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Dec 16th 2004

Tandem molecolare diagnostico-terapeuticoin oncologia: attualità e futuro del terzo millennio Roma, 16-18 dicembre 2004 Direttori del Corso: Fr. Grignani, S. Iacobelli, A.M. Liberati. Successi e insuccessi di IRESSA: dal non microcitoma polmonare al carcinoma della mammella V. Lorusso, Bari.

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Dec 16th 2004

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  1. Tandem molecolare diagnostico-terapeuticoin oncologia: attualità e futuro del terzo millennioRoma, 16-18 dicembre 2004Direttori del Corso: Fr. Grignani, S. Iacobelli, A.M. Liberati Successi e insuccessi di IRESSA: dal non microcitoma polmonare al carcinoma della mammellaV. Lorusso, Bari Dec 16th 2004

  2. The epidermal growth factor receptor (EGFR) signalling pathway and the mechanism of action of gefitinib

  3. The epidermal growth factor receptor(EGFR; erbB) family and its ligands EGF, TGF Amphiregulin -cellulin HB-EGF Epiregulin No specific ligands - often acts as dimer partner NRG2 NRG3 Heregulins -cellulin Heregulins Cysteine-rich domains R R R R Extracellular Membrane Intracellular Tyrosine kinase domain K K K K C-terminus erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4

  4. Survival(anti-apoptosis) Proliferation /maturation Metastasis Chemotherapy / radiotherapy / hormonal resistance Angiogenesis Activation of the EGFR: a pivotal driver of malignancy Ligand EGFR EGFR-TK GRB2 pY SOS PI3-K pY pY RAS RAF STAT3 Akt PTEN MEK Gene transcription Cell-cycle progression MAPK P P Cyclin D1 DNA Myc JunFos Cyclin D1 Myc

  5. gefitinib • gefitinib is an orally active EGFR tyrosine kinase inhibitor (TKI) • gefitinib is the first approved EGFR-TKI for the treatment of advanced NSCLC • The mechanism of action of gefitinib is distinct from cytotoxic chemotherapy

  6. EGFR inhibition by gefitinib Ligand EGFR EGFR-TK EGFR-TKI Inhibition of apoptosis Proliferation Invasion Metastasis Angiogenesis

  7. Pharmacokinetics of gefitinib • gefitinib is given as a once-daily tablet • peak plasma concentration within 3-7 h • terminal half-life 24-85 h in cancer patients • steady-state concentrations were achieved within 7-10 days of daily dosing in cancer patients • The large volume of distribution in cancer patients indicates extensive distribution into tissue Swaisland et al 2001; Kelly et al 2000; McKillop et al 2003

  8. gefitinib targets tumours effectively in a mouse xenograft model Group Dosea Time after dosing (h) Tumour:plasma ratio 1 1 2 2 50 mg/kg single 50 mg/kg single 50 mg/kg multiple 50 mg/kg multiple 2 8 2 8 4:1 10:1 4:1 11:1 aOrally, either as a single dose or as four daily doses Tumour levels of gefitinib are significantly higher than plasma concentrations McKillop et al 2003

  9. Autoradiogram of section through an athymic mouse 4 h following oral dosing Tumour (LoVo xenograft) Skin Brown fat Spinal cord Bone marrow Blood Increasing levels of gefitinib McKillop et al 2003

  10. gefitinib tumour and plasma levels in patients with breast cancer • Tumour and plasma samples were taken from 19 women with breast cancer participating in an gefitinib presurgical study (BCIRG 103) • All patients received >14 doses of gefitinib • gefitinib concentrations were substantially greater (42-fold) in tumour samples than in plasma gefitinib in not approved in breast cancer

  11. Lung cancer

  12. Lung cancer • Lung cancer is the leading cause of cancer death,with approximately 1.1 million deaths/year worldwide • ~80% of lung cancers are of the non-small-cell histology • the majority of patients have locally advanced or metastatic disease • chemotherapy is the mainstay of treatment • Symptoms of advanced disease are often severe, debilitating and difficult to manage • Median survival, from the start of the last chemotherapy treatment, is short for patients with advanced lung cancer (4 months) Ferlay et al 2000; Cersosimo 2002; Massarelli et al 2003

  13. NSCLC response rates decrease with subsequent regimens of chemotherapy Objective response rate (%) 20.9 16.3 2.3 2.3 0.0 Line of therapy Massarelli et al 2003

  14. 3rd- and 4th-line chemotherapy is of limited benefit in NSCLC 1.0 Survivalprobability Median survival 4 months1-year survival 5.5% 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 24 12 18 Months after start of 3rd- or 4th-line therapy n=43 Massarelli et al 2003

  15. gefitinib Phase II data (250 mg/day):Efficacy

  16. Primary end points Randomisation • Objective tumour response • Symptom improvement (IDEAL 2) • Safety (IDEAL 1) • IDEAL 1 (n=209)1 or 2 prior regimens • IDEAL 2 (n=216)>2 prior regimens Continue gefitinib until diseaseprogression or unacceptable toxicity IDEAL 1 and 2 trial design gefitinib 250 mg/day gefitinib500 mg/day IDEAL, Iressa Dose Evaluation in Advanced Lung cancer Fukuoka et al 2003; Kris et al 2003

  17. Tumour response and disease control rates Patients(%) 60 Objective response 54.4 Disease control 50 42.2 40 30 18.4 20 11.8 10 0 IDEAL 1 IDEAL 2 Objective response, complete plus partial responseDisease control, objective response plus stable disease Fukuoka et al 2003;Kris et al 2003

  18. IDEAL 1 and 2: objective responses by thenumber of prior chemotherapy regimens Patients(%) IDEAL 1 IDEAL 2 Line of therapy Fukuoka et al 2003; Kris et al 2003

  19. IDEAL 1 and 2: survival • ~30% of patients are alive 1 year after starting therapy with gefitinib • Median survival in IDEAL 1 and 2 was 7.6 months (95% confidence interval [CI]: 5.3, 10.1) and 7.0 months (95% CI: 4.8, 8.0), respectively • Median progression-free survival in IDEAL 1 and 2 was 2.7 months (95% CI: 2.0, 2.8) and 1.9 months (95% CI: 1.8, 2.8), respectively Fukuoka et al 2003; Kris et al 2003

  20. STUDY IDEAL 1 (2nd or 3rd line CT) IDEAL2 (3rd or more line CT) ARMS Iressa 250 mg/d Iressa 500 mg/d Iressa250 mg/d Iressa500 mg/d No pts 103 106 102 114 RR % 18.4 % 19.0 % 11.8 % 8.8 % MS mos 7.6 8.1 6.5 5.9 IDEAL 1 & 2: results IDEAL 1: overall survival IDEAL 2: overall survival 1.0 Proportion 1.0 Proportion event free event free 0.8 0.8 250 mg/day 250 mg/day 0.6 500 mg/day 500 mg/day 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 16 18 Months from randomisation Months from randomisation

  21. 1-year survival rates with gefitinib and 3rd-/4th-line chemotherapy* 1-year survival* (%) (n=103) (n=21,064) (n=102) (n=43) IDEAL 1(2nd-/3rd-line) IDEAL 2(3rd-line +) gefitinibExpanded AccessProgramme(2nd-/3rd-line +) Chemotherapy (3rd-/4th-line; retrospective analysis) Ochs et al 2004; Fukuoka et al 2003;Kris et al 2003; Massarelli et al 2003 *Indirect comparison

  22. Social wellbeing Physicalwellbeing FACT-L Emotional wellbeing Functionalwellbeing Symptoms 7-item LCS • Shortness of breath • Cough • Tightness in chest • Difficulty breathing • Weight loss • Lack of clear thinking • Loss of appetite Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Subscale (LCS) Cella et al 2002

  23. IDEAL 1 and 2: symptom improvement IDEAL 1 (67 symptomatic at entry) Patients (%) IDEAL 2 (all 102 symptomatic at entry) Improved No change Worsened Other* Disease-related symptoms Fukuoka et al 2003; Kris et al 2003; AstraZeneca data on file *Missing or incomplete data

  24. IDEAL 1 and 2: rapid and durablesymptom improvement • Symptom improvement occurred rapidly; median time to symptom improvement was 8 days in IDEAL 1 and 10 days in IDEAL 2 • Moreover, symptom improvement was durable, with the median duration being >6 months in both studies

  25. IDEAL 1 and 2: tumour response andsymptom improvement 100 Symptom improvement rate (%) 100 IDEAL 1* 81 IDEAL 2 80 70 69 60 40 20 12 12 0 n: 13 12 20 31 34 59 Partial response Stable disease Progressive disease *Not all patients were symptomatic at entry in IDEAL 1 Fukuoka et al 2003; Kris et al 2003

  26. IDEAL 1 and 2: overall survival bysymptom improvement Probability IDEAL 1 IDEAL 2 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 0 4 8 12 16 20 Months from randomisation Months from randomisation Patients(n) Deaths(n) Median (months) Patients (n) Deaths(n) Median (months) Improvement No improvement 27 40 18 30 13.3 3.5 44 58 26 56 13.6 3.7 Douillard et al 2002

  27. Summary of efficacy Life-enhancing benefit • ~50% of patients achieve clinical benefit with gefitinib Survival • ~30% of patients are alive 1 year after starting treatment with gefitinib Symptom improvement • Over 40% of symptomatic patients experienced improvement in theirdisease-related symptoms Objective response and symptom improvement • The majority of patients with objective response or disease stabilisation also had an improvement in disease-related symptoms

  28. gefitinib Phase II data (250 mg/day):Safety

  29. IDEAL 1 and 2: adverse drug reactions(ADRs) in >10% of patients Patients(%) Acne Rash Pruritus Nausea Dry skin Vomiting Diarrhoea AST increased ALT increased No grade 4 ADRs in IDEAL 1 ALT, alanine aminotransferase; AST, aspartate aminotransferase Fukuoka et al 2003; Herbst et al 2002; Schiller et al 2002; Kris et al 2003

  30. IDEAL 1 and 2: grade 3/4 ADRs compared with tumour response Patients (%) 54 42 36 30 Stable disease 9 7 18 12 Objective response IDEAL 1 IDEAL 2 IDEAL 1 IDEAL 2 Grade 3/4 ADRS Tumour response Fukuoka et al 2003; Kris et al 2003

  31. Summary of safety Generally mild ADRs • Most common ADRs (rash and diarrhoea) are generally mild (grade 1 and 2) • gefitinib is not associated with adverse events typically seen with conventional chemotherapy agents, including myelosuppression and neuropathy • At 250 mg/day, <2% of patients withdrew from the IDEAL trials due to ADRs • <10% patients experience grade 3/4 ADRs Favourable safety profile Few withdraw due to ADRs Low incidence of grade3/4 ADRs Fukuoka et al 2003; Kris et al 2003

  32. INTACT 1 & 2: schema Chemotherapy* x 6 cycles + 250 mg ZD1839 Continue ZD1839 or placebo until disease progression Chemotherapy* x 6 cycles Randomize + 500 mg ZD1839 Chemotherapy* x 6 cycles + placebo * Gemcitabine/cisplatin or paclitaxel/carboplatin

  33. STUDY INTACT 1 INTACT 2 ARMS GP+ ZD 1839 500 mg/d GP+ ZD 1839 250 mg/d GP+ Placebo TC+ ZD 1839 500 mg/d TC+ ZD 1839 250 mg/d TC+ Placebo No pts 365 365 363 347 345 345 III/IV % 33/67 28/72 31/69 18/82 16/82 21/78 PS % 0-1/2 90/10 90/10 90/10 87/13 90/10 90/10 ORR % 50 50 45 32 35 33.5 TTP mos 5.5 5.8 5.9 4.6 5.3 5.0 INTACT 1&2: results

  34. GEM-CIS+ Placebo TAX-CB+ Placebo STUDY INTACT 1 INTACT 2 ARMS GP+ ZD1839 500 mg/d GP+ ZD1839 250 mg/d GP+ Placebo TC+ ZD1839 500 mg/d TC+ ZD1839 250 mg/d TC+ Placebo No pts 365 365 363 347 345 345 MST mos 9.9 9.8 11 8.7 9.8 9.9 1- YS % 43 41 45 37 41 42 INTACT 1 & 2: SURVIVAL

  35. Why Intact Studies Failed ? • Lack of “patient selection” • Chemotherapy and gefitinib “ target” the same of cancer cells • Gefitinib is more effective in previously treated NSCLC • Negative interaction pharmacodynamic between drugs • Gefitinib is more different tnan any other “ third “ drug • Another explanation for the failure of Intact Trials: Molecular heterogeneity ( Betensky RA et al JCO 2003) Gene and protein expression profiling (Ramaswamy S. et al Nat Genet 2003) (Van’t Veer VJ. Et al Nat 2002) (Petricoin EF. Et al Lancet 2002)

  36. Exploring predictivemarkers

  37. Exploring predictive markers • Sex • Non smokers • Brochiolo-alveolar histology • Asian race

  38. EGFR-TK mutations and response to gefitinib (1) • Over 30 somatic mutations in the EGFR-TK domain (exons 18-24) have been observed in primary tumour biopsies from patients with NSCLC • Lynch et al found that 8/9 (89%) of patients with striking responses to gefitinib (>50% tumour shrinkage) had primary tumours with EGFR-TK mutations • Paez et al noted that: • the frequency of EGFR-TK mutations in primary NSCLC samples from patients who had not been exposed to gefitinib correlated with previously identified clinical factors associated with response to gefitinib (female gender, adenocarcinoma histology, Japanese ethnicity) • 5/5 patients who responded to gefitinib had EGFR-TK mutations Lynch et al 2004; Paez et al 2004

  39. EGFR-TK mutations and response to gefitinib (2) • Mutation data were also presented at ASCO 2004 • Franklin et al noted a high frequency of EGFR-TK mutations in bronchioalveolar carcinoma tumour biopsies • Jänne et al analysed 47 TKs for mutations using 242 lung cancer biopsies • mutations were only found in the EGFR-TK • in women with adenocarcinoma, a higher mutation frequency was seen in non-smokers compared with smokers: 54% vs 11% (p=0.0027) • in patients treated with gefitinib, 7 with response all had mutations and 6 with progressive disease did not have mutations Franklin et al 2004; Jänne 2004

  40. Mutation of the EGFR tyrosine kinase in human NSCLC (Paez J., Janne, PA., Lee J.C., et al, Science, April 29th 2004) • Mutation appears almost exclusively in NSCLC • Mutation is activating, in ATP-binding site • Mutation renders tumours dependent on EGFR-drive • Mutant kinase is 6-fold more sensitive to inhibition by gefitinib • Frequency of mutation approx. 12% in Caucasian, 26% in Japanese population • Mutation explains dramatic responses, but not all of clinical benefits of gefitinib in NSCLC

  41. EGFR Mutations in Patients Responding to gefitinib Treatment

  42. Response According to P-Akt/P-MAPK Status Cappuzzo JNCI 2004,

  43. Survival(anti-apoptosis) Proliferation /maturation Metastasis Chemotherapy / radiotherapy / hormonal resistance Angiogenesis Activation of the EGFR: a pivotal driver of malignancy Ligand EGFR EGFR-TK GRB2 pY SOS PI3-K pY pY RAS RAF STAT3 Akt PTEN MEK Gene transcription Cell-cycle progression MAPK P P Cyclin D1 DNA Myc JunFos Cyclin D1 Myc

  44. Response According to P-Akt/P-MAPK Status Cappuzzo JNCI 2004,

  45. Is skin rash a response indicator? • The development of early-onset skin toxicity in patients who survived >28 days was analysed retrospectively • 67% of patients who ultimately responded did not have skin toxicity by Day 24 • 25% of patients who ultimately responded did not have skin toxicity by Day 28 • There was no statistically significant difference in the objective response rate between those with or without early-onset skin toxicity Fukuoka et al 2003

  46. Summary of predictive markers • Mutations in the EGFR-TK domain are seen in patients who have a striking response to gefitinib. However, responses to gefitinib may also be observed in patients who lack EGFR-TK mutations • The role of EGFR-TK mutation status in patients with stable disease or symptom improvement is unclear • Further translation research is underway to explore the clinical significance of these somatic mutations and of the p-Akt status as a predictor of response • Early development of skin rash does not predict for response to gefitinib

  47. Ongoing and planned trials in NSCLC • Randomised 2nd- or 3rd-line Phase II/III trials comparing: • gefitinib plus BSC vs BSC alone (ISEL and IBREESE trials) • gefitinib with docetaxel (SIGN and INTEREST trials) • Trials in chemonaive patients comparing: • gefitinib plus BSC vs BSC in patients with poor performance status (Trial 0711) • gefitinib with vinorelbine in elderly patients (INVITE trial) • gefitinib as maintenance therapy vs placebo (EORTC 08021 - ILCP [van Meerbeeck/Scagliotti], SWOG 0023 trials) • Adjuvant gefitinib (BR19 trial) • gefitinib and radiotherapy, +/- chemotherapy (CALGB trial)

  48. Experience with gefitinib (IRESSA) in breast cancer

  49. Addition of trastuzumab significantly improves overall survival (ITT analysis) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Estimatedsurvivalprobability Trastuzumab + chemotherapy Chemotherapy alone 20.3 25.4 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 p=0.025 Time (months) ITT, intent to treat

  50. Properties of gefitinib • Chemical class: quinazoline • Orally available • EGFR-TKI • EGFR IC50 = 0.023 µM • erbB2 IC50 = 1.2-3.7 µM • Competitive inhibitor of ATP • Inhibits ligand-induced cell growth • IC50 = 0.080 µM • Inhibits the growth of breast cancer cell lines expressing EGFR and erbB2 Ligand Ligand R R û û Gefitinib Gefitinib K K EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor

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