Targeted Therapies in Metastatic Colorectal Cancer: An Update

Targeted Therapies in Metastatic Colorectal Cancer: An Update

ASCO 2007: Targeted Therapies in Metastatic Colorectal Cancer: An Update Bevacizumab is effective in combination with XELOX or FOLFOX-4 Bevacizumab use beyond first progression linked to improvement in survival outcomes Cetuximab in combination with FOLFIRI is an effective first-line therapy Panitumumab is generally well tolerated and has a consistent toxicity profile across studies FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan FOLFOX-4 = 5-fluorouracil/leucovorin/oxaliplatin XELOX = capecitabine/oxaliplatin

Bevacizumab is effective in combination with XELOX or FOLFOX-4 Bevacizumab (Bev) in combination with XELOX or FOLFOX-4: updated efficacy results from XELOX-1/NO16966, a randomized phase III trial in first-line metastatic colorectal cancer Saltz L, et al. ASCO 2007: Abstract 4028.

Background Colorectal cancer is the second leading cause of death from cancer in Canada Approximately 20,800 new cases of colorectal cancer will be diagnosed in 2007 alone 1 Monoclonal antibodies (MAbs) such as bevacizumab, cetuximab, and panitumumab in combination with chemotherapy drugs are showing considerable promise Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that inhibits the vascular endothelial growth factor (VEGF), secreted by tumour cells to bring about new blood vessel formation Cancer Care Ontario guidelines recommend the addition of bevacizumab to improve overall survival As first-line therapy in patients with advanced colorectal cancer receiving 5-fluorouracil (5-FU) based chemotherapy As second-line therapy to patients who did not receive bevacizumab as part of their initial treatment 2 1. Canadian Cancer Statistics, 2007. 2. Welch, et al. Cancer Care Ontario, 2005.

Background (continued) The NO16966 trial 1 was started as a randomized phase III study to compare the efficacy of XELOX (capecitabine and oxaliplatin) versus FOLFOX-4 (5-fluorouracil, leucovorin, and oxaliplatin) The protocol was amended to include bevacizumab in a partially blinded 2 x 2 factorial design to determine the following objectives: Non-inferiority of XELOX versus FOLFOX-4 Superiority of bevacizumab in combination with chemotherapy (XELOX and FOLFOX-4) versus chemotherapy alone for progression-free survival (PFS). 1. Saltz L, et al. ASCO 2007: Abstract 4028.

Study design The study was a double-blind study with regard to bevacizumab and placebo administration Enrolled patient criteria included: ECOG PS 1 Number of unidentified measurable lesions 1 No prior systemic therapy for advanced metastatic colorectal cancer No prior treatment with oxaliplatin or bevacizumab Patients who had undergone prior adjuvant therapy should not have progressed during or within 6 months of completion Saltz L, et al. ASCO 2007: Abstract 4028. ECOG = Eastern Cooperative Oncology Group

Study design (continued) Saltz L, et al. ASCO 2007: Abstract 4028. FOLFOX-4 = 5-fluorouraci/leucovorin/oxaliplatin XELOX = capecitabine/oxaliplatin

Study design (continued) Patients randomized to XELOX ± bevacizumab or FOLFOX-4 ± bevacizumab XELOX + bevacizumab or placebo for 21-day cycle Bevacizumab (or placebo) 7.5 mg/kg day 1 Oxaliplatin 130 mg/m 2 day 1 Capecitabine 1,000 mg/m 2 twice daily days 1 14 FOLFOX-4 + bevacizumab or placebo for 14-day cycle Bevacizumab (or placebo) 5 mg/kg day 1 Oxaliplatin 85 mg/m 2 day 1 Folinic acid 200 mg/m 2 days 1, 2 Fluorouracil 400 mg/m 2 bolus days 1, 2 followed by 600 mg/m 2 over 22 h Primary endpoint was progression-free survival Secondary endpoints were overall survival, response rate assessed according to RECIST; safety evaluated using NCI CTC v3.0 Saltz L, et al. ASCO 2007: Abstract 4028. NCI CTC= National Cancer Institute Common Toxicity Criteria RECIST = response evaluation criteria in solid tumours

Key findings Significant prolongation of progression-free survival (PFS) in the bevacizumab + oxaliplatin based chemotherapy arm (HR = 0.83 [97.5% CI: 0.072 0.95]; p = 0.0023) Trend toward prolonged overall survival (OS) Higher proportion of discontinuation of therapy because of adverse effects (AEs) that occurred in the bevacizumab-containing arms versus the placebo-containing arms (31% versus 21%) Most treatment discontinuations, however, due to chemotherapy rather than bevacizumab-related events Most common reasons for treatment discontinuation: neurotoxicity, GI events, general disorders, and hematological events Saltz L, et al. ASCO 2007: Abstract 4028.

Grade 3 or 4 events with chemotherapy ± bevacizumab Saltz L, et al. ASCO 2007: Abstract 4028.

Key conclusions Significant improvement in progression-free survival (PFS) with the addition of bevacizumab to front-line oxaliplatin-based chemotherapy Analysis of on treatment PFS versus general PFS suggests that continuation of bevacizumab until disease progression may be necessary to optimize effect of bevacizumab on PFS Observed overall survival (OS) difference did not reach statistical significance (p = 0.077) Saltz L, et al. ASCO 2007: Abstract 4028.

Canadian perspective by Dr. Cripps Equivalence of XELOX to FOLFOX-4 and FOLFOX-6 in both first-line and second-line chemotherapy Infusional lines not needed with XELOX; this is especially relevant for pockets in Canada where infusional pumps not available There are changing toxicities with XELOX versus FOLFOX, but toxicities can be managed easily Recently completed phase I study 1 found response rates of first-line capecitabine (X), irinotecan (I), and oxaliplatin (O) to be very high, overall survival 79%, disease control rate 92; five patients have gone in for surgical resection. XIO well tolerated Targeted therapies are here to stay Level 1 evidence suggests targeted therapy such as bevacizumab can add 4.4 months to progression-free survival Now we need to confirm the efficacy and safety of XIO with and without bevacizumab in a phase II trial 1. Maroun J, et al. ASCO 2007: Abstract 4086. FOLFOX-4 = 5-fluorouraci/leucovorin/oxaliplatin FOLFOX-6 = infusional 5-fluorouracil/leucovorin/oxaliplatin XELOX = capecitabine/oxaliplatin

Bevacizumab use beyond first progression linked to improvement in survival outcomes Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mcrc): results from a large observational study (BRiTE). Grothey A, et al. ASCO 2007: Abstract 4036..

Background No data exist regarding Effects of bevacizumab beyond first progression (BBP) Optimal duration of VEGF inhibition, including long-term safety and efficacy of using BBP BRiTE is an observational, non-controlled bevacizumab treatment registry: Initiated in 2004 Evaluates safety and efficacy of bevacizumab in combination with chemotherapy in large, less-selected, community-based population of patients with previously untreated mcrc (metastatic colorectal cancer) Grothey A, et al. ASCO 2007: Abstract 4036. BRiTE = Bevacizumab Regimens: Investigation of Treatment Effects and Safety VEGF = vascular endothelial growth factor

Study design Patients enrolled from 248 study sites in 49 states between February 2004 and June 2005: Group of 1,953 evaluable patients Metastatic or locally advanced and unresectable colorectal cancer No prior therapy for their metastatic disease Patients with poor ECOG PS also included in the study Investigator decided on Dose, schedule, and duration of bevacizumab Dose, schedule and choice per duration of chemotherapy regimen Primary endpoint: survival beyond first progression Secondary endpoints: time to progression, and overall survival or study termination Grothey A, et al. ASCO 2007: Abstract 4036. ECOG PS = Eastern Cooperative Oncology Group performance status

Key findings In bevacizumab beyond first progression (BBP) subgroup: Longer survival beyond first progression Longer median overall survival No appreciable difference in bevacizumab-associated safety events between BBP and No BBP subgroups No appreciable increase in incidence of bevacizumab-associated safety events post first progression observed in BBP subgroup: Arterial thromboembolic events Grade 3 or 4 bleeding events GI perforation No apparent increase in incidence of bevacizumab-specific adverse events (AEs) in BBP subgroup Grothey A, et al. ASCO 2007: Abstract 4036.

Key conclusions Median overall survival (OS) in BRiTE is 25.1 months, longer than OS previously reported from phase III trial AVF2107 (median OS 20.3 months), despite unselected population Substantially longer median OS and survival beyond first progression in the BBP versus the No BPP subgroups Similar overall rates of bevacizumab-associated safety events prior to first progression or after first progression in the BBP subgroup, compared to patients who received bevacizumab only First report of improvement in survival outcomes associated with BBP for patients who started bevacizumab in first-line setting Grothey A, et al. ASCO 2007: Abstract 4036. BBP = bevacizumab beyond first progression BRiTE = Bevacizumab Regimens: Investigation of Treatment Effects andsafety

Cetuximab in combination with FOLFIRI is an effective first-line therapy Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mcrc): the CRYSTAL trial Van Cutsem E, et al. ASCO 2007: Abstract 4000.

Background The epidermal growth factor receptor (EGFR) belongs to the human epidermal growth factor receptor (HER) family of transmembrane receptors Aberrant cell signalling, mediated through EGFR, plays a pivotal role in tumorigenesis and disease progression Monoclonal antibodies such as cetuximab and panitumumab prevent the binding of the epidermal growth factor and TGF-alpha to the EGFR, and bring about inhibition of cell proliferation 1 Common side effects of anti-egfr therapy include skin toxicities such as acneiform dermatitis, pruritis, erythema, rash, and dry skin 1. McKarney L, et al. New Evidence in Oncology 2006. TGF = transforming growth factor

Background (continued) Appearance of skin rash may be useful as a surrogate marker of EGFR efficacy Ongoing studies are attempting to elucidate characteristics of target rashes that may correlate with better anti-egfr response CRYSTAL trial initiated to investigate addition of cetuximab to FOLFIRI as first-line treatment EGFR-expressing metastatic colorectal cancer 1 The correlation of severity of skin toxicity with PFS was a secondary endpoint 1. Van Cutsem E, et al. ASCO 2007: Abstract 4000. EGFR = epidermal growth factor receptor FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan TGF = transforming growth factor

Study design Patients (n = 1,217) enrolled from 32 countries had: Histologically confirmed unresectable metastatic colorectal cancer EGFR expression in primary tumour or metastasis as detected by IHC Tumours 1 bi-dimensionally measurable lesion No previous chemotherapy for metastatic disease; adjuvant therapy allowed if stopped minimum 6 months previous (no irinotecan) ECOG PS 2 at study entry Randomized 1:1 to receive either: Group A: cetuximab plus FOLFIRI QW: cetuximab: 400 mg/m 2 initial dose, then 250 mg/m 2 /week Q2W: irinotecan 180 mg/m 2, folinic acid 400 mg/m 2, 5-FU bolus 400 mg/m 2, 5-FU infusion 2,400 mg/m 2 over 46 hours, or Group B: FOLFIRI alone Q2W: irinotecan 180 mg/m 2, folinic acid 400 mg/m 2, 5-FU bolus 400 mg/m 2, 5-FU infusion 2,400 mg/m 2 over 46 hours ECOG = Eastern Cooperative Oncology Group FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan Van Cutsem E, et al. ASCO 2007: Abstract 4000. IHC = immunohistochemistry

Study design (continued) Patient population: Total randomized patients (n = 1,217) Population evaluated for safety (n = 1,202) Intent to treat population (n = 1,198) Primary endpoint: progression-free survival Secondary endpoints: Overall survival Overall response rate (ORR) Disease control rate (DCR) QoL (EORTC QLQ C30) Safety Van Cutsem E, et al. ASCO 2007: Abstract 4000. EORTC = European Organisation for Research and Treatment of Cancer QLQ C30 = Quality of Life Questionnaire QoL = quality of life

Key findings Progression-free survival (PFS) found to be significantly prolonged with addition of cetuximab to FOLFIRI Subgroup analysis of PFS: Pronounced PFS benefit seen in patients with metastases only to liver More favourable PFS with cetuximab plus FOLFIRI in other subgroups, except for patients with ECOG PS 2 at baseline Significantly longer median PFS for Group A versus Group B (8.9 months and 8 months, respectively, stratified log-rank p-value = 0.0479) (Table 1) Van Cutsem E, et al. ASCO 2007: Abstract 4000. ECOG PS = Eastern Cooperative Oncology Group performance status FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan

Progression-free survival Van Cutsem E, et al. ASCO 2007: Abstract 4000.

Key findings (continued) Significant increase in response rate with cetuximab (46.9% versus 38.7%, p = 0.0038) (Figure 1) Van Cutsem E, et al. ASCO 2007: Abstract 4000.

Key findings (continued) Significantly more patients underwent surgery with curative intent (p = 0.0034) and had successful resection in cetuximab arm (Figures 2 and 3) Van Cutsem E, et al. ASCO 2007: Abstract 4000.

Key findings (continued) Van Cutsem E, et al. ASCO 2007: Abstract 4000. FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan

Safety Treatment generally well tolerated; neutropenia, diarrhea, and skin reactions most common grade 3 or 4 adverse events (Table 2) Van Cutsem E, et al. ASCO 2007: Abstract 4000.

Safety (continued) More grade 3 skin reactions associated with cetuximab vs. control Slightly higher incidence of diarrhea Other adverse events, including neutropenia, comparable in groups Better PFS outcomes associated with severity of skin reaction seen in cetuximab-treated patients. Median progression-free survival (PFS): Grade 3 skin reactions: 11.3 months Grade 2 skin reactions: 9.4 months Grade 0 or 1 skin reactions: 5.4 months Van Cutsem E, et al. ASCO 2007: Abstract 4000

Key conclusions Significant increase in response rate and progression-free survival in the cetuximab plus FOLFIRI arm Relative risk of progression reduced by approximately 15% in the cetuximab plus FOLFIRI group Treatment-related side effects of cetuximab plus FOLFIRI as expected: moderate occurrence of diarrhea and significantly more frequent skin reactions compared to FOLFIRI alone Van Cutsem E, et al. ASCO 2007: Abstract 4000. FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan

Panitumumab is generally well tolerated and has a consistent toxicity profile across studies Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR), in patients (pts) with metastatic colorectal cancer (mcrc) across clinical trials Peeters M, et al. ASCO 2007: Abstract 4138.

Background Study presented pooled safety data of panitumumab monotherapy from ten phase I to III clinical trials 1 Many studies report clinical activity and tolerability of panitumumab in EGFR-expressing mcrc patients who had progressed during or after completion of chemotherapy with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens Panitumumab: Recombinant fully human IgG2 MAb Binds specifically to the EGFR Competitively inhibits the binding of ligands to receptor 1. Peeters M, et al. ASCO 2007: Abstract 4138. EGFR= epidermal growth factor receptor IgG = immunoglobulin G MAb = monoclonal antibody mcrc = metastatic colorectal cancer

Study design Pooled safety data from ten clinical studies (n = 966) of panitumumab monotherapy in patients with mcrc Patients with mcrc and ECOG PS 0-2 included in study (one patient ECOG PS 3) Primary endpoints: clinical safety events including Incidence of adverse events, including skin-related toxicity and infusion reactions Deaths Drug exposure Incidence of dose changes Immunogenicity of panitumumab Secondary endpoints: changes in metabolic and laboratory assessments after panitumumab infusions Peeters M, et al. ASCO 2007: Abstract 4138. ECOG PS = Eastern Cooperative Oncology Group performance status mcrc = metastatic colorectal cancer

Study design (continued) Panitumumab administered by infusion over 30 to 60 minutes per protocol; premedication not required. Dosing schedule shown in Table 1 Peeters M, et al. ASCO 2007: Abstract 4138.

Key findings Safety results summarized in Tables 2, 3, and 4 Peeters M, et al. ASCO 2007: Abstract 4138. Fifteen percent of patients (149) died during the study (including deaths within 30 days of last dose of panitumumab). Two deaths considered to be treatment related: Pulmonary edema in patient with history of hypercoagulation, deep vein thrombosis, peripheral vascular disease, and diabetes mellitus Myocardial infarction and cerebrovascular accident observed in patient with history of anemia, diabetes mellitus, deep vein thrombosis, hyperlipidemia, hypertension, and supraventricular tachycardia Antibodies to panitumumab: patients who were predose negative and had persistent postdose positive results: ELISA found 2/778 patients (0.3%) tested positive for anti-panitumumab antibodies Biacore found 2/638 patients (0.4%) tested positive for anti-panitumumab antibodies Bioassay determined 6/638 patients (1%) had neutralizing antibodies to panitumumab

Incidence of skin-related toxicity Peeters M, et al. ASCO 2007: Abstract 4138.

Adverse events excluding skin-related toxicity Peeters M, et al. ASCO 2007: Abstract 4138.

Infusion reactions reported per investigator Peeters M, et al. ASCO 2007: Abstract 4138.

Key conclusions Panitumumab generally well tolerated with consistent toxicity profile across studies Common toxicities included fatigue, gastrointestinal side effects, and skin-related (majority were grade 1 or 2) Grade 3 or 4 infusion reactions rare (0.4% of patients); no premedication required Treatment-related adverse events of grade 3 or 4 reported in 20% patients Four percent of patients permanently discontinued panitumumab or withdrew from study due to treatment-related adverse events Anti-panitumumab antibody formation postdose was detected in <1% of patients by ELISA and Biacore Incidence of skin-related adverse events in Figure 1 Peeters M, et al. ASCO 2007: Abstract 4138.

Figure 1 : Any skin-related adverse events Peeters M, et al. ASCO 2007: Abstract 4138.