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

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Presentation on theme: "ADVANCES FOR TREATMENT OF LUNG CANCER ASCO 2004, NOLA Jennifer Garst, M. D. Assistant Professor of Medicine Thoracic Oncology Program Duke University Medical."— Presentation transcript:

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

2 ADVANCES FOR TREATMENT 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 GUIDELINES 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 2 nd COPD 3D, stereotactic procedure cGy 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 Surgery plus Chemotherapy Surgery Percentage Survival Time from Randomization (months) BMJ 31: , 1995 Slide by Dr. Pisters 1995 Meta-Analysis Adjuvant Cisplatin Trials n=1394 HR 0.87 p=0.08

9 IALT - Overall Survival NEJM 2003 Slide by Dr. Pisters ___ Control ___ Chemotherapy Years At risk

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

11 UFT Meta-Analysis Background 6 UFT: Uracil and Tegafur ! Tegafur - prodrug of fluorouracil ! Uracil - inhibits DPD,  serum FU 6 Studied extensively in Japan 6 Well tolerated oral agent, long-term 6 Possible anti-angiogenic properties Slide by Dr. Pisters

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

13 UFT Meta-Analysis Patient 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-Analysis 6 Trials: Intervention UFT* Stage nSurvival p Reference 1I-III %.022 JCO 96 2 I % NS (ECCO 01) 3 I-II219+ 4% NS Lung Ca 03 4 I %.045 (ASCO 02) 5I Ad-S % NS (Lu Ca 03) 6I Ad979+ 3%.04 NEJM 04 Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters *400 mg PO daily x 1-2 years 2003

15 < 2 cm, n= cm, n=599 UFT Meta-Analysis Exploratory Analysis T1 p=0.357 p= Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters

16 UFT Meta-Analysis Conclusions Pisters 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 Trials After the 1995 Meta-Analysis Lung Ca 04; JNCI 03; NEJM 04; Lung Cancer 03; ASCO 04; ASCO 04 Slide by Dr. Pisters TrialStage nChemo  Survival JapanIII-N2 119VdPNo ALPII-III1209MVdPNo IALTI-III1867Vinca or EPYes BLTI-III 381Platin-basedNo NCICIB-II 482VbPYes CALGBIB 344PacCbYes

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 T2N0M0 (IB) T1-2 N1(II) NSCLC (Complete resection) Observation Cisplatin (50mg/m2 d1,8) Vinorelbine (25mg/m2) 4 cycles RANDOMIZERANDOMIZERANDOMIZERANDOMIZE 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 Survival Winton, ASCO 23:7018, 2004 ____ VbP ____ Observation HR [ ] p= % 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 T2N0M0 (IB) NSCLC(Completeresection) Observation Carboplatin (AUC=6) Taxol (200mg/m2) 4 cycles/12 wk RANDOMIZERANDOMIZERANDOMIZERANDOMIZE Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico

24 CALGB 9633 VariableChemo (n=173)Control (n=171) P value Age61 yr (34-78)62 yr (40-81)0.42 PS=055%58%0.92 Sx present78%74%0.39 size4.7cm (0-15)4.6cm (1-12)0.87 Squam39% 0.98 Poorly diff50% 0.99 Mediastin80%79%0.78 Lobectom89% 0.98 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 Overall Survival Strauss, ASCO 23:7019, Chemotherapy Observation HR 0.62 [ ] p= % 59% 4 yr Slide by Dr. Pisters Survival Time (Months) Probability

27 NCIC & CALGB Adjuvant Chemotherapy Conclusions 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 Chemotherapy Conclusions 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 2004 Conclusions 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 Cell Lung Cancer ASCO GL 1997: Not addressed Importance of PS, PFT’s Imply that bulky N 2 disease should not be considered resectable.

31 Resectable Stage III Non-Small Cell Lung 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 Cell Lung 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 Cell Lung Cancer N= 481, 18% women, med age 59yo, PS0-1, 32% Stage IIIA, 68% Stage IIIB Neo Chemo->Chemo/XRTNeoChemo/Adj XRT Esoph15%4% IndResp52%47% Resction45%50% TxRlDeath 5.6%5.3% 3yrS24%23% Abstract #7004

34 Unresectable Stage III Non-Small Cell Lung 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 Cell Lung 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 Cell Lung 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 Cell Lung Cancer N=366, 34%women, 63%>60yo Ind  concChemo/XRTChemo/XRT ANC27%15% Eso35%31% SOB19%12% 4Tox41%24% MS14mo11.4mo 1yrS54%48% -Poor 1yrS in both arms, SWOG 76%1yS -?Wrong Chemotxor 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 2 nd line; Gefitinib (Iressa) 3 rd line Consider treatment on a clinical trial

39 Advanced Non-Small Cell Lung 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 EGF TGF-  Amphiregulin  -cellulin HB-EGF Epiregulin Heregulins HB-EGF Heregulins  -cellulin Tyrosine Kinase Domain ErbB-1 HER1 EGFR ErbB-2 HER2 neu ErbB-3 HER3 ErbB-4 HER4 Extracellular Intracellular No Known Ligands The ErbB Family and Ligands

41 Proliferatio n Invasion Angiogene sis Metastasis Inhibition of apoptosis 1. Leserer M et al. IUBMB Life. 2000;49: Raymond E et al. Drugs. 2000;60(suppl 1): Prenzel N et al. Endocr Relat Cancer. 2001;8: Turning Off the EGFR-TK Signal At the Source 1-3 Inhibition of the EGFR- TK itself—inside the cell—completely inhibits EGFR-TK signaling regardless of the triggering event

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 Cell Lung Cancer N=1172 Chemo-naïve StageIIIB/IV, PS0-1 6 cycles Cis/Gem + drug/placebo  maint tablet Erlotinib 150mg qd po ErlotinibPlacebo Diarh 6%<1% Rash 10%<1% OS10.8mo11.2 mo Gatzemeier et al, Abstract #7010

44 Advanced Non-Small Cell Lung 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 Cell Lung Cancer n=1059 Same design ErlotinibPlacebo OS 10.8mo10.6mo Proper sequencing of targeted therapies is under study Herbst et al, Abstract #7011

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

47 Advanced Non-Small Cell Lung 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 ErlotinibPlacebo D/C 5%2% TTDS-c 4.9mo3.68mo TTDS-p 2.79mo1.91mo PFS2.23mo1.84mo (p<0.001) OS6.7mo4.7mo (p<0.001) Shepherd et al, Abstract #7022

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

49 Advanced Non-Small Cell Lung 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 Cell Lung Cancer Chemo naïve Previously Tx RR 21%, 6 %CRRR 10% 1yrS50%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

51 Advanced Non-Small Cell Lung Cancer Interstitial Lung Disease During Gefitinib Treatment of Japanese Patients with Non-small Cell Lung Cancer Abstract #7063

52 Advanced Non-Small Cell Lung Cancer N=325, retrospective chart analysis 32% women, med age 67yr, 34% PS 2-4 Hepato Tox 5% Rash 2.2% Diarrhea 0.6% 22pts (6.8%) developed ILD,10died (3.1%) MTD 18 days s/p Iressa, ½ acute onset SOB Risk factors: Poor PS, previous PF, possibly men with history of smoking Abstract # 7063

53 Advanced Non-Small Cell Lung Cancer A Multicenter Phase III Randomized Trial for Stage IIIB/IV NSCLC of Weekly Paclitaxel and Carboplatin vs Standard Paclitaxel and Carboplatin Given Every Three Weeks Followed by Weekly Paclitaxel Belani et al, Abstract #7017

54 Advanced Non-Small Cell Lung Cancer Arm1 CarboAUC6 D1, Taxol 100mg/m2 D1,8,15 Arm2 CarboAUC6 D1, Taxol 225mg/m2 D1 Followed by maintenance weekly Taxol 70mg/m2 WeeklyQ3W ANCgr44.6%7.9% FN3/40.9%3.3% Neuro16%24% HCT17%7% RR20%18% Belani et al, Abstract #7017

55 Advances for the Treatment of Lung Cancer 1. A New Standard of care: Adjuvant platin-based chemotherapy should be recommended to completely resected NSCLC patients with good performance status. 2.Multi-modality treatments may offer a modest survival benefit for appropriately selected patients with resectable Stage III NSCLC. More to learn about role and timing of chemo, XRT and surgery. 3.Concurrent chemotherapy/XRT appears to offer a survival benefit for patients with Inoperable Stage III NSCLC although induction therapy and Carbo/Taxol may not be the best therapeutic choices. 4.Targeted therapies are making an impact in advanced and relapsed NSCLC. More to learn about sequencing, mutations, population selection, other targets. Warning: Pulmonary tox risk in PS2, PF 5.Platinum-based combinations remain the standard of care for advanced NSCLC. Q3 Week Carbo/Taxol is here to stay!

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