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Malcolm Moore Professor of Medicine and Pharmacology, Princess Margaret Hospital, University of Toronto, Toronto, Canada Director of the Bras Family New Drug Development Program, Princess Margaret Hospital, University of Toronto, Canada Head of Division of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto Senior Scientist in the Division of Experimental Therapeutics at the Ontario Cancer Institute, Canada He is the author of more than 160 peer- reviewed publications and has given over 140 invited lectures worldwide Princess Margaret Hospital Charting a new landscape in advanced pancreatic cancer Malcolm Moore Princess Margaret Hospital University of Toronto Toronto, Canada Pancreatic cancer: a major therapeutic challenge Major health burden – fourth leading cause of cancer death in the USA – fifth leading cause of cancer death in the EU Fatal disease with 98% mortality rate1,2 – OS rate is among the shortest of any solid tumour Poor prognosis – usually locally advanced or metastatic at diagnosis – most patients unsuitable for surgery – current treatment options are limited 1Parkin OS = overall survival DM, et al. CA Cancer J Clin 2005;55:74–108 2Michaud DS. Minerva Chir 2004;59:99–111 Gemcitabine: a standard of care in pancreatic cancer Patients surviving (%) 100 Gemcitabine (n=63) 5-FU (n=63) p value 5.65 4.41 0.0025 Median survival (months) 80 60 40 Gemcitabine 5-FU 20 0 0 2 5-FU = 5-fluorouracil 4 6 8 10 12 Months 14 16 18 20 Burris H, et al. J Clin Oncol 1997;15:2403–13 Lack of progress in therapy for advanced pancreatic cancer Treatment options remained limited over last decade despite promising phase II results with gemcitabine plus various different agents More than 10 phase III trials of new drug versus gemcitabine or in combination with gemcitabine – none demonstrated a survival benefit Increased toxicity with several combination regimens Randomised phase III trials in pancreatic cancer (median OS in months) Gem Gem + X p value Gem ± marimastat (Bramhall, Br J Cancer 2002) Gem ± tipifarnib (Van Cutsem, J Clin Oncol 2004) Gem ± exatecan (Abou-Alfa, J Clin Oncol 2006) Gem ± CPT-11 (Rocha-Lima, J Clin Oncol 2006) Gem ± pemetrexed (Oettle, Ann Oncol 2006) 5.5 6.0 6.2 6.6 6.3 5.5 6.4 6.7 6.3 6.2 NS NS NS NS NS Gem ± 5-FU bolus (Berlin, J Clin Oncol 2002) Gem ± capecitabine (Herrmann, J Clin Oncol 2007) Gem ± 5-FU/LV (Riess, J Clin Oncol 2005) Gem ± capecitabine (Cunningham, ECCO 2005) (preliminary results) Gem ± cisplatin (Heinemann, J Clin Oncol 2006) Gem ± oxaliplatin (Louvet, J Clin Oncol 2005) Gem ± oxaliplatin (Poplin, ASCO 2006) 5.4 7.3 6.2 6.0 6.7 8.4 5.9 7.4 NS NS NS 0.026 6.0 7.1 4.9 7.5 9.0 5.9 NS NS NS Gem ± erlotinib (Moore, J Clin Oncol 2007) Gem ± bevacizumab (Kindler, ASCO 2007) Gem ± cetuximab (Philip, ASCO 2007) 5.9 6.1 5.9 6.4 5.8 6.4 0.011 NS NS Gem = gemcitabine; Gem + X = combination regimen being investigated LV = leucovorin; NS = not significant Gemcitabine/cetuximab versus gemcitabine alone: phase III study (n=735) Gemcitabine + cetuximab Gemcitabine monotherapy 6.5 6.0 Median OS (months) HR=1.09 (95% CI: 0.93–1.27) p=0.14 Progression-free survival (PFS) (months) 3.5 Response rate (RR) (%)* 12 Patients experiencing ≥1 grade 4 toxicity (%) 14 HR=1.13 (95% CI: 0.97–1.30) p=0.058 3.0 14 11 *Includes unconfirmed responses HR = hazard ratio; CI = confidence interval Phase III data did not confirm promising phase II results Philip PA, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):s199 (Abstract 4509) Gemcitabine/bevacizumab versus gemcitabine/placebo: phase III CALGB study Gemcitabine + bevacizumab (n=302) Gemcitabine + placebo (n=300) Median OS (months) 5.7 6.0 PFS (months) 4.8 4.3 1.9 11.2 40.7 3.0 8.3 35.7 RR (%)* Complete response Partial response Stable disease *Includes unconfirmed responses Phase III data did not confirm promising phase II results Kindler HL, et al. J Clin Oncol 2007;25(Suppl. 18 Pt.I):s199 (Abstract 4508) Rationale for targeting EGFR in anticancer therapy Epidermal growth factor receptor (EGFR) Extracellular Intracellular P PI3K Akt P MAPK JNK Proliferation Invasion Metastasis Angiogenesis Inhibition of apoptosis Woodburn J. Pharmacol Ther 1999;82:241–50; Lynch TJ, et al. N Engl J Med 2004;350:2129–39 Knowlden JM, et al. Endocrinology 2003;144:1032–44 Chakravarti A, et al. Cancer Res 2002;62:4307–15 Rationale for targeting EGFR in pancreatic cancer EGFR overexpression is common (30–95%)1,2 Elevated EGFR and EGF is thought to be associated with3–5 – more aggressive disease – increased tumour size – late clinical stage – poor prognosis – reduced sensitivity to chemotherapy 1Tobita K, et al. Int J Mol Med 2003;11:305–9 A, et al. Hum Pathol 2001;32:1184–9 3Ueda S, et al. Pancreas 2004;29:1–8 4Nicholson R, et al. Eur J Cancer 2001;37:S9–S15 5Xiong H, et al. Semin Oncol 2002;29:31–7 2Srivastava Data overview: PA.3 study PA.3: study schema Stratified by Centre ECOG PS (0/1 vs 2) Stage of disease (locally advanced/ distant metastases) (n=569) Primary endpoint = overall R A N D O M I S E* Gemcitabine 1,000mg/m2 i.v. weekly + erlotinib 100/150mg/day p.o. (n=285) Gemcitabine 1,000mg/m2 i.v. weekly + placebo 100/150mg/day p.o. (n=284) survival Secondary endpoints include progression-free survival (PFS), quality of life (in selected countries), response rate (RR), toxicity, biomarkers *1:1 randomisation ECOG = Eastern Cooperative Oncology Group; PS = performance status; i.v. = intravenous; p.o. = oral Moore M, et al. J Clin Oncol 2007;25:1960–6 PA.3: key eligibility criteria Locally advanced or metastatic adenocarcinoma of the pancreas Age 18 years PS 0–2 Measurable or non-measurable disease Prior radiotherapy for local disease allowed No prior chemotherapy, except for 5-FU or gemcitabine as a radiosensitiser EGFR-positive status not required Moore M, et al. J Clin Oncol 2007;25:1960–6 PA.3: patient characteristics* 569 patients randomised – 521 patients at 100mg/placebo – 48 patients at 150mg/placebo Gemcitabine + erlotinib (n=285) Gemcitabine + placebo (n=284) 64 64 52/48 43/57 30/51/19 30/52/18 Locally advanced/metastatic (%) 24/76 25/75 Pain score 20/>20/unknown (%) 46/51/3 45/53/2 94 92 Median age (years) Female/male (%) PS 0/1/2 (%) Measurable disease (%) *Baseline characteristics of the 100mg cohort did not differ substantially from the whole population Moore M, et al. J Clin Oncol 2007;25:1960–6 Data on file, OSI Pharmaceuticals Inc. PA.3: OS in the total population* (ITT) Survival probability (%) 100 80 Median survival (months) 1-year survival Gemcitabine + erlotinib 6.24 23 Gemcitabine + placebo 5.91 17 60 p=0.038 HR=0.82 (95% CI: 0.69–0.99) 40 20 0 0 6 *Includes patients with locally advanced and metastatic disease at both 100mg/day and 150mg/day doses of erlotinib ITT = intent to treat; HR = hazard ratio; CI = confidence interval 12 Months 18 24 Moore M, et al. J Clin Oncol 2007;25:1960–6 PA.3: overall survival in the 100mg cohort Median survival 1-year (months) survival Survival probability (%) 100 80 Gemcitabine + erlotinib (n=261) 6.4 23.8 Gemcitabine + placebo (n=260) 6.0 19.4 p<0.028 HR=0.81 (95% CI: 0.68–0.97) 60 40 20 0 0 6 12 Months 18 24 Moore M, et al. J Clin Oncol 2007;25:1960–6 PA.3: PFS in the 100mg cohort Erlotinib + gemcitabine (n=261) Placebo + gemcitabine (n=260) Survival probability (%) 100 75 p=0.006 HR=0.76* (95% CI: 0.64–0.92) 50 30% increase in PFS 25 0 0 *HR adjusted for PS and extent of disease at baseline 6 12 Months 18 24 Data on file, OSI Pharmaceuticals Inc. PA.3: all subgroups benefit from treatment with erlotinib plus gemcitabine Factors n HR 95% CI Erlotinib: placebo* 521 0.81 0.7–1.0 PS 0–1 PS 2 432 89 0.87 0.70 0.7–1.1 0.5–1.1 Locally advanced Distant metastases 124 397 0.93 0.80 0.6–1.3 0.7–1.0 Pain intensity 20 Pain intensity >20 238 268 0.72 1.00 0.6–0.9 0.8–1.3 EGFR positive EGFR negative EGFR unmeasured 70 66 385 0.82 0.75 0.86 0.5–1.3 0.5–1.2 0.7–1.1 Male Female 273 240 0.74 1.00 0.6–0.9 0.8–1.3 Age <65 years Age 65 years 274 247 0.78 0.94 0.6–1.0 0.7–1.2 Caucasian Black Asian Prior radiosensitising chemotherapy** No prior radiosensitising chemotherapy** 456 13 34 0.88 0.67 0.61 0.7–1.1 0.2–2.2 0.3–1.3 42 0.62 0.3–1.2 479 0.86 0.7–1.0 *Stratified by PS and extent of disease **No prior chemotherapy allowed, other than as a radiosensitiser 0 0.50 1.00 HR 1.50 2.00 2.50 Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):s1 (Abstract 1) Genentech: Tarceva® full prescribing information Importance of stable disease Median duration of SD >5 months Gemcitabine + erlotinib SD Gemcitabine + placebo SD 0 10 20 CR/PR CR/PR 30 40 50 Patients (%) Disease control rate (CR + PR + SD): gemcitabine plus erlotinib 59%; gemcitabine plus placebo 49.4%; p=0.036 CR = complete response PR = partial response; SD = stable disease 60 Data on file, OSI Pharmaceuticals Inc. Acceptable safety profile with addition of erlotinib: no synergistic toxicities Grade 3/4 AEs 20 Gemcitabine + erlotinib Gemcitabine + placebo Patients (%) 15 10 5 0 Rash Diarrhoea Infections Weight loss Serious adverse drug reactions are infrequent AE = adverse event Tarceva® Summary of Product Characteristics Significance of PA.3 First randomised trial to show significantly prolonged survival with any regimen versus single-agent gemcitabine in advanced pancreatic cancer – first demonstration of OS benefit with EGFR inhibitor in combination with chemotherapy Results led to – FDA approval of the combination in patients with locally advanced and metastatic pancreatic cancer – EMEA approval of the combination in patients with metastatic pancreatic cancer EGFR = epidermal growth factor receptor FDA = Food and Drug Administration; EMEA = European Medicines Agency Erlotinib in the routine clinical setting: a case study Case study: patient history 20-year-old university student History of abdominal pain for 6 months and gradually increasing abdominal distension Felt a lump in upper abdomen Past medical health was good but there was a strong family history of cancer CT scan was performed in December 2005 CT = computerised tomography Case study: imaging at baseline Liver biopsy found well-differentiated adenocarcinoma of pancreatic or biliary tract origin Case study: initial treatment Patient commenced treatment with gemcitabine plus erlotinib 100mg/day Two days after starting erlotinib, the patient developed pustular rash that increased in intensity – stopped erlotinib and came to clinic On examination, confirmed as grade 3 rash Erlotinib-related rash: NCI-CTC grade 3 Definition Severe, generalised erythroderma (generalised reddening and scaling of skin) Macular, papular or vesicular eruption (small fluid-filled blisters) Desquamation covering >50% of BSA – OR <50% of BSA, but very symptomatic with vesicular eruption NCI-CTC = National Cancer Institute-Common Toxicity Criteria; BSA = body surface area Management recommendations for symptomatic rash Mild No treatment OR Moderate Severe Hydrocortisone 2.5% cream AND OR Hydrocortisone 1% or 2.5% cream AND/OR Clindamycin 1% gel Treat as moderate Clindamycin 1% gel Systemic steroids† AND OR Pimecrolimus 1% cream Consider dose interruption AND Synthetic tetracycline* 2-weekly assessments *Doxycycline or minocycline 100mg b.i.d. †Prednisone, methylprednisolone 30mg once daily (tapered over 30 days) b.i.d. = twice daily Lynch TJ, et al. Oncologist 2007;12:610–21 Case study: rash management Erlotinib stopped for 1 week while rash treated with oral minocycline and topical steroids Restarted erlotinib at 100mg/day Grade 3 rash recurred by week 7 at which point erlotinib was temporarily halted, then restarted at a reduced dose of 50mg/day Case study: continuing status Repeat CT scan after 8 weeks showed stable pancreatic mass and reduction in liver metastases Patient continued on gemcitabine plus 50mg/day erlotinib After 6 months of treatment, the patient had chronic grade 1 rash and diarrhoea – CT scan showed further improvement in liver lesions Case study: imaging at 6 months Case study: current status September 2006: patient underwent resection of pancreatic tail mass and liver lesions – confirmed well-differentiated cystic adenocarcinoma Patient remained well until May 2007 when two new liver lesions were observed – treated with radiofrequency ablation December 2007 – three new liver lesions observed – restarted gemcitabine plus erlotinib Future developments Identifying patients most likely to benefit from gemcitabine plus erlotinib Prior to treatment – molecular markers – demographic/clinical characteristics (e.g. age, gender, histology, PS) During treatment – RR; disease control rate – other surrogate markers (e.g. presence of rash) PA.3: significant improvement in OS in PS 2 patients Survival probability (%) 100 Gemcitabine + erlotinib (n=53) Median: 4.16 months 95% CI: (4.37–6.34) Gemcitabine + placebo (n=52) Median: 3.20 months 95% CI: (2.63–4.11) 80 60 p≤0.001 HR=0.47 (95% CI: 0.31–0.71) 40 20 0 0 6 12 Months 18 24 Data on file, OSI Pharmaceuticals Inc. PA.3: skin rash associated with erlotinib 72% of patients developed skin rash Significantly higher likelihood of skin rash in – patients younger than 65 years (p=0.01) – patients with a good PS (p=0.03) Presence of rash was associated with – higher rate of disease control (p=0.05) – longer survival (HR=0.74, p=0.037) Generally develops within 7–10 days of starting therapy and may spontaneously resolve and reappear No correlation with duration of therapy Reversible following drug discontinuation PA.3: degree of rash correlates with OS (100mg cohort) Survival probability (%) 100 Grade 0 Grade 1 Grade 2 (n=79) (n=108) (n=103) Median survival (months) 80 5.29 5.75 10.51 16 11 43 1-year survival (%) 60 40 Grade 0 Grade 1 Grade 2 20 p<0.0001, HR=0.71 0 0 5 10 Months 15 20 Data on file, OSI Pharmaceuticals Inc. PA.3: observed skin rash Potential reasons – variability of drug absorption – variability of metabolism – ability of rash to predict a more immunocompetent individual – pharmacogenomic basis Further study in this area is necessary to understand the value of rash in predicting survival in individual patients – some patients with no rash do obtain clinical benefit from erlotinib – some patients who develop grade 2 rash had grade 1 rash initially Phase II trial: assessing potential predictive markers and dose escalation according to skin reactions Advanced pancreatic cancer: gemcitabine + erlotinib 100mg (n~400) No rash or grade 1 rash 4 weeks Grade 2 rash Gemcitabine + erlotinib dose escalation to grade 2 rash or DLT PD Gemcitabine + erlotinib 100mg PD Gemcitabine + erlotinib 100mg PD Primary endpoint: OS Mandatory tissue collection for biomarker testing Secondary endpoints: PFS, disease control, safety, correlation of EGFR-related biomarkers with outcome (EGFR, EGF, TGF-α, KRAS, pAkt, pMAPK) DLT = dose-limiting toxicity; PD = progressive disease EGFR: a predictive factor? In NSCLC, EGFR IHC and EGFR FISH status have not yet been demonstrated to correlate with benefit from EGFR inhibitors in a prospective, randomised trial In NSCLC, activating mutations of EGFR (exons 18–21) may be correlated with increased benefit from EGFR TKIs such as gefitinib or erlotinib These appear to be the most promising candidate biomarkers for EGFR-targeted therapy, e.g. erlotinib HOWEVER, incidence of activating mutations in pancreatic cancer = 1.5% Results from one tumour type can not be extrapolated to another tumour type NSCLC = non-small cell lung cancer; IHC = immunohistochemistry FISH = fluorescence in-situ hybridisation; TKIs = tyrosine-kinase inhibitors PA.3: survival by EGFR IHC status (100mg cohort) EGFR IHC+ (n=70) 1.00 Erlotinib (n=34) Placebo (n=32) 0.75 HR=0.75 0.50 95% CI: 0.46–1.23 (p=NS) 0.25 0 Survival probability Survival probability EGFR IHC– (n=66) 1.00 Erlotinib (n=41) Placebo (n=29) 0.75 HR=0.82 0.50 95% CI: 0.50–1.32 (p=NS) 0.25 0 0 6 12 Months 18 24 0 6 12 18 24 Months Data on file, OSI Pharmaceuticals Inc. PA.3: implications of EGFR gene copy number for survival EGFR FISH+ (n=50) EGFR FISH– (n=57) HR p value Number of partial responses 5/48 4/53 1.36 0.68 Median OS (months) 5.3 7.8 1.24 0.32 Median PFS (months) 3.6 4.2 1.85 0.004 N.B. results are irrespective of treatment received Gemcitabine Gemcitabine + erlotinib + placebo HR HR + p value for p value interaction Survival (months) EGFR FISH+ 5.2 5.2 0.90 0.73 EGFR FISH– 8.4 6.7 0.60 0.08 1.41 (p=0.31) Moore M, et al. J Clin Oncol 2007(Suppl. 18 Pt I):s203(Abstract 4521) KRAS: a predictive factor? KRAS point mutations in codon 12 KRAS mutations associated with resistance to cetuximab in CRC KRAS mutations associated with shorter survival in pancreatic cancer compared with wild-type KRAS CRC = colorectal cancer Lee J, et al. Cancer 2007;109:1561–9 PA.3: implications of KRAS mutations for survival KRAS mutant (n=92) KRAS WT (n=25) HR p value Number of partial responses 9/90 0/21 – 0.20 Median OS (months) 6.7 5.4 0.63 0.37 Median PFS (months) 3.8 3.7 0.86 0.53 N.B. results are irrespective of treatment received Gemcitabine Gemcitabine + erlotinib + placebo HR HR + p value for p value interaction Survival (months) KRAS mutant 6.0 7.4 1.07 0.78 KRAS WT 6.1 4.5 0.66 0.34 WT = wild-type 1.71 (p=0.29) Moore M, et al. J Clin Oncol 2007(Suppl. 18 Pt I):s203:(Abstract 4521) Limitations of PA.3 biomarker data Data are from retrospective analyses and include only small numbers of patients – no data as yet from prospective, randomised study designed to investigate biomarkers for predicting clinical benefit with erlotinib plus gemcitabine – studies are planned but are in early stages No studies or guidelines to date suggest use of a specific biomarker to select patients to receive erlotinib plus gemcitabine Randomised phase II biomarker study Advanced pancreatic cancer failing previous chemotherapy or unsuitable for first-line chemotherapy PS 0–2, n=200 Erlotinib 150mg Placebo + BSC PD Subsequent treatment at investigators’ discretion PD Erlotinib 150mg or other active treatment Primary endpoint: PFS – biomarkers: EGFR IHC, EGFR FISH, EGF, TGF-α, amphiregulin, KRAS mutations, EGFR mutations, RANTES Secondary endpoints: response, disease control, OS, CA19-9, safety BSC = best supportive care Challenges of finding predictive biomarkers in pancreatic cancer Practical difficulties of tissue acquisition in pancreatic cancer – numbers of patients with samples often small Current status of translational research – EGFR FISH positivity (only in 5–10% of patients) – EGFR mutations (no activating mutations) – KRAS mutation status (90% tumours positive, simulations suggest benefit in PA.3 highly unlikely to be driven by wild-type carriers only) Recent analyses inconclusive – NCIC • EGFR FISH • KRAS False results have major implications – may deny patient access to life-extending treatment – patients may receive a therapy they are unlikely to benefit from Randomised phase III trial: adding bevacizumab to erlotinib plus gemcitabine Previously untreated metastatic pancreatic cancer (n=600) Erlotinib (100mg) + gemcitabine + bevacizumab (5mg/kg every 2 weeks) PD Standard regimen used in PA.3., i.e. erlotinib (100mg) + gemcitabine + placebo PD Primary endpoint of OS not met Secondary endpoints were met, however, demonstrating that the combination has some clinical activity Confirmed efficacy of gemcitabine plus elotininib control arm, in line with PA.3 Data will be presented at an upcoming congress in 2008 Bevacizumab plus gemcitabine plus erlotinib or cetuximab Previously untreated advanced pancreatic cancer (measurable disease), PS 0–2 Bevacizumab + gemcitabine + cetuximab R Bevacizumab + gemcitabine + erlotinib BGC (n=27) BGE (n=24) RR 19% 21% SD 59% 67% Median PFS (months) 3.6 3.6 6-month survival rate 41% 38% Preliminary results (n=51) Kindler HL, et al. J Clin Oncol 2006;24(Suppl. 18 Pt I):s188 (Abstract 4040) Randomised phase III trial: erlotinib plus concurrent/sequential gemcitabine/capecitabine Advanced pancreatic cancer Erlotinib + capecitabine PD Gemcitabine PD Erlotinib + gemcitabine PD Capecitabine PD R Primary endpoint = time to second progression n=132/250 PI: Prof V Heinemann (Germany) Erlotinib plus gemcitabine: conclusions Erlotinib plus gemcitabine = a new treatment option for patients with advanced pancreatic cancer Further research underway to establish if patients who will obtain greatest benefit from this regimen can be identified – also investigating relationship between rash and clinical benefit Erlotinib and gemcitabine now provides a backbone of therapy for pancreatic cancer – future trials will evaluate addition of other novel agents, e.g. bevacizumab, to further extend survival