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Elderly Patients with Advanced NSCLC: Emerging Role of Targeted Therapy

Elderly Patients with Advanced NSCLC: Emerging Role of Targeted Therapy. Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology University of Pennsylvania, Philadelphia, PA Corey.langer@uphs.upenn.edu. Demographics of Lung Cancer in the Older Patient.

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Elderly Patients with Advanced NSCLC: Emerging Role of Targeted Therapy

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  1. Elderly Patients with Advanced NSCLC: Emerging Role of Targeted Therapy Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology University of Pennsylvania, Philadelphia, PA Corey.langer@uphs.upenn.edu

  2. Demographics of Lung Cancer in the Older Patient • Individuals > age 65: fastest growing segment of U.S. population • More than 2/3 of patients with adv. lung cancer older than 65* • Median age of diagnosis for lung cancer in the U.S. is 70* • 35% of lung cancer patients > 75* • Likelihood of receiving treatment decreases with advancing age • Clinical trial participation also decreases with advancing age • Analysis of SWOG trials 1993 – 1996 (Hutchins NEJM 341:2061,1999) • 39% of patients on lung trials > 65 vs. 66% of general population > 65 • NCI analysis 1997 – 2000 (Lewis J Clin Oncol 21:1383, 2003) • 42% of patients on lung trials > 65 vs. 70% of general population > 65 *SEER Data 2000 - 2003

  3. Elderly Patients - Representation in Clinical Trials • 65% of lung cancer patients are  65 • 50% of lung cancer patients are 70 • Elderly representation on US NSCLC Trials Study% 70 E5592 15% S9509/9305 19% E1594 20% E4599 26% CALGB 9730 27%

  4. Chemotherapy in the Elderly Patient: Special Challenges • Higher frequency of comorbid conditions • Higher prevalence of polypharmacy increasing the risk of adverse drug interactions • Reduced hepatic, renal, lung function, immune competence and bone marrow reserve • Impaired social, emotional or financial resources

  5. Prospective Phase III Chemotherapy Trials in Elderly Patients with Advanced NSCLC • ELVIS (1999) (154 pts) • vinorelbine vs. BSC: improved survival and QOL with vinorelbine • SIOG (2000) (120 pts) • vinorelbine vs. vinorelbine + gemcitabine: improved survival, but enhanced toxicity with the combination • MILES (2003) (698 pts) • vinorelbine vs. gemcitabine vs. vinorelbine + gemcitabine: overall survival similar among arms; combination regimen more toxic • WJTOG (2006) (182 pts) • vinorelbine vs. docetaxel: improved response, PFS and survival with docetaxel (though underpowered to show a statistically significant benefit wrt OS)

  6. Single Agent Chemotherapy in Elderly Patients with Advanced NSCLC Author Regimen N Response MS (mo) 1 YR Vinorelbine 78 20% 6.5 32%* BSC 76 -- 4.9 14% Gemcitabine + Vinorelbine 76 22% 7 30%* Vinorelbine 76 15% 4.5 13% Vinorelbine 233 18.4% 8.8 41% Gemcitabine 233 17.3% 6.6 26% Gemcitabine + Vinorelbine 237 20% 7.6 31% Gridelli* Frasci‡ Gridelli *Gridelli, J Natl Cancer Inst 1999; 85:365-376. ‡Frasci et al, JCO 2000; 18(13): 2529-2536  Gridelli, J Natl Cancer Inst 2003; 95: No5 *p<0.05

  7. Docetaxel (D) Day 1 8 15 22 29 Docetaxel 60 mg/m2 Vinorelbine (V) Day 1 8 15 22 29 Vinorelbine 25 mg/m2 TREATMENT SCHEMA – WJTOG 2005 RANDOMIZE • Stratification • Institution • Stage IV/IIIB • PS 0-1/2 Both treatments were repeated over 4 cycles to disease progression. Takeda ASCO 2005, A-7009

  8. Docetaxel vs Vinorelbine for Elderly Patients with Advanced NSCLC • 182 pts accrued • Toxicities consistent with known profile of each agent • Global QoL similar but overall symptom improvement better with D than V • Higher ORR with D (23% vs. 10%; p=0.019) • Longer PFS with D (5.4 vs. 3.1 mo; p<0.001) • Survival: MST 1-y Surv • D 14.3mo 59% • V 9.9 mo 37% HR=0.780 (0.561-1.085) p=0.138 WJTOG – ASCO 2005

  9. Retrospective Analyses of Platinum-based Doublets in Elderly (> 70) Patients with Advanced NSCLC • Several subset analyses conducted assessing outcome in patients > age 70 • SWOG 9509/9308 - carbo/paclitaxel vs. cis/vinorelbine (Kelly 2001) • ECOG 5592 – carbo/etoposide vs. carbo/paclitaxel (Langer 2002) • CALGB 9730 – carbo/paclitaxel (Lilenbaum 2002) • ECOG 1594 – four platinum doublets (Langer 2003) • TAX 326 – cis/docetaxel vs. cis/vinorebine vs. carbo/docetaxel (Fossella 2003) • No differences in survival • Trend for greater toxicity in some studies, particularly myelosuppression • Trend for improved tolerance of carboplatin vs. cisplatin • Major potential limitation – these elderly subsets may not be representative of the general elderly population

  10. JCOG phase III randomized trial in advanced NSCLC elderly patients R a n d o m iz a ti o n Weekly Docetaxel DOC 25 mg/m2day 1, 8, 15every 4 weeks Age > 70 yrsIIIB-IV NSCLC PS 0- 1 Weekly CDDP+ Docetaxel CDDP 25 mg/m2 DOC 20 mg/m2day 1, 8, 15every 4 weeks Tsukada et al, ASCO ’07, A-7629

  11. Phase II Trial of Cisplatin + Docetaxel in the Elderly Schema: CDDP 25 mg/m2 DOC 20 mg/m2 Days 1, 8, 15 Q 4 wks Results: • N= 33 • Median age: 77 • Median cycles: 3 • ORR: 52% • MS: 15.8 mos • 1 YR OS: 64% • 2 YR OS: 26% Ohe Y et al: Ann Onc 15:45-50, 2004

  12. JCOG phase III randomized trial in advanced NSCLC elderly patients • Premature Termination • Trial aborted after DSMC determined that the 70-74 age group benefitted from DP over D Tsukada et al, ASCO ’07, A-7629

  13. Molecularly Targeted Agents: Role in Elderly Patients with Advanced NSCLC • Potential for increased use given “favorable” toxicity profile • Limited prospective data to date • Retrospective analysis of BR21 showed that age did not dilute the survival benefit of erlotinibvs placebo in the 2nd and 3rd line setting • Prospective phase II trial with erlotinib suggests benefit • Subset analyses of extended access trials with single-agent gefitinib have demonstrated clinical activity and modest toxicity • Phase II trial of gefitinib + gemcitabine or vinorelbine (Scagliotti ASCO 2004); antineoplastic activity not enhanced; excessive toxicity for vinorelbine and gefitinib • Prospective phase III trial of gefitinibvsvinorelbine shows equivalent survival, improved QoL (IASLC ’07) • Retrospective analysis of bevacizumab combined with chemotherapy suggests caution

  14. BR.21: overall survival 100 80 60 40 20 0 HR=0.70 (0.58–0.85) Stratified log-rank p<0.001 Percentage Erlotinib Placebo 0 6 12 18 24 30 Time (months) At risk Erlotinib 488 255 145 23 4 0 Placebo 243 107 50 9 0 0 Shepherd F, et al. N Engl J Med 2005.

  15. Forest plot of survival by subsets erlotinib:placebo PS 0–1 PS 2–3 Male Female <65 years 65 years Adenocarcinoma Squamous-cell carcinoma Other histology Prior weight loss <5% Prior weight loss 5–10% Prior weight loss >10% Never-smoker Current/ex-smoker 1 prior regimen 2+ prior regimens 0 1 2 3 4 HR

  16. Forest plot of survival by subsets erlotinib:placebo PS 0–1 PS 2–3 Male Female <65 years 65 years Adenocarcinoma Squamous-cell carcinoma Other histology Prior weight loss <5% Prior weight loss 5–10% Prior weight loss >10% Never-smoker Current/ex-smoker 1 prior regimen 2+ prior regimens 0 1 2 3 4 HR

  17. Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21 • No significant demographic differences between age groups randomly assigned to erlotinib or placebo • Response rates were similar between age groups. • Elderly patients, compared with young patients, had significantly more overall and severe (grade 3 and 4) toxicity (35% v 18%; P < .001), were more likely to discontinue treatment as a result of treatment-related toxicity (12% v 3%; P < .0001), and had lower relative dose-intensity (64% v 82% received > 90% planned dose; P < .001). • Conclusion: Elderly pts treated with erlotinib have similar survival and QOL benefits compared to younger pts, with somewhat greater toxicity J Wheatley-Price P, Ding K, Seymour L, Clark GM, Shepherd FA JCO 2008 May 10;26(14):2350-7.

  18. Phase II Study of Erlotinib in Elderly Patients with Previously Untreated Advanced NSCLC. • PIs: Janne, Jackman & Johnson MD • Location: Dana Farber and MGH • Regimen: single agent 150 mg/d in chemo-naïve, PS 0-2 pts ≥70yrs until PD or toxicity • N = 80; median age 76 (70-91); 63% Adenoca or BAC; 95% never/former smokers • Toxicities: gr > 1rash 79%; grade 3 rash (5); diarrhea 69%; 9 pts D/C for toxicity; ILD (4), 1 fatality • OR%: 10% -- of 8 responders, 5 female, 2 never and 6 former smokers; all had rash • DC%: 51%; TTP: 3.5 mos • Median Survival: 10.9 mos (95% CI 7.8 – 14.6 mo) • 1yr OS: 46%: 2yr OS: 19% • EGFr Mutations: (+) in 9/43 tested, corelated with RR, DC, TTP and OS Jackman D ASCO-2005, A-7148, JCO ‘07

  19. Conclusions: SA Erlotinib in Elderly NSCLC • Single agent activity and survival in Tx-naïve pts matches that observed with conventional cytotoxics • Untoward toxicity not observed; no unusual safety concerns Jackman D ASCO-2005, A-7148, JCO ‘07

  20. Gefitinib in Elderly NSCLC (Japanese experience) • Retrospective comparison comparing toxicity, response and survival outcomes for gefitinib in patients aged 75 years or older (elderly group) with patients aged younger than 75 years. • 350 patients were eligible for this analysis, • Multivariate analysis revealed elderly patients with lower Brinkman index tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence interval: 0.91-22.72, p = 0.0642). • Conclusions: Tx with gefitinib appeared to be as safe and effective in elderly patients (aged 75 or older) with NSCLC as in non-elderly patients Hotta K, Ueoka H, Kiura K, Tabata M, Ogino A, Umenura S, Harita S, Gemba K, Yonei T, Bessho A, Maeda T, Tanimoto M Acta Oncol. 2005;44(7):717-22 (Okayamo)

  21. Gefitinib in the Elderly with NSCLC • Prospective study of gefitinib 250 mg/d in advanced chemo-exposed NSCLC pts > 70. From August 2001 to May 2003, • 40 consecutive pts enrolled from three Italian institutions from 8/01 to 5/03 • OR% - 5% (1 CR, 1 PR) 18 disease stabilizations (NC: 45%) lasting at least 2 mos • six patients (15%) who had disease stabilisation of 6 months or longer, • median duration of response was 4.4 months (range 1.7-9.2). • No data on PFS or OS • Side effects generally mild and consisted of diarrhoea and skin toxicity. • Grade 1-2 diarrhoea in 23.6%; one pt experienced grade 4 diarrhoea, requiring hospitalization. • Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne in 20 pts (50%). • Conclusions: Gefitinib is safe and well tolerated in elderly pretreated NSCLC patients with reasonable disease control rate. Cappuzzo F, Bartolini S, Ceresili GL, Tamberi S, Spreafico A, Lombardo L, Gergorc V, Toschi L, Calandri C, Villa E, Crino L Br J Cancer. 2004 Jan 12;90(1):82-6

  22. INVITE trial in advanced NSCLC elderly (>70 yrs) pts with PS < 2 Vinorelbine 30 mg/m2 days 1 + 8 RP2 Gefitinib (250 mg/d) Prim. Obj.= time to progression Crino et al IASLC ’07 Crino L, Cappuzzo F, Zatloukal R et al J ClinOncol. 2008 Sep 10;26(26):4253-60

  23. INVITE trial in advanced NSCLC elderly (>70 yrs) pts with PS < 2 *PSI – Pulmonary symptom improvement HR for Vnr vs Gef for 54 FISH (+) PFS: 3.13 (1.45, 6.73) OS: 2.88 (1.21, 6.83) HR for Gef vs Vnr PFS: 1.19 (0.85, 1.69) OS: 0.98 (0.66, 1.47) • Conclusions: • Gefitinib and vinorelbine similar efficacy • Gefitinib better tolerated • Paradoxical benefit for VNR in FISH (+) pts Crino et al IASLC ’07 Crino L, Cappuzzo F, Zatloukal R et al J ClinOncol. 2008 Sep 10;26(26):4253-60

  24. Phase II randomized trial of IRESSA + GEM or VNR in elderly NSCLC pts GEM+Gefitinib GEM 1200 mg/m2, i.v., d 1-8, q21 IRESSA 250 mg/die, p.o., until to PD VNR+Gefitinib VNR 30 mg/ m2, i.v., d 1-8, q21 IRESSA 250 mg/die p.o., until to PD Accrual completed R Study Coordinators: C. Gridelli – G.V. Scagliotti

  25. Phase II randomized trial of IRESSA + GEM or VNR in elderly NSCLC pts GEM+Gefitinib GEM 1200 mg/m2, i.v., d 1-8, q21 IRESSA 250 mg/die, p.o., until to PD VNR+Gefitinib VNR 30 mg/ m2, i.v., d 1-8, q21 IRESSA 250 mg/die p.o., until to PD Accrual completed R Study Coordinators: C. Gridelli – G.V. Scagliotti

  26. Randomized Phase II of Gefitinib in Combination with Vinorelbine or Gemcitabine in Elderly Pts with NSCLC • Gr 3-4 ADRs in 87.5% in the 1st 24 pts on VG • Including 72% gr 3-4 neutropenia • 3 deaths which may have been Tx-related (1 septic shock and cerebral infarct) Results VG GG • No 24 35 • CR/PR 1/3 3 • TTP (d) 91 94 • MS (d) 371 275

  27. Phase 2 trial of docetaxel and gefitinib in Tx-naïve pts with advanced NSCLC > 70 yrs of age • Eligibility: chemotherapy-naïve NSCLC patients, 70 years of age or older • Tx Design: • Docetaxel 75 mg/m(2) every 3 weeks - 2 cycles beyond maximal response • Gefitinib 250 mg po until PD • Primary endpoint - response rate (RR); Secondary endpoints : OS and PFS • RESULTS: 44 patients initiated therapy between March 2003 and May 2005. • Seventeen patients (40%; 95% confidence interval [CI], 26%-57%) had a partial response • 48% had stable disease. • Median PFS was 6.9 months (95% CI, 3.95-7.8 months). • Median survival time was 9.6 months (95% CI, 4.6-16.3 months). • Univariate analyses: sex; ECOG PS, and Charlsoncomorbidities index (CCI) score proved predictors of improved survival • Multivariate analyses: female sex was a statistically significant predictor of survival. • median survivals were 22.8 months in women and 4.8 months in men. • Most common adverse events being hyperglycemia, fatigue. • CONCLUSIONS: Combination docetaxel and gefitinib: active and well tolerated in patients with advanced NSCLC who are 70 years of age and older; merits further investigation especially in women Simon et al Cancer. 2008 May 1;112(9):2021-9.

  28. Randomised phase II trial in NSCLC pts unsuitable for Plat-based CT (Elderly or PS 2) Cetuximab + Gemcitabine X 6 cycles R Gemcitabine Cetuximab at PD Gridelli C, Mencoboni M, Carrozza F et al. C225 and Gemcitabine in elderly or adult PS 2 advanced NSCLC pts : the CALC-1 randomized phase II trials. JCO 2008: 2(15S): 452s (A8117)

  29. Results Elderly (n=58) PS 2 (n=42) * 34% of elderly and 60% of PS 2 pts were unable to start C225 maintenance or 2nd line Tx. Gridelli C, Mencoboni M, Carrozza F et al. C225 and Gemcitabine in elderly or adult PS 2 advanced NSCLC pts : the CALC-1 randomized phase II trials. JCO 2008: 2(15S): 452s (A8117)

  30. NCCTG: N0422: Cetuximab (C225) and RT in Elderly &/or Poor Performance Status Patients with Stage III NSCLC: A Phase II Study to Evaluate Survival & Toxicity • Eligibility: • >65 yrs old or younger and PS=2 • Stage III NSCLC • Adequate organ function • Treatment • Cetuximab, 400 mg/m2: Day 1 • Then, Cetuximab 250 mg/m2: Days 8, 15, 22, 29, 36, 43+ concurrent RT(60 Gy/30 fxs) • Major endpoint: survival

  31. Inhibition of Tumor Vascularization:Reduced Metastases and Tumor Volume VEGF mAb Control mAb 226 250 • Human CRC xenograft model • Anti-VEGF mAb–treated animals showed significant reductions in the mean number of metastases per liver (10-fold less) and tumor volume (nearly 20-fold less) 200 Tumors per liver, no. 150 100 22 50 0 Growth of experimental liver metastases Control mAb VEGF mAb Warren et al. J Clin Invest. 1995;95:1789–1799.

  32. rhuMAb VEGF (Recombinant Humanized Monoclonal Antibody to VEGF) aka Bevacizumab • Humanized to avoid immunogenicity (93% human, 7% murine). • Recognizes all isoforms of vascular endothelial growth factor, Kd = 8 x 10-10 M • Terminal half life 17-21 days

  33. Survival by Tx Arm 12 mo. 24 mo. 44.4% 15.4% 51.0% 22.0% 1.0 PC PCB 0.8 P = 0.003 HR: 0.80 (0.65, 0.93) 0.6 Medians: 10.3, 12.3 Probability 0.4 0.2 0.0 0 6 12 18 24 30 36 Months Sandler et al NEJM 12/06

  34. E4599: Outcome* * All Differences were statistically significant p< 0.05

  35. Outcomes for Elderly Advanced Stage Non-small Cell Lung Cancer Patients Treated With Bevacizumab in Combination with Carboplatin and Paclitaxel: Analysis of ECOG 4599 Study Abstract # 7535, ASCO ‘07 S. Ramalingam1, S. E. Dahlberg2, C. J. Langer3, R. Gray2, C. P. Belani1, J. R. Brahmer4, A. Sandler5, J. H. Schiller6, D. H. Johnson5 1University of Pittsburgh Cancer Institute, Pittsburgh, PA, 2 Dana Farber Cancer Institute, Boston, MA. 3 Fox Chase Cancer Center, Philadelphia, PA. 4 The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. 5 Vanderbilt-Ingram Cancer Center, Nashville, TN. 6 University of Texas Southwestern Medical Center, Dallas, TX.

  36. Introduction • Elderly patients (> 70 years) account for approximately 50% of all cases of lung cancer • Elderly patients with a good performance status can be treated with platin-based two drug combinations • Two drug combinations appear to have superior efficacy when compared to monotherapy for the elderly (Lilenbaum et al, J ClinOncol 2005; Sederholm et al J ClinOncol 2005) • In general, when compared to younger patients, the elderly have: • Reduced hepatic and renal function • Altered volume of distribution • More co-morbid illness

  37. Objectives • To compare the outcomes between carboplatin and paclitaxel combination (PC) chemotherapy and PC with Bevacizumab (PCB) for elderly patients enrolled to ECOG 4599. • To study the differences in safety and efficacy between elderly and younger patients treated with PCB in ECOG 4599

  38. Methods • Subset analysis of ECOG 4599 database • Elderly patients defined as those > 70 years of age at the time of study entry • < 70 years comprised the non-elderly group • Data available as of November 1, 2005 (same release date as that used for the final ECOG technical report for the study)

  39. Results • Eligible cases = 850 (PC : n=433; PCB : n=417) • > 70 years: n=224 (26%) • > 80 years: 1.6% • Median age: • Non-elderly: 63 years • Elderly: 74 years • Median number of cycles of therapy for patients > 70 yrs • PC : 5 cycles • PCB : 7 cycles

  40. Baseline Characteristics * Indicates statistically significant difference

  41. Efficacy

  42. PFS in Elderly: PCB vs. PC Hazard ratio: 0.76 (0.57,1.01)

  43. Overall Survival in Elderly: PCB vs. PC

  44. Toxicity Data for Elderly Patients

  45. Non-Hematological Toxicity in Elderly Patients

  46. Treatment-related Deaths among Elderly Patients * P = not significant

  47. Toxicity on PCB Arm: Elderly vs. Non-Elderly

  48. Representation of Elderly Patients in ECOG phase III Trials for NSCLC

  49. Conclusions: Elderly enrolled in E 4599 • Proportion of elderly patients on ECOG 4599 is the highest recorded among ECOG phase III trials. • PCB is associated with higher degree of toxicity in elderly patients, when compared to treatment with PC alone. • No significant improvement in survival or PFS was noted with PCB over PC for the elderly (but PC out-performed historic controls in this study). • When compared to younger patients, the elderly experienced more toxicity and more TRDswith PCB. • The observations are limited by the post-hoc, retrospective nature of this analysis. • The safety and efficacy of bevacizumab-chemotherapy combinations in elderly patients with NSCLC merits further scrutiny.

  50. An Open-label, Phase II Trial of nab-paclitaxel, Carboplatin, and Bevacizumab in first-line Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Reynolds C, Barrera D, Vu DQ, et al. ASCO 2007, Abstract # 7610

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