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  • 1. Clinical Update and Advances in the Treatment of NSCLC
  • 2. Program Overview
    • Incidence and epidemiology
      • Subtypes
      • Staging
    • Adjuvant therapy for resectable disease
      • Management of treatment-related toxicities
      • Neoadjuvant therapy
    • Treatment of metastatic disease
    • Treatment of the elderly and poor PS patients
    • Targeted therapy
      • Anti-EGFR targeted agents
      • Antiangiogenic agents
    • Summary and future directions
  • 3. Lung Cancer Incidence and Epidemiology
  • 4. Leading Causes of Cancer-related Deaths 564,830 cancer deaths; 162,460 (29%) due to lung cancer 174,470 new cases of lung cancer MEN Lung and bronchus 31% † Colon and rectum 10% Prostate 9% Pancreas 6% Leukemia 4% WOMEN Lung and bronchus 26% † Breast 15% Colon and rectum 10% Pancreas 6% Ovary 6% Leading Sites* by Sex, United States, 2006 Estimates *Excludes basal and squamous cell skin cancer and carcinoma in situ, except urinary bladder. † Includes both non-small cell lung cancer (NSCLC) and small cell lung cancer. American Cancer Society. Cancer Facts and Figures, 2006 .
  • 5. Lung Cancer: High Incidence, High Mortality American Cancer Society. Cancer Facts and Figures, 2006 .
  • 6. Risk Factors for Lung Cancer
    • Environmental factors
      • Smoking/second-hand smoke
      • Air pollution
      • Lung disease (tuberculosis)
      • Asbestos
      • Radon
    • Genetic predisposition
      • Chronic obstructive pulmonary disease (COPD)
    • Prevention
    NCCN Guidelines. Version 2.2006; April 2006.
  • 7. Lung Cancer Subtypes Non-small Cell Lung Cancer ~85% http://www.ncbi.nlm.nih.gov. Small Cell Lung Cancer ~15% Large Cell Carcinoma 10%-15% Adenocarcinoma 35%-40% Squamous Cell Carcinoma 25%-30%
  • 8. Squamous Cell Carcinoma
    • Occurs most frequently in men and older people of both sexes
    • Strongly associated with smoking
    • Prominent EGFR over-expression and increased gene copy number per cell
    McDoniels-Silvers A. Clinical Cancer Research . 2002;8:1127-1138 ; Movsas B, et al. Non-small cell lung cancer. Cancer Management : A Multidisciplinary Approach . CMP Media LLC, Lawrence KS, 2005, 111-154.
  • 9. Adenocarcinoma
    • Most common type of lung cancer
    • Includes bronchioaveolar carcinoma (BAC) as a subtype
    McDoniels-Silvers A. Clinical Cancer Research . 2002;8:1127-1138 ; Movsas B, et al. Non-small cell lung cancer. Cancer Management : A Multidisciplinary Approach . CMP Media LLC, Lawrence KS, 2005, 111-154.
  • 10. Prognostic Factors in NSCLC
    • Stage at presentation
    • Performance status
    • Weight loss
    • Sex
    • Age
    • Molecular markers associated with poor prognosis
      • ras mutations
      • Overexpression of EGFR
    Ciardiello F. Curr Opinion Oncology. 2004;16:130-135.
  • 11. Non-small Cell Lung Cancer Stages: TNM Staging System Stage IV=M1 T, primary tumor; N, regional lymph nodes; M, distant metastasis. N3 N2 N1 N0 Nodes IIIB IIIA IIA IA T1 T4 T3 T2 IIIB IIIB IIIB IIIB IIIA IIIA IIIB IIIA IIB IIIB IIB IB Tumor
  • 12. NSCLC Stages at Presentation 31% Stage III 38% Stage IV 24% Stage I 7% Stage II Mountain CF. Semin Surg Oncol. 2000;18:106-115.
  • 13. NSCLC Survival Mountain CF. Semin Surg Oncol. 2000;18:106-115; Fry WA, et al. Cancer. 1996;77:1949-1995. Stage IV Stage IIIB Stage IIIA Stage IIB Stage IIA Stage IB Stage IA Stage Any T, Any N, M1 T4N0-3M0 T1-4N3M0 T1-2N2M0 T3N1-2M0 T2N1M0 T3N0M0 T1N1M0 T2N0M0 T1N0M0 Pathologic TNM 23% 23%-25% 39% 38% 67% <1% 5% 5% 55% 57% 5-y Survival
  • 14. NSCLC: Stage IA/B  2 cm Stage IA N0: No lymph node involvement M0: No distant metastasis Stage IB T: T < 3 cm; no lobar bronchus involvement
    • Any of the following
      • T >3 cm
      • Main bronchus involvement 2 cm distal to carina
      • Tumor invades visceral pleura
      • Tumor with distal atelectasis
  • 15. NSCLC: Stage IIA/B Stage IIA T: T < 3 cm; no lobar bronchus involvement N1: Ipsilateral peribronchial and/or hilar nodes involved M0: No distant metastasis Stage IIB  2 cm
      • Any of the following
      • Tumor with main bronchus involvement <2 cm distal to carina
      • Tumor that invades chest wall, diaphragm, mediastinal pleura, parietal pericardium
      • Tumor with distal atelectasis
  • 16. NSCLC: Stage IIIA N1: Ipsilateral peribronchial and/or hilar nodes involved N2: Ipsilateral mediastinal and/or subcarinal nodes involved M0: No distant metastasis <2 cm  2 cm T3N1-2M0 Tumor that invades chest wall, diaphragm, mediastinal pleura, parietal pericardium T1-2N2M0 T >3 cm Tumor invades visceral pleura Tumor with distal atelectasis T  3 cm; no lobar-bronchus involvement
  • 17. Current Treatment Approaches *Strauss GM, et al. ASCO 2006. Abstract 7007. **Single-agent chemotherapy recommended for the elderly and individuals with poor performance status (PS 2). Surgical resection/adjuvant chemotherapy Stage IIB Stage IV Stage IIIB Stage IIIA Stage IIA Stage IB Stage IA Stage Surgical resection +/- adjuvant chemotherapy* Surgical resection Doublet chemotherapy** Concurrent chemotherapy/RT Surgical resection/adjuvant chemo and/or RT Concurrent chemotherapy/RT Surgical resection/adjuvant chemotherapy Standard Treatment
  • 18. Adjuvant Therapy for Resectable Non-small Cell Lung Cancer
  • 19. Adjuvant Chemotherapy Rationale
    • Adjuvant treatment decisions are based on determining the relative benefit of a treatment
    • Reducing the risks for relapse and mortality vs potential side effects and complications
  • 20. Adjuvant Therapy for Resectable NSCLC: Recommendations *Strauss GM, et al. ASCO 2006. Abstract 7007. Surgical resection +/- cisplatin-based* chemotherapy Stage IB Surgical resection in select patients + cisplatin-based chemotherapy Stage IIIA Surgical resection + cisplatin-based chemotherapy Stage II Surgical resection + observation Stage IA Recommended Treatment Stage
  • 21. Common Adjuvant Therapy Combinations
    • Drug combinations most frequently used in first-line chemotherapy for NSCLC
      • Vinorelbine and cisplatin
      • Gemcitabine and cisplatin
      • Paclitaxel and cisplatin
      • Docetaxel and cisplatin
  • 22. Meta-analysis of Prior Adjuvant Chemotherapy Studies Efficacy of Adjuvant Chemotherapy vs Observation Alone Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899-909. 5% Absolute Benefit at 5 Years 0.08 0.87 (0.74-1.02) Meta-analysis of cisplatin-based drugs P -value Hazard Ratio (95% CI) Overall Survival by Therapy Type
  • 23. Meta-analysis of Prior Adjuvant Chemotherapy Studies (cont.) No. at risk: Surgery plus chemotherapy 706 649 590 526 462 419 371 330 295 255 206 Surgery 688 633 648 482 433 382 353 307 258 215 177 Surgery plus chemotherapy Surgery Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899-909. HR=0.86 [0.74-1.02] P =0.08 0 10 20 30 40 50 60 70 80 90 100 0 6 12 18 24 30 36 42 48 54 60 Time from randomization (months) Percentage survival
  • 24. Randomized Adjuvant Chemotherapy Trials
    • IALT
      • Cisplatin-based chemotherapy vs observation
    • BR.10
      • Cisplatin/vinorelbine vs observation
    • CALGB 9633
      • Carboplatin/paclitaxel vs observation
    • ANITA
      • Cisplatin/vinorelbine vs observation
  • 25. IALT Schema: Cisplatin-based Adjuvant Chemotherapy RANDOMIZE Cisplatin-based chemotherapy + etoposide or vinorelbine (as prespecified by treating center) (n=935) Observation (n=932) Follow-up analysis
    • N=1867
    • Completely resected stage I-III NSCLC
    • Age > 18
    • PS 0-1
    Le Chevalier T, et al . N Engl J Med . 2004;350:351-360.
  • 26. IALT: Patient Characteristics Le Chevalier T, et al . N Engl J Med . 2004;350:351-360. 80%/20% 81%/19% Sex (M/F) 53% 40% 7% 54% 38% 8% PS 0 1 2 59 59 Median age 935 932 N Control Chemotherapy Outcome
  • 27. IALT: Effects of Cisplatin on Overall Survival 0% 20% 40% 60% 80% 100% 0 1 2 3 4 5 Years Chemotherapy Control Arriagada R, et al . N Engl J Med . 2004;350:351-360. At risk: Chemotherapy 932 775 624 450 308 181 Control 935 774 602 432 286 164 HR=0.86 [0.76-0.98] P <0.03
    • Absolute benefit at 5 years: 4.1%
    • 7,000 lives saved per year worldwide
  • 28. IALT Survival Rates and Toxicities
    • Survival
      • OS at 5 years: 44.5% vs 40.4% ( P <0.03)
        • 4.1% absolute benefit
      • DFS at 5 years: 39.4% to 34.3% ( P <0.003)
        • 5.1% absolute benefit
      • ERCC1 may predict benefit of cisplatin-based adjuvant chemotherapy
    • Toxicities
      • 0.8% risk of treatment-related death with chemotherapy (7 patients)
      • 23% risk of grade 4 toxicity, primarily neutropenia
    Arriagada R, et al . N Engl J Med . 2004;350:351-360; Soria J, et al . ASCO. 2006. Abstract 7010.
  • 29. JBR.10 Schema: Phase III Trial of Adjuvant Chemotherapy RANDOMIZE Vinorelbine 25 mg/m 2 every week for 16 weeks + cisplatin 50 mg/m 2 on days 1 and 8 every 4 weeks for 4 cycles (n=242) Observation (n=240) Follow-up analysis
    • N=482
    • Completely resected stage IB/II NSCLC
    • Age ≥18
    • PS 0-1
    • +/- K- ras mutations
    Winton T, et al. N Engl J Med . 2005;352:2589-2597.
  • 30. JBR.10: Effects of Vinorelbine and Cisplatin Adjuvant Chemotherapy Efficacy of Adjuvant Chemotherapy vs Observation Alone Winton T, et al. N Engl J Med . 2005;352:2589-2597. 0.03 54% 69% 5-year survival 0.009 73 months 94 months Median overall survival P -value Observation Group Chemotherapy Group Outcome
  • 31. JBR.10: Effects of Vinorelbine and Cisplatin Adjuvant Chemotherapy P =0.006 Winton T, et al. N Engl J Med . 2005;352:2589-2597. Overall Survival, All Patients 0 20 40 100 0 2 4 6 8 10 Years Probability (%) Vinorelbine plus cisplatin Observation 60 80 Hazard ratio for death: 0.69 ( P =0.04) 69% 54%
  • 32. JBR.10: Survival for Stage IB and Stage II Subsets No. at risk: Observation 108 91 57 29 8 0 Vinorelbine 111 91 65 27 6 0 plus cisplatin Winton T, et al. N Engl J Med . 2005;352:2589-2597. 0 20 40 60 80 100 0 2 4 6 8 10 Observation Vinorelbine plus cisplatin 0 20 40 60 80 100 0 2 4 6 8 10 Observation Vinorelbine plus cisplatin Years Probability (%) Overall Survival, Patients with Stage IB Non-small Cell Lung Cancer Overall Survival, Patients with Stage II Non-small Cell Lung Cancer No. at risk: Observation 112 91 57 18 5 0 Vinorelbine 111 100 54 24 6 0 plus cisplatin P =0.79 P =0.004 Years Probability (%)
  • 33. JBR.10: Adjuvant Chemotherapy in the Elderly Pepe C, et al. ASCO 2006. Abstract 7009. All randomized patients N=482 Observation N=240 *18 patients who received vinorelbine 30 mg/m 2 /week excluded Prognostic factors Dose intensity (N=150 vs 63 Chemotherapy toxicities (N=150 vs 63) Elderly (>65) N=67 Young (<65) N=157 *Chemotherapy N=224
  • 34. JBR.10: Adjuvant Chemotherapy in the Elderly Pepe C, et al. ASCO 2006. Abstract 7009. 0 2 4 6 8 10 12 1.0 0.8 0.6 0.4 0.2 0.0 H-R=0.61 Log-rank, P =0.04 Overall Survival by Treatment Arm, Age >65 Observation N=78 Chemotherapy N=77 66% 46% Time in years 0 2 4 6 8 10 12 1.0 0.8 0.6 0.4 0.2 0.0 H-R=0.66 Log-rank, P =0.13 Disease Specific Survival by Treatment Arm, Age >65 Observation N=78 Chemotherapy N=77 73% 46% Time in years Probability Probability
  • 35. JBR.10 Survival Rates and Toxicities
    • Survival
      • OS at 5 years was 69% vs 54% ( P =0.012)
      • RFS at 5 years was 61% vs 48% ( P =0.012)
    • Toxicities
      • Febrile neutropenia occurred in 7% of patients
      • Neurotoxicity (paresthesias, numbness, and hearing problems) was also observed
    RFS, relapse-free survival.
  • 36. CALGB 9633 Schema: Randomized Trial of Adjuvant Chemotherapy RANDOMIZE Paclitaxel 200 mg/m 2 over 3 hours + carboplatin AUC 6 both on day 1 every 3 weeks for 4 cycles (n=173) Observation (n=171) Follow-up analysis
    • N=384
    • Completely resected stage IB NSCLC
    • Age >18
    CALGB, cancer and leukemia group B. Strauss GM, et al. J Clin Oncol. 2004;22:7019; Strauss GM, et al. ASCO 2006. Abstract 7007.
  • 37. CALGB 9633: Overall Survival - ASCO 2004 vs ASCO 2006 Strauss GM, et al. J Clin Oncol. 2004;22:7019; Strauss GM, et al. ASCO 2006. Abstract 7007. ASCO: 2004 ASCO: 2006 0 2 4 6 8 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 0 1 2 3 4 5 6 7 8 9 0 2 4 6 8 Survival Time (Years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 0 1 2 3 4 5 6 7 8 9 HR=0.62; 90% CI: 0.44-0.89 P =0.01 HR=0.80; 90% CI: 0.60-1.07 P =0.10 Observation Chemo Observation Chemo Survival time (years) Survival time (years)
  • 38. CALGB 9633: Disease-free Survival – ASCO 2004 vs ASCO 2006 ASCO: 2004 ASCO: 2006 0 2 4 6 8 Survival time (years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability 0 1 2 3 4 5 6 7 8 9 Observation Chemo 0 2 4 6 8 Survival time (years) 0.0 0.2 0.4 0.6 0.8 1.0 Probability Observation Chemo 0 1 2 3 4 5 6 7 8 9 HR=0.69; 90% CI: 0.51-0.92 P =0.02 HR=0.74; 90% CI: 0.57-0.96 P =0.03 Strauss GM, et al. J Clin Oncol. 2004;22:7019;Strauss GM, et al. ASCO 2006. Abstract 7007.
  • 39. CALGB 9633 Survival Rates and Toxicities
    • Study was closed early after an interim analysis showed a P -value for OS less than pre-specified stopping boundary
      • DFS improved in intent to treat analysis with adjuvant chemotherapy
      • Trend toward improvement in OS but not significant ( P =0.10)
      • 3-year survival (79% vs 70%, P =0.45) compared with 5-year survival (60% vs 57%, P =0.32)
    • Toxicities
      • No treatment-related deaths were observed
      • Myelosuppression was the most common grade 3 or 4 toxicity
      • Grade 3 neuropathy occurred in 5% of patients
    Strauss GM, et al. J Clin Oncol. 2004;22:7019 2 ; Strauss GM, et al. J Clin Oncol. 2004;Suppl. 22:621a; Strauss GM, et al. ASCO 2006. Abstract 7007.
  • 40. ANITA Schema: Randomized Phase III Trial of Adjuvant Chemotherapy RANDOMIZE Vinorelbine 30 mg/m 2 /week for 16 weeks + cisplatin 100 mg/m 2 on day 1 every 4 weeks for 4 cycles (n=407) Observation (n=433) Follow-up analysis
    • N=840
    • Completely
    • resected stage
    • IB, II, or IIIA NSCLC
    • PS 0,1, or 2
    • Age 18-75
    Douillard J, et al. ASCO 2005. Abstract 7013 .
  • 41. ANITA: Effects of Vinorelbine and Cisplatin Adjuvant Chemotherapy Efficacy of Adjuvant Chemotherapy vs Observation Alone Douillard J, et al. ASCO 2005. Abstract 7013 . 0.013 P -value 7-year survival Median overall survival Outcome Hazard Ratio (95% CI) Observation Group Chemotherapy Group 0.79 (0.66-0.95) 36.8% 45.2% 43.8 months 65.8 months
  • 42. ANITA: Effects of Vinorelbine and Cisplatin in Stage I (p T2N0) Disease Stage I (p T2N0) Douillard J, et al. ASCO 2005. Abstract 7013 . 0.00 0.25 0.50 0.75 1.00 0 20 40 60 80 100 OBS NVB + CDDP Months Survival distribution function Overall Survival 120 Not reached 99.7 Median months 58 61 Death NVB + CDDP n=146 OBS n=155 Stage I (p T2N0)
  • 43. ANITA: Effects of Vinorelbine and Cisplatin in Stage II Disease Stage II Douillard J, et al. ASCO 2005. Abstract 7013 . 0.00 0.25 0.50 0.75 1.00 0 20 40 60 80 100 OBS NVB + CDDP Months Survival distribution function 120 65.8 36.5 Median months 46 70 Death NVB + CDDP n=89 OBS n=114 Stage II
  • 44. ANITA: Effects of Vinorelbine and Cisplatin in Stage IIIA Disease Stage IIIA Douillard J, et al. ASCO 2005. Abstract 7013 . 0.00 0.25 0.50 0.75 1.00 0 20 40 60 80 100 OBS NVB + CDDP Months Survival distribution function 120 38.6 24.1 Median months 99 118 Death NVB + CDDP n=166 OBS n=159 Stage IIIA
  • 45. ANITA Survival Rates and Toxicities
    • Survival
      • Median survival was 65.8 months vs 43.7 months ( P =0.0131)
      • OS at 2 years was 68% vs 63%
      • OS at 5 years was 51% vs 43%
      • OS at 7 years was 45% vs 37%
    • Toxicities
      • Grade 3/4 toxicities
        • Neutropenia 86%
        • Febrile neutropenia 8.5%
        • Peripheral neuropathy 3%
      • 5 patients (1%) died of drug-related toxicity
  • 46. Summary: Randomized Adjuvant Chemotherapy Trials
    • IALT
      • Supported platinum-based chemotherapy, results were moderately significant
    • BR.10
      • Statistical advantage in prolonging overall survival demonstrated
    • CALGB 9633
      • Risk of death found to be significantly lower
    • ANITA
      • Overall survival and relapse rate significantly improved
  • 47. LACE: Adjuvant Cisplatin-based Chemotherapy Improves Survival
    • Meta-analysis of individual patient data collected and pooled from the 5 largest trials (ALPI, ANITA, BLT, IALT and JBR10) of cisplatin-based therapy in completely resected patients
    • Compared cisplatin-based CT vs no CT, or cisplatin-based CT + radiotherapy vs postoperative radiotherapy
    • Primary endpoint
      • Overall survival
    Pignon JP , et al. ASCO 2006. Abstract 7008 .
  • 48. LACE: Overall Survival By Trial Trials (associated drug(s)): ALPI, MTC+VDS; ANITA, NVB; BLT, NVB/VDS/MTC+VDS/MTC+IFM; JBR10, NVB; IALT, NVB/VDS/VLB/VP16. Pignon JP , et al. ASCO 2006. Abstract 7008 . OS by Trail Tests for heterogeneity: P =0.34 Chemotherapy effect: P =0.004 Chemotherapy better Control better 0.0 0.5 1.0 1.5 2.0 0.89 [0.82; 0.96] 2356/4584 Total 0.71 [0.54; 0.94] 197/482 JBR10 0.91 [0.80; 1.03] 980/1867 IALT 1.00 [0.72; 1.38] 152/307 BLT 0.82 [0.68; 0.98] 458/840 ANITA 0.95 [0.81; 1.12] 569/1088 ALPI HR [95% CI] Hazard Ratio (Chemotherapy/Control) No. Deaths/ No. Entered Trail
  • 49. LACE: Benefit Appears to Be Stage Dependent Pignon JP , et al. ASCO 2006. Abstract 7008 . CT Effect and Stage Tests for trend: P =0.051 CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin+vinorelbine (13% of stage IA patients vs ~43% for other stages) Chemotherapy better Control better 0.5 1.0 1.5 2.0 2.5 0.83 [0.73; 0.95] 865/1247 Stage III 0.83 [0.73; 0.95] 880/1616 Stage II 0.92 [0.78; 1.10] 509/1371 Stage IB 1.41 [0.96; 2.09] 102/347 Stage IA HR [95% CI] Hazard Ratio (Chemotherapy/Control) No. Deaths/ No. Entered Category
  • 50. LACE: Summary
    • Cisplatin-based chemotherapy improves overall and disease-free survival in patients with NSCLC
    • Multi-variant analyses were not able to study the role of the associated drug and cisplatin dose, despite the large number of patients
    • Cisplatin-based chemotherapy is effective in stage II and III NSCLC
    Pignon JP , et al. ASCO 2006. Abstract 7008 .
  • 51. CISCA: Cisplatin vs Carboplatin Meta-analysis
    • Randomized trials comparing cisplatin- and carboplatin-based chemotherapy
      • Primary endpoint
        • Overall survival
      • Secondary endpoints
        • Response rate and toxicity
    • 2,968 patients were randomized to receive CT with cisplatin (1,489) or with carboplatin (1,479), respectively
      • RR was 30% (cisplatin) vs 24% (carboplatin)
    • Carboplatin was associated with a relative risk of death 7% higher compared with cisplatin, P =0.101)
    Ardizzoni A. ASCO 2006. Abstract 7011.
  • 52. Adjuvant Chemotherapy: Summary
    • Adjuvant chemotherapy in the setting of completely resected NSCLC is a subject of controversy
    • Statistically significant survival benefit to such chemotherapy
    • Toxicities related to treatment call into question whether this apparent clinical benefit warrants the risk
  • 53. Management of Treatment-related Toxicities
  • 54. Common Symptoms/Side Effects in NSCLC
    • Symptoms related to disease
      • Dyspnea
      • Pain
      • Fatigue
    • Symptoms related to treatment
      • Myelosuppression
      • Pain
      • Fatigue
  • 55. Management of Dyspnea
    • Assessment challenging, subjective; based on patient’s responses
    • Activity planning to avoid symptoms and allow relief
    • Medications
      • Corticosteroids
      • Opioids
      • Oxygen therapy
    • Nontraditional/investigational therapies
      • Acupuncture
      • Massage
      • Exercise
    Bruera E, et al. Principles and Practice of Supportive Oncology. Philadelphia, PA: Lippincott-Raven Publishers; 1998:295-308.
  • 56. Management of Pain
    • Assessment
      • Must identify etiology for effective treatment
    • Medications
      • Opioids
      • NSAIDs
      • Corticosteroids
    • Nonpharmacologic interventions
      • Heat/cold
      • Topical agents
      • Massage
      • Behavioral therapy
    National Cancer Institute. Pain (PDQ) Health Professional Version. Available at: http://www.cancer.gov/cancertopics/pdq/supportivecare/pain/Patient/page4. Accessed January 30, 2006.
  • 57. Myelosuppression
    • Most common side effect of chemotherapy
      • Neutropenia
      • Anemia
    • Neutropenia is the primary dose-limiting toxicity of chemotherapy
      • Often results in dose reductions or delays in treatment
    Rivera E. Breast Cancer Res. 2003; 5(5): R114-R120; Crawford J. J Support Oncol . 2004;2(suppl 2):36-39.
  • 58. Neutropenia
    • Chemotherapy-induced neutropenia can lead to febrile neutropenia
    • Febrile neutropenia (FN)
      • ANC >1.0×10 9 /L with a temperature >100.6°F
      • ~30% of patients receiving CT for NSCLC
      • Regimens with an intermediate risk of FN (10%-20%)
        • Cisplatin, paclitaxel
      • Regimens with a high risk of FN (>20%)
        • Docetaxel, carboplatin
        • Gemcitabine, ifosfamide, vinorelbine
    ANC, absolute neutrophil count; CT, chemotherapy. Rivera E. Breast Cancer Res . 2003; 5(5): R114–R120 ; Kuderer NM, et al. Proc Am Soc Clin Oncol . 2002;21:250a; Bonadonna G, et al. BMJ . 2005;330:217.
  • 59. Neutropenic Complications and Considerations
    • Febrile neutropenia, severe neutropenia, or dose delay or reduction due to neutropenia
    • Prophylactic use of colony-stimulating factors can reduce the risk, severity, and duration of severe and FN
    • Maintaining chemotherapy dose intensity in the initial cycles may be associated with improved outcomes
    Caggiano V, et al. Cancer . 2005;103:1916-1924; Kuderer NM, et al. Proc Am Soc Clin Oncol . 2002;21:250a; Bonadonna G, et al. BMJ . 2005;330:217.
  • 60. Assessment of Febrile Neutropenia
    • Assessment
      • Risk factors predictive for febrile neutropenia
    Ozer H, et al. J Clin Oncol . 2000;18:3558-3585. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment . v2.2005. 2005. Comorbid disease Bone marrow involvement Preexisting neutropenia from radiation therapy to bone marrow History of recurrent chemotherapy-induced neutropenia Poor performance status Preexisting neutropenia from prior myelosuppressive therapy Active tissue infection Increasing age
  • 61. 2005 NCCN Guidelines: D ecision Tree for Primary Prophylaxis Disease Intermediate10%-20% Risk 1. Evaluate 2. Assess Risk* 3. Intervene Chemotherapy Regimen Patient Risk Factors Treatment Intent High >20% Risk Low <10% Risk *Risk of FN or neutropenic event compromising treatment. Consider G-CSF Use G-CSF No Routine G-CSF
  • 62. Clinical Benefit of Pegfilgrastim in First and Subsequent Cycles S CR E E N I NG C H EMO T H E RA P Y * RANDOM I Z A T I ON Febrile Neutropenia Placebo n = 465 Pegfilgrastim n = 463 Double-blind Phase Docetaxel + Pegfilgrastim OR Docetaxel Alone Open-label Phase * Docetaxel 100 mg/m 2 IV given on day 1 and blinded product given on day 2. Four 21- day cycles were planned. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184.
  • 63. Clinical Benefit of Pegfilgrastim in First and Subsequent Cycles (cont.) Efficacy of Pegfilgrastim for Preventing Febrile Neutropenia Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 10% 14% 17% Placebo (n=465) 80 93 94 % Reduction <0.001 2% Use of IV anti-infectives <0.001 1% Hospitalization for febrile neutropenia <0.001 1% Febrile neutropenia P -value Pegfilgrastim (n=463) Outcome
  • 64. Use of Pegfilgrastim in NSCLC
    • 2 small trials performed in NSCLC patients
      • A single pegfilgrastim dose per cycle maintains neutrophil counts after docetaxel and gemcitabine chemotherapy for advanced NSCLC 1
      • A single pegfilgrastim dose per cycle of dose-dense carboplatin/vinorelbine protects against FN 2
    1. Fortner BV, et al. 2003 ASCO Annual Meeting. Abstract 2799; 2. Riedel R, et al. Abstract 2826 .
  • 65. Prevention of FN: Growth Factor Support Misset JL, et al. Ann Oncol. 1999;10:553-560; Green MD, et al. Ann Oncol. 2003;14:29-35; Holmes FA, et al. J Clin Oncol . 2002;20:727-731. 18 20 38 9 13 0 5 10 15 20 25 30 35 40 FN rate (%) (n=42) (n=80) (n=77) (n=156) (n=154) Misset et al. Green et al. Holmes et al*. N=42 N=157 N=310 Pegfilgrastim Control Filgrastim
  • 66. Colony Stimulating Factor Support: Summary
    • Dose delay and dose reduction can result in care that is less than optimal
    • Reductions in total dose and dose intensity have an adverse effect on DFS and OS
    • Prophylactic growth-factor support appears to decrease treatment-related morbidity and to increase the likelihood of the administration of full-dose chemotherapy on time
    Crawford J. J Support Oncol. 2004;2(suppl 2):36-39.
  • 67. Growth Factor Support: Unanswered Questions
    • If growth factor support is provided, would the dose intensity delivered increase and by how much?
    • Would the rate of neutropenic complications increase because of the higher chemotherapy dose delivered?
    Crawford J. J Support Oncol. 2004;2(suppl 2):36-39.
  • 68. Anemia
    • Anemia defined as hemoglobin <11 g/dL
    • Anemia is a common complication of cancer and cancer treatment
      • 50%-60% patients will develop anemia
      • Severity of anemia increases with the use of platinum combination chemotherapy
    • Anemia treatment can improve quality of life (QOL) and clinical outcomes
    Okamoto, et al. Ann Oncol . 1992;3:819-824; Langer C. Chemotherapy Foundation Symposium XXI 2003.
  • 69. Causes of Cancer-related Anemia
    • Disease-related anemia
      • Tumor type
      • Stage and duration of disease
      • Presence of infection
    • Treatment-related anemia
      • Regimen and intensity of therapy
        • Chemotherapy
        • Radiation therapy
        • Surgical intervention
      • Prior cancer treatment
  • 70. Hemoglobin and Performance Status
    • A significant correlation was found between poor performance status score and low Hb level breast cancer ( P <0.001)
    Barrett-Lee P. Oncologist , 2005;10:743-757. WHO Performance Score 0 10.0 10.5 11.0 11.5 12.0 13.0 12.5 0 1 2 3 4 Hb level (g/dL) Breast cancer Gynecologic cancer 95% CI: WHO 0, 12.654-12.785; WHO 1, 12.423-12.587; WHO 2, 11.878-12.222; WHO 3, 11.484-12.223; WHO 4, 8.613-13.634
  • 71. Clinical Consequences of Anemia
    • Chemotherapy may be more toxic or less effective when patients are anemic
      • Fatigue
      • “ Full dose on time”
    Decreased Quality of Life Reduced Treatment Success Decreased Survival Cella D. Semin Oncol. 198;25(suppl 7):43-46; Ludwig H, et al. Semin Oncol. 198;25 (suppl 7):2-6; Grogan M, et al. Cancer . 1999;86:1528-1536; Dubray B, et al. Radiology . 1996;201:553-558; Lee W, et al. Int. J. Radiol. Oncol Biol. Phys. 1998;42:1069-1075.
  • 72. Patient-reported Areas Negatively Affected by Fatigue Vogelzang NJ, et al. Semin Hematol . 1997;34(suppl 2):4-12. 0 10 20 30 40 50 60 70 Concerns about mortality and survival Relationships with family and friends Ability to take care of family Intimacy with partner Emotional well-being Ability to enjoy life in the moment Physical well-being Ability to work Patients (%) 61 60 57 51 44 42 38 33
  • 73. Anemia and Risk of Death 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Lung Head and neck Prostate Lymphoma Overall Relative risk of death (%) Stasi R, et al. Oncologist . 2005;10:539-554.
  • 74. Management of Anemia
    • Iron supplementation
    • Change in chemotherapy regimen
    • RBC transfusion
    • Erythropoietic-stimulating agents
      • Recombinant human erythropoietin (rHuEPO)
        • eg, epoetin alfa, epoetin beta
        • Only 50%-60% of patients respond
      • Darbepoetin alfa (erythropoiesis-stimulating protein)
        • 2 to 3 times longer serum half-life than rHuEPO
    Dicato M. Oncologist . 2003;8:19-21. Gordon MS. Oncologist . 2002;7:331-341; NCCN. Clinical Practice Guidelines in Oncology: Cancer- and Treatment-Related Anemia . v1.2006. 2006.
  • 75. Erythropoietin Therapy
    • Advantages
      • Avoids risks of transfusion therapy
        • Allergic/febrile reactions
        • Transfusion-associated immunosuppression
        • Formation of alloantibodies
    • Disadvantages
      • Response not as rapid as therapy via transfusion
        • Response can take > 4 weeks
      • Can cause hypertension or splenomegaly
    Dicato M. Oncologist . 2003;8:19-21. Goodnough LT, et al. N Engl J Med . 1999;340:438-447;Ludwig H, et al. Semin Oncol .1998;25(suppl 7)2-6.
  • 76. Erythropoietic Agents for Treatment of Anemia in Cancer Patients
    • Recombinant human erythropoietin (rHuEPO)
      • eg, epoetin alfa, epoetin beta
      • Has the same biological effects as erythropoietin
      • Only 50%-60% of patients respond
    • Darbepoetin alfa
      • Erythropoiesis-stimulating protein
      • 2 to 3 times longer serum half-life than rHuEPO
  • 77. Erythropoietic Therapy Recommendations
    • National Comprehensive Cancer Network (NCCN)
      • Initiate erythropoietic therapy in patients with Hg <11 g/dL
    • American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO)
      • Initiate erythropoietic therapy in patients with Hg < 10 g/dL
      • RBC transfusion should be considered depending on the severity of anemia or clinical consequences
    NCCN Practice Guidelines in Oncology – v.1.2006. Rizzo JD, et al. J Clin Oncol. 2002;20: 4083-4107.
  • 78. Erythropoietic Intervention Late Intervention/ Hb Correction Early Intervention/ Hb Maintenance 11 10 Erythropoietic Treatment Transfusion? Chemotherapy treatment 6 Hemoglobin (g/dL) Adapted from Rearden, TP. J Clin Oncol , 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 8064. Transfusion Chemotherapy treatment Hemoglobin (g/dL) 12 11 13 10 6 8.5 Erythropoietic Treatment 12 13 8.5
  • 79. Clinical Benefit of Darbepoetin alfa and Epoetin alfa Schwartzberg LS, et al. Oncologist . 2004;9:696-707. Darbepoetin alfa 200  g q2 wk END OF TREATMENT 2 weeks after last dose of darbepoetin alfa or 1 week after last dose of epoetin alfa Epoetin alfa 40,000 U q wk END OF STUDY 2 weeks after end-of-treatment visit Concurrent chemotherapy 1 5 9 13 17 19 (Baseline) Study week RANDOMIZE
  • 80. Clinical Benefit of Darbepoetin alfa and Epoetin alfa Schwartzberg LS, et al. Oncologist . 2004;9:696-707. Individual Analysis by Tumor Type 6% 27% 21% 16% 18% 17% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% Breast Lung Gyn Proportion of patients requiring a transfusion Q2W Darbepoetin alfa QW Epoetin alfa n= 72 69 51 51 34 35 Combined Analysis by Baseline Hemoglobin and Overall 21% 14% 16% 42% 9% 17% 0% 10% 20% 30% 40% 50% 60% 70% <10 g/dL > 10 g/dL Overall Proportion of patients requiring a transfusion n= 38 38 119 117 157 155 Q2W Darbepoetin alfa QW Epoetin alfa
  • 81. Clinical Benefit of Darbepoetin alfa and Epoetin alfa Darbepoetin alfa vs Epoetin alfa for Treating Anemia Schwartzberg LS, et al. Oncologist . 2004;9:696-707. 12.2 g/dL 12.1 g/dL Mean hemoglobin level after achieving target 10.1 weeks 9.3 weeks Mean duration of treatment 4 weeks 5 weeks Median time to target hemoglobin 86% 82% Patients achieving target hemoglobin ≥11 g/dL Epoetin alfa (n=155) Darbepoetin alfa (n=157) Outcome
  • 82. Noninferiority Study of Darbepoetin alfa (DA) and Epoetin alfa (EA)
    • Randomized, open-label, active-controlled, multicenter study
      • DA at a starting dose of 200 µg Q2W over 16 weeks for the treatment of anemia in patients receiving multicycle chemotherapy
      • The active control arm received EA at a starting dose of 40,000 U QW
    • After the 16-week treatment period, patients were monitored for 2 weeks for adverse events, concomitant medications, and transfusions received
    Glaspy J, et al. J Clin Oncol . 2006;24:2290-2297.
  • 83. Incidence of RBC Transfusions and Sensitivity Analyses A: Percentages of patients receiving ≥ one transfusion B: Sensitivity analyses—adjusted by screening hemoglobin category (<10 g/dL vs 10 g/dL) and type of chemotherapy administered (platinum-based vs nonplatinum-based) Glaspy J, et al. J Clin Oncol . 2006;24:2290-2297. Mean (95% CI) Difference between Treatment Groups In favor of darbepoetin alfa In favor of epoetin alfa Per protocol analysis set (16 week cohort) Primary transfusion analysis set/ primary analysis set (16 week cohort) Per protocol analysis set (all cohorts) -16 -12 -8 -4 0 4 8 12 16 Noninferiority margin 11.5% 1.3% 5.0% 3.6% In favor of darbepoetin alfa In favor of epoetin alfa -16 -12 -8 -4 0 4 8 12 16 11.5% 0.4% 3.0% 4.4% 0 0.1 0.2 0.3 0.4 0.5 0.6 Darbepoetin alfa Epoetin alfa Historical (placebo) Historical (epoetin alfa) Proportion of patients (95% CI) 0 0.1 0.2 0.3 0.4 0.5 0.6 Darbepoetin alfa Epoetin alfa Historical (placebo) Historical (epoetin alfa) Proportion of patients (95% CI) 21% 16% 45% 26% 27% 22% 51% 25%
  • 84. Effect of Darbepoetin alfa and Epoetin alfa on Hemoglobin Glaspy J, et al. J Clin Oncol . 2006;24:2290-2297. Hemoglobin (Hb) Concentration over Treatment Period Achievement of Target Hemoglobin Range (11 g/dL to 13 g/dL) by Study Week 10.18 11.44 11.75 10.21 11.76 11.85 8 9 10 11 12 13 14 Baseline Week 9 Week 17 Mean (upper 95% CI) Hb levels (g/dL) Darbepoetin alfa Epoetin alfa Target range n=606 n=603 n=433 n=431 n=278 n=245 0 0.2 0.4 0.6 0.8 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time (weeks) Proportion of patients Darbepoetin alfa Epoetin alfa Patients at risk: Darbepoetin alfa 606 606 586 521 395 360 290 266 220 194 164 150 122 116 98 86 69 42 Epoetin alfa 603 603 577 515 344 302 220 195 147 132 106 97 66 57 48 38 30 21
  • 85. Darbepoetin alfa and Epoetin alfa Provide Comparable Outcomes
    • Safety profiles of DA and EA were consistent with adverse events in anemic cancer patients receiving chemotherapy with no differences observed between groups
    • The ability to extend dosing intervals represents an important potential benefit for patients and their caregivers
    Glaspy J, et al. J Clin Oncol . 2006;24:2290-2297. Overall health Daily activity Energy FACT-anemia FACT-fatigue -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 Mean (95% CI) Difference between Treatment Groups In favor of epoetin alfa In favor of darbepoetin alfa
  • 86. Darbepoetin alfa 300  g Q3W: Study Schema Boccia R, et al. Oncologist . 2006;11:409-417. N=1225, 29% breast cancer S C R E E N I N G E N R O L L M E N T E N D O F S T U D Y 7 days max 4 days max 2 3 4 5 6 7 * 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 Darbepoetin alfa 300  g Q3W Darbepoetin alfa administration Study week Darbepoetin alfa 300  g Q3W 500  g Q3W
    • No erythropoietic agent within 4 weeks of screening
    • At least 8 additional weeks of chemotherapy
    • Adequate renal and liver function
    • Patients ≥18 years old with nonmyeloid malignancies
    • Baseline Hb ≥11 g/dL
    • No RBC transfusion within 2 weeks of screening
    Key Eligibility Criteria
  • 87. Darbepoetin alfa (DA) 200  g Q2W vs 300  g Q3W
    • DA 200  g Q2W has been shown to be as effective as epoetin alfa 40000 U QW for the treatment of chemotherapy-induced anemia 1
    • DA 300  g Q3W is well-tolerated and effective for achieving and maintaining evidence-based target Hb levels, allowing for synchronous administration with common chemotherapy regimens 2
    1. Schwartzberg LS, et al. Oncologist . 2004;9:696-707; 2. Boccia R, et al. Oncologist . 2006; 11:409-417.
  • 88. 500  g Darbepoetin alfa Q3W for Chemotherapy-induced Anemia
    • Chemotherapy-induced anemia can be treated with a fixed dose of 500  g Q3W of darbepoetin alfa with comparable efficacy to 2.25  g/kg weekly dosing
    • Patients receiving Q3W dosing received fewer blood transfusions than in the weekly arm
    • 84% of Q3W patients achieved the target hemoglobin levels ( > 11 g/dL) compared with 77% QW patients
    • Synchronous administration of darbepoetin alfa Q3W with many chemotherapy schedules would be convenient to patients and their healthcare providers
    Canon JL et al. J Natl Cancer Inst. 2006;98(4):273-284.
  • 89. Anemia and Erythropoietic Therapy: Summary
    • Cancer-related anemia is common but under-recognized and under-treated
    • Anemia is associated with reduced survival
    • Darbepoetin alfa has an approximate threefold longer half-life than epoetin alfa and is effective at weekly, Q2W, and Q3W dosing intervals
    • Less frequent dosing schedules that have equal efficacies are an obvious benefit to patients
  • 90. Neoadjuvant Therapy
  • 91. Neoadjuvant Chemotherapy
    • Preoperative chemotherapy may improve the prognosis and survival
    • Goal
      • Downstage the tumor before surgery, increasing the chances for resection
  • 92. Neoadjuvant Therapy Plus Surgery vs Surgery Alone
    • Survival improves significantly with neoadjuvant therapy
    Rosell R, et al. N Engl J Med . 1994;330(3):153-158. 8 months 5 months 74 months Surgery alone 20 months 56 months 26 months Induction CT  surgery <0.001 0.65 Disease-free survival Rate of recurrence <0.001 Median overall survival P -value Treatment (N=60)
  • 93. SWOG 9900 Trial: Schema Paclitaxel carboplatin x 3 cycles Surgery Surgery E L I G I B L E
    • N=600
    • Clinical stage: T2N0,
    • T1-2N1, T3N0-1
    Pisters K, et al. ASCO 2005. Abstract 7012. RANDOMIZE
  • 94. SWOG 9900: Induction Chemotherapy Pisters K, et al. ASCO 2005. Abstract 7012. HR=0.84 [0.60-1.18] P= 0.32 0% 20% 40% 60% 80% 100% 0 12 24 36 48 60 Months Preop Control 64% 79% 40 mo Control 68% 82% 47 mo Preop 2 y 1 y Median
  • 95. SWOG 9900: Induction Chemotherapy (cont.)
    • Overall survival favors and the role of preoperative chemotherapy
    Pisters K, et al. ASCO 2005. Abstract 7012. 40 months Surgery alone 0.32 47 months Induction CT  surgery SWOG 9900 P -value Median Overall Survival Treatment
  • 96. Treatment-related Toxicities and Induction Therapy
    • Death
    • Neutropenia
    • Esophagitis
    • Nausea/emesis
    • Pneumonia
  • 97. Adjuvant vs Neoadjuvant Therapy: Summary
    • Preoperative treatment may have a favorable effect on outcome
    • Aggressive neoadjuvant approaches may be accompanied by treatment-related toxicities, including death
  • 98. Treatment of Advanced Non-small Cell Lung Cancer
  • 99. Stage IV Disease: Goals of Therapy
    • Stage IV NSCLC
      • Indicates presence of metastatic disease
      • Largely incurable
      • Properly selected patients may benefit from chemotherapy with regard to survival and palliation
    • Goals of treatment are
      • To prolong survival
      • Palliative
      • To improve quality of life
  • 100. Best Supportive Care vs Chemotherapy in Advanced Patients Socinski M. Chest . 2003;123:226S-243S. 0 10 20 30 40 50 60 70 80 90 100 0 6 12 18 24 Time from randomization (months) Percentage survival Best supportive care (BSC) + chemotherapy Supportive care No. at risk: BSC + chemotherapy 416 219 98 47 28 Supportive care 362 125 55 28 14
  • 101. Best Supportive Care and Chemotherapy Prolong Survival Socinski M. Chest . 2003;123:226S-243S. 0 10 20 30 40 BSC CT+BSC BSC CT+BSC 1-y survival % 5 10 15 20 No. of patients alive in the US at 1 year
  • 102. Current Treatment Guidelines for Metastatic NSCLC
    • BSC, best supportive care
    Stage IV NSCLC PS 3, 4 PS 0-2 BSC 1 st Line Platinum-based Chemotherapy Progression PS 3, 4 PS 0-2 BSC 2 nd Line Platinum-based Chemotherapy Progression PS 3, 4 PS 0-2 BSC Gefitinib or Phase I/II Clinical Trial Adapted from NCCN Practice Guidelines in Oncology v.2.2006.
  • 103. ECOG E1594 Schema: Efficacy in Comparable Platinum-based Regimens RANDOMIZE Paclitaxel 175 mg/m 2 /week over 24 hours, day 1 Cisplatin 75 mg/m 2 day 2, every 3 weeks (n=288) Follow-up analysis
    • N=1155
    • Stage IIIB/IV
    • PS 0-2
    • Weight loss
    • Brain metastases (+/-)
    Gemcitabine 1000 mg/m 2 day 1, 8, 15 Cisplatin 100 mg/m 2 day 1, every 4 weeks (n=288) Docetaxel 75 mg/m 2 day 1 Cisplatin 75 mg/m 2 day 1, every 3 weeks (n=289) Paclitaxel 225 mg/m 2 over 3 hours, day 1 Carboplatin AUC=6 day 1, every 3 weeks (n=289)
  • 104. ECOG E1594: Comparable Efficacy in Platinum-based Regimens Cis/Paclitaxel Cis/Gemcitabine Cis/Docetaxel Carbo/Paclitaxel 0 0.2 0.4 0.6 0.8 1.0 0 5 10 15 20 25 30 Months Schiller JH, et al. N Engl J Med. 2002;346:92-98. Survival by Treatment Group
  • 105. ECOG 1594: Regimens and Efficacy Schiller JH, et al. N Engl J Med. 2002;346:92-98. 3.5 31% 7.8 21% Paclitaxel 175 mg/m 2 Cisplatin 75 mg/m 2 3.6 31% 7.4 17% Docetaxel 75 mg/m 2 Cisplatin 75 mg/m 2 4.5 36% 8.1 21% Gemcitabine 1000 mg/m 2 d1, 8, 15 Cisplatin 100 mg/m 2 d1 3.3 Time to Progression (months) 38% 1-year Survival 8.2 15% Paclitaxel 225 mg/m 2 Carboplatin AUC=6 Median Survival (weeks) Response Rate Regimen
  • 106. ECOG 1594 Findings
    • Survival curves demonstrate comparable efficacy between various platinum-based regimens
    • No difference in long-term survival was observed
  • 107. “Modern Agents” for Treatment of Advanced NSCLC
    • Paclitaxel-based regimens
    • Docetaxel-based regimens
    • Vinorelbine-based regimens
    • Gemcitabine-based regimens
    • Irinotecan-based regimens
  • 108. Comparison of Advanced NSCLC Therapies Wakelee H, Belani CP . Oncologist . 2005;10(suppl 3):1-10. 30% 20% 10% 1 year ~10 months 6 months 4 months Median survival time Modern Doublet Chemotherapy Platinum-based Chemotherapy Supportive Care Survival <5% 10% 0% 2 years
  • 109. First-line Chemotherapy in Advanced Disease: Summary
    • Platinum-based therapy is standard first-line treatment for advanced NSCLC
    • Non-platinum regimens have similar efficacy and prolong survival to similar extents as platinum-based therapy
    • Non-platinum regimens do not show substantially decreased toxicity but may be better tolerated
    1. Georgoulias V, et al. J Clin Oncol. 2005;23:2937-2945; 2. Pujol JL, et al. Ann Oncol . 2005;16:602-610; 3. Kosmidis PA, et al. J Clin Oncol . 2005;23:621s; 4. Gridelli C, et al. J Clin Oncol . 2003;21:3025-3034.
  • 110. Stage IV Disease: Second-line Therapy Second-line Treatment for Advanced NSCLC 1. Hanna N, et al. J Clin Oncol . 2004;22:1589-1597; 2. Shepherd FA, et al. N Engl J Med . 2005;353:123-132; 3. Shepherd FA, et al. J Clin Oncol . 2000;18:2095-2103. 7.9 months 8.8% Docetaxel NS 8.3 months 9.1% Pemetrexed Hanna et al. 1 4.6 months Best supportive care 0.047 7.0 months Docetaxel Shepherd et al. 3 4.7 months <1.0% Placebo <0.001 6.7 months 8.9% Erlotinib Shepherd et al. 2 P- value Median Survival Time Overall Response Rate Treatment Study
  • 111. Second-line Therapy vs BSC: Shepherd et al. Shepherd FA, et al. J Clin Oncol . 2000;18:2095-2103 . RANDOMIZE Docetaxel 100 mg/m 2 (n=49) Best supportive care (n=100)
    • N=204
    • Stage IIIB/IV NSCLC
    • Failed/intolerant to ≥1 prior chemotherapy regimen
    • PS 0-2
    • Primary endpoint
    • Overall survival
    • Secondary
    • endpoints
    • Objective tumor response
    • Duration of response
    • Changes in quality of life
    Docetaxel 75 mg/m 2 (n=55)
  • 112. Chemotherapy Still Shows Benefits vs BSC as Second-line Therapy Shepherd FA, et al. J Clin Oncol . 2000;18:2095-2103 . 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 3 6 9 12 15 18 21 Survival time (months) Cumulative probability 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 3 6 9 12 15 18 21 Survival time (months) Cumulative probability Docetaxel 100 mg/m 2 (n=49) BSC100 (n=51) Log-rank test, P =0.780 Log-rank test, P =0.010 Docetaxel 75 mg/m 2 (n=55) BSC75 (n=49)
  • 113. Chemotherapy Still Shows Benefits vs BSC as Second-line Therapy (cont.) Shepherd FA, et al. J Clin Oncol . 2000;18:2095-2103 . 19% 29% 1-year survival 0.047 4.6 months 7.0 months Median overall survival P -value Best Supportive Care Arms Outcome
  • 114. Hematologic Toxicities Associated with Treatment *Incidence of grade 3/4 toxicity per patient. Shepherd FA, et al. J Clin Oncol . 2000;18:2095-2103 . 6.1 3 0 0 2.9 3 Septic deaths 22.4 11 1.8 1 11.5 12 Febrile neutropenia 2.0 1 0 0 1.0 1 Thrombocytopenia 85.7 42 67.3 37 76.0 79 Neutropenia 16.3 8 5.5 3 10.6 11 Anemia 49 55 104 Total no. of patients % No. % No. % No. 100 mg/m 2 75 mg/m 2 Overall Docetaxel * Toxicity
  • 115. Phase III Pemetrexed vs Docetaxel for Second-line NSCLC Hanna N, et al. J Clin Oncol . 2004;22:1589-1597. RANDOMIZE Pemetrexed 500 mg/m 2 + Vitamin B 12 + Folic acid + Dexamethasone (n=283) Docetaxel 75 mg/m 2 + Dexamethasone (n=288)
    • N=571
    • Stage IIIB/IV NSCLC
    • Failed/intolerant to 1 prior chemotherapy regimen
    • PS 0-2
    • Primary endpoint
    • Overall survival
    • Secondary
    • endpoints
    • Toxicity
    • Objective response rate
    • Progression-free survival
    • Time to progression
    • Quality of life
  • 116. Phase III Pemetrexed vs Docetaxel for Second-line: Survival Hanna N, et al. J Clin Oncol . 2004;22:1589-1597. 0 0.25 0.5 0.75 1 0 5 10 15 20 Survival time (months) Survival distribution function Pemetrexed (n=265) Docetaxel (n=276) Patients at risk: Pemetrexed 283 189 78 16 0 Docetaxel 288 177 78 19 1 HR=0.99 (95% CI, 0.8 to 1.2) 29.7% 29.7% 1-y OS 47 mo 40 mo MST
  • 117. Stage IV Disease: Current Questions
    • In which patients is chemotherapy appropriate?
    • What is the optimal chemotherapeutic approach?
      • Regimen?
      • Duration?
    • Does second-line chemotherapy improve survival?
    • How do outcomes and adverse effects associated with chemotherapy compare with the natural history of the disease?
  • 118. Treatment in the Elderly Population and Poor Performance Status Patients
  • 119. Elderly and Poor Performance Status Patients
    • Cisplatin regimens provide a slight advantage over supportive care but can induce severe toxic effects
    • Consequently, treatment is frequently contraindicated in the elderly and patients with poor PS
      • Reduction in the functional reserve of many organs and comorbid conditions
  • 120. CALGB 9730: Monotherapy vs Combination Therapy Lilenbaum RC, et al. J Clin Oncol . 2005;23:190-196. <0.0001 30 17 Response rate, % 1-year survival, % Median failure-free survival, mo Outcome NS 27 32 0.0002 4.6 2.5 P -value Paclitaxel + Carboplatin Paclitaxel
  • 121. CALGB 9730: Age >70 Lilenbaum RC, et al. J Clin Oncol . 2005;23:190-196. 31% 35% 1-year survival 5.8 8.0 Median survival 21% 36% Response rate Paclitaxel Paclitaxel + Carboplatin
  • 122. CALGB 9730: PS 2 Lilenbaum RC, et al. J Clin Oncol . 2005;23:190-196. 50 40 n 14% 17% 1-year survival 2.4 4.7 Median survival 10% 24% Response rate Paclitaxel Paclitaxel + Carboplatin
  • 123. Efficacy of Platinum-based Doublets: STELLAR 3 * P <0.05. Langer CJ, et al. ASCO 2005. Abstract 7011.
    • Efficacy and tolerability similar in older vs younger patients and poor vs good PS patients
    43% 14% Alopecia* 6% 2% All cardiac events* 31% 17% Arthralgia/myalgia* (all grades) 17% 28% Grade 3/4 neutropenia* 10% 17% Grade 3/4 neuropathy 31% 31% 1-year overall survival 8.0 7.9 Median overall survival, months Paclitaxel + Carboplatin (n=198) Paclitaxel Poliglumex + Carboplatin (n=199) Outcome
  • 124. SWOG 9308 and 9509: Retrospective Analysis in Advanced NSCLC SWOG 9308: Vinorelbine + cisplatin vs cisplatin. SWOG 9509: Paclitaxel + carboplatin vs vinorelbine + cisplatin. Kelly K, et al. ASCO 2001. Abstract 1313. 117 (19%) 79 (19%) 38 (18%) Age > 70 491 (71%) 327 (81%) 164 (82%) Age <70 Total (N=608) Vinorelbine/Cis* (N=406) Paclitaxel/Carbo (N=202) SWOG 9308 SWOG 9509
  • 125. SWOG 9308 and 9509: Results Kelly K, et al. ASCO 2001. Abstract 1313. 22% 10% 16% 2-y OS 21% 30% 40% 1-y OS 0.06 6.9 8.6 Median survival (mo) 0.62 3.9 4.2 TTP (mo) P -value  70 (n=117) <70 (n=491)
  • 126. Poor Performance Status Patients Sweeney CJ, et al . Cancer. 2001;92:2639-2647.
    • ECOG E1594 adverse events
      • High number of adverse events in PS 2 and PS 0-1 groups
      • Events and shorter survival in PS 2 patients (n=64) related to disease process rather than treatment
    3% 4% Death due to drug toxicity 27%-33% 28%-53% Paclitaxel + carboplatin 12%-59% 22%-61% Docetaxel + cisplatin 8%-67% 20%-69% Gemcitabine + cisplatin 30%-60% 20%-68% Paclitaxel + cisplatin PS 2 PS 0-1 Treatment Arm Grade 3/4 Toxicity, %
  • 127. ECOG 1594: Outcome Based on Age <70 y  70 y n=912 n=227 P - value Grade  4 toxicity 66% 71.2% 0.04 OR(%) 22.1 24.5 0.76 PFS (mo) PS 0-1 3.71 3.75 PFS 1-y (%) 6.5 8.6 0.37 PFS 2-y (%) 0.5 2.2 0.04 MS (mo) 8.15 8.25 1-y OS(%) 32.8 35.2 0.53 2-y OS(%) 10.6 13.7 0.24 Langer CJ, et al. ASCO 2003. Abstract 2571.
  • 128. ELVIS (Elderly Lung Cancer Vinorelbine Italian Study)
    • Statistically significant benefit for patients receiving vinorelbine
    Gridelli C. J Nat Cancer Inst . 1999;85:365-376. 14% 32% 1-y survival 21 wk 28 wk Median survival 0 19.7 Response rate BSC Vinorelbine
  • 129. Efficacy of Nonplatinum Single-agent vs Doublet Chemotherapy MILES Comparison of Single-agent vs Double-agent Chemotherapy Gridelli C, et al. J Natl Cancer Inst . 2003;95:362-372. 22% 18% 20% Overall survival among patients with PS=2 21% 16% 18% Tumor response rate 19 17 18 Median time to progression, weeks 30% 28% 38% Overall survival Vinorelbine + Gemcitabine Gemcitabine Vinorelbine Outcome
  • 130. Targeted Therapy for Non-small Cell Lung Cancer
  • 131. Targeted Therapy Goals
    • Identify drug targets that
      • Are responsible for tumor growth
      • Are key mechanisms in cancer progression
      • Are reversible by inhibition
      • Are dispensable to normal cells
      • Can be measured in tumor tissue
    • Identify tumor-specific molecules to minimize risk to other cells
      • Increased specificity leads to reduced toxicity
    Thomas M. Chemotherapy Foundation Symposium and Online Education Program. Advances In Research and Practice. November 15, 2003. 
  • 132. Tumorigenic Pathways in the Cell Are Complex Sigma Aldrich, Inc., St. Louis, MO
  • 133. Targets for Drug Development
    • Angiogenesis
      • VEGF
      • VEGFR
      • FGF
      • Integrin
    • Apoptosis
      • Bcl-2
      • Survivin
      • XIAP
      • p53
      • Clusterin
    • Signaling
      • Ras
      • Raf kinase
      • MEK
      • mTOR
      • PKC
    • HER family
      • EGFR
      • HER-2
    • Cell cycle
      • Cdks
    • Extracellular
      • MMP
    • Receptors/kinases
      • c-Kit
      • PDGFR
      • Abl
    • Other
      • DNA MTase
      • HDAC
      • Proteasome
  • 134. EGFR Targeting Strategies in NSCLC
  • 135.
    • EGFR is a tyrosine kinase growth factor receptor
    • Activated by binding of natural ligands
      • TGF- 
      • EGF
    • Activated EGFR signals through multiple pathways
    • Potential to block at various steps in the pathway
      • Extracellular surface
      • Intracellular targets
    Invasion/ metastasis Proliferation Survival/ anti-apoptosis Angiogenesis MAPK MEK Gene transcription Cell-cycle progression PI3K Raf Ras SOS Grb2 PTEN Akt STAT pY K K pY EGF pY p27 X X X EGFR Anti-EGFR (+) X Perez-Soler R. Oncologist . 2004;9:58-67. X EGF-induced Signal Transduction and Tumorigenesis M G1 S G2
  • 136. Anti-EGFR Targeted Agents: Biological Rationale
    • Activation of EGFR linked with
      • Increased cell proliferation
      • Angiogenesis
      • Metastasis
    • Agents that selectively target EGFR could inhibit and prevent the pathogenesis of various cancers
    • EGFR expression correlates with
      • Poor response to treatment
      • Disease progression
      • Poor survival
  • 137. Anti-EGFR Strategies Signal transduction mAbs TKIs Ligand TKI K K Ligand Survival and metastasis mAb Cetuximab Gefitinib Erlotinib Ligand Cell death Ligand Protein synthesis K K K K K K Toxin conjugates Antisense Panitumumab mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor. Adapted from Raymond E, et al. Drugs . 2000;60(suppl 1):15-23.
  • 138. Monoclonal Anti-EGFR Antibodies
  • 139. Monoclonal Anti-EGFR Antibodies Pao W, Miller VA. J Clin Oncol . 2005;23:2556-2568. EGFR
  • 140. Monoclonal Antibodies Monoclonal Antibodies Under development mAb 80 Under development h-R3 (TheraCIM) Under development MDX-447 (HuMab-Mouse) Under development EMD-72000 (matuzumab) Under development ABX-EGF (panitumumab) Approved, refractory metastatic CRC, pancreatic, head and neck Cetuximab Status Agent
  • 141. Phase I/II EGFR Antibodies
    • Cetuximab competes with endogenous ligands for binding at EGFR, functioning as an EGFR antagonist at EGFR
    • Once bound to EGFR, cetuximab induces the internalization of EFGR
    Ng M, Cunningham D. Int J Clin Pract . 2004;58:970-976. Treatment-naive and previously treated NSCLC II Human monoclonal antibody Cetuximab Previously treated metastatic CRC II Humanized, chimeric monoclonal antibody Panitumumab Treatment Phase Class Compound
  • 142. Phase II Trials of Cetuximab in Advanced NSCLC PR, partial response. 1. Rosell R, et al. Proc Am Soc Clin Oncol. 2004;23:618a; 2. Robert F, et al . J Clin Oncol . 2005;23:9089-9096; 3. Thienelt CD, et al. J Clin Oncol . 2005;23:8786-8793. Median Survival PR Patients, n Treatment Study No Prior Chemotherapy 11.0 months 26% 31 Cetuximab + paclitaxel + carboplatin Thienelt et al. 3 7.0 months 20% 43 Cetuximab + vinorelbine 10.3 months 28.6% 35 Cetuximab + gemcitabine + carboplatin Robert et al. 2 8.3 months 31.7% 43 Cetuximab + cisplatin + vinorelbine Rosell et al. 1
  • 143. Phase II Trials of Cetuximab in Advanced NSCLC PR, partial response; TTP, time to progression. 1. Lynch TJ, et al. Proc Am Soc Clin Oncol . 2004;23:634a; 2. Kim ES, et al. Proc Am Soc Clin Oncol. 2003;22:642a. Median Survival PR Patients, n No. Prior Chemo Treatment Study Prior Chemotherapy TTP 3 months 28% 47 > 1 Cetuximab + docetaxel Kim et al. 2 7% 29 > 1 Cetuximab Lynch et al. 1
  • 144. Phase III Trial of Cetuximab in Advanced NSCLC RANDOMIZE Cetuximab + cisplatin + vinorelbine Cisplatin + vinorelbine
    • N=1037
    • Stage IIIB/IV
    • EGFR-expressing NSCLC
    • Primary endpoint
    • Overall survival
    • Secondary
    • endpoints
    • Progression-free survival
    • Tumor response
    • Disease control
    • Safety
    • Quality of life
    Von Pawel J, et al. ASCO 2006. Abstract 7109.
  • 145. EGFR-targeted Agents: Small Molecule Tyrosine Kinase Inhibitors
  • 146. Tyrosine Kinase Inhibitors Small molecule tyrosine kinase inhibitors Class Under development Under development Under development CI-1033 HKI 272 BIBW2922 Under development EKB-569 Approved for advanced NSCLC Erlotinib Approved for advanced NSCLC Gefitinib Status Agent
  • 147. EGFR Tyrosine Kinase Inhibitors: Gefitinib and Erlotinib
    • Gefitinib and erlotinib selectively inhibit EGFR tyrosine kinase (aka HER-1 or ErbB-1)
    Pavletich N. Structural Biology Program, Memorial Sloan-Kettering Cancer Center. Gefitinib Molecular Structure Erlotinib Molecular Structure
  • 148. EGFR Tyrosine Kinase Inhibitors in Recurrent NSCLC Phase II Trials Assessing Second-line Treatment 1. Fukuoka M, et al. J Clin Oncol . 2003;21:2237-2246; 2. Kris MG, et al. JAMA . 2003; 290:2149-2158; 3. Perez-Soler R, et al. Proc Am Soc Clin Oncol . 2001;20:310a. Abstract. 18.7% N=210 Gefitinib Monotherapy 1 2.75 months Median progression-free survival 8.4 months 7.8 months Median overall survival 12.3% 10.3% Overall response rate N=57 N=216 Study population Erlotinib Monotherapy 3 Gefitinib Monotherapy 2 Parameter
  • 149. Patient Characteristics Associated with Response Response to Second-line Treatment with Gefitinib Fukuoka M, et al. J Clin Oncol . 2003;21:2237-2246. Symptom Improvement Response Rate 30 4 Other 43 13 Adenocarcinoma 31 3 Men 49 19 Women 32 15 > 4 prior regimens 44 10 3 prior regimens 39 8 2 prior regimens 36 14 PS 2 40 9 PS 0-1 Rate (%) (%) Characteristic
  • 150. ISEL Trial 709: Phase III Gefitinib in Second- or Third-line NSCLC RANDOMIZE Gefitinib 250 mg/day + best supportive care (n=1129) Placebo + best supportive care (n=563)
    • N=1692
    • Stage IIIB/IV NSCLC
    • Failed/intolerant to prior chemotherapy regimen
    • Primary endpoints
    • Survival in overall population
    • Survival in those with adenocarcinoma
    ISEL, Iressa Survival Evaluation in Lung Cancer. Thatcher N, et al. Lancet . 2005;366:1527-1537.
  • 151. ISEL Trial 709: Phase III Gefitinib in Second- or Third-line NSCLC (cont.) Adenocarcinoma All patients Female PS 0,1 1 prior chemo Refractory Never smoked Non-adenocarcinoma Ever smoked Intolerant 2 prior chemos PS 2,3 Male Hazard ratio and 95% CI Favors gefitinib Favors placebo 11.4% 7.7% 14.0% 8.3% 7.4% 7.8% 17.2% 4.6% 5.2% 7.2% 8.0% 6.6% 4.9% Survival Response Rate 0.4 0.6 0.8 1 1.5 Thatcher N, et al. Lancet . 2005;366:1527-1537.
  • 152. Gefitinib Efficacy and Somatic Mutations in EGFR
    • Gefitinib and erlotinib target the ATP cleft within the tyrosine kinase EGFR
    • Only about 10% of patients have a rapid and dramatic clinical response to gefitinib
    • Most NSCLC patients do not respond to gefitinib
    • Efficacy may be attributed to somatic mutations in EGFR gene
    Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139.
  • 153. Characteristics of Patients Responding to Gefitinib Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139. Partial Partial Partial Major Partial Minor Partial Major Major Response No Yes Yes Yes Yes Yes Yes Yes Yes EGFR Mutation >33.5 17.9 >4.3 >7.8 >14.7 >21.4 12.9 >14.0 18.8 Overall Survival (mo) >33.5 11.7 >4.3 >7.8 >14.7 >13.3 9.6 >14.0 15.6 Duration of Therapy BAC Adeno Adeno BAC Adeno Adeno Adeno BAC BAC Pathological Type 42 58 62 32 45 81 64 66 70 Age F F F M F F M M F Sex 9 8 7 6 5 4 3 2 1 Patient Never 2 Former 1 Former 1 Never 3 Never 2 Former 1 Never 2 Never 0 Never 3 Smoker? Prior Regimens
  • 154. Response to Gefitinib May Be Due to Somatic Mutation of EGFR
    • Majority of patients responding to gefitinib were
      • Women
      • Had never smoked
      • Had BAC
    • Heterozygous mutations were detected in 8/9 patients
      • 4 mutations were in frame deletions
      • No mutations were detected when matched with normal tissue
    • Diagnostic testing may identify patients for gefitinib therapy
    Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139.
  • 155. EGFR Somatic Mutation: Summary
    • A subgroup of patients have specific mutations in the EGFR gene that
      • Correlate with clinical responsiveness
      • Lead to increased growth factor signaling
      • Confer susceptibility to gefitinib
    • Screening for such mutations may identify patients who will respond to gefitinib therapy
  • 156. Fluorescence In Situ Hybridization (FISH) Testing
    • FISH testing can detect amplification (high gene copy number) of EGFR in NSCLC tumors 
    http://www.accessexcellence.org/AB/GG/fish.html
  • 157. Anti-EGFR Targeted Agents: EGFR Copy Number in NSCLC Hirsch FR, et al. J Clin Oncol . 2005;23:6838-6845; Cappuzzo F, et al. J Natl Cancer Inst . 2005;97:643-655. 0.072 0.042 P -value 4 months 9 months Median progression-free survival 8 months Not yet reached Median overall survival EGFR-FISH Negative EGFR-FISH Positive Outcome
  • 158. FISH and EGFR Summary
    • FISH may allow for informed treatment decisions based on patient characteristics
    • Recent data suggest an association between high EGFR gene copy number and favorable clinical benefit
  • 159. JBR.21 Trial: Phase III Erlotinib in Second- or Third-line NSCLC Shepherd FA, et al. N Engl J Med . 2005;353:123-132. RANDOMIZE Erlotinib 150 mg/day (n=488) Placebo (n=243)
    • N=731
    • Stage IIIB/IV NSCLC
    • Failed/intolerant to > 1 prior chemotherapy regimen
    • PS 0-3
    • Primary endpoint
    • Overall survival
    • Secondary
    • endpoints
    • Time to symptom deterioration
    • Progression-free survival
    • Tumor response rate
  • 160. BR.21 Trial: Overall Survival Shepherd FA, et al. N Engl J Med . 2005;353:123-132. No. at risk: Placebo 243 107 50 9 0 0 Erlotinib 488 255 145 23 1 0 HR=0.70 (95% CI, 0.58 to 0.85) P <0.001 by stratified log-rank test Erlotinib Placebo
  • 161. BR.21 Trial: Progression-free Survival Shepherd FA, et al. N Engl J Med . 2005;353:123-132. No. at risk: Placebo 243 20 3 0 0 0 Erlotinib 488 115 27 2 1 0 HR=0.70 (95% CI, 0.58 to 0.85) P <0.001 by stratified log-rank test Erlotinib Placebo
  • 162. BR.21 Trial: Outcomes Shepherd FA, et al. N Engl J Med . 2005;353:123-132. <0.001 1.8 2.2 Median PFS, mo <0.001 <1.0% 8.9% Response rate <0.001 4.7 6.7 Median overall survival, mo P -value Placebo Erlotinib Outcome
  • 163. BR.21 Trial: Survival in Expressing vs Nonexpressing EGFR Patients Survival in EGFR-negative Patients 0 0.25 0.5 0.75 1 0 6 12 18 24 30 Survival time (months) Survival probability Survival in EGFR-positive Patients 0 0.25 0.5 0.75 1 0 6 12 18 24 30 Survival time (months) Survival probability Shepherd FA, et al. N Engl J Med . 2005;353:123-132. HR: 1.01 95% CI: 0.65 to 1.57 Erlotnib (N=74) Placebo (N=37) HR: 0.65 95% CI: 0.43 to 0.97 Erlotinib (N=78) Placebo (N=49)
  • 164. BR.21 Trial: Survival in EGFR Unmeasured Patients Shepherd FA, et al. N Engl J Med . 2005;353:123-132. HR: 0.76 95% CI: 0.61 to 0.93 Survival in EGFR Unmeasured Patients 0 0.25 0.5 0.75 1 0 6 12 18 24 30 Survival time (months) Survival probability Erlotinib (N=336) Placebo (N=157)
  • 165. BR.21 Trial: K- ras Mutations Can Predict Outcome
    • K- ras analysis from 206 patient samples
      • Oncogenic missense mutations on codon 12 or 13 in 30 samples (14.6%)
          • 22 (erlotinib) vs 8 (placebo)
    • Overall response rates were 5% in K- ras mutant patients vs 10.2% in K- ras wild type patients
    • Patients with K- ras mutations do not appear to derive any survival benefit from erlotinib therapy
    Tsao C, et al. ASCO 2006. Abstract 7005 .
  • 166. Treatment-related Toxicities
    • Skin rash was seen in 76% of treated patients (9% grade 3)
    • 55% of treated patients experienced diarrhea (6% grade 3)
    • Pneumonitis was noted in 3% of patients
    • Mild ocular toxicities were reported in 28% of patients
    Shepherd FA, et al. N Engl J Med . 2005;353:123-132.
  • 167. EGFR Inhibitor-associated Rash
    • Rash associated with superior responses to treatment
    • Rash may be surrogate marker of activity
    • Presence of any rash conferred significant survival benefit ( P =0.02)
      • Trend toward improved survival with increasing severity of rash
    • Cause of correlation currently unknown
    Cunningham D, et al. N Engl J Med . 2004;351:337-345.
  • 168. EGFR Inhibitor-associated Rash Acneform rash on face Acneform rash on chest Paronychial inflammation
  • 169. MD Anderson Prospective Treatment Algorithm Consider dermatology consultation for grade 3/4 symptoms. Kim ES. ASCO 2005 Poster Session. Abstract 5546. Perfume-, alcohol-, dye-free lotion applied bid Grade 2/4 NA Grade 1 Dry skin Antibiotics: minocycline hydrochloride 200 mg bid, d1; then 100 mg bid OR trimethoprim/sulfamethoxazole bid Grade 2/4 Grade 1 Grade 3/4 Grade 2 Grade 1 Severity Antibiotics: clindamycin gel for limited single areas; clindamycin lotion for multiple scattered areas Pustular/ papular rash Oral steroids: methylprednisolone Topical steroids: fluticasone propionate Hydrocortisone cream 1% Treatment Macular rash Type
  • 170. MD Anderson Prospective Treatment Algorithm (cont.) Consider dermatology consultation for grade 3/4 symptoms. Kim ES. ASCO 2005 Poster Session. Abstract 5546. Silver sulfadiazine ointment Grade 4 Petroleum jelly or silver sulfadiazine ointment Grade 3 Grade 1/2 Grade 3/4 Grade 2 Grade 1 Severity NA Ulcerative lesions Antihistamine: diphenhydramine 25-50 mg PO q6 h prn OR hydroxyzine hydrochloride 25-50 mg PO q6 h prn Antihistamine: topical or oral diphenhydramine 25-50 mg q6 h prn OR hydroxyzine hydrochloride 25-50 mg PO q6 h prn NA Treatment Pruritus Type
  • 171. Rash Management: Recommendations for Patients
    • Moisturizer
      • Emollients to alleviate skin dryness
    • Sunlight
      • Appropriate sunscreens
    • OTC products
      • Acne medications are not recommended
    • Makeup
      • Dermatologist-approved cover-up
      • Skin-friendly liquid cleansers
    Perez-Soler R, et al. Oncologist . 2005;10:345-356.
  • 172. EGFR Tyrosine Kinase Inhibitors Plus Chemotherapy Phase III Trials Assessing First-line Treatment 1. Giaccone G, et al. J Clin Oncol . 2004;22:777-784; 2. Herbst RS, et al. J Clin Oncol. 2004;22:785-794; 3. Herbst RS, et al. ASCO 2004;23:617; 4. Gatzemeier U, et al. ASCO 2004;23:617. Negative N=1172 Paclitaxel + carboplatin Erlotinib TALENT 4 Negative N=1059 Gemcitabine + cisplatin Erlotinib TRIBUTE 3 Negative N=1037 Paclitaxel + carboplatin Gefitinib INTACT 2 2 Negative N=1093 Gemcitabine + cisplatin Gefitinib INTACT 1 1 Outcome Study Population Chemotherapy Agent Trial
  • 173. Additional TKIs of Interest Previously treated breast cancer, locally advanced or metastatic biliary tract or liver cancer, metastatic prostate cancer II Small-molecule ErbB-1 and ErbB-2 tyrosine kinase inhibitor Lapatinib Previously treated advanced ovarian cancer II Small-molecule EGFR tyrosine kinase inhibitor CI-1033 Previously treated advanced CRC II Small-molecule EGFR tyrosine kinase inhibitor EKB-569 Treatment Phase Class Compound
  • 174. Angiogenesis-targeted Agents in NSCLC
  • 175. Rationale for Targeting Angiogenesis in NSCLC
    • Angiogenesis is key to the metastatic process
    • VEGF is the most potent regulator of angiogenesis
    • Binds to the extracellular domain of the VEGF inhibitor
    • VEGF binds to VEGFR2
    • Anti-VEGF therapy may increase the efficacy of chemotherapy and have direct antitumor effect
    Duff SE, et al. Eur J Cancer . 2006;42:112-117.
  • 176. VEGF Family and Its Receptors RTK, receptor tyrosine kinase. Dvorak HF. J Clin Oncol. 2002;20:4368; Ferrara N, et al. Nat Med. 2003;9:669. VEGFR-3 (Flt-4) VEGFR-2 (Flk-1/KDR) VEGFR-1 (Flt-1) Angiogenesis (RTK) Angiogenesis, lymphangiogenesis (RTK) Lymphangiogenesis (RTK) PIGF VEGF-A VEGF-B VEGF-C VEGF-D 0 0 0 0 0 NRP-1 (Neuropilin) Unclear, but likely involved in tumor growth (non-RTK)
  • 177. Ligand sequestration: mAbs, soluble receptors (eg, bevacizumab) Receptor-blocking mAbs (eg, I MC-1121) Tyrosine kinase inhibition: TKIs (eg, SU11248) p85 PLC  GRB2 SOS ras Transcription factor inhibition VEGF Signal Inhibition VEGF VEGFR
  • 178. Inhibition of VEGF
    • Increases killing of established tumors
      • Improves chemotherapy delivery to entire tumor, including center of tumor
    • Inhibits metastasis
      • Blocks VEGF-induced increase in peritumor lymph drainage
      • Blocks VEGF(-A)-induced dysfunctional angiogenesis
      • Maintains endothelial cell barrier function; inhibits invasion of circulation by the tumor
      • Decreases vascular density of tumor
    Dafni H, et al. Cancer Res. 2002;62:6731-6739; Nagy JA, et al. J Exp Med. 2002;196:1497-1506; Weis S, et al. J Cell Biol. 2004;167:223-229.
  • 179. VEGF Overexpression in Select Tumors Vascular density 30%-100% Renal cell Recurrence, survival, vascular density 30% Prostate Recurrence, survival 30%-60% Breast Recurrence, survival 40%-60% Colorectal Recurrence, survival 45%-55% NSCLC Correlation % of Tumors with VEGF Overexpression Tumor Type
  • 180. Selected Agents Targeting the VEGF Ligand Phase I completed VEGF HuMV833 Agents Targeting the VEGF Ligand Phase III VEGF Bevacizumab Antibodies Phase I VEGF PlGF VEGF-Trap Soluble receptors Stage of Development Targets Examples Class
  • 181. Selected Agents Targeting the VEGF Receptors Agents Targeting the VEGF Receptors Phase I VEGFR-2 IMC-1121 Antibodies Phase III VEGFR-1 Angiozyme Ribozymes Stage of Development Targets Examples Class
  • 182. Bevacizumab
    • Recombinant humanized monoclonal antibody to VEGF-A
    • Selectively targets, binds to, and inhibits the activity of VEGF
  • 183. Risk Factors of Bevacizumab
    • Bevacizumab is associated with an increased risk of serious bleeding
      • Infrequent cases of hemoptysis
      • GI hemorrhage
      • Subarachnoid hemorrhage
      • Hemorrhagic stroke
    • Risk factors include pulmonary bleeding and life-threatening hemorrhages
  • 184. Bevacizumab: Patient Selection and Safety Considerations
    • Bevacizumab contraindications
      • History of thrombotic or hemorrhagic disorders
      • History of hemoptysis
      • Central nervous system metastases
    • Potential predictors of response
      • Treatment-induced reduction in VEGF expression
      • Reduced tumor blood flow on functional CT or MRI
      • Biopsy proof of decreased angiogenesis
      • VEGF molecule/receptor polymorphisms
  • 185. Phase II Bevacizumab Plus Chemotherapy in First-line NSCLC RANDOMIZE Bevacizumab* 7.5 mg/kg + PC 200 mg/m 2 + carboplatin AUC 6 on d 1 every 6 weeks (n=32) PC 200 mg/m 2 + carboplatin AUC 6 on d 1 every 6 weeks (n=32)
    • N=99
    • Stage IIIB/IV nonsquamous NSCLC
    • Treatment naive
    • PS 0-1
    • Adequate hematologic, renal, and hepatic function
    • Primary endpoints
    • Response rate
    • Time to progression
    *Bevacizumab continued beyond progression with crossover in chemotherapy: PC; paclitaxel. Johnson DH, et al. J Clin Oncol . 2004;22:2184-2191. Bevacizumab* 15 mg/kg + PC 200 mg/m 2 + carboplatin AUC 6 on d 1 every 6 weeks (n=35)
  • 186. Phase II Bevacizumab Plus Chemotherapy in First-line NSCLC Johnson DH, et al. J Clin Oncol . 2004;22:2184-2191. 4.2 months 7.4 months 4.3 months Median time to progression 14.9 months 17.7 months 11.6 months Median overall survival 18.8% 31.5% 28.1% Response rate Control Arm Bevacizumab 15 mg/kg Bevacizumab 7.5 mg/kg Outcome
  • 187. ECOG 4599: Phase II/III Paclitaxel/Carboplatin +/- Bevacizumab in First-line NSCLC RANDOMIZE Bevacizumab 15 mg/kg + paclitaxel 200 mg/m 2 + carboplatin AUC 6 on d 1 every 6 weeks (n=434) Paclitaxel 200 mg/m 2 + carboplatin AUC 6 on d 1 every 6 weeks (n=444)
    • N=878
    • Stage IIIB/IV nonsquamous NSCLC
    • Treatment naive
    • PS 0-1
    • Adequate hematologic, renal, and hepatic function
    • Primary endpoint
    • Overall survival
    • Secondary endpoints
    • Response rate
    • Time to progression
    • Tolerability
    Sandler AB, et al. ASCO 2005. Abstract LBA4.
  • 188. ECOG E4599: Median Survival Sandler AB, et al. ASCO 2005. Abstract LBA4. 12 mo 24 mo 43.7% 16.9% 51.9% 22.1% 0 0.2 0.4 0.6 0.8 1.0 Probability PC PCB P =0.007 0 6 12 18 24 30 36 Months Medians: 10.2, 12.5 HR: 0.77 (0.65, 0.93)
  • 189. ECOG E4599: Results Sandler AB, et al. ASCO 2005. Abstract LBA4. <0.0001 4.5 months 6.4 months Median progression-free survival 0.0075 10.2 months 12.5 months Median overall survival <0.0001 10.0% 27.2% Overall response rate P -value Paclitaxel + Carboplatin Bevacizumab + Paclitaxel + Carboplatin Outcome
  • 190. ECOG E4599: Toxicity *5 deaths due to hemoptysis, all in bevacizumab-treated arm. Sandler AB, et al. ASCO 2005. Abstract LBA4; Sandler AB, et al. ASCO 2006. Abstract 7068. 2 8 Deaths, n* <0.001 0.7% 6.0% Hypertension <0.01 0.0% 1.4% Grade 4 thrombocytopenia <0.01 16.4% 24.0% Grade 4 neutropenia <0.001 0.7% 4.5% Grade 3/4 hemorrhage P -value Paclitaxel + Carboplatin Bevacizumab + Paclitaxel + Carboplatin Outcome
  • 191. ECOG E4599: Risk Factors for Pulmonary Hemorrhage
    • Severe PH occurred in 2.3% of bevacizumab-treated patients
    • Primary radiographic analysis showed cavitation in intrathoracic lesion at baseline may be associated with increased risk of severe early-onset PH
      • Hemoptysis prior to treatment in 2/2 cases with cavitation
    • Tumor cavitation and hemoptysis confirmed as potential risk factors for severe PH
    Sandler AB, et al. ASCO 2006. Abstract 7068.
  • 192. ECOG E4599: Prognostic Biomarkers
    • VEGF, ICAM, and bFGF were assessed as potential biomarkers
    • ELISA measurements of pretreatment and week 7 bFGF, ICAM, and E-selectin and pretreatment of plasma VEGF
      • Low ICAM correlated with a higher response rate (29% vs 13%, P =0.03)
      • Low ICAM correlated with significantly better overall survival ( P =0.00005) as well as better 1-year survival (65% vs 25%)
    • Baseline ICAM levels are strongly prognostic for survival and response to chemotherapy
    Dowlati A, et al. ASCO 2006. Abstract 7027.
  • 193. ECOG E4599: Summary
    • Addition of bevacizumab to paclitaxel-carboplatin provides statistically and clinically significant survival advantage
    • Paclitaxel-carboplatin-bevacizumab is the new ECOG reference standard in this patient population
    • Other trials evaluating bevacizumab in combination with other chemotherapy doublets ongoing
    Sandler AB, et al. ASCO 2005. Abstract LBA4.
  • 194. Combining Bevacizumab and Erlotinib: Rationale
  • 195. Phase I/II Bevacizumab plus Erlotinib
    • Study design
      • Patients (34 patients) with nonsquamous stage IIIB/IV NSCLC with > 1 prior chemotherapy regimen
      • Erlotinib 150 mg/day + bevacizumab 15 mg/kg
      • Efficacy, tolerability, and pharmacokinetic parameters of erlotinib + bevacizumab assessed
    Herbst RS, et al. J Clin Oncol . 2005;23:2544-2555 .
  • 196. Phase I/II Bevacizumab plus Erlotinib: Results
    • Median overall survival
      • 12.6 months
    • Median progression-free survival
      • 6.2 months
    • Most common adverse events
      • Mild/moderate rash
      • Diarrhea
      • Proteinuria
    Herbst RS, et al. J Clin Oncol . 2005;23:2544-2555 .
  • 197. Efficacy of Bevacizumab in Combination with Chemotherapy or Erlotinib
    • Phase II trial
      • Combining bevacizumab with chemotherapy (docetaxel or pemetrexed) or with erlotinib
    • Assess the efficacy of combining bevacizumab with chemotherapy or erlotinib relative to chemotherapy alone
      • End-point
        • Progression-free survival
    • 120 patients were randomized and treated
      • 68/85 PFS events
    Fehrenbacher L, et al. ASCO 2006. Abstract 7062 .
  • 198. Antiangiogenic Tyrosine Kinase Inhibitors All agents in early phase I/I development except for PTK787 in phase III. + ? ? - + - AstraZeneca ZD6474 ? + + + + + Amgen AMG 706 ? + + + + + Pfizer AG013736 + + + - + - Pfizer SU11248 ? ? ? + + + GSK GW786034 ? ? ? + + + AstraZeneca AZD2171 ? + + + + + Novartis Schering PTK787 FGFR c-KIT PDGFR VEGFR-3 VEGFR-2 VEGFR-1 Company Inhibitor Target
  • 199. ZD6474: Antiangiogenic Tyrosine Kinase Inhibitor ZD6474 Mode of Action Image obtained from: http://www.cancerline.com/cancerlinehcp/15602_18171_10_1_1.aspx
    • Indirect tumour effects through endothelial cell targeting
    • VEGFR inhibition
    • Inhibits angiogenesis by decreasing endothelial cell proliferation and migration
    • Inhibits VEGF-dependent endothelial cell survival
    • Decreases vascular permeability
    • Direct effects at the tumour cell
    • EGFR inhibition
    • Inhibits cell proliferation
    • Decreases invasion
    • Promotes apoptosis
    • Inhibits metastasis
    • Decreases VEGF production
    • RET inhibition:
    • Inhibition of proliferation and survival in certain thyroid turmors
  • 200. Phase II Trial of ZD6474 vs Gefitinib
    • Study design
      • 168 patients with stage IIIB/IV NSCLC who had failed ≥1 platinum-based chemotherapy regimen administered
        • ZD6474 300 mg/day or
        • Gefitinib 250 mg/day
    • Adverse events for ZD6474 included diarrhea (grade 3/4, 8.4%), rash (grade 3/4, 4.8%) and asymptomatic QTc prolongation (grade 1, 20.5%)
    • There were no unexpected safety findings with gefitinib
    Natale R, et al. Chemotherapy Foundation Symposium XXIII 2005. Natale R, et al. ASCO 2006. Abstract 7000. 8.1 11.0 Median time to progression, weeks Gefitinib ZD6474 Outcome
  • 201. Phase II Trial of ZD6474 vs Gefitinib: Progression-free Survival Natale R, et al. Chemotherapy Foundation Symposium XXIII 2005. HR=0.632 (95% CI=0.44 to 0.90) Two-sided P -value=0.011 Primary Endpoint: Progression-free Survival 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 1 2 3 4 5 6 7 8 9 10 11 Progression-free survival in part A (months) Probability of remaining Progression free ZD6474 Gefitinib
  • 202. ZD6474 +/- Docetaxel: Schema Heymach R, et al. IASLC 11 th World Congress on Lung Cancer. 2005. Abstract 3023; Heymach R, et al. ASCO 2006. Abstract 7016. RANDOMIZE ZD6474 100 mg + Docetaxel 75 mg/m 2 q21 d (n=42)
    • N=127
    • Stage IIIB/IV NSCLC
    • Failure of 1 st -line platinum-based chemotherapy
    • Primary endpoint
    • Progression-free survival
    • Secondary endpoints
    • Overall survival
    ZD6474 300 mg + Docetaxel 75 mg/m 2 q21 d (n=44) Docetaxel 75 mg/m 2 q21 d (n=41)
  • 203. ZD6474 +/- Docetaxel: Progression-free Survival Kaplan-Meier Curve for Progression-free Survival 0 0.25 0.5 0.75 1 0 50 100 150 200 250 300 350 400 Progression-free survival (days) Survival distribution function Heymach R, et al. IASLC 11 th World Congress on Lung Cancer. 2005. Abstract 3023. Placebo + docetaxel ZD6474 100 mg + docetaxel ZD6474 300 mg + docetaxel Censored Censored Censored
  • 204. ZD6474 +/- Docetaxel: Results
    • No significant difference in overall survival, however a trend towards shorter survival in ZD6474 300 mg arm
    Heymach R, et al. ASCO 2006. Abstract 7016. 0.461 12.0 17.0 (ZD6474 300 mg) 0.074 P -value 12.0 18.7 (ZD6474 100 mg) Median TTP, weeks Docetaxel ZD6474 + Docetaxel Outcome
  • 205. Sunitinib: Multi-targeted Tyrosine Kinase Inhibitor
    • Targets VEGF-R, PDGF-R, KIT, FLT3, and RET
    • 63 patients treated with 50 mg/day of sunitinib (SU11248)
      • 6 confirmed partial responses (9.5%)
      • Stable disease observed in 12 additional patients (19.0%)
      • Survival data pending
    • Well tolerated
    • Provocative single agent activity
    Socinski MA, et al. ASCO 2006. Abstract 7001.
  • 206. Sorafenib: Multi-targeted Tyrosine Kinase Inhibitor
    • Targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases
    • 52/54 patients received sorafenib
      • 59% of patients 51 had stable disease (SD)
        • Median PFS of 23.7 weeks
      • Median PFS of 11.9 weeks and median OS of 29.3 weeks
    • Adverse events: diarrhea (40%), hand-foot skin reaction (37%), fatigue (27%), and nausea (25%)
    • 9 deaths within 30 days of discontinuation of sorafenib
    Gatzemeier, et al. ASCO 2006. Abstract 7002.
  • 207. Combining Targeting Strategies: VEGF + EGFR Synergy?
    • Combining agents targeting 2 critical pathways may be more effective than targeting 1 pathway
    • Potential targets
      • Growth factors, hormones, and receptors
        • HER-2/ neu , EGFR, PDGFR, ER
      • Signaling intermediate
        • Ras, Src, MAPK, Akt, Cox2
      • Nuclear/transcription factors
        • p53,VHL
  • 208. Targeted Therapy: Summary and Clinical Implications
    • Several new agents recently approved for treatment of NSCLC
      • Gefitinib
      • Erlotinib
      • Bevacizumab
    • Therapies targeting EFGR and antiangiogenic agents show promise
    • Ongoing investigation provides promise for more effective, less toxic treatment
  • 209. Targeted Therapy: Future Directions
    • Combining anti-EGFR agents with cytotoxic agents
      • May achieve additive or even synergistic benefits
      • Potent combinations inhibiting multiple signaling pathways to achieve greater activity
    • Signal transduction inhibitors are clinically viable therapeutic options
    • Selectively targeting oncogenes for suppression and/or destruction
    • Development of vaccines that stimulate the immune system to recognize cancer-promoting proteins as foreign and mark them for destruction
  • 210. Summary and Future Directions
  • 211. Summary and Clinical Implications
    • NSCLC is difficult to treat due to late diagnosis and high relapse rate
    • Current treatment approaches
      • Resectable NSCLC
        • Surgical resection + adjuvant platinum-based chemotherapy
      • Metastatic disease
        • Platinum- or nonplatinum-based chemotherapy with possible addition of targeted therapy agents
  • 212. Future Directions
    • Promising new agents currently under investigation
      • Epothilones
      • New topoisomerase I inhibitors
      • Paclitaxel poliglumex
      • Bortezomib and bexarotene
      • Cetuximab, panitumumab
      • ZD6474
    • Possibility of combining EGFR monoclonal antibodies and tyrosine kinase inhibitors to broaden spectrum of activity
    • Potential to use targeted agents alone in monotherapy, in combination with chemotherapy, and in combination with other targeted therapies
  • 213. Considerations in Future Directions
    • Patient selection
      • Which patients are most likely to benefit from a particular treatment?
      • Prognostic baseline variables or markers
    • Treatment based on tumor biology
    • Development of less toxic therapy
    • Design of more effective regimens
    • Optimal sequence of surgery, chemotherapy, radiation therapy, and/or targeted therapy
  • 214. Appendix
  • 215. Adjuvant Therapy Supplement
  • 216. ALPI: Effects of Mitomycin, Vindesine, and Cisplatin Adjuvant Chemotherapy Efficacy of Adjuvant Chemotherapy vs Observation Alone ALPI, Adjuvant Lung Project Italy. Scagliotti GV, et al. J Natl Cancer Inst. 2003;95:1453-1461. 1% 0.589 0.96 (0.81-1.13) Mitomycin + vindesine + cisplatin Absolute Benefit at 5 Years P -value Hazard Ratio (95% CI) Overall Survival by Therapy Type
  • 217. ALPI: Effects of Mitomycin, Vindesine, and Cisplatin Adjuvant Chemotherapy (cont.) N=1088 patients with resected stage I, II, or IIIA NSCLC ALPI, Adjuvant Lung Project Italy. Scagliotti GV, et al. J Natl Cancer Inst. 2003;95:1453-1461. HR=0.87 (95% CI=0.81 to 1.13) P =0.589 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 1 2 3 4 5 Years from randomization Overall survival 540 289 Control 548 279 MVP Total Events
  • 218. Treatment of Advanced NSCLC Supplement
  • 219. FDA-approved Treatment for Advanced NSCLC 75 mg/m 2 day 1 every 3 weeks 75 mg/m 2 day 1 every 3 weeks 1250 mg/m 2 days 1 and 8 every 3 weeks 100 mg/m 2 after gemcitabine day 1 1000 mg/m 2 days 1, 8, and 15 every 4 weeks 100 mg/m 2 after gemcitabine day 1 30 mg/m 2 weekly 120 mg/m 2 days 1 and 19, then every 6 weeks 135 mg/m 2 over 24 h every 3 weeks 75 mg/m 2 after paclitaxel every 3 weeks Gemcitabine Cisplatin Vinorelbine Cisplatin Docetaxel Cisplatin Gemcitabine Cisplatin Paclitaxel Cisplatin
  • 220. Second-line Therapy Studies 22 20 30 Gemcitabine 1000 mg/m 2 Gridelli, 1999 NR 14 22 Irinotecan 200 mg/m 2 Nakai, 1991 18 3 40 Paclitaxel 175 mg/m 2 Murphy, 1994 NR 17 35 Docetaxel 100 mg/m 2 Burris, 1993 NR 23 26 Paclitaxel 135 or 200 mg/m 2 Hainsworth, 1995 NR NR NR Median Survival (weeks) 8 35 0 Overall Response Rate (%) 22* 22+ Pemetrexed 500 mg/m 2 Mattson, 1999 18 Vinorelbine 20 mg/m 2 Rinaldi, 1994 N Dose/Schedule Study
  • 221. Targeted Therapy Supplement
  • 222. Anti-EGFR Targeted Agents: Patient Selection
    • No factors predict objective response, time to progression, and survival
    • EGFR expression levels may be able to select patients who are least likely to derive benefits from treatment
    • Subgroup of patients with mutated EGFR may derive great benefit from treatment
      • Patients who are female, nonsmokers, and who have adenocarcinoma (particularly those of Asian descent) might derive the most benefit from treatment
    • Most patients do not fall into categories of patients who might derive benefit; however, these patients should not be excluded from analyses
  • 223. Inhibition of Xenograft Tumor Growth: Gefitinib with Paclitaxel Control Paclitaxel Gefitinib Gefitinib + paclitaxel Tumor mass (mg) LX-1 Lung 0 200 400 600 800 1000 1200 0 4 8 12 16 20 24 28 32 36 Time (days) Sirotnak FM, et al. Clin Cancer Res . 2000;6:4885-4892.
  • 224. Preclinical Antitumor Activity of EGFR Tyrosine Kinase Inhibitors
    • Growth inhibition/regression observed in multiple tumor types in xenografts
    • Enhanced growth inhibition/regression observed with both chemotherapy and radiation
    • Activity observed in hormone-resistant tumor cell models
    Sirotnak FM, et al. Clin Cancer Res . 2000;6:4885-4892; Ciardiello F, et al. Clin Cancer Res . 2000;6:2053-2063; Ciardiello F, et al. Clin Cancer Res . 2001;7:1459-1465; Williams KJ, et al. Proc AACR . 2001;42:715. Abstract 3840.
  • 225. Anti-EGFR Targeted Agents: Measurement of Response
    • Response rate not an appropriate surrogate for survival in studies of agents that target EGFR
    CI, confidence interval; HR, hazard ratio. Shepherd FA, et al. N Engl J Med . 2005;353:123-132. 0.07 0.8 (0.6-1.0) 4.1% Other 0.008 0.7 (0.6-0.9) 13.9% Adenocarcinoma <0.001 By pathological subtype 0.01 0.8 (0.6-0.9) 6.0% Male 0.13 0.8 (0.6-1.1) 14.4% Female 0.006 By gender 0.9% Placebo <0.001 0.7 (0.6-0.9) 8.9% Erlotinib <0.001 Overall P -value HR (95% CI) for Survival P -value Response Rate Subgroup Analysis
  • 226. Antiangiogenic Targeted Agents: Biological Rationale Herbst RS, et al. J Clin Oncol. 2005;23:3243-3256.
  • 227. Other Emerging Antiangiogenic Agents
    • AMG 706
      • Multikinase inhibitor that targets all known VEGF receptors, the PDGF receptor, KIT, and RET
    • Open-label phase I study of 56 evaluable patients with advanced solid tumors, refractory to standard therapy or no standard therapy available
      • AMG 706 125 mg/day
    • Results
      • Partial response: 2 (4%)
      • Stable disease: 34 (61%)
        • 17 patients had up to 29% decrease in sum of longest diameter of target lesions
      • MRI showed tumor vascular permeability
        • Reduced by 37% in initial area under curve on day 3
        • Reduced by 61% in initial area under curve on day 21
    Rosen L, et al. ASCO 2005. Abstract 3013.
  • 228. Targeted Therapies for the Elderly and Patients with PS 2
    • Targeted therapies have the potential to be less toxic, especially beneficial for elderly/poor PS patients
      • Anti-EGFR
        • Gefitinib
        • Erlotinib
        • Cetuximab
      • Anti-VEGF antibodies
        • Bevacizumab
      • VEGF receptor tyrosine kinase inhibitors
        • ZD6474
        • ZD2171
      • Eicosanoid pathway inhibitors
        • COX-2 inhibitors
        • LOX inhibitors
    Gridelli C, et al. Cancer . 2004;101:1733-1744.
  • 229. Novel Cytotoxic Agents for the Treatment of NSCLC: Epothilones CR, complete response; ND, not determined; PR, partial response; SD, stable disease. Goodin S, et al. J Clin Oncol . 2004;22:2015-2025. Testicular, ovarian, pancreatic, and breast cancers ND I KOS-862 (epothilone D) Ovarian, prostate, breast, colorectal, and metastatic renal cell cancers ND II EPO906 Ovarian, bladder, stomach, and breast cancers 1 CR I BMS-310705 Metastatic gastric cancer, metastatic breast cancer, GI tract tumors 1 CR, 13 PR, and 31 SD in 111 assessable patients II BMS-247550 (aza-epothilone B) Other Cancers Tested Efficacy in NSCLC Patients Phase of Development Compound
  • 230. Novel Cytotoxic Agents for the Treatment of NSCLC: Topoisomerase I Inhibitors 1. Baka S, et al. Eur J Cancer . 2005;41:1547-1550; 2. Braybrooke JP, et al. Lung Cancer . 2003;41:215-219; 3. Springett GM, et al. J Clin Oncol. 2004;22(14S):3127; 4. Miller AA, et al. Lung Cancer . 2005;48:399-407; Sigma Tau Research Data on file. 15 (38.5%) 2 (5.1%) 39 Exatecan Braybrooke et al. 2 4 (21.1%; includes 2 lung cancer patients) – 19 Polyglutamate camptothecin (CT-2106) Springett et al. 3 24 (46.1%) 2 (3.8%) 52 Karenitecin Miller et al. 4 Gimatecan Rubitecan Treatment First-line Treatment Second-line Treatment In phase I analysis 30 (planned) Sigma Tau Research 10 (58.8%) 0 (0%) 17 Baka et al. 1 Minor Response/ Stable Disease, n (%) Partial Response, n (%) Patients, n Study
  • 231. Novel Agents: Bortezomib PR, partial response; SD, stable disease. 1. Stevenson JP, et al. Proc Am Soc Clin Oncol . 2004;23:649a; 2. Fanucchi MP, et al. ASCO 2005. Abstract 7034.
    • Bortezomib is a proteasome inhibitor
      • Interferes with the ubiquitin-proteasome complex
      • Causes breakdown of cell-cycle regulators and cell-cycle arrest
    19 (59.3%) 5 (15.6%) 32 Bortezomib + docetaxel 8 (26.7%) 3 (10.0%) 30 Bortezomib Fanucchi et al. 2 9 (39.1%) 1 (4.3%) 23 Bortezomib Stevenson et al. 1 SD, n (%) PR, n (%) Patients, n Treatment Study
  • 232. Novel Agents: Bexarotene RXR, retinoid X receptors. 1. Khuri FR, et al. J Clin Oncol . 2001;19:2626-2637; 2. Rizvi NA, et al. ASCO 2002; Abstract 1334; 3. Bordoni R. ASCO 2006. Abstract 17070. Not given 16 (31%) 1 CR + 5 PR (40%) 30 (58%) 15 56 Bexarotene + paclitaxel + carboplatin Bexarotene + paclitaxel + carboplatin Rizvi et al. 2 Bordoni 3 14 (50%) 7 (25%) 28 Bexarotene + cisplatin + vinorelbine Khuri et al. 1 SD, n (%) PR, n (%) Patients, n Treatment Study