Treatment of Unresectable Advanced Non –Small Cell Lung Cancer (NSCLC)

ASCO 2007: Treatment of Unresectable Advanced Non –Small Cell Lung Cancer (NSCLC)

 Bevacizumab improves progression-free survival in advanced NSCLC  Erlotinib has clinical activity in first-line treatment of unselected patients with advanced NSCLC, particularly in never smokers  Improved survival and response rates with cetuximab plus gemcitabine/platinum vs. gemcitabine/platinum alone as first-line treatment for advanced NSCLC  Bevacizumab plus chemotherapy fails to improve survival compared with chemotherapy alone in older patients with NSCLC

Bevacizumab improves progression-free survival in advanced NSCLC

Randomized, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC)

Manegold C, et al. ASCO 2007: Abstract LBA7514.

Background

  Bevacizumab is an antiangiogenic monoclonal antibody that targets the vascular endothelial growth factor ECOG (E4599) trial: • pivotal phase III study of bevacizumab (15 mg/kg) added to a combination of paclitaxel and carboplatin as first-line therapy for advanced NSCLC • demonstrated survival advantage of bevacizumab combination compared with chemotherapy alone (12.5 mos vs.10.2 mos;

p

<.0075) 1 • established a new standard for first-line therapy for eligible patients with advanced non-squamous NSCLC by showing that a triplet regimen containing a biologic agent can improve survival in this setting ECOG = Eastern Cooperative Oncology Group NSCLC = non –small cell lung cancer Q3W = every 3 weeks 1. Sandler A, et al.

N Engl J Med

2006.

Background

(continued)

     U.S. FDA subsequently approved bevacizumab (15 mg/kg Q3W) in combination with platinum-based therapy (carboplatin and paclitaxel) for initial systemic treatment of patients with unresectable, locally advanced, recurrent or metastatic, non-squamous NSCLC In Canada, bevacizumab currently only indicated for first-line treatment of advanced colorectal cancer Contraindications to bevacizumab use include squamous cell histology, brain metastases, history of hemoptysis, or need for anticoagulation therapy 1 AEs associated with combination therapy in E4599 included neutropenia, hemorrhage, hypertension and proteinuria Important to integrate results of the pivotal clinical trial into practice and appropriately expand use of antiangiogenics such as bevacizumab into the larger patient population 1. Sandler A, et al.

N Engl J Med

2006.

AE = adverse effect FDA = Food and Drug Adminstration (U.S.) NSCLC = non –small cell lung cancer Q3W = every 3 weeks

Background

(continued)

  Avastin in Lung (AVAiL) trial: • European and Canadian trial of similar design to the U.S. E4599 trial • Randomized, double-blind, multicentre phase III trial • Designed to evaluate 2 doses of bevacizumab (7.5 or 15 mg/kg Q3W) in combination with a platinum doublet (gemcitabine and cisplatin) chemotherapy in patients with previously untreated, advanced NSCLC with histology other than predominant squamous cell 1 PFS data (primary endpoint of this study) presented at ASCO 2007 ECOG = Eastern Cooperative Oncology Group NSCLC = non –small cell lung cancer PFS = performance-free status Q3W = every 3 weeks 1. Manegold C, et al. ASCO 2007: Abstract LBA7514.

Study design

 Total of 1,043 patients with treatment naïve advanced NSCLC (Table 1) enrolled and randomly assigned in this three-arm trial: • Cisplatin 80 mg/m 2 day 1 + gemcitabine 1,250 mg/m and 8 + placebo, day 1 2 days 1 • Cisplatin 80 mg/m 2 day 1 + gemcitabine 1,250 mg/m and 8 + bevacizumab 7.5 mg/kg, day 1 2 days 1 • Cisplatin 80 mg/m 2 day 1 + gemcitabine 1,250 mg/m and 8 + bevacizumab 15 mg/kg, day 1 2 days 1 Manegold C, et al. ASCO 2007: Abstract LBA7514.

Bv = bevacizumab CG = cisplatin/gemcitabine NSCLC = non –small cell lung cancer PD = progressive disease

Baseline characteristics

Manegold C, et al. ASCO 2007: Abstract LBA7514.

CG = cisplatin/gemcitabine

Study design

(continued)

       Treatment administered Q3W, for a maximum of 6 cycles Bevacizumab continued until progression or unacceptable toxicity Response assessed every 3 cycles of treatment (rather than every two cycles as in E4599) Inclusion criteria included non-squamous histology and PS of 0 to 1 Exclusion criteria included • Hemoptysis grade 2 or higher • Evidence of invasion of major blood vessels • Brain metastases • Uncontrolled hypertension Primary objective: demonstrate superiority in PFS of both bevacizumab-containing treatment arms vs. control Secondary outcomes: OS, RR, duration of response, and toxicity OS = overall survival PFS = progression-free survival PS = performance status Q3W = every 3 weeks RR = response rate Manegold C, et al. ASCO 2007: Abstract LBA7514.

Key findings

 HR for progression on bevacizumab (7.5 mg/kg) vs. pooled placebo was 0.75 (95% CI: 0.62−0.91;

p

= 0.0026) (Figure 1 below) (Figure 2 for 15 mg/kg bevacizumab) Manegold C, et al. ASCO 2007: Abstract LBA7514.

Bv = bevacizumab CG = cisplatin/gemcitabine CI = confidence interval HR = hazard ratio PFS = progression-free survivalRR = response rate

Manegold C, et al. ASCO 2007: Abstract LBA7514.

Bv = bevacizumab CG = cisplatin/gemcitabine CI = confidence interval HR = hazard ratio PFS = progression-free survival

Key findings

(continued)

 Tumour RR was 34% in the 7.5 mg/kg arm (

p

= 0.0017), 30% in the 15 mg/kg arm, and 20% in the control arm (

p

< 0.0001) (Table 2)  Bevacizumab therapy was associated with a more durable tumour response: 6.1 mos vs. 4.7 mos (Table 2) Manegold C, et al. ASCO 2007: Abstract LBA7514.

CG = cisplatin/gemcitabine CI = confidence interval PFS = progression-free survival RR = response rate

Key findings

(continued)

  Approximately 7% of patients in the trial had started second-line treatment prior to documented progressive disease After a pre-planned analysis to correct for these patients, HRs for PFS were 0.68 (95% CI, 0.56

–0.83;

p

= 0.0001) and 0.74 (95% CI, 0.60

– 0.09;

p

= 0.0021) for the bevacizumab 7.5 mg/kg and 15 mg/kg arms, respectively CI = confidence interval HR = hazard ration PFS = progression-free survival RR = response rate Manegold C, et al. ASCO 2007: Abstract LBA7514.

Safety

 Neutropenia, thrombocytopenia, and anemia were the most common AEs in all arms (Table 3 below) Manegold C, et al. ASCO 2007: Abstract LBA7514.

AE = adverse event CG = cisplatin/gemcitabine

Safety

(continued)

     Addition of bevacizumab did not significantly increase rate of AEs, SAEs, or treatment-related deaths when compared to control arm There were 4% treatment-related deaths in the control arm, 4% in the low-dose bevacizumab arm, and 5% in the 15 mg/kg arm Rate of severe (grade 3) pulmonary hemorrhage comparable between groups — 2 patients vs. 5 patients vs. 3 patients (control, 7.5, 15); of the 10 patients, only 4 had central lesions Nine per cent of total trial patients had therapeutic anticoagulation, but none suffered any severe pulmonary hemorrhage events Six per cent of patients in low-dose bevacizumab arm and 9% of patients in high-dose arm had grade 3 or higher hypertensions vs. 2% of control patients AE = adverse event SAE = serious adverse event Manegold C, et al. ASCO 2007: Abstract LBA7514.

Key conclusions

     This is the second randomized phase III trial to show benefit from bevacizumab therapy in advanced NSCLC for PFS and RR AVAiL confirms findings of E4599 in terms of improved RR and TTP with bevacizumab HRs of 0.75 and 0.82 observed slightly higher than the HR of 0.66 in E4599 trial. Dr. Thomas Lynch postulated that subtle differences in patient populations, assessment every 3 cycles in the AVAiL as opposed to 2 cycles in E4599, and use of a cisplatin-containing regimen may account for some of the difference Secondary endpoint data for survival expected in 2008 Bevacizumab in combination with cisplatin and gemcitabine well tolerated; no new safety signals observed, and incidence of severe hemoptysis or pulmonary hemorrhage was low at 1.5% HR = hazard ratio NSCLC = non –small cell lung cancer PFS = progression-free survival RR = response rate TTP = time to progression Manegold C, et al. ASCO 2007: Abstract LBA7514.

Canadian perspective by Dr. Hirsh

    Encouraging to see that bevacizumab plays a role in first-line treatment of NSCLC We now have 2 trials that show advantage of addition of bevacizumab to standard chemotherapy and as maintenance therapy in a selected group of patients; this therapy should become the new standard for treatment in non-squamous NSCLC Important to note that this study used a European standard chemotherapy regimen rather than the carboplatin-paclitaxel regimen used with bevacizumab in the U.S. However, clinical benefit of bevacizumab is independent of type of chemotherapy it is combined with Study not powered to test OS, nor designed to compare 2 doses of bevacizumab to each other but rather to non-bevacizumab arm NSCLC = non –small cell lung cancer OS = overall survival Manegold C, et al. ASCO 2007: Abstract LBA7514.

Canadian perspective

(continued)

   Difficult to distinguish which dose was best, as CIs in both bevacizumab arms crossed. No clear difference in efficacy between the 7.5 mg/kg and 15 mg/kg dose, and perhaps even a slight (statistically non-significant) improvement in tumour RR and PFS in the 7.5 mg/kg arm Demonstration of benefit of 7.5 mg/kg dose of bevacizumab is important for Canada, as drug will presumably be more cost-effective at this dose If we exclude all patients not eligible to enter the two bevacizumab phase III first-line trials of NSCLC with stage III B/IV, we will be able to treat only 25−30% of patients CI = confidence interval NSCLC = non –small cell lung cancer PFS = progression-free survival RR = response rate Manegold C, et al. ASCO 2007: Abstract LBA7514.

Erlotinib has clinical activity in first line treatment of unselected patients with advanced NSCLC, particularly in never smokers

Erlotinib for first-line treatment in unselected patients (p) with advanced or metastatic non –small cell lung cancer (NSCLC)

Jimenez U, et al. ASCO 2007: Abstract 7639.

Background

 Goals of therapy for advanced NSCLC are to improve survival and to provide palliation of symptoms  Recommended first-line treatment of patients with good PS is platinum-based chemotherapy, often in combination with a third generation cytotoxic compound such as gemcitabine, paclitaxel, or docetaxel 1  Degree of toxicity associated with platinum-based regimens, such as nephrotoxicity, neurotoxicity, and myelosuppression, may restrict use in older patients or those with a poor PS NSCLC = non –small cell lung cancer PS = performance status 1. Ramalingam S, Sandler AB.

Oncologist

2006.

Background

(continued)

 Erlotinib, an oral EGFR TKI, approved for patients with advanced or metastatic NSCLC who have failed at least one prior chemotherapy regimen  Erlotinib was first EGFR inhibitor to show survival benefit in previously treated NSCLC in a randomized, placebo-controlled setting 1  Single-agent therapy with erlotinib has been explored as option to combination chemotherapy in first-line treatment of unselected group of patients with advanced NSCLC 2 1. Shepherd FA, et al.

N Engl J Med

2005.

2. Jimenez U, et al. ASCO 2007: Abstract 7639.

EGFR = epidermal growth factor receptor NSCLC = non –small cell lung cancer TKI = tyrosine kinase inhibitor

Study design

 Spanish TargeT trial (1,796 patients enrolled) was an open-label, non-randomized phase II trial evaluating the efficacy and safety of erlotinib in patients with either locally advanced or metastatic NSCLC  Primary endpoint: TTP in the ITT population with erlotinib administered as first, second, and third or successive lines of treatment  Secondary endpoints included clinical benefit (CR, PR, and SD), overall survival, and safety  Patients received erlotinib 150 mg/day until disease progression or withdrawal Jimenez U, et al. ASCO 2007: Abstract 7639.

CR = complete response ITT = intent to treat NSCLC = non –small cell lung cancer PR = partial resonse SD = stable disease TTP = time to progression

Study design

(continued)

   Tumour response measured by CT scan, performed every 6 weeks, and evaluated according to RECIST criteria Safety of erlotinib was determined by NCI CTCAE v3.0

Present study is subanalysis of a subset of these unselected, chemotherapy naïve patients (n = 461). Of these patients, 259 had measurable disease and were evaluated for response (Table 1) Jimenez U, et al. ASCO 2007: Abstract 7639.

CTCAE = common terminology criteria for adverse events ECOG PS = Eastern Cooperative Oncology Group performance status NCI = National Cancer Institute NSCLC = non –small cell lung cancer RECIST = response evaluation criteria in solid tumours

Key findings

  Median TTP was 6.6 months among 259 evaluable patients (95% CI: 5.3−8.1) Never smokers receiving erlotinib had approximately 6 month longer TTP (Figure 1) and improved overall survival (Figure 2) than current or ever smokers Jimenez U, et al. ASCO 2007: Abstract 7639.

CI = confidence interval HR = hazard ratio TTP = time to progression PFS = progression-free survival

Jimenez U, et al. ASCO 2007: Abstract 7639.

CI = confidence interval HR = hazard ratio

Key findings

(continued)

  Overall response rate was 32% (Table 2) • Females, never smokers, and patients with adenocarcinoma histology had better response rates Safety • Mild-to-moderate rash was the most common AE (62.3% of patients); 3 cases of grade 4 rash (0.78%) • Diarrhea was next most common AE at 39.5%; of reported diarrhea cases 0.5% were grade 4 Jimenez U, et al. ASCO 2007: Abstract 7639.

AE = adverse event

Jimenez U, et al. ASCO 2007: Abstract 7639.

CI = confidence interval CR = complete response PR = partial response SD = stable disease

Key conclusions

    Study confirms clinical activity of erlotinib in unselected NSCLC patients who had not received prior chemotherapy for advanced disease: median TTP of almost 7 months in all patients and 11 months in never smokers First-line erlotinib therapy able to achieve disease control in 71% of patients, independent of disease histology Smoking history and gender predictive factors for tumour response In multivariate analysis, absence of smoking history and good PS associated with a longer survival NSCLC = non –small cell lung cancer PS = performance status TTP = time to progression Jimenez U, et al. ASCO 2007: Abstract 7639.

Canadian perspective by Dr. Hirsh

 Improved response in never smokers fits with previously published BR.21 study, which showed erlotinib beneficial in both smokers and never smokers, but more effective in patients who had never smoked 1  Most clinical benefit with TKI of EGFR is seen in never smokers, women, and adenocarcinomas; this trial confirms it EGFR = epidermal growth factor receptor TKI = tyrosine kinase inhibitor 1. Clark GM, et al.

Clin Lung Cancer

2006.

Improved survival and response rates with cetuximab plus gemcitabine/platinum vs. gemcitabine/platinum alone as first-line treatment for advanced NSCLC

Gemcitabine/platinum alone or in combination with cetuximab as first-line treatment for advanced non-small cell lung cancer (NSCLC)

Butts CA, et al. ASCO 2007: Abstract 7539.

Background

     Cetuximab is monoclonal antibody that blocks ligand binding to extracellular domain of the epidermal growth factor receptor 1 Cetuximab has been studied in phase I and II trials in combination with chemotherapy as first-line therapy for metastatic NSCLC, with resulting response rates of 23% to 53% 2-5 Addition of cetuximab to chemotherapy appears to be well tolerated and with acceptable toxicity Question remains whether cetuximab adds any clinical benefit over chemotherapy alone in unselected or selected patient populations Early, and encouraging, safety and efficacy results presented at ASCO 2007 of current open-label, randomized phase II study designed to compare gemcitabine and a platinum (cisplatin or carboplatin) alone with the same combination with cetuximab in patients with previously untreated, advanced NSCLC 6 1. Govindan R.

Clin Cancer Res

2004.

2. Rosell R, et al.

J Clin Oncol

2004.

3. Kelly K, et al.

Proc Am Soc Clin Oncol

2003.

4. Robert F, et al.

J Clin Oncol

2005.

5. Gatzemeier U, et al.

Proc Am Soc Clin Oncol

2003. 6. Butts CA, et al. ASCO 2007: Abstract 7539.

NSCLC = non –small cell lung cancer

Study design

     Trial was small noncomparative, open-label, randomized phase II trial of gemcitabine and platinum chemotherapy with or without the addition of cetuximab (Figure 1) Eligible patients were: • chemotherapy naïve • Stage IIIB or IV NSCLC and an ECOG PS of 0 or 1 (Table 1) No crossover allowed between treatment groups Primary outcome: overall response rate Secondary outcomes: progression-free survival, overall survival, and safety ECOG = Eastern Cooperative Oncology Group NSCLC = non –small cell lung cancer PS = performance status Butts CA, et al. ASCO 2007: Abstract 7539.

Figure 1:

Treatment schema

Butts CA, et al. ASCO 2007: Abstract 7539.

AUC = area under curve

Patient demographics

Butts CA, et al. ASCO 2007: Abstract 7539.

BAC = bronchoalveolar carcinoma

Key findings

 Cetuximab added to chemotherapy suggests possibility of improvements in overall response rate, progression-free survival, and overall survival (Table 2) Butts CA, et al. ASCO 2007: Abstract 7539.

CI = confidence interval

Safety

 Addition of cetuximab to chemotherapy regimens appears to be relatively well tolerated, with fatigue, nausea, anorexia, and acneiform rash as distinguishing adverse events in the cetuximab arm (Table 3) Butts CA, et al. ASCO 2007: Abstract 7539.

Key conclusions

 Response rates improved when cetuximab was added to gemcitabine and platinum-based chemotherapy regimens, compared with gemcitabine and platinum-based chemotherapy alone, as first-line therapy in advanced NSCLC  Early results suggest that addition of cetuximab may also prolong progression-free and overall survival  Cetuximab plus chemotherapy regimen well tolerated  Two other randomized phase III trials have completed recruitment and should report next year NSCLC = non –small cell lung cancer Butts CA, et al. ASCO 2007: Abstract 7539.

Canadian perspective by Dr. Hirsh

     This randomized phase II trial was too small to make any firm conclusions; at this point, the survival data look promising Benefit of cetuximab of a similar magnitude to that of bevacizumab in the ECOG 4599 trial Main difference between studies was that this cetuximab trial enrolled a group of patients using a wider eligibility criteria; data may be more widely applicable to the general population It will be interesting to see if results of two other trials compare well to this trial We certainly need a larger, phase III trial results to see impact on our practice Butts CA, et al. ASCO 2007: Abstract 7539.

Bevacizumab plus chemotherapy fails to improve survival compared with chemotherapy alone in older patients with NSCLC

Outcomes for elderly advanced stage non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P): analysis of Eastern Cooperative Oncology Group (ECOG) 4599 study

Ramalingam SS, et al. ASCO 2007: Abstract 7535.

Background

   Older patients (≥65 years of age) account for approximately 50% of all lung cancer patients, yet few randomized clinical trials enroll significant numbers of older patients, making it difficult to assess efficacy and toxicity of new agents in this subgroup 1 Older patients often have comorbidities or physiologic characteristics, such as altered drug metabolism and reduced hepatic and renal functions, that make their treatment more challenging 1 Present study 2 is retrospective analysis of the safety and efficacy profiles in the subgroup of older patients (aged 70 years or older) enrolled in published E4599 trial 3 (see the earlier discussion of the AVAiL trial 4 on slides 3 to 17) 1. Gridelli C, et al.

Ann Oncol

2006.

2. Ramalingam SS, et al. ASCO 2007: Abstract 7535. 3. Sandler AB, et al.

N Engl J Med

2006. Erratum in:

N Engl J Med

. 2007.

4. Manegold C, et al. ASCO 2007: Abstract LBA7514.

Study design

   Eligibility criteria for the initial trial included non-squamous NSCLC and ECOG PS 0 or 1 For subgroup analysis, elderly patients defined as age 70 or older at the time of study entry (Table 1) Those younger than 70 years of age comprised the non-elderly group ECOG = Eastern Cooperative Oncology Group NSCLC = non –small cell lung cancer PS = performance status Ramalingam SS, et al. ASCO 2007: Abstract 7535.

Baseline characteristics

Ramalingam SS, et al. ASCO 2007: Abstract 7535.

ECOG = Eastern Cooperative Oncology Group NOS = not otherwise specified PC = paclitaxel/carboplatin PCB = paclitaxel/carboplatin/bevacizumab PS = performance status

Key findings

    Number of eligible cases from E4599 was 850 (PC: n = 433, PCB: n = 417) ≥ 70 years: n = 224 (26%) ≥ 80 years: (1.6%) Proportion of elderly patients in ECOG 4599 was highest recorded among ECOG phase III trials (26%) Median age of elderly group was 74 years, while median age of non-elderly group was 63 years Efficacy data comparable between treatment regimens in both elderly and non-elderly cohorts (Table 2) ECOG = Eastern Cooperative Oncology Group PC = paclitaxel/carboplatin PCB = paclitaxel/carboplatin/bevacizumab Ramalingam SS, et al. ASCO 2007: Abstract 7535.

Efficacy data for elderly vs. non-elderly group

Ramalingam SS, et al. ASCO 2007: Abstract 7535.

CR = complete response PC = paclitaxel/carboplatin PCB = paclitaxel/carboplatin/bevacizumab PFS = progressive-free disease PR = partial response SD = stable disease

Safety

  Grade 3 or 4 toxicity more common in elderly patients (Table 3) More treatment-related deaths in elderly group (7 deaths vs. 2 deaths in non-elderly,

p

= 0.10) Ramalingam SS, et al. ASCO 2007: Abstract 7535.

PC = paclitaxel/carboplatin PCB = paclitaxel/carboplatin/bevacizumab

Key conclusions

     Analysis shows similar outcome of triplet therapy for elderly patients compared with younger counterparts in terms of RR and OS Improvement in survival and PFS seen in non-elderly cohort with addition of bevacizumab to standard chemotherapy; no significant improvement noted in elderly Addition of bevacizumab associated with higher degree of toxicity when compared to paclitaxel-carboplatin alone Note that this is retrospective study —percentage of elderly patients enrolled in E4599 study 1 with bevacizumab did not exceed 26% of actual study population Safety and efficacy of bevacizumab-chemotherapy combinations in elderly patients with NSCLC requires more scrutiny NSCLC = non –small cell lung cancer OS = overall survival PFS = progession-free survival RR = response rate 1. Sandler AB, et al.

N Engl J Med

2006. Erratum in:

N Engl J Med

. 2007.

Canadian perspective by Dr. Hirsh

    Comparatively large number of older patients (n = 222) who had a PS of 0 or 1 enrolled in this trial Clinical trials generally designed to test efficacy of a treatment intended for a population consisting of a majority of younger patients; only selected proportion of elderly patients will be considered for enrollment, as in this study Results of such trials may not necessarily extend to general non-selected elderly population (which would include patients with a PS of 2) and should be treated with caution Caution is required as to whether to give patients older than 70 years of age bevacizumab in addition to chemotherapy, because of increased toxicity seen in retrospective subanalysis of elderly patients in this trial and lack of survival benefit with bevacizumab in this group PS = performance status Ramalingam SS, et al. ASCO 2007: Abstract 7535.

Canadian perspective

(continued)

    Three drugs may not be better than two in case of elderly patients with advanced NSCLC Standard third-generation, single-agent chemotherapies such as vinorelbine and gemcitabine already have proven efficacy with manageable toxicity in this population Functional status can be measured as activities of daily living (ADL) and instrumental ADL (IADL); IADL may prove to be significant prognostic value for survival of elderly patients with advanced NSCLC treated with chemotherapy Use of these scores in clinical practice might improve prediction for patients who will likely benefit from agents like bevacizumab; this needs to be tested prospectively ADL = activities of daily living IADL = instrumental activities of daily living NSCLC = non –small cell lung cancer Ramalingam SS, et al. ASCO 2007: Abstract 7535.