1. Outcomes for Elderly, Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis of Eastern Cooperative Oncology Group Trial 4599 Suresh S. Ramalingam, Suzanne E. Dahlberg, Corey J. Langer, Robert Gray, Chandra P. Belani, Julie R. Brahmer, Alan B. Sandler, Joan H. Schiller, and David H. Johnson From the Division of Hematology- Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh VOLUME 26 NUMBER 1 JANUARY 1 2008 J Clin Oncol 26:60-65

2. Introduction Lung cancer ◦ The leading cause of cancer-related deaths in the United States ◦ 213,000 new cases of lung cancer in the year 2007. ◦ Non–small-cell lung cancer (NSCLC) : more than 85% Advanced – stage NSCLC ◦ At the time of diagnosis : 40% of NSCLC present ◦ The standard treatment : systemic chemotherapy  Improving both quality of life (QOL) and survival. ◦ Platinum or non–platinum based, two-drug regimens : The standard of advanced NSCLC with ECOG 0 or 1

3. Introduction Bevacizumab ◦ A monoclonal antibody targeting the vascular endothelial growth factor (VEGF) ◦ VEGF  An important mediator of new blood vessel formation(neoangiogenesis)  A critical event for progression of cancer ECOG 4599 trial ◦ A large randomized study ◦ A survival advantage for patients with advanced nonsquamous NSCLC treated with the regimen of bevacizumab, carboplatin and paclitaxel (PCB) versus carboplatin and paclitaxel alone(PC) ◦ The regimen of PCB : neutropenia, hemorrhage, hypertension, proteinuria and an incidence of treatment-related deaths (TRDs) N Engl J Med 355:2542-2550, 2006

4. Introduction In this journal… ◦ A subset analysis of ECOG 4599 ◦ The outcomes for elderly patients, comparing results with PCB versus PC ◦ Among those receiving PCB, comparing outcome between patients younger than 70 and 70 years or older

5. Patients and Methods Patients ◦ 878 patients were randomly assigned to treatment with PCB or PC ◦ Treatment cycles : every 3 weeks ◦ Reassessment : every 6 weeks ◦ Inclusion criteria  Stage IIIB or IV NSCLC  ECOG PS of 0 or 1  Adequate bone marrow, hepatic, and renal function ◦ Exclusion criteria  Predominant squamous histology  History of major hemoptysis, brain metastasis, recent history of bleeding or thrombotic events  Uncontrolled hypertension  Ongoing therapeutic anticoagulation The primary end point of the study : overall survival (OS)

6. Results – Baseline characteristics

7. Results - Toxicity The median number of treatment cycles ◦ PC arm : 5 cycles vs PCB arm : 7 cycles Incidence of Grade 3 or worse toxicity ◦ PC arm : 61% < PCB arm : 87% (P<.001) Treatment related Death rate ◦ PC arm : 2 deaths (infection and cardiac ischemia and GI bleeding) ◦ PCB arm : 7 deaths  hemoptysis (n=2), infection (n=2), febrile neutropenia (n=1), hematemesis (n=1) and cerebrovascular ischemia (n=1)

8. Results - Toxicity Epistaxis 1.8% Hemoptysis 1.8% Hematemesis 0.9% GI bleeding 2.6%

9. Results - Toxicity

10. Results - Efficacy CR: 0 PR: 18 CR: 0 PR: 29

11. Results - Efficacy

12. Discussions Elderly NSCLC ◦ Patients with a good PS : platinum-based combination chemotherapy ◦ With the addition of bevacizumab to chemotherapy  A higher incidence of certain hematologic and nonhematologic toxicities ◦ >70 years : 26% in ECOG 4599 ◦ >80 years : 1.6% in ECOG 4599 ◦ Our analysis to this very elderly subgroup is limited, and it is conceivable that octogenarians might be at an even higher risk of adverse events with three-drug combinations ◦ No differences in OS between the two regimens. ◦ A superior response rate and improved PFS with PCB ◦ Treatment related deaths : PCB>>PB in elderly patients  The 15 TRDs recorded in the PCB arm  The incidence in the elderly group : 6.3% compared with 2.6% in the younger group

13. Discussions Limitations ◦ Higher numbers of patients of age more than 75 years were randomly assigned to PCB compared with PC (58 v 40 patients) -> the increased toxicities noted with PCB in the elderly patients ◦ Differences in poststudy treatment ◦ Imbalances in the distribution of comorbid illness ◦ No data of baseline QOL and instrumental activities of daily living (IADL)

14. Discussions Manegold C, Von Pawel J, Zatloukal P, et al: J Clin Oncol 25:967s, 2007 ◦ Two different doses of bevacizumab (7.5 mg/kg and 15 mg/kg) in combination with cisplatin and gemcitabine for advanced nonsquamous NSCLC. ◦ Improvements in PFS over chemotherapy alone ◦ No major differences in toxicity ◦ If a dose-related reduction in toxicity is noted in elderly patients, then the lower dose could be considered for the treatment of elderly patients. Herbst RS, Johnson DH, Mininberg E, et al: J Clin Oncol 23:2544-2555, 2005 ◦ A recent phase II study for patients with recurrent NSCLC for the combination of bevacizumab and erlotinib ◦ Erlotinib : monotherapy for elderly NSCLC patients in the front-line setting ◦ Bevacizumab with erlotinib ? Optimal utilization of bevacizumab in elderly patients with NSCLC ◦ Elderly-specific prospective studies are critical to establish the safety of combinations of novel agents for treatment of advanced NSCLC

15. Conclusion In elderly NSCLC patients, PCB was associated with a higher degree of toxicity, but no obvious improvement in survival compared with PC.