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Hot Topics from the 10th World Conference on Lung Cancer “From Genome to Clinic”

Hot Topics from the 10th World Conference on Lung Cancer “From Genome to Clinic”. Janessa Laskin, MD FRCPC Medical Oncology. 3200 delegates from 77 countries Europe: 39% N. America: 36% Asia: 18%. Objectives. Adjuvant Therapy Locally Advanced Advanced NSCLC second line

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Hot Topics from the 10th World Conference on Lung Cancer “From Genome to Clinic”

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  1. Hot Topics from the 10th World Conference on Lung Cancer “From Genome to Clinic” Janessa Laskin, MD FRCPC Medical Oncology

  2. 3200 delegates from 77 countries • Europe: 39% • N. America: 36% • Asia: 18%

  3. Objectives • Adjuvant Therapy • Locally Advanced • Advanced NSCLC • second line • Molecular targeting • EGFR • BAC • Tools of the future

  4. Incidence Mortality Lung Cancer High Incidence, High Mortality American Cancer Society. Cancer Facts & Figures–1999.

  5. NCI Research $$ Spent Per Patient Death JNCI 2001

  6. Adjuvant Chemotherapy

  7. Meta-Analysis Adjuvant Cisplatin in NSCLCAnonymous. BMJ 311:899, 1995 100 90 • Hazard ratio= 0.87 • P= 0.08 80 70 60 Survival (%) 50 40 • Surgery + chemotherapy 30 • Surgery 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Months

  8. Adjuvant CT Adjuvant CT/RT Control Control - RT 1.0 1.0 0.8 0.8 0.6 0.6 Probability of Survival Probability of Survival 0.4 0.4 P=0.56 P=0.589 0.2 0.2 0.0 0.0 0 10 20 30 40 50 60 70 80 90 0 1 2 3 4 5 Time from Randomization (Mo) Time from Randomization (Yr) S. Keller et al. NEJM 343:1217, 2000 M. Tonato et al. PASCO 21:290a, 2002 Adjuvant CT in NSCLCE3590 & ALPI Survival G. Scagliotti et al. JNCI, Oct. 2003

  9. International Adjuvant Lung Cancer Trial - IALT: PL#3 • 1995 - 2000, with resected stage I - IIIA NSCLC • Randomized to: observation or cisplatin-based chemotherapy • Each center determined cisplatin dose (total 300 - 400 mg/m2), combination agent (etoposide or vinca alkaloid) and radiation therapy • Powered to detect 5% benefit (50 to 55%) • Planned 3300 but closed early : 1867 patients

  10. R A N O M I Z E • No chemotherapy • Eligibility: • pStage I-III NSCLC • Age: 18-75 yr • No prior malignancy • Informed consent • Chemotherapy* IALT Trial DesignOpen Design Phase III * PE: 56%; PVin: 27%; PVlb: 11%; PVnd: 6%

  11. IALT – LeChevalier et al • Patient characteristics • Median age - 59 yrs • Males - 80% • Histology - SqCC - 47%, AdenoCa - 40% • Surgery - • lobectomy - 64% • pneumonectomy - 35% • Stages: 37% (pI); 25% (pII); 39% (pIII)

  12. IALT – LeChevalier et al • Chemotherapy combined with cisplatin (N=935) • 92% compliance in chemotherapy arm • 74% received > 240 mg/m2 cumulative doses of cisplatin • Chemo associated lethal toxicity: 0.8% (7 pts) • Thoracic RT planned in 30%: • 71% compliance in chemo arm • 85% compliance in observation arm

  13. IALT – LeChevalier et al • Median f/u of 56 months ChemoObservation Med survival:50.8m 44.4m 2-year OS: 70% 67% 5-year OS: 45% 40% • HR = 0.86; p < 0.03 • Would prevent 7000 deaths annually worldwide

  14. Overall Survival 775 181 932 450 308 624 At risk 935 602 432 286 164 774 Chemotherapy Control Years

  15. Adjuvant CMF in Breast CancerG. Bonadonna et al. NEJM 332:901, 1995 100 Status: 5-Yr: Node -ve: 3-4% 80 Node +ve: 2-7% 60 Probability of Survival 40 CMF 20 Control 0 0 5 10 15 20 Years After Mastectomy

  16. 100 100 P<0.03 P=0.08 80 80 60 60 % Survival % Survival 40 40 Surgery + CT Surgery + CT 20 20 Surgery only Surgery only 0 0 0 1 2 3 4 5 Years Years 0 1 2 3 4 5 IALT Survival Results Meta-analysis Survival Results IALT and Meta-analysis Survival Data

  17. Adjuvant Therapy Why are the results different from ECOG & ALPI? • Different study populations? • European trials; more men and more squamous • Differences in the chemotherapy delivered? • IALT more compliant with chemo (74% vs. 69%) • Trial design? • Maybe PORT is harmful?? (MA - Lancet, 1998) • Statistics – ECOG and ALPI powered for 40% and 20% survival advantage (vs. 5%)

  18. Adjuvant Summary • BMJ meta-analysis & IALT trial positive with similar results • Unlikely to conduct another chemotherapy versus no chemotherapy trial • BR 19: gefitinib vs placebo (+/- chemo) • Platinum-based doublet (80-100mg/m2) • Choose pts carefully but ….many unanswered questions

  19. Locally Advanced NSCLC Role of Surgery?

  20. Lung Intergroup Trial 0139Albain, et al. PL#4 • Locally advanced – IIIA • Chemo/RT was standard of care: is there a benefit to adding surgery? • PS 0,1 • T 1-3 and pathN2 • 1994 – 2001 • Closed early because of poor accrual but had sufficient events

  21. Lung Intergroup Trial 0139 Study Design if no PD R A N D O M I Z E Cis/VP16 x 2 cycles w/concurrent XRT 45Gy Surgery Cis/VP16 x 2 cycles Stage IIIA NSCLC N = 429 if no PD Cis/VP16 x 2 cycles w/concurrent XRT 61Gy Cis/VP16 x 2 cycles

  22. Lung Intergroup Trial 0139 Treatment Delivered Treatment CT/RT/S CT/RT p-value Induction CT 96% 95% NS according to protocol Consolidation 42% 21% p<0.0001 CT not received RT delivered 97% 81% p=.002 per protocol

  23. Treatment related toxicities • Grade 3/4 Esophagitis: 9% versus 20%, p= 0.001 Treatment related deaths: Induction: none in either arm CT/RT arm (during or after consol): 3 (1.6%) CT/RT/S arm: Total 14 (7%) Post-op CT 10 (5%) Misc 4 (2%)

  24. Further 9 months of follow-up: 71 months

  25. INT 0139 CT/RT +/- Surgery • No difference in patterns of failure • PFS • 14.0 versus 11.7 months, p = 0.03 • @ 3-year - 29% versus 19% • Survival • MST - 22.1 versus 21.7 months, p= 0.51 • @ 3-year - 38% versus 33% • Path N-0 CR (36%): 3-y survival of 50%

  26. INT 0139 CT/RT +/- Surgery • More patients are alive without PD on Surgery Arm (p=0.004) • But more died without PD on Surgery Arm (p=0.007) • Surgery had some toxicities • 8 deaths from respiratory/ARDS • R pneumonectomy worst outcome

  27. Advanced NSCLC Second-line therapy

  28. NSCLC Second-line TherapyShepherd et al; PL#5 • Docetaxel FDA approved for second-line treatment (Shepherd, JCO 2000) • Pemetrexed (Alimta) vs. docetaxel • N = 571 Toxicities DocetaxelPemetrexed Gr 3 / 4 ANC 40.2% 5.3% Febrile neut 12.7% 1.9% GCSF 19.2% 2.6% Hospitalizations 13.4% 1.5% 192 days 29 days

  29. NSCLC Second-line Therapy DocetaxelPemetrexed Med OS 7.9m 8.3m 1-y OS 29.7% 29.7% • Similar to median OS for Shepherd (7.5 months) • Option for second-line therapy

  30. Molecular Biology

  31. Molecular Biology • Epidermal growth factor receptor (EGFR) • Tyrosine kinase inhibitors • Monoclonal antibodies • Vascular endothelial growth factor (VEGF) • Anti-sense oligonucleotides • Protein kinase inhibitors

  32. EGF TGF- EGFR Cell Membrane TK TK P P PI3 kinase Ras/Raf STATs PTEN Akt P MAPK/ERK Apoptosis Proliferation Invasion & metastasis Angiogenesis Nucleus

  33. EGFR & HER2 in NSCLCF. Hirsch et al. Semin Oncol 29(s4):51,2002

  34. Relationship of HER1 & HER2 to Survival in NSCLC HER1 & HER2 in NSCLCJ. Brabender et al. Clin Cancer Res 7:1850,2001

  35. Issues with EGFR • Differing measures of EGFR – problems with comparisons across studies • EGFR +ve required for entry into study? • Is over-expression related to response? • Analogous to HER2 and Herceptin • Difference within sub-types? • Phase I and II studies adenocarcinoma and BAC appear to respond preferentially

  36. Using molecular biology to improve therapeutic strategies

  37. C225 ABX-EGF EMD 72000 EGFR Gefitinib Erlotinib CI 1033 Cell Membrane TK TK P P PI3 kinase Ras/Raf STATs PTEN Akt P MAPK/ERK Apoptosis Proliferation Invasion & metastasis Angiogenesis Nucleus

  38. EGFR expression and response • Is over-expression or any degree of EGFR necessary for a response? • Pre-clinical evidence (Arteaga et al: level of EGFR has no effect on response) • Natale et al (Abst #244) • 31 pts with NSCLC treated with gefitinib (single agent) • 7 had PR and 6 had SD • RNA extracted (17 pts); quantitive gene expression via RT-PCR • a gene possibly related to gefitinib resistance was identified

  39. EGFR expression and response • Perez-Soler (abst # 247) • theory: repeated exposure to chemotherapy may cause increased dependence on EGFR • cell lines demonstrated minimal cross resistance between chemotherapy and erlotinib • cells resistnat to erlotinib had down-regulated EGFR • EGFR levels were elevated in chemo-resistant cell lines

  40. EGFR expression and response • Bailey (abst #242) • 157 pts from IDEAL 1 and 2 trials • 26 (17%) had OR • 96 / 35 were adeno or squamous respectively • 1 /2 />3 prior chemos : 39/ 78/ 40 • IHC assay of EGFR (blinded; scored 0 - +3) Results: • 15% (5/35) with OR had NO EGFR detectable • no consistent correlation between EGFR intensity and OR

  41. Phase II Trial of Erlotinib (Tarceva) in BACPatel,Miller, et. al. #188 • EGFR -TKI • June 2002 - Feb 2003 • 86 patients with suspected BAC • path review: 56 patients had BAC or a variant • 44 patients received treatment to date • Adeno with BAC features- 29 • Pure BAC -11 • BAC with focal invasion - 4

  42. Erlotinib in BAC • Patient characteristics (N = 42) • Female - 28 • KPS: 100 - 1, 90 - 11, 80 - 25, 70 - 5 • Prior chemotherapy - None - 32, 1 - 10 • Smoking history - Never - 11, Former/Current - 31, • Responses seen in 9 of 42 patients (21%) • longest duration 7.2 months

  43. Erlotinib in BACCharacteristics of Responders

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