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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

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
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

elderly patients representation in clinical trials
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%

chemotherapy in the elderly patient special challenges
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
prospective phase iii chemotherapy trials in elderly patients with advanced nsclc
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)
slide6

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

treatment schema wjtog 2005

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

docetaxel vs vinorelbine for elderly patients with advanced nsclc
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

retrospective analyses of platinum based doublets in elderly 70 patients with advanced nsclc
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
jcog phase iii randomized trial in advanced nsclc elderly patients
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

phase ii trial of cisplatin docetaxel in the elderly
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

jcog phase iii randomized trial in advanced nsclc elderly patients1
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

molecularly targeted agents role in elderly patients with advanced nsclc
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
br 21 overall survival
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.

forest plot of survival by subsets
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

forest plot of survival by subsets1
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

slide17

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.

phase ii study of erlotinib in elderly patients with previously untreated advanced nsclc
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

conclusions sa erlotinib in elderly nsclc
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

gefitinib in elderly nsclc japanese experience
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)

gefitinib in the elderly with nsclc
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

slide22

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

slide23

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

slide24

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

slide25

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

slide26
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
phase 2 trial of docetaxel and gefitinib in tx na ve pts with advanced nsclc 70 yrs of age
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.

slide28

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)

results
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)

slide30

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
inhibition of tumor vascularization reduced metastases and tumor volume
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.

rhumab vegf recombinant humanized monoclonal antibody to vegf aka bevacizumab
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
slide33

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

e4599 outcome
E4599: Outcome*

* All Differences were statistically significant p< 0.05

slide35

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.

introduction
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
objectives
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
methods
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)
results1
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
baseline characteristics
Baseline Characteristics

* Indicates statistically significant difference

pfs in elderly pcb vs pc
PFS in Elderly: PCB vs. PC

Hazard ratio: 0.76 (0.57,1.01)

conclusions elderly enrolled in e 4599
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.
slide50

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

study design abx036
Study Design: ABX036
  • Open label, nonrandomized, multicenter Phase II study.
  • Intravenous (IV) Abraxane 300 mg/m2, carboplatin IV AUC=6, and Bevacizumab 15 mg/kg on Day 1 of each 21-day cycle.
  • Responding patients received minimum of 4 cycles of treatment.
  • Bevacizumab was notcontinued after completion of chemotherapy
  • Patients with progressive disease or intolerable toxicity came off study. Responses were assessed every two cycles
survival

Median overall survival

15.8 months (95% CI: 10.4, NA))

Survival

Median overall survival

15.8 months (95% CI: 10.4, NA))

combination bevacizumab and erlotinib results n 40
Combination Bevacizumab and Erlotinib: Results (n=40)
  • Overall response rate 20% in 2nd and 3rd line setting
  • Median TTP = 7.0 months
    • 38% FFP @ 12 mos
  • Median survival = 12.6 months
  • No unexpected toxicities

Herbst RS et al. J Clin Oncol. 2005;23:2544

bevacizumab and erlotinib
Bevacizumab and Erlotinib
  • Phase II Trial in two separate Tx-naïve cohorts:
    • PS 2
    • Elderly
  • Schema
    • Erlotinib: 150 mg/d
    • Bevacizumab: 10 mg/kg Q 2wks
    • Tx until PD or unacceptable toxicity

PI: H Borghaei, CJ Langer

bevacizumab and erlotinib1
Bevacizumab and Erlotinib
  • Phase II Trial in two separate Tx-naïve cohorts:
    • PS 2
    • Elderly
  • Schema
    • Erlotinib: 150 mg/d
    • Bevacizumab: 10 mg/kg Q 2wks
    • Tx until PD or unacceptable toxicity

PI: H Borghaei, CJ Langer

efficacy comparison for antiangiogenic agents without chemotherapy
ZD64741

Sunitinib2

Sorafanib3

Erlotinib4

Bevacizumab5

Docetaxel/

Premetrexed6

Efficacy Comparison for Antiangiogenic Agents(Without Chemotherapy)

n

PR (%)

SD (%)

DCR

PFS*

OS†

-

-

8.0

1.0

45.0

34.0

11.0

8.1

83

85

ZD6474

Gefitinib

Crossover

-

63

52

9.5

0.0

11.3

11.7

23.9

29.5

43

59

-

-

Erlotinib

Placebo

488

283

8.9

< 1

45.0

-

9.7

7.7

29.0

20.3

-

-

19

0.0

-

NA

12

-

288

283

Docetaxel

Premetrexed

8.8

9.1

46.4

45.8

-

-

12.6

12.6

34.0

35.9

*Weeks; †Median weeks; 1Natale RB, ASCO 2006 (abstr 7000); 2Socinski AM, ASCO 2006 (abstr 7001);

3Gatzemeier U, ASCO 2006 (abstr 7002); 4Shepherd FA, NEJM 353(2):123-32, 2005;

5Johnson DH, J Clin Oncol 22(11):2184-88, 2004; 6Hannah N, J Clin Oncol 22(9):158997, 2004

early stage nsclc in the elderly
Early Stage NSCLC in the Elderly
  • Implications of the BR10 Subanalysis
  • LACE Meta-analysis
  • Ongoing Trials evaluating Targeted Therapies
jbr 10 outcomes by patient age
JBR.10 –Outcomes by Patient Age

Cisplatin 50 mg/m2 d1, 8

Vinorelbine 30*25 mg/m2/wk x4

N = 242 (*-18 excl. for Vin 30/m2) = 224

Young (≤ 65 years) = 157

Elderly (> 65 years) = 67

R

A

NDOMIZE

D

T1-2, N0-1 NSCLC

N2 nodes sampled

N = 482

Stratified by:

N0 vs N1

Ras pos, neg, or unknown

No chemotherapy/Observation

N = 240

Young (≤ 65 years) = 162

Elderly (> 65 years) = 78

Pepe, J Clin Oncol. 2007 Apr 20;25(12):1553-61

jbr 10 outcomes by age
JBR-10 Outcomes by Age
  • Worse PS in older; fewer PS0 >65 (53% vs 41%, = 0.01)
  • adeno>squam in younger, squam>adeno in older pts.
  • Patients >65 received significantly less chemo
    • no significant diffs in toxicity, or growth factor support
    • more elderly patients refused treatment
  • Older patients (>75) had worst survival regardless of Rx, but same when corrected for disease-specific survival
  • OS 46% vs. 66% for obs. vs. chemo in pts. >65
  • OS 58% vs. 70% for obs. vs. chemo in pts <65
  • Benefit from chemo not seen in pts >75 (?harmful)
    • However, patient numbers are too small to answer clearly

Pepe, J Clin Oncol. 2007 Apr 20;25(12):1553-61

elderly specific analyses br10 toxicity pepe et al asco 06 a 7009
Elderly Specific Analyses - BR10: ToxicityPepe et al ASCO ’06, A-7009
  • Other differences re: elderly
    • Fewer doses of VNR (p=0.014) and DDP (p=0.006)
    • Fewer completed Tx; more refused Tx (p=0.03)
    • Less myalgias/arthralgias and mood alterations
  • No significant difference with respect to other toxicities, G-CSF use, and hospitalizations
br10 overall survival by age group
BR10: Overall Survival by Age Group

1.0

1.0

0-65 N = 327

H-R =

2.38

66-70 N = 84

0.8

0.0006

Log-Rank, p =

71-75 N = 48

0.8

>75 N = 23

0.6

63%

0.6

Probability

0.4

0.4

 75 N = 459

>75 N = 23

0.2

0.2

26%

0.0

0.0

0

2

4

6

8

10

12

0

2

4

6

8

10

12

Time (Years)

Pepe, J Clin Oncol. 2007 Apr 20;25(12):1553-61

e1505 phase iii trial of adjuvant chemotherapy bevacizumab
E1505: Phase III Trial of Adjuvant Chemotherapy +/- Bevacizumab

R

A

N

DOM

I

Z

E

Chemotherapy*

X 4 cycles

  • Eligibility:
  • #Resected IB - IIIA
  • Lobectomy

No prior chemo

No planned XRT

No h/o CVA/TIA

No ATE w/in 12 mo

Stratification:

Stage

Histology

Gender

Type of Chemo

Chemo* x 4 cycles +

Bevacizumab

x 1 year

N=1500

  • Primary endpoint: overall survival
  • - 1500 pts to detect 26.5 % difference in Med OS with 85% power and 2.5% type 1 significance level
  • Secondary endpoints: disease-free survival, safety [bleeding and arterial thromboembolic events (ATEs)]
  • Biomolecular correlatives
  • No age cut-offs
  • *Specified regimens
  • Cisplatin and docetaxel
  • Cisplatin and vinorelbine
  • Cisplatin and gemcitabine
  • Cisplatin and pemetrexed
  • ^ > 4 cm

.

elderly patients with advanced nsclc treatment principles
Elderly patients with Advanced NSCLC: Treatment Principles
  • Age alone should not be a criterion for treatment selection in advanced disease
  • PS is the primary determinant of prognosis in elderly patients with advanced NSCLC
  • Dedicated trials in patients aged 70 to 79 with PS 0-1 may no longer be necessary, but we have yet to show the superiority of a platinum-based regimen compared to a single agent in an elderly specific trial
  • Dedicated studies are urgently needed in octogenarians
  • Assessment of co-morbidities and potential impact on outcome is an important research goal
targeted tx in elderly patients with advanced nsclc basic tenets
Targeted Tx in Elderly Patients with Advanced NSCLC: Basic Tenets
  • Erlotinib as a single agent is safe and feasible in both the Tx-naïve setting and in the 2nd/3rd line venue
  • Bevacizumab in combination with standard chemotherapy in Tx-naïve NSCLC yields
    • improved OR% and a trend toward increased PFS, but
    • demonstrates no survival advantage in post-hoc analysis
    • And it causes significantly more toxicity, including neutropenia, FN, GI bleeding, proteinuria, motor neuropathy, dizziness, and TRDs.
  • E1505, while it allows elderly pts to be enrolled, does not permit carboplatin-based therapy.
  • The role of other molecular-targeted agents and angio-inhibitory agents merits further investigation in the adjuvant setting, especially in the elderly, who are likely to be under-represented in current chemo-based adjuvant efforts