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Integration of EGFR targeting into first line therapy: is it time?

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Presentation on theme: "Integration of EGFR targeting into first line therapy: is it time?"— Presentation transcript:

1 Integration of EGFR targeting into first line therapy: is it time?
Prof Eric Van Cutsem, MD, PhD Leuven, Belgium

2 The Epidermal Growth Factor Receptor pathway
Scaltriti M & Baselga J. Clin Cancer Research 2006

3 Anti-EGFR antibodies in mCRC
3rd line BOND: cetuximab ± irinotecan NCIC C0.17: cetuximab vs BSC Panitumumab vs BSC (K-ras wild type) Benefit demonstrated 2nd line EPIC: irinotecan ± cetuximab Benefit 1st line (randomized) Phase II studies CRYSTAL: FOLFIRI ± cetuximab PACCE: chemo/bevacizumab ± panitumumab Other phase III studies in progress

4 Cetuximab +/- irinotecan in irinotecan refractory EGFR+ mCRC: Response rate (primary endpoint)
56 [49-62] ** 60 50 * 32 [24-42] 40 Percentage 23 [18-29] 30 20 11 [6-18] 10 Response Rate Disease Control (CR+PR+SD) cetuximab + irinotecan (n=218) cetuximab (n=111) * p=0.0074; ** p<0.001; [] = 95% CI Cunningham D … Van Cutsem E. N Engl J Med 2004

5 Cetuximab and panitumumab in chemorefractory EGFR expressing CRC
Panitumumab vs BSC¹ n = 463 Cetuximab vs BSC² n = 572 Cross over allowed No cross over Primary endpoint: met PFS HR=0.54 (95% CI: ) Stratified log-rank test: p < Survival HR=0.77 (95% CI: ) Stratified log rank test: p = Secondary endpoints Survival: HR 1.00; p= NS RR: 10% vs 0% PFS: HR 0.68 ( ); p < RR: 7% vs 0% KRAS analysis Activity confined to wild type KRAS³: HR for PFS: 0.45 RR: 17 % in wild type 0 % in KRAS mutated Pending ¹Van Cutsem E et al, J Clin Onc 2007; ²Jonker D et al, N Engl J Med 2007; ³ Amado R, Van Cutsem E et al; Eur J Cancer (Proc ECCO), 2007

6 EPIC trial: Cetuximab in second line treament of mCRC
Irinotecan + cetuximab Irinotecan n = n = 650 cross over allowed Survival (median) 10.71 mo mo HR = (95% CI = – 1.114) p = PFS (median) 4.0 mo mo HR = (95 % CI 0.617–0.776) p < RR DCR (CR+PR+SD) 16.4 % % 61.4 % % Sobrero A et al. AACR 2007

7 Anti-EGFR antibodies in first line treatment of mCRC
Phase II studies: high response rates and high disease control rates Fluoropyrimidine/irinotecan + cetuximab Fluoropyrimidine/oxaliplatin + cetuximab Randomized phase II studies CALGB Opus SAKK BOS - EORTC Randomized phase III studies COIN: 3 arm question on duration and on ± cetuximab CAIRO-2: XELOX/bevacizumab ± cetuximab US intergroup: 3 arm: bevacizumab vs cetuximab vs combination Nordic: FOLFOX ± cetuximab FOLFOX ± panitumumab …….

8 Advanced Colorectal Cancer: CALGB 80203
+ cetuximab RANDOMI ZAT ION n = 238/2200 FOLFIRI - cetuximab Stratify Prior adj Prior XRT + cetuximab FOLFOX - cetuximab Venook A et al ASCO 2006

9 CALGB 80203: Response Cetuximab - / +
CR + PR 46 (38%) 61 (52%) Other 75 (62%) 56 (48%) p = 0.029; chi-sq p = 0.029; chi-sq Venook A et al ASCO 2006

10 SAKK Phase II Study: Preliminary Results
Capox (n=37) Capox + cetuximab Partial response 21% 43% Helbling D, et al. ESMO 2006 A328 AIO CRC Study Group Phase II First-Line study Capox+ cetuximab (n=29) CapIri+ cetuximab (n=33) P-value Response rate (CR + PR) 65.5% 42% 0.081 Disease control rate (CR + PR + SD) 93% 91% 1.0 Heinemann V, et al. ASCO GI, 2007

11 OPUS trial in first line mCRC: large randomized phase II study
FOLFOX n = 168 FOLFOX/cetuximab n = 169 Response Rate (%) 36 46 p =0.06 Response duration (mo) (95 % CI) 5.7 [5.4–7.7] 9.0 [5.9–11.1] Disease control (%) 81.5 [74.8–87.1] 85.2 [78.3–89.7] PFS (mo) 7.2 [6.0–7.8] [5.6–7.7] HR = (0.705–1.230) Bokemeyer C, et al. ECCO 2007 (Abstract No. 3004)

12 OPUS: safety Incidence, n (%) Adverse event (AE) FOLFOX-4 (n=168)
Cetuximab + FOLFOX-4 (n=170) Any grade 3/4 AE occurring in 3 subjects Neutropenia 53 (31.5) 47 (27.6) Diarrhea 10 (6.0) 12 (7.1) Neurotoxicitya 6 (3.5) Leukopenia 9 (5.4) Fatigue 5 (3.0) Other grade 3/4 toxicity Skin reactions 24 (14.1)b Infusion-related reactions 3 (1.8) 7 (4.1) Treatment-related deaths Cetuximab Chemotherapy 1 (0.6) aIncludes peripheral sensory neuropathy and neuropathy bThere were no grade 4 skin reactions or acne-like rash Magnesium measurements were available only from a subset of patients Bokemeyer C, et al. ECCO 2007 (Abstract No. 3004)

13 COIN trial: Phase III study
Previously untreated patients with mCRC Cetuximab + oxaliplatin/5-FU or capecitabine R Oxaliplatin + 5-FU or capecitabine Intermittent oxaliplatin + 5-FU or capecitabinea UK National Cancer Research Institute study, 84 participating centers Current accrual: 1800 (n=2421 planned) Preliminary safety analysis on 804 patients randomized up to June 20061 Explanation of third bullet: The outcome of the safety analysis was that the treatment arm with ERBITUX + oxaliplatin + capecitabine (as the 5-FU drug), capecitabine will be reduced to 850 mg/m2 bid (instead of having 1000 mg/m2 bid), due to an increase in diarrhea. a12 weeks, monitor and repeat on PD 1Maughan T, et al. ASCO 2007 (Abstract No. 4070)

14 COIN trial: Any Grade 3 /4 toxicity (%) in the first 12 weeks
† = p<0.001 compared to same regimen minus cetuximab 1Maughan T, et al. ASCO 2007 (Abstract No. 4070)

15 COIN study: Chemo-type toxicities (%) in the first 12 weeks
No cetuximab (Arms A + C) Cetuximab (C) (Arm B) Significance * p<0.05 † p<0.001 Regimen Ox + Cap OxMdG Ox + Cap OxMdG +/- cap +/- cet n 333 203 166 102 Neutropenia 2 18 1 26 N & vomiting 7 3 14 7 * * Diarrhoea 15 7 25 13 * All cause 60 day mortality 5.65 5.0 7.2 4.9 Treatment related deaths 0.6 0.5 1.8 1.0 1Maughan T, et al. ASCO 2007 (Abstract No. 4070)

16 CRYSTAL trial in first line mCRC
Cetuximab + FOLFIRI Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks EGFR-expressing metastatic CRC R FOLFIRI irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks Stratification factors: Regions ECOG PS Populations Randomized patients n=1217 Safety population n=1202 ITT population: n=1198 Van Cutsem E, et al. Proc ASCO, 2007

17 CRYSTAL trial: Primary endpoint PFS ITT population independent review
1.0 FOLFIRI, n=599 Cetuximab + FOLFIRI, n=599 0.8 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 HR = 0.851; 95% CI = [ ] Stratified log-rank p-value = 8.9 mo PFS estimate 1-year PFS rate 23% vs 34% 8.0 mo 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 499 392 298 196 103 58 29 12 5 Progression-free survival time (months) Van Cutsem E, et al. Proc ASCO, 2007

18 CRYSTAL trial: Response Rate and Surgery with curative intent
FOLFIRI alone Cetuximab + FOLFIRI Liver metastases only population (exploratory) ITT population (pre-planned) p=0.0034* odds ratio 3.0 [95% CI: ] 4.5 9.8 1 2 3 4 5 6 7 8 9 10 Percentage (%) n=134/n=122 No residual tumor in patients with liver metastases *CMH test Van Cutsem E, et al. Proc ASCO, 2007

19 CRYSTAL trial: Safety: Grade 3/4 AE
FOLFIRI n=602, % Cetuximab + FOLFIRI n=600, % Any 59.5 78.0 Neutropenia 23.3 26.7 Febrile neutropenia 2.2 2.7 Diarrhea 10.5 15.2 Vomiting 5.0 4.5 Fatigue Skin reactionsa 0.2 18.7 Infusion-related reactions 2.3 aThere were no grade 4 skin reactions Magnesium levels were measured in only 20% of the patients (0.2% vs. 1.8%) Van Cutsem E, et al. Proc ASCO, 2007

20 PACCE: Panitumumab Advanced Colorectal Cancer Evaluation
Randomized, Open-Label, Controlled Phase 3b Trial Panitumumab 6 mg/kg Q2W Ox-CT Bevacizumab Ox-based CT (eg, FOLFOX) N = 800 Inv choice S C R E N I G R A N D O M I Z E 1:1 Ox-CT Bevacizumab Panitumumab 6 mg/kg Q2W Iri-CT Bevacizumab Iri-basedCT (eg, FOLFIRI) N = 200 Inv choice 1:1 Iri-CT Bevacizumab Stratification Factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs Hecht R et al, Ann Oncol, WCGIC Barcelona 2007

21 PACCE trial: Progression-free Survival: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff)
Central Reviewa Local Reviewb # PFS events (%) Median (95%CI), mos 59 9.6 ( ) 52 11.1 ( ) # PFS events (%) Median (95% CI), mos 70 9.6 ( ) 64 11.0 ( ) pmab+bev/Ox-CT bev/Ox-CT HR = 1.27 (95% CI: 1.05–1.53)* HR = 1.27 (95% CI: 1.07–1.50)* *Descriptive only *Descriptive only aCensoring based on last available scan read centrally Q12W bCensoring based on last day of patient contact or visit Q2W Hecht R, Mitchel E et al, GI Cancers Symposium, Orlando, jan 2008

22 CALGB 80405 trial: Phase III study
FOLFOX or FOLFIRI, and bevacizumab Previously untreated patients with mCRC FOLFOX or FOLFIRI, and cetuximab R FOLFOX or FOLFIRI, bevacizumab and cetuximab Primary endpoint: overall survival Secondary endpoints include response, PFS, toxicity and resection rate Accrual = 1084/2289 No safety concerns (regular IDMC review)

23 CAIRO-II trial: Phase III study
Previously untreated patients with mCRC Cetuximab + bevacizumab + XELOX R Bevacizumab + XELOX Accrual complete (n=755) Interim safety analysis (n=381) reported acceptable AEs in both treatment groups Except for cetuximab-associated skin reactions, there was no difference in the incidence of grade 3/4 AEs between treatment groups Tol J, et al. ECCO 2007 (Abstract No. 3000)

24 CAIRO-2 study Overall toxicity
Arm A n = 197 Arm B n = 192 p-value All grade 3-4 72% 81% 0.03 (skin excluded) 71% 0.87 60-day mortality 2% 3% Tol J, et al. ECCO 2007 (Abstract No. 3000)

25 EORTC phase II BOS study
Previously untreated patients with resectable mCRC (liver) FOLFOX + cetuximab for 3 months (n=50) Resect ion Adjuvant therapy for 3 months (same schedule as pre-operatively) R FOLFOX + cetuximab + bevacizumab for 3 months (n=50) Neoadjuvant therapy

26 EGFR inhibitors in mCRC: questions & challenges
Optimal cytotoxic partner? Optimal setting: more advanced disease or first line treatment? Predictive markers for response and activity? Selection of patients? Prediction of and decreasing toxicity? Relevance of correlation skin toxicity and efficacy What is the clinical significance of increased resection rate of metastases with cetuximab in first line ? Can EGFR antibodies be combined with other biologics? bevacizumab? How can we explain negative results of chemo + bevacizumab and panitumumab in first line? Economic burden

27 Patient Selection After EGFR Inhibitors
Skin rash EGFR - IHC Downstream markers? Gene Mutations KRAS EGFR gene copy number, as assessed by FISH ? Ligands: amphiregulin, epiregulin

28 Cetuximab / panitumumab and K-RAS
Khambata-Ford S et al, J Clin Onc 2007

29 Amado R, Van Cutsem E et al, J Clin Oncol 2008, in press
Chemorefractory patients: Panitumumab + BSC vs BSC Maximum Percent Decrease in Target Lesions Final Analysis, KRAS Evaluable Group 160 140 120 100 80 60 40 20 % Change -20 -40 -60 -80 PR (0%) SD (12%) PD (70%) Mutant Patient Pmab + BSC PR (17%) SD (34%) PD (36%) Wild-Type SD (8%) PD (60%) BSC Alone PD (75%) Amado R, Van Cutsem E et al, J Clin Oncol 2008, in press

30 First line treatment with cetuximab
First line treatment: cetuximab (n = 33) Response rate: 10 %; Stabile disease: 34% Pessino A, Sobrero A et al, Ann Oncol epub 2007 First line treatment: cetuximab followed by FOLFIRI/cetuximab (n = 52) Tabernero J et al, GI Cancers symp 2008

31 Anti-EGFR antibodies in first line treatment of mCRC
Specific issues/questions? Do anti-EGFR antibodies increase the activity of chemotherapy in first line? yes (cetuximab trial), but which subgroup? no data in comparison with bevacizumab Do anti-EGFR antibodies increase the toxicity? yes Is the toxicity in first line acceptable? Is there an interaction between panitumumab and bevacizumab? Is KRAS a predictive marker for activity in first line in combination with chemotherapy? more data expected Does cetuximab increase the resection rate in first line metastatic CRC? probably yes

32 EGFR inhibitors in CRC Are EGFR inhibitors an option in first line treatment of mCRC? Probably yes For who? Biomarker or clinically driven selection? Data: Cetuximab Panitumumab under evalution Are EGFR inhibitors today a standard treatment in first line mCRC? No


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