FIRST-LINE THERAPY FOR ADVANCED NSCLC Rogerio C. Lilenbaum, MD Clinical Associate Professor of Medicine University of Miami School of Medicine Director,

FIRST-LINE THERAPY FOR ADVANCED NSCLC

Rogerio C. Lilenbaum, MD

Clinical Associate Professor of Medicine

University of Miami School of Medicine

Director, Thoracic Oncology Program

The Mount Sinai Comprehensive Cancer Center

Miami Beach, FL

QUESTIONS FOR DISCUSSION

• What are the options for 1st line therapy?

• What is the optimal management of the elderly and the PS 2 patients?

• What is the role of the non-platinum regimens?

• What is the role of the molecular targeted agents in 1st line therapy?

Cis/Vin and Cis/Gem vs. Cisplatin : Overall Survival

100%

80%

60%

40%

20%

0%0 12 24 36 48 60

J Clin Oncol 2000, 18:122-30.

P=.004

Su

rviv

al P

rob

abili

ty

1.0

0.90.80.70.6

0.50.40.30.20.10.0

0 5 10 15 20 25

Gem/Cis 260 9.0 39% 15%Cis 262 7.6 28% 8%

N MS 1YS 2YS N MS 1YS 2YSVin/Cis 206 8 36% 12%Cis 209 6 21% 7%

Cis/Vin vs Cisplatin

J Clin Oncol 1998, 16:2459-64.

Cis/Gem vs Cisplatin

MedianSurvival Survival

N Deaths (Months) 1-Year 2-Year1CBDCA+Pac 208 159 8 38% 15% CDDP+Vin 202 156 8 36% 16%

0 6 12 18 24 30Months

100%

80%

60%

40%

20%

0%

Cis-Vinorelbine vs Carbo-Paclitaxel SWOG 9509

1J Clin Oncol. 2001;19:3210-3218.

A Phase III Four-Arm Trial in Advanced NSCLC

Paclitaxel 135 mg/m2 over 24 hours, day 1Cisplatin 75 mg/m2, day 2

Gemcitabine 1000 mg/m2 days 1, 8, and 15Cisplatin 100 mg/m2 day 1

Docetaxel 75 mg/m2 day 1Cisplatin 75 md/m2 day 1

Paclitaxel 225 mg/m2 over 3 hours, day 1Carboplatin AUC=6 day 1

RANDOMIZED

Stratification

PS 0-2

WT Loss

Stage - IIIB, IV

Brain mets (+/-)

Schiller, NEJM 2002:92-98


Regimen RR (%)

MST (mo.)

TTP

(mo.)

1-yr Survival

(%)

Cis/Paclitaxel 21.3 7.8 3.5 31

Cis/Gemcitabine 21.0 8.1 4.5* 36

Cis/Docetaxel 17.3 7.4 3.6 31

Carbo/Paclitaxel 15.3 8.2 3.3 35

*P = .002 by log rank test


CIS-PAC CIS-GEM CIS-DOC CARBO-PAC

N = 282 N = 273 N = 278 N = 272

GR 4 ANC 55 37 49 42

Gr 4 thrombocytopenia 2 26* 1 2

Gr 3 nausea 25 36 23 8*

Gr 3 neuropathy 4 8 5 8

Gr 3-4 febrile neutropenia 16 4* 10 3*

Gr 3-5 renal 3 9* 3 1

Worst Gr 4-5 89 70 86 57*

*P < 0.05 vs. Arm A

Tax 326: Randomized Phase III Trialfor Advanced NSCLC

RANDOMIZE

Stratification Factors:

Stage of DiseaseIIIB vs. IV

Region

US/Canada

Latin America

Europe/LebanonIsrael

South Africa/AustraliaNew Zealand

Response assessment every 2 cycles

Docetaxel 75mg/m2 IV

Carboplatin AUC 6 IV Q 3 wks

Vinorelbine 25mg/m2 IV D 1, 8, 15 & 22Cisplatin 100mg/m2 IV D 1Q 4 wks

Docetaxel 75mg/m2 IVCisplatin 75mg/m2 IV Q 3 wks

vs.

406 396 401

10.9 10.0 9.1

46 41 38

21 14 16

Tax 326: Randomized Phase III Trialfor Advanced NSCLC

Docetaxel/ Navelbine/ Docetaxel/

Cisplatin CisplatinCarboplatinN

Median survival (mo)

1-Yr survival (%)

2-Yr survival (%)

Belani et al. 2001

P=.044, Adjusted Log-Rank

2y Survival 21 vs 14%, p=.035

P=.66, Adjusted Log-Rank

2 y Survival 18 vs 14%

Cis/Tax vs. Cis/Nav Carbo/Tax vs Cis/Nav

ASCO 2002

Clinical Trials of 2-Drugs vs 1

Study Therapy MST 1-Yr Surv

CALGB1Paclitaxel

P + Carbo

6.7 m

8.8 m

33%

37%

SLUSG2Gemcitabine

G + Carbo

9.0 m

11.0 m

32%

44%

GCGLC3Docetaxel

D + Cispl

8.0 m

10.1 m

42%

48%

1Proc ASCO 21:1a (A #2), 2002; 2Proc ASCO 21:291a (A #1162), 2002; 3Proc ASCO 21:291a (A #1163), 2002

CALGB 9730 - DESIGN

RANDOMIZE

Paclitaxel 225 mg/m2 over 3 hours on day 1

Paclitaxel 225 mg/m2 + Carboplatin to AUC 6

Every 3 weeks for up to 6 cycles

IIIB/IV

PS 0-1/2

Age / 70

Lilenbaum, ASCO 2002

CALGB 9730 – SURVIVAL

P = 277 CP = 284

FFS (mo)(95% CI)

2.5(2.3 , 2.8)

4.6(4.1 , 5.3)

MST (mo)(95% CI)

6.7(5.8 , 7.9)

8.8(8.8 , 9.9)

1-Y SURV(95% CI)

33%(28% , 39%)

37%

(32% , 43%)

Median follow-up was 19.7 months

CALGB 9730 – OVERALL SURVIVAL

0 10 20 30 40

Months

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

PaclitaxelPaclitaxel and Carboplatin

Log-rank = 0.2022

Wilcoxon = 0.0125

Gemcitabine/Carboplatin versus MIC

Gemcitabine 1200 mg/m2d 1, 8

Carboplatin AUC = 5 d 1 q.21 days

Mitomycin 6 mg/m2

Ifosfamide 3 g/m2

Cisplatin 50 mg/m2

Day1 q.21 days

Stage IIIb/IV NSCLCPS 0-3

Rudd, ASCO 2002:A1164

LLCG: GC vs MIP in Advanced NSCLCSurvival

0 3 6 9 12 15 18 21 24 27 30 33 36

0

.2

.4

.6

.8

1

GC

MIP

Pro

po

rtio

n S

urv

ivin

g P

ts.

Med 1-Y

GC 10.2m 38%MIP 6 .9m 28%

Months

What are the options for 1st line therapy?

• Patients with advanced NSCLC and good PS should be treated with a platinum-based doublet.

• Platinum-based doublets are better than an old single agent (Cis) and a new single agent (Paclit)

• All platinum-based doublets have comparable efficacy, but vary in cost and toxicity

• Three-drug regimens are more toxic and no better than doublets

• The preferred platinum analog remains controversial

CISPLATIN

CARBOPLATIN

PACLITAXELDOCETAXEL

VINORELBINEGEMCITABINE

+






Non-Platinum Regimens

• Deliver comparable survival with less toxicity better therapeutic index

• Represent alternative regimens to patients who are not optimal candidates for platinum-based therapy

Non-Platinum, Taxane-Based Doublets

• Paclitaxel + gemcitabine• Docetaxel + gemcitabine• Paclitaxel + vinorelbine• Docetaxel + vinorelbine

Non-Platinum, Non-Taxane Doublets

• Vinorelbine + Gemcitabine• Gemcitabine + Irinotecan• Vinorelbine + Ifosfamide

A EORTC Randomized Phase III Trial of Three Chemotherapy Regimens In Advanced Non-Small Cell

Lung Cancer

NSCLC

PS 0-2

Stage IIIB or IV

Paclitaxel 175 mg/m2 d 1

Cisplatin 80 mg/m2 d 1

every 21 days

Gemcitabine 1250 mg/m2 d 1, 8

Cisplatin 80 mg/m2 d 1

every 21 days

Gemcitabine 1250 mg/m2 d 1, 8

Paclitaxel 175 mg/m2 d 1

every 21 days

Van Meerbeeck et al, Proc Am Soc Clin Oncol, 20: #1228, 2001

RANDOMIZED

Van Meerbeeck - Efficacy

Cis/Pac Cis/Gem Pac/Gem

Response Rate

31% 36% 27%

PFS 4.4 mo 5.6 mo 3.9 mo

Median Survival

8.1 mo 8.8 mo 6.9 mo

1-year Survival

35.5% 32.6% 26.5%

Van Meerbeeck - Toxicity

Toxicity (% of pts) Cis/Pac Cis/Gem Pac/Gem

Gr. 3/4 ANC 33 43 30

Neutropenic Fever 1 3 2

Gr. 3/4 Thrombocytopenia 1 36 6

Gr. 3/4 Bleeding 1 0 1

Gr. 3/4 Anemia 3 11 4

Gr. 3/4 Nausea 8 13 6

Gr. 3/4 Vomiting 8 13 5

Gr. 3/4 Sensory Neurotoxicity

3 2 1

Gr. 3/4 Motor Neuropathy 3 1 3

Gr. 3/4 Lethargy 9 11 11

Gr. 3/4 Dyspnea 8 10 12

Toxic deaths 3 1 4

GEMVIN – Study designGEMVIN – Study design

RANDOM

Cisplatin 80 mg/ /m², d 1 Vinorelbine 30 mg/m², d 1&8

or (at random)

Cisplatin 80 mg/ /m², d 1 Gemcitabine 1200 mg/m², d 1&8

Gemcitabine 1000 mg/m², d 1&8

Vinorelbine 25 mg/m², dd 1&8

Every 3 weeks, for a maximum of 6 cyclesGridelli, ASCO 2002

GEMVIN – Progression-free survivalGEMVIN – Progression-free survival

CDDP-based

(n=250)

GemVin

(n=251)

# events (%) 212 (85) 222 (88)

Median PFS (95% CI) (wks)

23 (18-27) 17 (14-20)

6 – month PFS probability

0.44 0.26

1 – year PFS probability 0.13 0.09

GemVin vs CDDP-based 1.29 (1.10-1.52)* p=0.004

GEMVIN – Overall survivalGEMVIN – Overall survival

CDDP-bsed

(n=250)

GemVin

(n=251)

# events (%) 175 (70) 180 (72)

Median OAS (95% CI) (wks)

38 (35-45) 32 (30-39)

6 – month OAS probability 0.66 0.62

1 – year OAS probability 0.37 0.31

GemVin vs CDDP-based 1.15 (0.96-1.37)* p=0.08

Phase II Study of Vinorelbine-Gemcitabine vs Paclitaxel-Carboplatin

Stratification • Stage IIIB/IV• PS 0−1/2

RANDOMIZ A T I O N

Vinorelbine 25 mg/m2 days 1, 8Gemcitabine 1,000 mg/m2 days 1, 8

Paclitaxel 200 mg/m2 day1Carboplatin (AUC=6) day 1

Every 3 weeks, for a maximum of 6 Cycles

Primary endpoint:QoL analysis (LCSS)

What is the role of the non-platinum regimens?

• Taxane-based regimens appear to offer comparable efficacy to platinum-based combinations

• Toxicity, however, is not significantly reduced and ca be substantial, especially in patients with less than optimal performance status

• The non-platinum, non-taxane based regimens are less toxic, but questions about equivalent efficacy remain. They are a viable option for patients unable to tolerate platinum-based therapy






Biological Agents for Solid TumorsSignal Transduction/Cell-Cycle

Inhibitors– Farnesyl transferase– Flavopiridol– Retinoids– UCN-101

Gene Therapy– GM-CSF– Wild-type p53– Antisense

– c-myc– PKC

Vaccines– Tumor cells– Peptides– Dendritic cells– Viral vaccines

Angiogenesis Inhibitors

– SU5416/SU6668

– Anti-VEGF antibodies

– Interferon-/– Marimastat

– ZD6474

– LY317615

– TNP-470

– Endostatin/angiostatin

Receptor-Targeted Therapy– Trastuzumab

– Anti-EGFR

– ZD1839

– C225

– OSI-774

Stage III/IV NSCLC N=1029/Trial

*Gemcitabine/cisplatin (trial 14)

*Paclitaxel/carboplatin (trial 17)

Randomize

Chemotherapy * x6 cycles + 250 mg ZD1839

Chemotherapy * x6 cycles + 500 mg ZD1839

Chemotherapy * x6 cycles + Placebo

Continue ZD1839 or placebo until disease progression

Primary endpoint: Survival

ZD1839 Randomized Trials With Chemotherapy in Advanced NSCLC

Bevacizumab (rhuMAb-VEGF) in NSCLC:ECOG4599 Schema

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

Eligibility:

• No prior Rx

• Stage IIIB or IV

• Non-SqCCa

• ECOG PS 0-1

Eligibility:

• No prior Rx

• Stage IIIB or IV

• Non-SqCCa

• ECOG PS 0-1

CBDCA: AUC = 6

Paclitaxel: 200 mg/m2

CBDCA: AUC = 6


CBDCA: AUC = 6


rhuMAb-VEGF: 15 mg/kg

CBDCA: AUC = 6


rhuMAb-VEGF: 15 mg/kg

Upon PD crosssover to Anti-VEGF NOT ALLOWED

The Affinitac Phase III TrialThe Affinitac Phase III Trial

Eligible patientsrandomized to:

Eligible patientsrandomized to:

Restaging for response every 2 cyclesRestaging for response every 2 cycles

Treatment continues up to 6 cycles(more if patient is benefiting)

Treatment continues up to 6 cycles(more if patient is benefiting)

Post-Treatment follow-up•Survival•Tumor progression

Post-Treatment follow-up•Survival•Tumor progression

Day 0: Paclitaxel 175 mg/m2

Carboplatin AUC 6 21-day cycle

Day 0: Paclitaxel 175 mg/m2

Carboplatin AUC 6 21-day cycle

ARM AARM A ARM BARM B

Days 0-14: ISIS 3521, CIVDay 3: Paclitaxel 175mg/m2

Carboplatin AUC 6Days 15-21: Rest

Days 0-14: ISIS 3521, CIVDay 3: Paclitaxel 175mg/m2

Carboplatin AUC 6Days 15-21: Rest

Stratified for: Stage History of CNS Disease

Stratified for: Stage History of CNS Disease

Sample size = 600

What is the role of the molecular targeted agents in 1st line therapy?

Documents

FIRST-LINE THERAPY FOR ADVANCED NSCLC Rogerio C. Lilenbaum, MD Clinical Associate Professor of Medicine University of Miami School of Medicine Director,