Update Nsclc

67 %
33 %
Information about Update Nsclc
Health & Medicine

Published on February 4, 2009

Author: fovak

Source: slideshare.net

Clinical Update and Advances in the Treatment of NSCLC

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

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

Lung Cancer Incidence and Epidemiology

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 .

Lung Cancer: High Incidence, High Mortality American Cancer Society. Cancer Facts and Figures, 2006 .

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.

Environmental factors

Smoking/second-hand smoke

Air pollution

Lung disease (tuberculosis)

Asbestos

Radon

Genetic predisposition

Chronic obstructive pulmonary disease (COPD)

Prevention

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%

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.

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

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.

Most common type of lung cancer

Includes bronchioaveolar carcinoma (BAC) as a subtype

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.

Stage at presentation

Performance status

Weight loss

Sex

Age

Molecular markers associated with poor prognosis

ras mutations

Overexpression of EGFR

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

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.

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

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

Any of the following

T >3 cm

Main bronchus involvement 2 cm distal to carina

Tumor invades visceral pleura

Tumor with distal atelectasis

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

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

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

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

Adjuvant Therapy for Resectable Non-small Cell Lung Cancer

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

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

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

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

Drug combinations most frequently used in first-line chemotherapy for NSCLC

Vinorelbine and cisplatin

Gemcitabine and cisplatin

Paclitaxel and cisplatin

Docetaxel and cisplatin

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

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

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

IALT

Cisplatin-based chemotherapy vs observation

BR.10

Cisplatin/vinorelbine vs observation

CALGB 9633

Carboplatin/paclitaxel vs observation

ANITA

Cisplatin/vinorelbine vs observation

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.

N=1867

Completely resected stage I-III NSCLC

Age > 18

PS 0-1

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

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

Absolute benefit at 5 years: 4.1%

7,000 lives saved per year worldwide

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.

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

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.

N=482

Completely resected stage IB/II NSCLC

Age ≥18

PS 0-1

+/- K- ras mutations

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

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%

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 (%)

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

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

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.

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

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.

N=384

Completely resected stage IB NSCLC

Age >18

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)

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.

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.

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

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 .

N=840

Completely

resected stage

IB, II, or IIIA NSCLC

PS 0,1, or 2

Age 18-75

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

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)

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

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

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

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

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

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

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 .

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

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

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

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 .

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

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.

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)

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

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

Management of Treatment-related Toxicities

Common Symptoms/Side Effects in NSCLC Symptoms related to disease Dyspnea Pain Fatigue Symptoms related to treatment Myelosuppression Pain Fatigue

Symptoms related to disease

Dyspnea

Pain

Fatigue

Symptoms related to treatment

Myelosuppression

Pain

Fatigue

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.

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

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.

Assessment

Must identify etiology for effective treatment

Medications

Opioids

NSAIDs

Corticosteroids

Nonpharmacologic interventions

Heat/cold

Topical agents

Massage

Behavioral therapy

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.

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

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.

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

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.

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

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

Assessment

Risk factors predictive for febrile neutropenia

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

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.

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

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 .

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

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

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.

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

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.

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?

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.

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

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

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

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

A significant correlation was found between poor performance status score and low Hb level breast cancer ( P <0.001)

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.

Chemotherapy may be more toxic or less effective when patients are anemic

Fatigue

“ Full dose on time”

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

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.

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.

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

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.

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

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

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

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.

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

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

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

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

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

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.

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

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%

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

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

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

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

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

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.

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

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.

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

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

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

Neoadjuvant Therapy

Neoadjuvant Chemotherapy Preoperative chemotherapy may improve the prognosis and survival Goal Downstage the tumor before surgery, increasing the chances for resection

Preoperative chemotherapy may improve the prognosis and survival

Goal

Downstage the tumor before surgery, increasing the chances for resection

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)

Survival improves significantly with neoadjuvant therapy

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

N=600

Clinical stage: T2N0,

T1-2N1, T3N0-1

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

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

Overall survival favors and the role of preoperative chemotherapy

Treatment-related Toxicities and Induction Therapy Death Neutropenia Esophagitis Nausea/emesis Pneumonia

Death

Neutropenia

Esophagitis

Nausea/emesis

Pneumonia

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

Preoperative treatment may have a favorable effect on outcome

Aggressive neoadjuvant approaches may be accompanied by treatment-related toxicities, including death

Treatment of Advanced Non-small Cell Lung Cancer

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

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

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

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

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.

BSC, best supportive care

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)

N=1155

Stage IIIB/IV

PS 0-2

Weight loss

Brain metastases (+/-)

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

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

ECOG 1594 Findings Survival curves demonstrate comparable efficacy between various platinum-based regimens No difference in long-term survival was observed

Survival curves demonstrate comparable efficacy between various platinum-based regimens

No difference in long-term survival was observed

“Modern Agents” for Treatment of Advanced NSCLC Paclitaxel-based regimens Docetaxel-based regimens Vinorelbine-based regimens Gemcitabine-based regimens Irinotecan-based regimens

Paclitaxel-based regimens

Docetaxel-based regimens

Vinorelbine-based regimens

Gemcitabine-based regimens

Irinotecan-based regimens

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

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.

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

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

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)

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

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)

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

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

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

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

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

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?

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?

Treatment in the Elderly Population and Poor Performance Status Patients

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

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

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

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

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

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

Efficacy and tolerability similar in older vs younger patients and poor vs good PS patients

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

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)

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, %

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

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.

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

Statistically significant benefit for patients receiving vinorelbine

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

Targeted Therapy for Non-small Cell Lung Cancer

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. 

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

Tumorigenic Pathways in the Cell Are Complex Sigma Aldrich, Inc., St. Louis, MO

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

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

EGFR Targeting Strategies in NSCLC

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

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

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

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

Anti-EGFR Strategies Signal transduction mAbs

Add a comment

Related presentations

Related pages

Lungenkarzinom, nicht-kleinzellig (NSCLC) — Onkopedia

5–15 % der Patienten mit NSCLC in Europa und den USA haben ... 2011 Focused update of 2009 American Society of Clinical Oncology Clinical Practice ...
Read more

NCCN Guidelines for Patients® Version Updates: Non-Small ...

NCCN Guidelines for Patients ® Version Updates: Non-Small Cell Lung Cancer. Following are the major updates that were included in the NCCN Guidelines for ...
Read more

Lung Cancer | ASCO

Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer Update. August 31, ...
Read more

Non-Small Cell Lung Cancer Treatment (PDQ®)—Health ...

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large ...
Read more

ASCO Updates Stage IV NSCLC Treatment Guideline

ASCO has updated its clinical practice guideline for the treatment of patients with stage IV non-small cell lung cancer (NSCLC), based on a systemic review ...
Read more

Clinical Updates in NON–SMALL CELL LUNG CANCER

(ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): An Update of ASCEND-1. Felip E, et al. Ann Oncol. 2014;25(suppl 4):iv436-iv470 abstr 1295P.
Read more

Clinical Practice Guideline Update on Chemotherapy for ...

Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small ... • Establish more data on biologic factors of NSCLC in parallel with
Read more

Update on Targeted Therapies of NSCLC - Klinika Golnik

Update on Targeted Therapies of NSCLC Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty Ljubljana, Slovenia Bled 2014 1
Read more

Non-Small Cell Lung Cancer Treatment (PDQ®)—Patient ...

Expert-reviewed information summary about the treatment of non-small cell lung cancer.
Read more

UPDATE: LUNGENKARZINOM 41 - cme.medlearning.de

UPDATE: LUNGENKARZINOM 41 Q u ... NSCLC durchgesetzt. Die Mehrzahl der Patienten wer-den weiterhin im lokal fortgeschrit-tenen (mit bereits sichtbarer Metas-
Read more