Targeting EGFR in Advanced Colorectal Cancer. Eric - Chen, MD, PhD

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1 Targeting EGFR in Advanced Colorectal Cancer Eric - Chen, MD, PhD

2 Outline Review of clinical data Kras and beyond Management of common side effects Alternative dosing regimens

3 Treatment of Colorectal Cancer and beyond 5-FU Leucovorin 5-FU Leucovorin Capecitabine Irinotecan 5-FU Leucovorin Capecitabine Irinotecan Oxaliplatin 5-FU Leucovorin Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Panitumumab

4 Key Milestones: Bevacizumab 1971, Folkman review in NEJM, Tumor-angiogenesis factor postulated 1989, VEGF gene 1997, humanized mab described by Ferrara et al 1997, phase I study, 25 patients/3 months 2000, phase III initiated,813 patients/21 months 2004, FDA approval Cetuximab / panitumumab 1962, Cohen, EGF identified 1980, Cohen, EGFR purified 1981, Mendelsohn and Sato, therapeutic implication 1983, mab 225 described 1991, Phase I study mab 225, JNCI 1994, chimeric version, C , Phase I study of C225, JCO 2001, initial application rejected by FDA 2004, approval by FDA 2006, panitumumab approval

5 The Epidermal Growth Factor Receptor Pathway Shc PI3-K Grb2 Sos-1 AKT MEKK-1 Ras Raf mtor MKK-7 MEK JNK ERK Apoptosis Resistance Proliferation Angiogenesis Metastasis

6 Monoclonal Antibodies Targeting the EGFR Antibody Type Affinity K d Half-life, hrs Cetuximab Panitumumab Matuzumab Nimotuzumab IgG1 Chimeric MoAb IgG2 Human MoAb IgG1 Humanized MoAb IgG1 Humanized MoAb 0.39 nm pm nm Dosing q1wk (q2w) q1w q2w q3w q1w q2w q3w 1 nm 240 q1w Development Phase Approved Approved II I/II approved in India, Cuba

7 3 rd Line Trials of Anti-EGFR Therapy NCIC.CO17 Randomized phase III of cetuximab vs BSC Van Cutsem 2007 Randomized phase III of panitumumab vs BSC

8 NCIC CTG CO.17 TRIAL R E G I S T E R Cetuximab + BSC vs. BSC: Phase III Trial EGFR testing by IHC Failed or intolerant to all recommended therapies ECOG PS* 0-2, no prior EGFR-directed therapy R A N D O M I Z E 1:1 *ECOG PS: Eastern Cooperative Oncology Group Performance Status **Cetuximab 400 mg/m 2 IV week 1, then 250 mg/m 2 IV weekly IHC: Immunohistochemistry Cetuximab** + BSC BSC alone Primary endpoint: Secondary endpoints: Disease Progression or Unacceptable Toxicity Overall Survival (OS) Progression-free survival (PFS) Objective response rate (ORR) RECIST criteria Safety and quality of life (QoL) Jonker DJ et al, NEJM 2007, 357;20:2040-8

9 NCIC CTG CO.17 TRIAL 1.0 Overall Survival Proportion Alive Study arm MS (months) 95% CI Cetuximab + BSC BSC alone HR 0.77 (95% CI: 0.64, 0.92) Stratified log rank p = SUBJECTS AT RISK CET+BSC Months BSC MS = Median Survival HR = Hazard Ratio CETUXIMAB + BSC CENSORED BSC CENSORED Jonker DJ et al, NEJM 2007, 357;20:2040-8

10 NCIC CTG CO.17 TRIAL 1.0 Progression-Free Survival Proportion Progression-Free Study arm Med PFS 95% CI (months) Cetuximab + BSC BSC alone HR 0.68 (95% CI: 0.57, 0.80) Stratified log rank p < Months CETUXIMAB + BSC CENSORED BSC CENSORED Jonker DJ et al, NEJM 2007, 357;20:2040-8

11 Panitumumab vs BSC TRIAL R A N D O M I Z E Study Design Panitumumab PD Follow-up 6.0 mg/kg Q2W + BSC Optional BSC PD Panitumumab Follow-up Crossover Study 1:1 EGFR+ Randomization stratification ECOG score: 0-1 vs. 2 Geographic region: Western EU vs. Central & Eastern EU vs. Rest of World Primary endpoint: Progression-free survival (PFS) Secondary endpoints: Objective response Overall survival Safety PD = Progressive disease VanCutsem E et al, JCO 2007, 25;13:

12 Panitumumab vs BSC TRIAL Event-free Probability Progression-Free Survival Panitumumab BSC HR 0.54 (95% CI: 0.44, 0.66) Stratified log-rank test p < Weeks from Randomization Patients at risk: Panitumumab BSC All Randomly assigned analysis set VanCutsem E et al, JCO 2007, 25;13:

13 Panitumumab vs BSC TRIAL Overall Survival % Surviving Panitumumab (N=231) BSC (N=232) HR 0.93 (95% CI: 0.73, 1.19) Stratified log-rank p = Patients at risk: Panitumumab BSC Months from randomization VanCutsem E et al, JCO 2007, 25;13:

14 Not all patients benefit from anti-egfr antibodies Objective Tumor Response CO-17 Panitumumab (N = 287) (N = 231) PR, n (%) 19 (6.6) 22 (10) SD, n (%) 84 (29.3) 62 (27) PD, n (%) 133 (46.3) 147 (63) PR + SD, n (%) 103 (35.9) 84 (37) Van Cutsem, E. et al. J Clin Oncol; 25: Jonker, D. et al AACR 2007

15 EGFR Pathway and KRAS Gene EGFR signaling pathway is activated in response to ligand binding to cellsurface receptors: these ligands include TGFα and EGF In the early part of the signaling cascade, the protein RAS (RAt Sarcoma) regulates downstream proteins involved in these effects Kras gene is the gene that encodes the Kras protein. It could be normal (wild-type) or mutated. Kras protein cycles between on and off states. It is activated (on) for a short period of time once EGFR is activated. TGF α = Transforming Growth Factor alpha EGF = Epidermal Growth Factor VEGF = Vascular Endothelial Growth Factor Source:

16 EGFR Pathway and KRAS Wild-type KRAS protein is active for a short period when the EGFR is stimulated The effects of the protein are closely controlled When KRAS is mutated the protein is permanently turned on (constitutively activated), even without being triggered by EGFR-mediated signaling The effects of KRAS that lead to tumor growth and spread continue unregulated 40% patients with advanced colorectal cancer have K-ras mutation Adapted from

17 RAS-GDP Khambata et al JCO 2008

18 NCIC CTG CO.17 TRIAL KRAS Analysis N=572 randomized: ITT subset N=394: K-Ras assessed subset (69%) N=164 (42%) mutant N=230 (58%) wild-type Genomic DNA extracted from FFPET slides or sections Assessed by bidirectional sequencing for codon 12/13 mutations No difference between KRAS-mutated and wild-type patients re: demographics, previous treatment or other variables ITT = Intent to treat FFPET = Formalin-fixed paraffin-embedded tissue Karapetis C et al, NEJM 2008, 359;17:

19 NCIC CTG CO.17 TRIAL 1 PFS in Wild-Type KRAS Patients Proportion Progression Free Study arm MS (months) 95% CI Cetuximab + BSC BSC alone HR 0.40 (95% CI: 0.30,0.54) Stratified Log rank p< Cetuximab BSC Time from Randomisation (Months) Cetuximab BSC Karapetis C et al, NEJM 2008, 359;17:

20 NCIC CTG CO.17 TRIAL 1 PFS in KRAS Mutant Patients Study arm MS (months) 95% CI Proportion Progression Free Cetuximab + BSC BSC alone HR 0.99 (95% CI: 0.73,1.35) Stratified Log rank p= Cetuximab BSC Time from Randomisation (Months) Cetuximab BSC Karapetis C et al, NEJM 2008, 359;17:

21 NCIC CTG CO.17 TRIAL Overall Survival in KRAS Wild-Type Patients 1 Study arm MS (months) 95% CI Proportion Alive Cetuximab + BSC BSC alone HR 0.55 (95% CI: 0.41,0.74) Stratified Log rank p < Cetuximab BSC 0 Cetuximab BSC Time from Randomisation (Months) Karapetis C et al, NEJM 2008, 359;17:

22 NCIC CTG CO.17 TRIAL Overall Survival in KRAS Mutant Patients 1 Study arm MS (months) 95% CI Proportion Alive Cetuximab + BSC BSC alone HR 0.98 (95% CI: ) Stratified Log rank p < Cetuximab BSC Cetuximab BSC Time from Randomisation (Months) Karapetis C et al, NEJM 2008, 359;17:

23 Maximum Percent Decrease in Target Lesions Final Analysis, KRAS Evaluable Group Pmab + BSC BSC Alone % Change % Change Mutant PR (0%) SD (12%) PD (70%) Patient PR (0%) SD (8%) PD (60%) Patient % Change % Change Wild-Type PR (17%) SD (34%) PD (36%) Patient PR (0%) SD (12%) PD (75%) Patient

24 Mutant KRAS Subgroup: PFS by Treatment Proportion with PFS Pmab + BSC BSC Alone Events/N (%) Median In Weeks 76/84 (90) /100 (95) HR = 0.99 (95% CI: ) Mean In Weeks Patients at Risk 0.0 Pmab + BSC BSC Alone Weeks

25 Wild-type KRAS Subgroup: PFS by Treatment p < for quantitative-interaction test comparing PFS log-hr (pmab/bsc) between KRAS groups Events/N (%) Median In Weeks Mean In Weeks Proportion with PFS Pmab + BSC BSC Alone 115/124 (93) /119 (96) HR = 0.45 (95% CI: ) Stratified log-rank test, p < Patients at Risk Weeks Pmab + BSC BSC Alone

26 Study Treatment Total number of patients with KRAS tested/total number of patients on trial KRAS Summary Mutated KRAS patients treated with anti-egfr antibody Mutated KRAS patients NOT treated with anti-egfr antibody Wild-type KRAS patients treated with anti-egfr antibody Wild-type KRAS patients NOT treated with anti-egfr antibody Per Protocol PFS Hazard Ratio (HR) Per Protocol PFS Hazard Ratio (HR) Jonker 2007 C0.17: BSC +/- cetuximab (3rd line) 394/572 (69%) 1.8 mos 1.8 mos HR mos 1.9 mos HR 0.40 Amado 2008 Panitumumab vs BSC (3 rd line) 427 / 463 (62%) 7.4 wks 7.3 wks HR wks 7.3 wks HR 0.45 Van Cutsem 2008 CRYSTAL: FOLFIRI +/- cetuximab (1 st line) 540 / 1198 (45%) 7.6 mos 8.1 mos HR mos 8.7 mos HR 0.68 Bokemeyer 2008 OPUS: FOLFOX +/- cetuximab (1 st line) 233 / 337 (69%) 5.5 mos 8.6 mos HR mos 7.2 mos HR 0.57 Punt 2008 CAIRO2: CapOx/BV +/- cetuximab (1 st line) 501 / 755 (66%) 8.6 mos 12.5 mos HR not reported 10.5 mos 10.7 mos HR not reported

27 Objective Tumor Response (Central Radiology) KRAS All Evaluable n (%) Mutant n (%) Wild-type n (%) Response Pmab (N = 208) BSC (N = 219) Pmab (N = 84) BSC (N = 100) Pmab (N = 124) BSC (N = 119) CR 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) PR 21 (10) 0 (0) 0 (0) 0 (0) 21 (17) 0 (0) SD 52 (25) 22 (10) 10 (12) 8 (8) 42 (34) 14 (12) PD 104 (50) 149 (68) 59 (70) 60 (60) 45 (36) 89 (75) CR, PR, SD 73 (35) 22 (10) 10 (12) 8 (8) 63 (51) 14 (12) Pmab, panitumumab; BSC, best supportive care; CR, complete response; PR partial response; SD, stable disease; PD, disease progression

28 7 Common Mutations Mutation Gly12Ala Gly12Asp Gly12Arg Gly12Cys Gly12Ser Gly12Val Gly13Asp Base Change GGT>GCT GGT>GAT GGT>CGT GGT>TGT GGT>AGT GGT>GTT GGC>GAC These mutations cover 98.5% of KRAS mutations in CRC

29 Possible Reasons for resistance to anti-egfr antibodies detection technique direct sequencing with PCR vs mutation-enriched sequencing Mutations on other codons or in other memebers of ras family mutations in other members of the EGFR pathway BRAF, PTEN over-production of EGFR ligands epiregulin, amphiregulin

30 Rajagopalan et al Nature 2002

31 Fig 1. KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting epidermal growth factor receptor Di Nicolantonio, F. et al. J Clin Oncol; 26: Copyright American Society of Clinical Oncology

32 Tol et al NEJM 2009

33 Loupakis et al JCO 2009

34 Loupakis et al JCO 2009

35 Amphiregulin and epiruglin mrna expression in primary tumors predicts outcomes in metastatic colon cancer treated with cetuximab Jacobs et al JCO patients participated in 4 trials and treated with single agent cetuximab gene expression and kras mutation on archival formalin-fixed paraffin-embeded primary tumor samples

36 Jacobs et al JCO 2009

37 Kaplan-Meier plots of (A) PFS and (B) OS by K-ras status and dichotomized epiregulin expression levels Jacobs et al JCO 2009

38 Khambata-Ford et al JCO 2008

39 Cetuximab or Panitumumab? Cetuximab Panitumumab Antibody IgG1, chimeric IgG2, human Approved Schedule Q weekly Q 2 weeks Loading Dose Yes No Mechanism other than EGFR ligand inhibition Approved Indication Antibody dependent cell cytotoxicity EGFR+, irinotecanpretreated mcrc in combination with irinotecan or as monotherapy Not described EGFR+, wild-type KRAS mcrc, after failure of 5FU, oxaliplatin and irinotecan as monotherapy ERBITUX Product Monograph, September 2008 VECTIBIX Product Monograph, July 2008

40 Managing Common Adverse Effects of anti-egfr Antibodies

41 Hypersensitivity Reactions Infusion reaction: 20% cetuximab, 4% panitumumab usually after 1 st dose Severe (grade 3/4) relatively rare 0.5% for CO-17 Grade 3/4 reaction: symptomatic bronchospasm, associated with edema/hypotension anaphylaxis

42 O Neil et al JCO 2007

43 Chung et al NEJM 2008

44 Potential antigenic sites on cetuximab

45 Management of infusion reactions Mild/moderate discontinue infusion H1 and H2 antihistamines, corticosteroids Severe epinephrine, s.c mg in cases of respiratory distress/hypotension H1 and H2 antihistamines, corticosteroids, inhaled bronchodilators Subsequent treatments Antihistamine/corticosteroids pre-med slower infusion rate for patients with mild/moderate reactions discontinue for patients with severe reactions

46 Langerak et al CCC, 2009

47 hypomangnesiumia Magnesum homeostasis absorption: intestine excretion: renal re-absorption: loop of Henle EGFR strongly expressed in kidney EGF: paracrine hormone in Mg reabsorption EGFR inhibition: reduced Mg reabsorption and wasting

48 Vincenzi et al CCR 2008

49 Vincenzi et al CCR 2008

50 Magnesium Supplement IV MgSO4, 2-5 g over 2 hours Oral various magnesium salts magnesium oxide: highest content of Mg tablets BID

51 EGFR Inhibitor Induced Skin Reactions Acne-like rash Post inflammatory effects Dry skin Fissura Pruritus Paronychia Description of severe cases Therapy Suggestions Topical antiacne creams (drying effect) ± tetracyclines ±antihistamines Pulse dye laser Emollients Hydrocolloid dressing or propylene glycol ± acetylsalicyl Antiseptic soaks, silver nitrate (pyogenic granuloma) Segaert S, et al. Ann Oncol. 2005;16:

52 Impact of Pre-emptive skin toxicity treatment on panitumumab-related skin toxicities and quality of life in patients with metastatic colorectal cancer (STEPP) LaCouture et al, ASCO GI 2009

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54 Prophylactic skin treatment Skin moisturizer apply to face, hands, feet, neck, chest and back daily in the morning upon rising Sunscreen (PABA free, SPF 15, UVA/UVB protection) apply to exposed areas before going outdoors Topical steroids (1% hydrocortisone cream) apply to face, hands, feet, neck, back and chest at bedtime Doxycycline 100 mg BID LaCouture et al ASCO GI 2009

55 Endpoints Primary rates of grade 2 skin toxicity in 2 groups Secondary efficacy of skin toxicity events efficacy of panitumumab with chemotherapy patient-reported outcomes safety

56 Primary endpoint Prophylactic skin treatment (n=48) Reactive skin treatment (n=47) Patients with grade 2 or higher skin toxicity, n (%) 14 (29) 29 (62) Odd ratio (95% CI) 0.3 ( ) Total panitumumab dose administered, n Total panitumumab dose delayed, n (%) 1 (1) 9 (8)

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58 Best Overall Response Prophylactic skin treatment (n=48) Reactive skin treatment (n=47) Best Overall Response, n (%) 7 (15) 5 (11) complete response 0 (0) 0 (0) partial response 7 (15) 5 (11) Stable disease 24 (50) 25 (53) Disease progression 9 (19) 10 (21) Not evaluable/available 8 (17) 7 (15)

59 Fig 1. Study schema, patient disposition, and attrition data by study week Scope, A. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

60 Fig 2. Scatter plot of log lesion counts for minocycline and placebo groups for each of the four study time points Scope, A. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

61 Fig 5. Scatter plot of differences in lesion counts for tazarotene and observation sides of the face for each of the four study time points Scope, A. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology

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64 Martin-Martorell et al BJC 2008

65 Martin-Martorell et al BJC 2008

66 Stephenson et al CCC 2009

67 Comparison of panitumumab Cmax after 30 min and 60 min infusions Stephenson et al CCC 2009

68 Summary Anti-EGFR mabs prolong survival in mcrc patients with WT K-ras Biomarkers could predict responses to cetuximab/panitumumab Skin toxicity could be reduced/delayed by prophylactic use of topical and systemic treatments Cetuximab could be administered Q2W without compromising its efficacy or increasing toxicty