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Emerging Treatment Paradigms in NSCLC

Emerging Treatment Paradigms in NSCLC. Edward S. Kim, MD MD Anderson Cancer Center. Per capita cigarette consumption. Male lung cancer death rate. Female lung cancer death rate. Tobacco Use in the USA 1900-1999. *Age-adjusted to 2000 US standard population.

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Emerging Treatment Paradigms in NSCLC

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  1. Emerging Treatment Paradigms in NSCLC Edward S. Kim, MD MD Anderson Cancer Center

  2. Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate Tobacco Use in the USA1900-1999 *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

  3. Male Female 80 80 Pancreas Liver Prostate Stomach Lung & bronchus Colon & rectum Uterus† Breast Pancreas Ovary Stomach Lung & bronchus Colon & rectum 60 60 Rate per 100,000 Rate per 100,000 40 40 20 20 0 0 Year 1990 1970 1930 1940 1980 1950 1960 1960 1970 1940 1930 1980 1990 1950 Cancer Deaths in the US †Uterine cancer death rates are for uterine cervic and uterine corpus combined. Source: US Mortality Public Use Data Tapes 1960-1996. US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 1999.

  4. Docetaxel2002 Gefitinib2003 First-line Second-lineThird-line Not approved ErlotinibPemetrexed2004 Docetaxel1999 PaclitaxelGemcitabine1998 Bevacizumab2006 Vinorelbine1994 12+ Medianoverallsurvival,months Carboplatin*1989 Cisplatin*1978 ~8–10 ~6 ~2–4 1970 1980 1990 2000 Best supportive care Single-agent platinum Doublets Bevacizumab + PC Standard Therapies *Label does not include NSCLC-specific indication History of Therapy in Advanced NSCLC:FDA Approval Dates Food and Drug Administration. At http://www.fda.gov/cder/cancer/druglistframe.htm. Accessed August 28, 2006.; National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology. Non-small cell lung cancer v2.2006. Accessed August 28, 2006. Schrump et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

  5. FDA Approved Chemotherapy Regimens for Advanced NSCLC • First-Line • Cisplatin + paclitaxel (24 hour infusion) • Cisplatin + vinorelbine (4 week) • Cisplatin + gemcitabine (3 or 4 week) • Cisplatin + docetaxel (3 week) • Bevacizumab + carboplatin + paclitaxel • Second-Line • Docetaxel • Pemetrexed • Erlotinib

  6. Arm A* q 3 wk Paclitaxel: 135 mg/m2, day 1 Cisplatin: 75 mg/m2, day 2 RANDOM I ZE • Stage IIIB or IV • NSCLC • Stratified by: • Extent of disease • PS • Weight loss • Brain metastases Arm B q 4 wk Cisplatin: 100 mg/m2, day 1 Gemcitabine: 1000 mg/m2, days 1,8,15 Arm C q 3 wk Docetaxel: 75 mg/m2, day 1 Cisplatin: 75 mg/m2, day 1 Arm D q 3 wk Paclitaxel: 225 mg/m2, day 1 Carboplatin: AUC=6, day 1 *Control arm. ECOG 1594: Treatment Schema Schiller JH et al. N Engl J Med. 2002;346:92-98

  7. 1.0 Cisplatin + Paclitaxel Cisplatin + Gemcitabine Cisplatin + Docetaxel Carboplatin + Paclitaxel 0.8 0.6 0.4 0.2 0.0 30 0 5 10 15 20 25 Months ECOG 1594 Survival by Treatment Group Schiller JH et al. N Engl J Med. 2002;346:92-98

  8. RANDOM I ZE Docetaxel: 75 mg/m2 IV + Cisplatin: 75 mg/m2 IV q3 wk • Stratification by: • Stage IIIB or IV • Geographic region q3 wk Docetaxel: 75 mg/m2 IV + Carboplatin: AUC 6 IV Vinorelbine: 25 mg/m2 IV d 1, 8, 15, 22 + Cisplatin: 100 mg/m2 IV d 1 q4 wk Premed: Dexamethasone 8 mg PO bid  6 doses (first dose on evening prior to docetaxel infusion) for the docetaxel groups. TAX 326: Schema Fossella FV et al: JCO 2003

  9. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Docetaxel/Cisplatin Vinorelbine/Cisplatin P = .044, Adjusted Log-Rank 1-yr Survival 46 vs 41% 2-yr Survival 21 vs 14% Cumulative Probability 0 3 6 9 12 15 18 21 24 27 30 33 Survival Time (months) TAX 326: SurvivalDocetaxel/Cisplatin vs. Vinorelbine/Cisplatin Fossella FV et al: JCO 2003

  10. Study N ORR(%) MST (mos) SWOG 9509 Carbo-Pac 208 25 8.0 Cis-Vino 202 28 8.0 EGOG 1594 Cis-Pac 292 21.3 8.1 Cis-Gem 288 21 8.1 Cis-Doce 293 17.3 7.4 Carbo-Pac 290 15.3 8.3 Italian Study Cis-Gem 205 30 9.8 Carbo-Pac 201 32 9.9 Cis-Vino 201 30 9.5 EORTC 08975 Cis-Pac 159 31 8.1 Cis-Gem 160 36 8.8 Gem-Pac 161 27 6.9 TAX 326 Doce-Cis 408 NA 10.9 Doce-Carbo 406 NA 9.1 Cis-Vino 404 NA 10.0 The Bottom Line: Metastatic NSCLC

  11. Biological Agent Class Trial Phase Target Population Outcome Gefitinib EGFR-TKI III All NSCLC Negative for survival Gefitinib EGFR-TKI III All NSCLC Negative for survival Erlotinib EGFR-TKI III All NSCLC Negative for survival Erlotinib EGFR-TKI III All NSCLC Negative for survival Bexarotene Rexinoid III All NSCLC Negative for survival Bexarotene Rexinoid III All NSCLC Negative for survival Lonafarnib Farnesyl Transferase III All NSCLC Negative for survival Bevacizumab VEGF III Non-squamous, no brain mets Positive for survival Chemotherapy and Targeted Therapy

  12. Case 1: NSCLC • HPI: 76 year old female with choking episode. Heimlich maneuver x 3 successful. Hospital w/u revealed 2 cm RLL nodule. • PMH: Asthma, HTN, DM Type II, R RCCA – 1997 • Meds: HCTZ, Inderal, Nabumetone • Allergies: None • SH: Widow, cigarettes: 20 pack-years • ETOH: 3 beers/day • FH: Negative • ROS: Rib pain, unsteady gait, no weight loss • PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Abd: no masses Ext: no C/C/E Neuro: no focal deficits

  13. Case 1: NSCLC • What is the desired work-up for the nodule? • Biopsy • Biopsy, CT chest, abdomen • Biopsy, CT chest, abdomen, bone scan, MRI brain • Referral to medical oncology

  14. What is the desired work-up for the nodule? Biopsy Biopsy, CT chest, abdomen Biopsy, CT chest, abdomen, bone scan, MRI brain Referral to medical oncology

  15. Case 1: NSCLC • FNA: NSCLC • Bone Scan: Multiple increased rib lesions • MRI Brain: No metastases • CT Chest: 2 cm lesion RLL, no adenopathy • CT-PET: FDG avid lesion RLL, no other abns

  16. Case 1: NSCLC • What is the optimal treatment for this patient at this time? • Lobectomy • Lobectomy and nodal sampling • Lobectomy and nodal dissection • Surgery followed by radiation

  17. What is the optimal treatment for this patient at this time? Lobectomy Lobectomy and nodal sampling Lobectomy and nodal dissection Surgery followed by radiation

  18. VATS LobectomyTechnique Courtesy S. Swisher

  19. Case 1: NSCLC Pathology: T2N0M0

  20. Case 1: NSCLC • What is the appropriate next therapy for this patient? • Adjuvant chemotherapy • Adjuvant chemotherapy followed by radiation • Observation • Radiation alone

  21. What is the appropriate next therapy for this patient? Adjuvant chemotherapy Adjuvant chemotherapy followed by radiation Observation Radiation alone

  22. Cisplatin 80 mg/m2 q 3 wk  4 ORCisplatin 100 mg/m2 q 4 wk  3-4 ORCisplatin 120 mg/m2 q 4 wk  3 PLUS Etoposide 100 mg/m2 3 days/cycle ORVinorelbine 30 mg/m2 weekly ORVinblastine 4 mg/m2 weekly ORVindesine 3 mg/m2 weekly R A N D O M I Z E* • N=1867 • Select eligibility criteria: • Stage I-III • Complete surgical resection within 60 days • Age ≤ 75 No chemotherapy ± Thoracic Radiotherapy  60 Gy† Randomized International Adjuvant Lung Cancer Trial (IALT): Design *Each center selected chemotherapy regimen †Optional, but predefined by N stage at each center International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360

  23. Median 5-yr OS (mos)OS (%) Chemotherapy 50.8 44.5 Control 44.4 40.4 100% 80% Chemotherapy 60% Overall Survival (%) Control 40% HR = 0.86 [0.76-0.98] P < 0.03 20% 0% 0 1 2 3 4 5 Years 932 624 775 450 308 181 At risk: 935 602 774 164 432 286 IALT: Overall Survival International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360

  24. Phase III Trial of Adjuvant Chemotherapy in Completely Resected Stage IB/II NSCLC Intergroup JBR.10 Trial Winton et al. Proc Am Soc Clin Oncol. 2004;22(No 14S):621s. Abstract 7018

  25. 1.0 1.0 Observation Observation Chemo Chemo 0.8 0.8 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 HR = 0.80; 90% CI: 0.60-1.07 P = 0.10 HR = 0.62; 90% CI: 0.44-0.89 P = 0.01 0.0 0.0 0 0 1 2 2 3 4 4 5 6 6 7 8 8 9 0 0 1 2 2 3 4 4 5 6 6 7 8 8 9 Survival Time (Years) Survival Time (Years) ASCO: 2004 ASCO: 2006 CALGB 9633: Overall Survival Then and Now

  26. ANITA: Phase III Adjuvant Vinorelbine (N) and Cisplatin (P) vs. Observation (OBS) in Completely Resected (Stage I-III) Non-Small Cell Lung Cancer (NSCLC) Patients (pts) • 840 patients • Median age: 59 (range 18-75) • 35% stage I, 30% II, 35% IIIA • Median survival 65.8 vs. 43.7 months • 5-year survival by stage I-II-IIIA • NP: 62% - 52% - 42% • OBS: 63% - 39% - 26% • No benefit was observed in stage I

  27. Placebo • Eligible pts: • Stage IB / IIIA NSCLC 1st Line platinum–based chemo x 4 cycles Erlotinib Stratify by smoking HX Collect tissue Treatment for 2-years • Primary Endpoint: Progression-free survival • Overall population • Never smokers RADIANTErlotinib NSCLC Adjuvant Trial

  28. RANDOMI ZE • Eligibility • Resected IB–IIIA • ≥ lobectomy • No previous chemotherapy • No planned XRT • No CVA/TIA • No ATE in 12 months • N = 1,500 Chemotherapy* x 4 cycles Chemotherapy* x 4 cycles + Bevacizumabx 1 year E1505: Phase III Adjuvant Chemotherapy  Bevacizumab • *Specified regimens • Carboplatin and paclitaxel • Cisplatin and docetaxel • Cisplatin and vinorelbine • Cisplatin and gemcitabine • Primary end point: overall survival • Secondary end points: disease-free survival, safety [bleeding and arterial thromboembolic events (ATEs)] Approved: ECOG Executive Committee and CTEP Principal investigator: Heather Wakelee

  29. Case 2: NSCLC • HPI:69 year old female with h/o T1N1 breast CA x 22 yrs. F/U CXR reveals 3 cm RUL mass. • PMH:HTN, PVD, R Breast CA – 1983 • Meds: Lipitor, Atenolol, Naproxen • Allergies:None • SH:Widow, cigarettes: 50 pack-years • ETOH: none x 1 year • FH:Negative • ROS:Rib pain, unsteady gait, no weight loss • PE:No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Chest: well healed mastectomy scar, Abd: no masses, Ext: no C/C/E, Neuro: no focal deficits

  30. Case 2: NSCLC • What is the optimal work-up for this patient? • Biopsy • Biopsy, CT chest, abdomen • Biopsy, CT chest, abdomen, bone scan, MRI brain • Referral to medical oncology

  31. What is the optimal work-up for this patient? Biopsy Biopsy, CT chest, abdomen Biopsy, CT chest, abdomen, bone scan, MRI brain Referral to medical oncology

  32. Case 2: NSCLC • FNA:NSCLC • CT Chest:3.7 cm lesion RUL, no adenopathy • CT-PET:FDG avid lesion RUL, R paratrach node avid, no other nodes or metastases • EBUS:R4 LN: positive, all other negative

  33. Case 2: NSCLC • What is the preferred treatment at this time for this patient? • Surgery followed by radiation • Induction chemotherapy followed by surgery • Induction chemoradiotherapy followed by surgery • Concurrent chemotherapy and radiation

  34. What is the preferred treatment at this time for this patient? Surgery followed by radiation Induction chemotherapy followed by surgery Induction chemoradiotherapy followed by surgery Concurrent chemotherapy and radiation

  35. Case 2: NSCLC • Induction Chemotherapy: Docetaxel, cisplatin, no RT • Surgery: FOB/MED, RUL, MLND

  36. Case 2: NSCLC • What is the appropriate next therapy for this patient? • Adjuvant chemotherapy • Adjuvant chemotherapy followed by radiation • Observation • Radiation alone

  37. What is the appropriate next therapy for this patient? Adjuvant chemotherapy Adjuvant chemotherapy followed by radiation Observation Radiation alone

  38. Approach to Resectable Stage IIIA, N2 NSCLC

  39. Survival Comparison of Preoperative Chemotherapy Adapted from Pisters et al. J Clin Oncol. 2005;23(No16s):624s. Oral Presentation.

  40. Current Issues for Stage IIIA N2 LN+ Resectable NSCLC • The role of surgery? • Addition of RT to induction chemo increases pathologic CR rates, but also toxicity • Does RT add survival benefit to justify the increased toxicity of bimodality induction therapy for this group of patients? • An ongoing dilemma reflected by variability in treatment approaches across the country • Published clinical trials limited by heterogeneity of patient population(s) studied

  41. INT 0139: Definitive CT/RT vs Induction CT/RT  Surgery for Stage IIIA NSCLC Median F/U 81 months Re-evaluate 2 to 4 weeks post RT; if no PD R A N D O M I Z E Cis/VP16 x 2 cycles w/concurrent XRT 45Gy Cis/VP16 x 2 cycles Stage IIIA (T1-3, pN2, M0) NSCLC N = 429 (396 eligible) Considered Resectable Surgery Cis/VP16 x 2 cycles w/concurrent XRT 45Gy Cis/VP16 x 2 cycles Continue RT to 61GY Re-evaluate 7 days prior to RT completion; if no PD Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.

  42. INT 0139: Exploratory Analyses Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.

  43. Patients with stage I-III NSCLC No prior chemotherapy or radiotherapy Cisplatin 80 mg/m2 + Docetaxel 75 mg/m2 For 3 cycles Surgical resection ±XRT Erlotinib 150 mg po for 1 year MDACC Neoadjuvant Trial Schema

  44. Who’s Appropriate for Multimodality Surgical Resection? • Microscopic single station N2 • T4 N0-1 • Perhaps responding larger N2

  45. Stage IIIA “Bulky” N2 and Stage IIIB NSCLC • Multimodality approach with chemotherapy and radiation therapy • Randomized evidence of survival benefit of chemo-RT over RT alone • Concurrent: generally accepted as standard definitive treatment of patients with good PF • Sequential: less toxic; defendable treatment option • Unclear impact of surgery on local control in combined modality approach • Downstaging

  46. Case 3: NSCLC • HPI:62 year old male with DJD. C/o 8-10 months of progressive SOB. Spirometry normal. • Continued SOB for few months, saw pulmonologist. Repeat spirometry, Advair started. CXR revealed 4 cm RML lesion and moderate pleural effusion. • PMH:DJD • Meds: Celebrex prn • Allergies:None • SH:Married, never smoker • ETOH: Rare • FH:Negative • ROS:Rib pain, SOB, no weight loss • PE:No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Chest: well healed mastectomy scar, Abd: no masses, Ext: no C/C/E, Neuro: no focal deficits

  47. Case 3: NSCLC • What is the optimal work-up at this time? • Biopsy, CT chest, abdomen • Thoracentesis, CT chest, abdomen, bone scan • Thoracentesis, CT chest, abdomen, bone scan, brain scan • Hospice care

  48. What is the optimal work-up at this time? Biopsy, CT chest, abdomen Thoracentesis, CT chest, abdomen, bone scan Thoracentesis, CT chest, abdomen, bone scan, brain scan Hospice care

  49. Case 3: NSCLC • CT Chest:4.2 cm lesion extending across mediastinum, no adenopathy • Thoracentesis: 600 cc drained • Bone scan:Lytic bone lesion right 5th rib • Brain scan:Clean • Pathology:Metastatic adenocarcinoma

  50. Case 3: NSCLC • What is the optimal treatment for this patient? • Cisplatin doublet • Carboplatin + docetaxel • Carboplatin + paclitaxel • Carboplatin + gemcitabine • Carboplatin + taxane + bevacizumab • Bevacizumab + erlotinib

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