weakness Bevacizumab
    • Delay in tumor progression
    • Gain in time
    • Toxicity profile
    • No single agent activity
    • Weak effect on RR
    EGFR antibodies
    • Single agent activity
    • Consistent increase in RR
    • Activity independent of line of therapy
    • Predictive marker
    • Gain in time to progression moderate
    • Toxicity profile
  • Pazienti potenzialmente resecabili Strategia terapeutica
  • State of the art: first-line strategy Doublet chemotherapy plus bevacizumab Doublet chemotherapy plus cetuximab Doublet chemotherapy plus bevacizumab Does the patient need (and/or like) aggressive therapy? Yes No KRAS status FU/capecitabine plus bevacizumab Unavailable Wild-type Mutant Folfiri + cetuximab Or Folfiri + bevacizumab
  • 2011 a classical Hx of advanced CRC
    • 6 mo of FFOX-BEV , then BEV
    • 4 months SD then  P
    • 5 mo “II line” FFIRI, then slow P
    • 4 mo III line IRI-CET,then slow P
    • 2 mo of break
    • 4 mo capox then P “rechallenge”
    • 3 mo preterminal phase
    28 mo
  • Take-Home Messages: Optimized Medical Therapy of Advanced CRC
    • Identify the goal of therapy
      • RR only matters for
        • conversion therapy of liver metastases or
        • if patient is symptomatic from his tumor burden
      • For most patients gain of time and maintaining QOL is more important
    • Treat to progression
      • Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops
      • Some select patients can have CFI
  • Take-Home Messages: Optimized Medical Therapy of Advanced CRC
    • Expose patients to all potentially active agents
      • These agents are the oncologist’s tools to keep patients alive
      • Use fluoropyrimidine-based combinations as default backbone, reserve sequential single agent therapy for select patients
    • Reutilize chemotherapeutic agents (in different combinations?) in the course of the therapy
      • Continuum of care vs distinct lines of therapy
    • Keep in mind that personalized medicine in colorectal cancer did not start with KRAS