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ADVANCES FOR TREATMENT OF LUNG CANCER

ADVANCES FOR TREATMENT OF LUNG CANCER. ASCO 2004, NOLA Jennifer Garst, M. D. Assistant Professor of Medicine Thoracic Oncology Program Duke University Medical Center. ADVANCES FOR TREATMENT OF LUNG CANCER. ASCO 2004, NOLA Non-Small Cell Lung Cancer

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ADVANCES FOR TREATMENT OF LUNG CANCER

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  1. ADVANCES FORTREATMENT OF LUNG CANCER ASCO 2004, NOLA Jennifer Garst, M. D. Assistant Professor of Medicine Thoracic Oncology Program Duke University Medical Center

  2. ADVANCES FORTREATMENT OF LUNG CANCER ASCO 2004, NOLA Non-Small Cell Lung Cancer a. Early Stage Disease b. Locally Advanced Disease c. Advanced Disease

  3. ASCO PRACTICE GUIDELINESwww.ASCO.org Clinical Practice Guidelines for the Treatment of Lung Cancer, 1997 Updated 2003 For Unresectable NSCLC

  4. Stage I/II Non-Small Cell Lung Cancer ASCO GL (1997): • Surgical resection if operable • Role of neoadjuvant or adjuvant therapy cannot be ascertained at this time NCCN GL (2004): • Surgical resection if operable • Stage IA- Observation • Stage IB/II- Adjuvant Chemotherapy

  5. Stage I/II Non-Small Cell Lung Cancer Stereotactic Hypofractionated High-Dose Irradiation for Stage I Non-small Cell Lung Carcinoma: Clinical Outcomes in 273 Cases Of a Japanese Multi-Institutional Study Onishi et al, Abstract #7003

  6. Stage I/II Non-Small Cell Lung Cancer N=273 Med age 76yrs T1N0(175),T2N0(98), 7-58mm (28mm) 62% inop 2ndCOPD 3D, stereotactic procedure 1800-7500cGy given in 7-22 fractions Onishi et al, Abstract #7003

  7. Stage I/II Non-Small Cell Lung Cancer 2.9% with grade ¾ pulmonary compl CR 71%, PR 59% Local Progression in 12.5% 3yrS: 69% Bio Eff Dose<100Gy 95% BED >100Gy Interesting new technology Onishi et al, Abstract #7003

  8. 1995 Meta-Analysis Adjuvant Cisplatin Trials n=1394 100 HR 0.87 p=0.08 80 60 Percentage Survival 40 Surgery plus Chemotherapy Surgery 20 0 6 12 18 24 30 36 42 48 54 60 0 Time from Randomization (months) BMJ 31: 899-908, 1995 Slide by Dr. Pisters

  9. IALT - Overall Survival NEJM 2003Slide by Dr. Pisters ___ Chemotherapy ___ Control Years 775 181 932 450 308 624 At risk 935 602 432 286 164 774

  10. UFT Meta-AnalysisHamada, ASCO 23:7002, 2004 JBR.10Winton, ASCO 23:7018, 2004 CALGB 9633Strauss, ASCO 23:7019, 2004 Slide by Dr. Pisters

  11. UFT Meta-AnalysisBackground • UFT: Uracil and Tegafur • Tegafur - prodrug of fluorouracil • Uracil - inhibits DPD,  serum FU • Studied extensively in Japan • Well tolerated oral agent, long-term • Possible anti-angiogenic properties Slide by Dr. Pisters

  12. UFT Meta-AnalysisHamada, ASCO 23:7002, 2004 • 6 randomized trials • Conducted in Japan • 5 years follow-up Surgery UFT (no intravenous chemo) Slide by Dr. Pisters

  13. UFT Meta-AnalysisPatient Characteristics - 6 Trials • Stage I - 95% • Adenocarcinoma - 84% • Women - 45% • Median Age - 62 Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters

  14. UFT Meta-Analysis6 Trials: Intervention UFT* Stage n Survival p Reference 1 I-III 201 + 15% .022 JCO 96 2 I 332 + 15% NS (ECCO 01) 3 I-II 219 + 4% NS Lung Ca 03 4 I 172 + 17% .045 (ASCO 02) 5 I Ad-S 100 - 1% NS (Lu Ca 03) 6 I Ad 979 + 3% .04NEJM 04 2003 *400 mg PO daily x 1-2 years Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters

  15. UFT Meta-Analysis Exploratory Analysis T1 < 2 cm, n=670 2 - 3 cm, n=599 1.0 1.0 . 0.8 0.8 0.6 0.6 p=0.357 p=0.0157 0.4 0.4 0.2 0.2 0 0 5 1 3 7 1 3 5 7 Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters

  16. UFT Meta-Analysis ConclusionsPisters • This meta-analysis showed that long-term treatment with UFT is effective as postoperative adjuvant therapy for… • stage I • T>2 cm • adenocarcinoma • a study population with 45% women Slide by Dr. Pisters

  17. NSCLC Randomized Cisplatin Adjuvant TrialsAfter the 1995 Meta-Analysis Trial Stage n Chemo Survival Japan III-N2 119 VdP No ALPI I-III 1209 MVdP No IALT I-III 1867 Vinca or EP Yes BLT I-III 381 Platin-based No NCIC IB-II 482 VbP Yes CALGB IB 344 PacCb Yes Lung Ca 04; JNCI 03; NEJM 04; Lung Cancer 03; ASCO 04; ASCO 04 Slide by Dr. Pisters

  18. Prospective Randomized Trial of Adjuvant Vinorelbine and Cisplatin in Completely Resected Stage IB/II NSCLC (JBR10) 482 pts randomized after resection (stage IB/II) • Lobectomy or pneumonectomy, N2 sampling • Vin (25mg/m2 weekly) + Cis (50mg/m2 d1,8) q 4 weeks x 4 cycles versus observation • Stratified: N status, ras mutation Winton TL, et al. ASCO Abstract 7018 Slide by D’Amico

  19. NCIC JBR10 RANDOMIZE Cisplatin (50mg/m2 d1,8) Vinorelbine (25mg/m2) 4 cycles T2N0M0 (IB) T1-2 N1(II) NSCLC (Complete resection) Observation Winton TL, et al. ASCO Abstract 7018 Slide by D’Amico

  20. Prospective Randomized Trial of Adjuvant Vinorelbine and Cisplatin in Completely Resected Stage IB/II NSCLC (JBR10) • 59% received 3 or more cycles • Limited toxicity (neuro) • Overall survival improved Vin/Cis (94m vs 73 m) • 5-year survival longer for Vin/Cis (69% vs 54%) • 15% survival improvement at 5 years • 30% reduction in risk of death (p=0.012) Winton TL, et al. ASCO Abstract 7018 Slide by D’Amico

  21. JBR.10 - Overall SurvivalWinton, ASCO 23:7018, 2004 ____ VbP ____ Observation HR 0.696 [.524-.923] p=0.012 69% 54% Slide by Dr. Pisters

  22. Randomized Clinical Trial of Adjuvant Chemotherapy with Paclitaxel and Carboplatin following Resection in Stage IB NSCLC (CALGB 9633) • High risk stage I patients (T2) after resection • Stratified by histology, differentiation, mediastinoscopy • Lobectomy or pneumonectomy; N2 sampling • Closed by a planned interval analysis • Accrual 344/384 planned (90%) Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico

  23. CALGB 9633 RANDOMIZE Carboplatin (AUC=6) Taxol (200mg/m2) 4 cycles/12 wk T2N0M0 (IB) NSCLC (Complete resection) Observation Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico

  24. CALGB 9633 Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico

  25. Randomized Clinical Trial of Adjuvant Chemotherapy with Paclitaxel and Carboplatin following Resection in Stage IB NSCLC (CALGB 9633) • All 4 cycles delivered in 85% • Dose modification in 35% • 55% received all 4 cycles at full dose • Chemo well tolerated: no toxicity related deaths • Grade 3-4 neutropenia in 36% Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico

  26. CALGB 9633 - Overall SurvivalStrauss, ASCO 23:7019, 2004 1.0 ----- Chemotherapy ----- Observation 0.8 Probability 0.6 HR 0.62 [0.41-0.95] p=0.028 0.4 0.2 71% 59% 0.0 4 yr 0 20 40 60 80 Survival Time (Months) Slide by Dr. Pisters

  27. NCIC & CALGB Adjuvant ChemotherapyConclusions Why are the NCIC/CALGB results better? • Patient Selection • Earlier stage disease • Uniform patient population • 1.5 x more women than IALT • Therapy • 2 drug regimen • Inclusion of 3rd generation agent • Better compliance (CALGB) • Lack of radiation Slide by Dr. Pisters

  28. NCIC & CALGB Adjuvant ChemotherapyConclusions • The NCIC and CALGB studies confirm the positive IALT findings of a benefit for postoperative platin-based chemotherapy in completely resected NSCLC. Slide by Dr. Pisters

  29. Adjuvant Chemotherapy 2004Conclusions • Consistent reductions in the risk of death have been observed in recent adjuvant platin-based trials and the 1995 meta-analysis. • Adjuvant platin-based chemotherapy should be recommended to completely resected NSCLC patients with good performance status. Slide by Dr. Pisters

  30. Resectable Stage III Non-Small CellLung Cancer ASCO GL 1997: • Not addressed • Importance of PS, PFT’s • Imply that bulky N2 disease should not be considered resectable.

  31. Resectable Stage III Non-Small CellLung Cancer Cisplatin/Etoposide Followed by Twice-Daily Chemoradiation vs Cisplatin/ Etoposide Alone Before Surgery in Stage III Non-small Cell Lung Cancer: A Randomized Phase III Trial of the German Lung Cancer Cooperative Group Thomas et al, Abstract #7004

  32. Resectable Stage III Non-Small CellLung Cancer 3 Cycles Cis/VP16BID XRT4500cGySurgery w/Carbo/Vin VS 3 Cycles Cis/VP16 Surgery XRT 5400cGY Abstract #7004

  33. Resectable Stage III Non-Small CellLung Cancer N= 481, 18% women, med age 59yo, PS0-1, 32% Stage IIIA, 68% Stage IIIB Neo Chemo->Chemo/XRT NeoChemo/Adj XRT Esoph 15% 4% IndResp 52% 47% Resction 45% 50% TxRlDeath 5.6% 5.3% 3yrS 24% 23% Abstract #7004

  34. Unresectable Stage III Non-Small CellLung Cancer ASCO GL 2003 Update: • Chemotherapy in association with definitive thoracic irradiation is appropriate for selected patients (PS 0-1, ?2) with unresectable, locally advanced NSCLC. • XRT no less than 6000 cGy • Duration of chemotherapy should be 2-8 cycles.

  35. Unresectable Stage III Non-Small CellLung Cancer Induction Chemotherapy Followed By Concommitant Chemoradiotherapy vs CT/XRT Alone for Regionally Advanced Unresectable Non-small Cell Lung Cancer: Initial Analysis of a Randomized Phase III CALGB Trial Vokes, et al. Abstract #7005

  36. Unresectable Stage III Non-Small CellLung Cancer 2 Cycles CarboAUC6/Taxol200mg/m2 WeeklyCarbo/Taxol/XRT VS WeeklyCarboAUC2/Taxol50mg/m2/XRT66GY Vokes, et al. Abstract #7005

  37. Unresectable Stage III Non-Small CellLung Cancer N=366, 34%women, 63%>60yo IndconcChemo/XRT Chemo/XRT ANC 27% 15% Eso 35% 31% SOB 19% 12% 4Tox 41% 24% MS 14mo 11.4mo 1yrS 54% 48% -Poor 1yrS in both arms, SWOG 76%1yS -?Wrong Chemotx or wrong design Vokes, et al. Abstract #7005

  38. Advanced Non-Small Cell Lung Cancer ASCO GL 2003: • Platinum-based combination chemotherapy • Alternative non-platinum doublet or single agent as clinically indicated • No more than 6 cycles • Docetaxel 2nd line; Gefitinib (Iressa) 3rd line • Consider treatment on a clinical trial

  39. Advanced Non-Small CellLung Cancer Results of a Phase III Trial of Erlotinib (Tarceva) Combined with Cisplatin and Gemcitabine Chemotherapy in Advanced Non-small Cell Lung Cancer Gatzemeier et al, Abstract #7010

  40. The ErbB Family and Ligands EGF TGF- Amphiregulin -cellulin HB-EGF Epiregulin HB-EGF Heregulins -cellulin No KnownLigands Heregulins Extracellular Tyrosine Kinase Domain Intracellular ErbB-1HER1 EGFR ErbB-2 HER2 neu ErbB-3 HER3 ErbB-4 HER4

  41. Turning Off the EGFR-TK SignalAt the Source1-3 • Inhibition of the EGFR-TK itself—inside the cell—completely inhibits EGFR-TK signaling regardless of the triggering event Inhibitionof apoptosis Proliferation Invasion Metastasis Angiogenesis 1. Leserer M et al. IUBMB Life. 2000;49:405-409. 2. Raymond E et al. Drugs. 2000;60(suppl 1):15-23. 3. Prenzel N et al. Endocr Relat Cancer. 2001;8:11-31.

  42. EGFR in NSCLC • EGFR-TK plays a key role in growth, invasion, and metastasis of NSCLC • EGFR expression in up to 80% of tumors in patients with NSCLC • Novel EGFR-TK inhibitors target key signal transduction pathways • Once-daily oral EGFR-TK inhibitors appear to be well tolerated

  43. Advanced Non-Small CellLung Cancer N=1172 Chemo-naïve StageIIIB/IV, PS0-1 6 cycles Cis/Gem + drug/placebomaint tablet Erlotinib 150mg qd po Erlotinib Placebo Diarh 6% <1% Rash 10% <1% OS 10.8mo 11.2 mo Gatzemeier et al, Abstract #7010

  44. Advanced Non-Small CellLung Cancer A Phase III Trial of Erlotinib (Tarceva) Combined with Carboplatin and Taxol Chemotherapy in Advanced Non-small Cell Lung Cancer TRIBUTE Herbst et al, Abstract #7011

  45. Advanced Non-Small CellLung Cancer n=1059 Same design Erlotinib Placebo OS 10.8mo 10.6mo Proper sequencing of targeted therapies is under study Herbst et al, Abstract #7011

  46. Advanced Non-Small CellLung Cancer A Randomized Placebo-Controlled Trial of Erlotinib (Tarceva) in Patients with Advanced Non-small Cell Lung Cancer Following Failure of 1st or 2nd Line Chemotherapy: an NCIC CTG Trial Shepherd et al, Abstract #7022

  47. Advanced Non-Small CellLung Cancer N=731, Stage IIIB/IV 36% women, PS 0-3, 1-2 previous chemo comb 2:1 erlotinib 150 mg po qd vs placebo Erlotinib Placebo D/C 5% 2% TTDS-c 4.9mo 3.68mo TTDS-p 2.79mo 1.91mo PFS 2.23mo 1.84mo (p<0.001) OS 6.7mo 4.7mo (p<0.001) Shepherd et al, Abstract #7022

  48. Advanced Non-Small CellLung Cancer Gefitinib (Iressa) Therapy for Advanced Bronchioloalveolar Lung Cancer (BAC): SWOG S0126 West et el, Abstract #7014

  49. Advanced Non-Small CellLung Cancer BAC is increasing in incidence esp in young non-smoking women May be a subset to respond well to EGFR targeted tx N=138 (102 chemo naïve, 36 previously tx) 51% women, med age 68yr, 86% PS0-1 Gefitinib 500mg po qd, most dose reduced to 250 mg West et el, Abstract #7014

  50. Advanced Non-Small CellLung Cancer Chemo naïve Previously Tx RR 21%, 6 %CR RR 10% 1yrS 50% 50% Rash MS 12 mo vs no rash 5 mo Women MS 16 mo vs Men 5 mo Pulm Tox 3 patients died, ?IPF vs PD West et el, Abstract #7014

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