Transcript Modeling Protease Inhibitors

Keeping Pace with Targeted Therapies in Lung Cancer
Highlights from the ASCO 2006 Annual Meeting
1
Introduction
2
Overview of Targeted Therapies
and Focus on Monoclonals
Karen Kelly, MD
Professor of Medicine
Department of Medical Oncology
University of Colorado at Denver
Aurora, Colorado
3
FDA-Approved Agents Being
Investigated for Lung Cancer Treatment
Agent
Bevacizumab
(Avastin®; Genentech)
Class
Targets
Indications
Monoclonal (IV)
VEGF
CRC
EGFR
Head & neck cancer, CRC
HER1/EGFR
NSCLC
HER1/EGFR
NSCLC
VEGFR-1, -2, -3; PDGFR-α, -β;
KIT; RET; FLT3
RCC, GIST
VEGFR-2, -3; cRAF; bRAF;
PDGFR-β; FLT3; KIT
RCC
Proteasome inhibitor
(IV)
Proteasome
Multiple myeloma
Retinoid (oral)
RXRα, RXRβ, RXRγ
Cutaneous T-cell lymphoma
Cetuximab
(Erbitux®; ImClone)
Erlotinib
(Tarceva®; Genentech)
Reversible TKI (oral)
Gefitinib
(Iressa®; AstraZeneca)
Sunitinib
(Sutent®; Pfizer)
Sorafenib
(Nexavar®; Bayer)
Bortezomib
(Velcade®, Millennium)
Bexarotene
(Targretin®; Ligand)
VEGF = vascular endothelial growth factor; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; TK = tyrosine kinase; NSCLC = non–
small-cell lung cancer; PDGFR = platelet-derived growth factor receptor; RCC = renal cell carcinoma; GIST = gastrointestinal stromal tumor;
RXR = retinoid X receptor.
4
Examples of Novel Targeted Agents Being
Investigated for Lung Cancer Treatment
Biologic Target
Tumorigenesis
Angiogenesis
Angiogenesis +
tumorigenesis
Tumor
Class
Monoclonal
(IV)
Reversible
TKI (oral)
Molecular Targets
EGFR
VEGFR-1, -2, -3;
PDGFR-β
VEGFR-1, -2, -3;
PDGFR; RET
VEGFR-2
VEGFR-2, -3; RET;
EGFR
Agent
Panitumumab
(Amgen)
Vatalanib
(Novartis/Schering AG)
AMG706 (Amgen)
AZD2171 (AstraZeneca)
ZD6474 (Zactima;
AstraZeneca)
Dual
reversible TKI
(oral)
TGF-β antisense gene TGFβAS Vaccine (Lucanix;
Vaccine
(intradermal)
modified allogeneic
NovaRx)
tumor cell vaccine
EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; PDGFR = platelet-derived
growth factor receptor; TGF = transforming growth factor.
5
ASCO 2006 Update
Bevacizumab in NSCLC
Paclitaxel + carboplatin ± bevacizumab (updated
results from randomized phase III trial E4599)
 Sandler AB, et al.1
 Brahmer JR, et al.2
 Dowlati A, et al.3
1. Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4. 2. Brahmer JR, et al. 42nd ASCO;
June 2-6, 2006. Abstract 7036. 3. Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.
6
Paclitaxel/Carboplatin ± Bevacizumab
Previously Reported ECOG 4599 Results
PC
(n = 427)
PCB
(n = 420)
10
27.2
Median PFS, mo
6-mo PFS, %
4.5
32.6
6.4
55.0
1-y PFS, %
6.4
14.6
Median OS, mo
10.2
12.5
12-mo OS, %
43.7
51.9
24-mo OS, %
16.9
22.1
Response rate, %*
P-Value
< .0001
< .0001
.007
*As percent of patients with measurable disease, n = 350 for the PC arm and n = 357 for PCB arm.
ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab;
PFS = progression-free survival; OS = overall survival.
Sandler AB, et al. 41st ASCO; May 14-17, 2005. Abstract LBA4.
7
Paclitaxel/Carboplatin ± Bevacizumab
Possible Gender Differences in Overall Survival


Unplanned subgroup analysis of ECOG 4599
Key finding: compared with males, females did not appear to gain
same overall survival benefit from addition of bevacizumab
PC
PCB
P-Value
Overall survival, mo
Overall survival males, mo
10.3
8.7
12.3
11.7
.003
.001
Overall survival females, mo
13.1
13.3
.87
ECOG = Eastern Cooperative Oncology Group; P = paclitaxel; C = carboplatin; B = bevacizumab.
Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.
8
Paclitaxel/Carboplatin ± Bevacizumab
No Gender Differences in Overall Survival

Females on PCB arm had higher response rate and progressionfree survival compared with females in the PC arm
Males
PC
(n = 230)
Overall response
rate (CR + PR), %
15.7
Progression-free
survival, mo
4.3
Females
PCB
PC
PCB
(n = 191) P-Value (n = 162) (n = 190) P-Value
28.8
.001
14.2
41.1
< .0001
6.3
< .0001
5.3
6.2
.002
P = paclitaxel; C = carboplatin; B = bevacizumab; CR = complete response; PR = partial response.
Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.
9
Paclitaxel/Carboplatin ± Bevacizumab
Perspective on Unplanned Analysis by Gender




Treatments at time of disease progression were not different, except that in
the PCB arm, females were slightly less likely than males to get
chemotherapy as 2nd-line therapy
Reasons for observed differences in overall survival are unclear, possibilities
include
– Random chance
– Pitfalls of unplanned subgroup analysis
These results contrast with results in CRC trials where no gender differences
reported in overall survival
PCB remains ECOG reference treatment in NSCLC
PCB = paclitaxel/carboplatin/bevacizumab; CRC = colorectal cancer; ECOG = Eastern Cooperative Oncology
Group; NSCLC = non–small-cell lung cancer.
Brahmer JR, et al. 42nd ASCO; June 2-6, 2006. Abstract 7036.
Laskin JJ. 42nd ASCO; June 2-6, 2006. Lung Cancer I Poster Discussion. Discussant.
Hurwitz H, et al. N Engl J Med. 2004;350:2335.
Genentech data on file
10
Prospective Correlative Assessment of
Biomarkers from ECOG 4599
Biomarkers studied
 Endothelial leukocyte adhesion molecule-1 (E-selectin)
– Expressed only on endothelial cell after activation by
inflammatory cytokines
– Elevated E-selectin seen in disorders characterized by endothelial
cell apoptosis and malignancies
 Intercellular adhesion molecule-1 (ICAM-1; CD54)
– Expressed on endothelial, epithelial, lymphocytes, monocytes,
hepatocytes, and hemapoietic cells
– Elevated levels seen in many malignancies and alterations seen
with vascular targeting and antiangiogenic agents
 Vascular endothelial growth factor (VEGF) and basic-fibroblast growth
factor (b-FGF)
– Well-known angiogenic factors
Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027.
11
Prospective Correlative Assessment of
Biomarkers From ECOG 4599—Results

Baseline plasma ICAM may be
prognostic for response and survival
in advanced NSCLC
– This might be useful stratification
factor in future trials
– Low levels indicate a 2-fold
increase in likelihood of response
to chemotherapy (unclear if this is
prognostic or predictive)
Future trials are needed to determine
if these will be better markers for
clinical outcome than conventional
radiographic response assessment
Survival by Baseline ICAM
1.0 -
Probability

0.8 -
<260.5 (62 deaths/75 cases)
>260.5 (70 deaths/75 cases)
0.6 -
P = .000050
1 y 60%
0.4 -
0.2 -
1 y 25%
0.0 0
10
20
30
40
Months
Dowlati A, et al. 42nd ASCO; June 2-6, 2006. Abstract 7027. Reprinted with permission from Dr. Dowlati.
Hirsch F. 42nd ASCO; June 2-6, 2006. Lung Cancer III. Discussant.
12
Risk Factors for Pulmonary Hemorrhage (PH)
in Bevacizumab-Treated Patients
Retrospective study of ECOG 4599 data examining association
between baseline clinical factors and incidence of early onset
(< 150 d from initial treatment) PH
 Grade  3 PH occurred in 2.3% of patients
 Of 10 cases identified, 6 met criteria for early onset PH related
to bevacizumab
 Pretreatment cavitation may be associated with increased risk
of PH
 Hemoptysis was predicative of possible future PH
Sandler AB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7068.
13
ASCO 2006 Update on
Cetuximab in NSCLC


SWOG 0342 phase II trial of chemotherapy +
cetuximab vs chemotherapy followed by
cetuximab1
FLEX phase III trial of cisplatin/vinorelbine ±
cetuximab2
1. Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
2. Von Pawl, J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
14
Preliminary Results of SWOG 0342 Phase II
Trial of Paclitaxel/Carboplatin + Cetuximab
Primary objectives
 Compare response rate and toxicity of concurrent vs sequential
platinum-based chemotherapy + cetuximab regimens as 1st-line
treatment for advanced NSCLC
 Select regimen for future trials based on overall survival
Randomize
stage IIIB/IV
NSCLC
Paclitaxel/
carboplatin +
cetuximab
× 4 cycles
(n = 106)
Cetuximab
weekly × 1
year
Paclitaxel/
carboplatin
× 4 cycles
(n = 119)
Cetuximab
weekly × 1
year
Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.
15
Phase II Trial of
Paclitaxel/Carboplatin + Cetuximab
Preliminary Efficacy Results
Complete response
Partial response, % (95% CI)
Stable disease, % (95% CI)
Disease stabilization, %
(95% CI)
Progression-free survival, mo
Median overall survival, mo
1-year overall survival, %
Chemo 
Cetuximab
(n = 119)*
0
25 (17–36)
44 (33–55)
69 (58–78)
Chemo +
Cetuximab
(n = 106)*
0
37 (26–49)
38 (27–50)
75 (63–84)
4
9
43
4
10
49
*Patients evaluable for response: 71 in the chemo + cetuximab arm and 87 in the chemo-only arm.
Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
16
SWOG 0342—Phase II Trial of
Paclitaxel/Carboplatin + Cetuximab
Preliminary Safety Results
Adverse Events (grade 3/4)
% of Evaluable Patients
80 -
67
70 -
60 50 -
55
Grade 3/4 AE (>5%) on Chemo (+/-C)
N=101 N=94
Sequential
40 -
27
30 -
Concurrent
20
20 -
N=20 N=22
10 0Chemo +/- C
Post-Chemo C
Rash (grade 3/4)
% of Evaluable Patients
14 -
12
12 -
10
10 -
N=94
8-
N=20 N=22
6420-
1
N=101
Chemo +/- C
No new
cases
concurrent
ann
Post-Chemo C
Adverse
Event
Chemo + C
N = 94
Chemo
N = 94
C
Dyspnea
6.4
4
NS
Fatigue
8.5
9
NS
Leukocytes
16
18.8
NS
Joint pain
6.4
3
NS
Nausea
6.4
2
NS
Neuropathy
15
5.9
.04
Neutrophils
41.4
36.6
NS
P-Value
Sequential
Concurrent
Chemo = paclitaxel/carboplatin; C = cetuximab.
Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015. Reprinted with permission from Dr. Kelly.
17
Phase II Trial of
Paclitaxel/Carboplatin + Cetuximab
Preliminary Conclusions





Concurrent cetuximab + chemotherapy arm met
predetermined 10-month minimal median survival
requirement
Trend toward higher response rate in concurrent arm
Rash only significant additional toxicity seen with
concurrent administration of cetuximab + chemotherapy
Biomarker correlative studies ongoing
New trials with this concurrent regimen + bevacizumab
planned
Kelly K, et al. 42nd ASCO; June 2-6, 2006. Abstract 7015.
18
Phase III Trial of
Cisplatin/Vinorelbine ± Cetuximab
Preliminary Safety Report






Stage IIIB with documented malignant pleural effusion or stage
IV previously untreated NSCLC
Epidermal growth factor receptor expression by
immunohistochemistry
Patients recruited from 166 centers in 29 countries in Europe,
Asia, Australia, and South America
Primary objective: overall survival
Preplanned analysis by Data Safety Monitoring Board (DSMB) of
baseline and safety data from 365 patients
Results
– Recruitment completed in February 2006
– 1125 patients randomized
– Trial continues
Von Pawl J, et al. 42nd ASCO; June 2-6, 2006. Abstract 7109.
19
SWOG S0339—Phase II Trial of Bortezomib +
Gemcitabine/Carboplatin


Design
– Primary endpoint: OS (goal 10 month median OS to rule
out null hypothesis)
– Stage IIIB (with pleural effusion) or IV NSCLC,
chemotherapy-naive
– PS = 0 or 1
Results
– N = 121 accrued (116 eligible)
– Median age: 64 years (range, 28–78)
– 11% stage IIIB, 86% stage IV
– Median follow-up: >15 months
– Median number of cycles: 3.6
SWOG = Southwest Oncology Group; OS = overall survival; PS = performance status.
Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.
20
Phase II Trial of Bortezomib
+ Gemcitabine/ Carboplatin
Efficacy and Safety Results
Response
ORR
CR
PR
No. (%)
(n = 114)
24 (21)
2 (2)
22 (19)
SD
51 (45)
PD
21 (18)
Not evaluable
18 (16)



Grade 3/4 Toxicity in
> 10% of Patients
No. (%)
(n = 114)
Neutropenia
59 (52)
Thrombocytopenia
72 (63)
Anemia
15 (13)
Fatigue
15 (13)
AST/ALT
14 (12)
Overall survival 11 months (95% CI 8.2–13 months)
1-year survival 47%; 2-year survival 14%
Results above predetermined statistical endpoint to proceed to a phase III trial
ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease;
PD = progressive disease; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
Davies AM, et al. 42nd ASCO; June 2-6, 2006. Abstract 7017.
21
Summary



Clarification with regards to carboplatin/paclitaxel ±
bevacizumab phase III trial ECOG 4599
– Bevacizumab does have some differential gender effect
on overall survival, but not clinically meaningful
– Potential predictive or prognostic biomarkers
– Risk factors for bevacizumab-associated pulmonary
hemorrhage
Promising results from phase II trials
– Cetuximab + carboplatin/paclitaxel
– Cetuximab + cisplatin/vinorelbine
– Bortezomib + gemcitabine/carboplatin
Data from phase III trials needed for cetuximab and bortezomib
22
Focus on Small Molecules and
Investigational Agents
Roy S. Herbst, MD, PhD
Professor of Medicine
Department of Thoracic/Head
and Neck Medical Oncology
University of Texas
M.D. Anderson Cancer Center
Houston, Texas
23
Update on Small Molecule
and Investigational Agents

Tyrosine kinase inhibitors
with FDA approvals
– Sunitinib
– Sorafenib
– Erlotinib
– Gefitinib


Investigational agents
– Vatalanib
– ZD6474
– ABI-007
– AMG706/panitumumab
Biomarkers
– Osteopontin
– EGF, Her2, p-Akt
– RXR-beta, pPARy
24
Tyrosine Kinase Inhibitors Target Both the Tumor and Endothelial Cells
Growth Factor Receptor
VEGFR/PDGFR
EGFR
RAS-RAF
VEGFR
NRP1
VEGFR 1,2,3
PDGFR
Nucleus
Nucleus
Tumor Cell
VEGF
Endothelial Cell
PDGF
Endothelial Cell
Pericytes
25
Similarities and Differences in Targets for TKIs
and Monoclonals
Inhibitor
Mechanism
Erlotinib
Bevacizumab
Inhibits tumor cell growth
and blocks synthesis of
angiogenetic proteins
(eg, bFGF, VEGF, TGFby tumor cells
Inhibits endothelial cells from
responding to the angiogenic
protein VEGF
bFGF
VEGF
TGF-
Tumor
Endothelial cells
Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from the
American Society of Clinical Oncology.
26
Sunitinib Phase II Trial in Previously Treated
Advanced NSCLC





Open-label, single-arm, 2-stage multicenter trial
Patients had recurrent stage IIIB/IV NSCLC that had failed 1 or more
chemotherapy regimens (with/out EGFR inhibitor)
Sunitinib given at 50 mg/d for 4 wk followed by 2 wk off treatment
before next 6-week cycle
Primary endpoint: overall confirmed objective response rate (ORR)
Enrollment
– 63 patients
– 64% had adenocarcinoma, 90% had stage IV disease
– 43% had 1 prior regimen, 44% had 2 prior regimens, 13% had 3
or more prior regimens
– 33% had received prior EGFR inhibitor
Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.
27
Sunitinib Phase II Trial in
Previously Treated Advanced NSCLC
Safety Results
Severe Events Occurring in  10% of Patients
% of Patients
Adverse Event
Grade 3
Grade 4
Fatigue/asthenia
Pain/myalgia
Nausea/vomiting
Dyspnea
22
14
10
13
5
3
0
0


Most toxicities were grade 1 or 2
3 hemorrhage-related deaths on study: 2 (a pulmonary hemorrhage and
a cerebral hemorrhage) were considered study-drug related
Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001.
28
Sunitinib Phase II Trial in
Previously Treated Advanced NSCLC
Efficacy Results
ORR
100
6 (9.5)
95% CI (3.6–19.6)
PR
6 (9.5)
SD
27 (42.9)
PD
14 (22.2)
Not evaluable
16 (25.4)
80
Change from Baseline (%)
Response
Best Response for
Target Lesions by Patient
No. (%)
(n = 63)
60
Partial Responses by RECIST
Stable Disease/Progressive Disease
40
20
0
-20
-40
-60
-80
-100
Median duration of response: 12.2 weeks (range, 4.3–30.1+ weeks)
 Median PFS: 11.3 weeks (95% CI 10.0–15.7)
 Median OS: 23.9 weeks (95% CI 17.0–28.3)
ORR = overall response rate; PR = partial response; SD = stable disease; PD = progressive disease;
RECIST = response evaluation criteria in solid tumors.

Socinski MA et al. 42nd ASCO; June 2-6, 2006. Abstract 7001. Reprinted with permission from Dr. Socinski.
29
Phase II Trial of Sorafenib in Advanced NSCLC



Primary objective: tumor response by RECIST of sorafenib 400 mg BID in
previously treated pts
Eligibility
– 1–2 prior treatments
– No prior gefitinib
– Asymptomatic brain metastases permitted
Enrollment
– 52 patients
– Median age 62 years (range, 26–85)
– 85% ECOG PS = 1
– 54% adenocarcinoma, 31% squamous cell carcinoma
– 94% stage IV
– 67% 1 prior chemotherapy; 29% 2 prior chemotherapy
RECIST = response evaluation criteria in solid tumors; ECOG = eastern cooperative oncology group;
PS = performance status.
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.
30
Phase II Trial of Sorafenib in Advanced NSCLC
Efficacy Results
Maximum Percentage Reduction of
Target Lesion by Patient (N = 48)†
Response
SD
PD
Not evaluated*
No. (%)
(n = 51)
30 (59)
18 (35)
3 (6)
60
SD Patients
PD Patients
40
20
0
-20
-40
-60




Tumor cavitation in 4 patients
Median PFS: 2.7 mo; median OS: 6.7 mo
SD patients: median PFS 5.5 mo
2 patients treated for > 2 years with ongoing treatment
SD = stable disease; PD = progressive disease; PFS = progression-free survival; OS = overall survival.
*Patients died prior to tumor assessment. †48 patients with postbaseline tumor measurements available.
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.
31
Phase II Trial of Sorafenib in Advanced NSCLC
Safety and Biomarker Analysis Results
Safety
– No grade 4 events
– Grade 3 events: hand-foot skin
reactions (20%), hypertension
(4%), diarrhea (2%), fatigue (2%),
headache (2%)
– 4 patients had sorafenib-related
bleeding events (3 epistaxis, 1 fatal
pulmonary hemorrhage 30 days
after stopping sorafenib)

Survival Fraction

Biomarker analysis
– Plasma biomarkers evaluated
by ELISA
– High VEGF at baseline
correlated with shorter survival
(P < .05)
1.0
Low VEGF
High VEGF
0.5
0.0
0
100 200 300 400 500 600 700
Time to Death (Days)
ELISA = enzyme-linked immunosorbent assay; VEGF = vascular endothelial growth factor.
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002. Reprinted with permission from Dr. Gatzemeier.
32
Phase II Trial of Sorafenib in Advanced NSCLC
Conclusions






Sorafenib has some activity in NSCLC
Historical comparisons show that 59% stable disease is in
same range as other targeted agents in NSCLC
Agent generally well tolerated, with low incidence of bleeding
Deterioration of quality of life not seen
Shorter median overall survival correlated with high baseline
VEGF and greater decreases in plasma VEGF during sorafenib
treatment
Phase III study of carboplatin/paclitaxel ± sorafenib is currently
accruing patients
Gatzemeier U, et al. 42nd ASCO; June 2-6, 2006. Abstract 7002.
33
Randomized Phase II Trial of Chemotherapy ±
Bevacizumab vs Erlotinib + Bevacizumab





Phase II, multicenter 3-arm randomized trial
– Arm 1: chemotherapy (docetaxel or pemetrexed) + placebo
– Arm 2: chemotherapy (docetaxel or pemetrexed) + bevacizumab
– Arm 3: erlotinib + bevacizumab
Arms 1 and 2 were double-blinded
Patients stratified by ECOG performance status and smoking history
Eligibility: recurrent unresectable NSCLC
Primary endpoint: safety and preliminary efficacy
Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062.
34
Phase II Chemotherapy ± Bevacizumab vs
Erlotinib + Bevacizumab
Efficacy
(n = 41)
Chemotherapy +
Bevacizumab
(n = 40)
Erlotinib +
Bevacizumab
(n = 39)
3.0
4.8
4.4
21.5%
30.5%
33.6%
Adjusted HR* (95% CI)
NA
0.66 (0.38, 1.16)
0.72 (0.42,1.23)
Unadjusted HR (95% CI)
NA
0.78 (0.47, 1.30)
0.76 (0.45, 1.28)
62.4%
72.1%
78.3%
CR/PR
12.2%
12.5%
17.9%
CR/PR/SD
39.0%
52.5%
51.3%
Chemotherapy
Progression-free survival
Median, mo
6-mo rate
Overall survival
6-mo rate
Response rate
*Adjusted by randomization stratification factors (ECOG PS, smoking history).
HR = hazard ratio; NA = not applicable; CR = complete response; PR = partial response; SD = stable disease.
Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.
35
Phase II Chemotherapy ± Bevacizumab vs
Erlotinib + Bevacizumab
Safety
Percent of Patients
Chemotherapy
(n = 41)
Chemotherapy +
Bevacizumab
(n = 40)
Erlotinib +
Bevacizumab
(n = 39)
Fatigue
66
70
56
Nausea
48
42
41
Diarrhea
17
40
69
Rash/dermatitis/acneform
29
20
82
Anemia
22
32
10
Neutropenia
24
30
10
Fatigue
12
12
7
Neutropenia
17
20
5
2
3
1
Toxicities
Most common overall
Most common grade 3/4
Drug-related deaths
Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Reprinted with permission from Dr. Fehrenbacher.
36
Phase II Trial of Erlotinib vs
Carboplatin/Paclitaxel in NSCLC




Primary endpoint: PFS (treatment worthy of further evaluation if PFS  3.5
months)
Study design
– Eligibility: stage IIIB or IV no prior chemotherapy
– Performance status 2
– No prior treatment with any EGFR inhibitor; no uncontrolled brain
metastases
– Optional cross-over to erlotinib
Enrollment: 103 patients
Arms well balanced in demographics and baseline characteristics
PFS = progression-free survival; EGFR = epidermal growth factor receptor.
Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.
37
Phase II Trial of Erlotinib vs Carboplatin/
Paclitaxel (CP) in NSCLC
Efficacy Results
Progression-Free Survival (PFS)
No. of Pts (%)
1.0 -
Response
Group
N Median(M) 95% Cl
Erlotinib 52
1.91
(1.28, 2.69)
PC
51
3.52
(1.48, 4.87)
0.9 0.8 -
PFS Probability
0.7 -
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
6
12
18
PFS (Months)
24
36
Erlotinib
(n = 52)
CP
(n = 51)
PR
1 (2)
6 (12)
SD
PD
19 (37)
23 (44)
21 (41)
10 (20)
Unable to
determine/not
evaluated
8 (15)
13 (25)
Still on active
therapy
1 (2)
1 (2)
Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022. Reprinted with permission from Dr. Lilenbaum.
38
Phase II Trial of Erlotinib vs
Carboplatin/Paclitaxel in NSCLC
Conclusions





Single-agent erlotinib treatment did not meet progression-free
survival endpoint to warrant further evaluation
Results in erlotinib-treated patients who developed grade 2+
rash were “in closer range to chemotherapy”
Sample size too small to make significant correlation between
biomarkers analyzed and outcome
Quality of life parameters similar between 2 treatment arms
Development of erlotinib in 1st-line NSCLC centers on
– Molecular selection of patients
– Combination with other targeted agents
– Dosing optimization
Lilenbaum R, et al. 42nd ASCO; June 2-6, 2006. Abstract 7022.
39
Molecular Predictors of Outcome with Erlotinib in
Bronchioloalveolar Cell Carcinoma (BAC)



Results of a prospective phase II trial
Objective: compare clinical, pathologic, and molecular characteristics of tumor
specimens associated with response, PFS, and OS
Marker analysis: EGFR (mutations, amplification, polysomy, chromogenic in situ
hybridization [CISH]), KRAS (mutations)
Outcome of Patients Treated with Erlotinib
n Median PFS Median OS
(mo)
(mo)
All
CR+PR
Stable disease
Progression
Not evaluable
102
22
38
36
6
4
15
6
1
1
17
24
29
8
1
P < .01
Molecular Characteristics and Outcome
EGFR mut +
EGFR wt
CISH ≥ 4
CISH < 4
IHC ≥ 1
IHC 0
KRAS mut +
KRAS wt
n
RR(%)
P
18
64
24
53
25
39
19
62
83
7
43
13
20
21
0
32
<.01
<.01
.99
<.01
Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003. Adapted with permission from Dr. Miller.
Median PFS
(mo)
P
13
2
9
2
4
4
4
5
<.01
<.01
.76
.25
Median OS
(mo)
P
23
17
25
16
19
16
13
21
.65
.38
.60
.24
40
Molecular Predictors of Outcome
with Erlotinib in BAC
Conclusions







Erlotinib resulted in 23% overall response rate (ORR) and 17 mo
median overall survival (OS) in BAC
Presence of EGFR mutation associated with an 83% ORR,
13 mo progression-free survival (PFS) and 22 mo OS
EGFR amplification in BAC rare
EGFR polysomy predictive of improvement in PFS
KRAS exon 2 mutation associated with no responses and poorer OS
Patients with EGFR mutation + CISH  4 had ORR 90%,
PFS 15 mo, OS 35 mo
Patients with wild type EGFR + CISH < 4 had ORR 4%, PFS 2 mo,
OS 15 mo
Miller VA, et al. 42nd ASCO; June 2-6, 2006. Abstract 7003.
41
Phase II Trial 1st-Line Erlotinib in Patients
with NSCLC and EGFR Mutations


Primary endpoint: time to progression
Eligibility
– Stage IIIB/IV NSCLC + mutated EGFR
– No prior chemotherapy
– No prior EGFR targeted agents
Response, % (95% CI)
All (n = 38)
Exon 19 (n = 20)
Exon 21 (n = 18)
82
(66–92)
95
(75–100)
67
(41–87)
CR
13.2
20
5.5
PR
68.4
75
61.1
SD
13.2
5
22.2
PD
5.3
0
11.1
ORR
Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020.
42
Phase II Trial 1st-Line Erlotinib in NSCLC
with EGFR Mutations
Results
TTP According to Mutational Status
Response Predictors
ORR
EGFR Mutation
Exon 19
Exon 21
.038
Gender
22 (88%)
9 (69%)
.754
Adeno
BAC
Other
.203
8 (73%)
18 (86%)
5 (83%)
Histology
24 (90%)
7 (70%)
0 (0%)
Log Rank P =.06
Breslow P =.06
P-value
.662
0
1
2
.038
Female
Male
PS
19 (95%)
12 (67%)
Smoking
Never
Former
Current
ORR
P-value
23 (79%)
4 (100%)
4 (80%)
Stage
1.0
IIIB
IV
4 (100%)
27 (79%)
TTP According to Smoking Habits
Conclusions

Most benefit: Exon 19 deletions, patients who never
smoked, visceral site other than lung

Phase III trial planned (erlotinib vs platinum-based
chemotherapy in EGFR-mutated NSCLC)
Paz-Ares L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7020. Reprinted with permission from Dr. Paz-Ares.
Log Rank P =.12
Breslow P =.02
43
Randomized Phase II Trial of ZD6474 vs
Gefitinib in Advanced NSCLC
Part A Results
Hazard ratio = 0.69
95% Cl = 0.50 to 0.96
Two-sided P-value = .025
Median PFS
ZD6474 = 11.0
Gefitinib = 8.1 weeks
Individual Changes in Size of Target
Lesions from Baseline: Part A
Best Confirmed Change from Baseline
in Target Lesion Size (%)
Probability of Remaining
Progression-Free
Primary Endpoint in Part A:
Progression-Free Survival
ZD6474
Gefitinib
Final data cut-off, July 2005
Progression-free survival in Part A (months)
Secondary Efficacy Endpoint in Part A
Objective response
Disease control > 8 wk
No. of Patients (%)
ZD6474 (n = 83)
Gefitinib (n = 85)
7 (8)
1 (1)
37 (45)
29 (34)
Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
44
Randomized Phase II Trial of ZD6474 vs
Gefitinib in Advanced NSCLC
Part B Results
Probability of Remaining Alive
Secondary Endpoint:
Overall Survival
Median PFS
ZD6474 then gefitinib = 6.1 months
Gefitinib then ZD6474 = 7.4 months
Hazard ratio = 1.19
(95% Cl = 0.84 to 1.68)
Two-sided P-value = .34
Time to Death (months)
Final data cut-off, July 2005
Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
45
Randomized Phase II Trial of ZD6474 vs Gefitinib in
Advanced NSCLC: Adverse Events
Event*
ZD6474 (n = 83)
Gefitinib (n = 85)
Diarrhea
58%
41%
4/2
1/0
46%
49%
Grade 3, no.
4
1
Nausea/vomiting
28%
34%
Grade 3, no.
1
1
18%
13%
2
0
Dizziness
14%
9%
Hypertension
12%
1%
Grade 3, no.
3
0
QT-related events
21%
5%
Grade 3/4, no.
Rash
Headache
Grade 3, no.
*AEs are all CTC grade 1 or 2 except where noted.
Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000. Reprinted with permission from Dr. Natale.
46
Randomized Phase II Trial of ZD6474 vs
Gefitinib in Advanced NSCLC
Conclusions




Part A met primary endpoint of prolonging progression-free
survival (PFS)
– ZD6474 prolonged PFS by 45% compared with gefitinib
PFS prolongation did not result in overall survival
advantage in Part B
– Why? Not clear, maybe optional switchover confounded
survival assessment
Adverse events (AEs) for both agents mostly mild
Slight differences in AE profiles
Natale RB, et al. 42nd ASCO; June 2-6, 2006. Abstract 7000.
47
Novel Targeted Agents Under
Investigation for Lung Cancer Treatment
Highlights of ASCO 2006
Agent
Study
Results
AMG706
Blumenschein
Abstract 7119
Ongoing phase Ib trial in advanced NSCLC of AMG706 + CP, AMG706 +
panitumumab ± CP
TGFβAS
Vaccine
Nemunaitis
Abstract 7018
75 patients, safety of optimal dose determined, results suggest greater
survival compared with historical controls
Vatalanib
Jahan
Abstract 7081
Tolerated in mesothelioma
Activity: 8.5% PR, 68.1% SD
But 3-mo PFS (53.3%) did not met protocol-specified level of 75%
ZD6474
Natale
Abstract 7000
As shown in previous slides, ZD6474 produced longer PFS compared with
gefitinib in refractory NSCLC
Heymach
Abstract 7016
ZD6474 + docetaxel is being tested in ongoing double-blind, randomized
phase II trial in 2nd-line NSCLC
ABI-007
Rizvi
Abstract 7105
Phase I/II trial, 1st-line in advanced NSCLC, MTD reached; ORR 30% and
10.9 mo OS; grade 3 sensory neuropathy and fatigue, minimal
myelosuppresion
AZD2171
Laurie
Abstract 3054
Phase I trial in advanced NSCLC of AZD2171 + CP; manageable toxicities
including hypertension; evidence of activity
CP = carboplatin/paclitaxel.
48
Other Searches for Useful
Biomarkers in NSCLC—ASCO 2006
Mack PC, et al1

Elevated osteopontin plasma
levels may have prognostic
value in advanced NSCLC

Osteopontin is a secreted
glycoprotein involved in
induction of urokinase (uPA) and
increased cell migration
1. Mack PC, et al. 42nd ASCO, June 2-6, 2006. Abstract 7198.
2. Toschi L, et al. 42nd ASCO, June 2-6, 2006. Abstract 7111.
Toschi L, et al2

FISH or IHC analysis of samples
from 190 consecutive patients
treated for advanced NSCLC

EGFR, HEr2, and p-Akt status
are not predictors of sensitivity
to chemotherapy

EGFR FISH + and/or HER2
FISH+ patients seemed to
benefit more from nonplatinum
vs platinum-based combinations
(but N small)

In EGFR FISH+ patients, RR
and TTP after EGFR-TKI used
as 2nd-line treatment were at
least equal to 1st-line
chemotherapy
49
Summary




First-generation TKIs (gefitinib, erlotinib) the search continues for
– Molecular markers for patient selection
– Optimal combinations
– Improved dosing
Multitargeted TKIs currently on the market (sorafenib, sunitinib)
– Some promising, but not yet conclusive results
Investigational multitargeted TKIs (vatalanib, ZD6474, AMG706, AZ2171)
– Need data from randomized trials
– Some differences in adverse event profiles
General areas of need
– Surrogate markers for evaluation of agents
– Biomarkers for patient selection
– Optimization of clinical trial design
50
Toxicity Management of Targeted
Therapies: Implications for
Nursing and Managed Care
Michelle Purdom, RN, BSN
Manager, Clinical Trials Operations
Phase I Program
University of Texas
M.D. Anderson Cancer Center
Houston, Texas
51
Overview


Management of side effects associated with
targeted therapies
Pharmacoeconomics of cancer management
and role/implications of targeted therapies in
managed care setting
52
Targeted Therapies and Approval Dates
QuickTime™ and a
TIFF(LZW) decompressor
are needed to see thi s picture.
May 2, 2003*
2003
February 12, 2004
2004
May 13, 2003
February 26, 2004
* Iressa was approved with contingencies on May 2, 2003.
November 19, 2004
2005
January 26, 2006
2006
December 20, 2005
53
Most Common Side Effects Associated
with FDA-Approved Targeted Therapies
Side Effect
Abdominal pain
Acne and/or rash
Alopecia
Altered taste
Anemia
Anorexia and/or
weight loss
Appetite decrease/
taste disorder
Arthralgia/myalgia
Asthenia
Bleeding
Constipation
Cough
Dehydration
Diarrhea
Dizziness
Dry and/or
discolored skin
Dysesthesia and/or
paresthesia
Dyspepsia
Dyspnea
Bevacizumab*

Sunitinib


Bortezomib
Sorafenib




Cetuximab**



Erlotinib† Gefitinib‡












































Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; †+gemcitabine
and monotherapy; ‡250 mg/d and 500 mg/d.
54
Most Common Side Effects Associated
with FDA-Approved Targeted Therapies (cont’d)
Side Effect
Bevacizumab*
Edema
Epistaxis

Fatigue
Fever

GI hemorrhage

Hand-foot skin reaction
Headache

Hypertension

Insomnia
Leukopenia and/or
neutropenia and/or
thrombocytopenia
Mucositis/stomatits

Nausea and/or
vomiting

Pain

Peripheral neuropathy
Pharyngitis
Proteinuria

Pruritis
Upper respiratory
infection

Xerostomia
Sunitinib
Bortezomib


Sorafenib
Cetuximab**



Erlotinib†

Gefitinib‡

























Includes: *+IFL, +5-FU/LV, +FOLFOX4, and monotherapy; **+radiation, +irinotecan, and monotherapy; †+gemcitabine
and monotherapy; ‡250 mg/d and 500 mg/d.
55
Management of Bevacizumab-Associated
Side Effects
Side Effect
Scope
Symptoms and Management
Hypertension
Incidence Gr 3/4: B + C 12% vs C 2%
Not infusion related; usually observed
during course of treatment
Standard oral antihypertensives
If severe, temporarily suspend treatment
If hypertensive crisis, discontinue treatment
Monitor BP at least every 2–3 weeks
AT events
Incidence B + C 4.4% vs C 1.9%
Permanently discontinue treatment
GI perforation
Incidence: B + C 2–4% vs C 0.3%
Symptoms: abdominal pain, constipation, vomiting
Wound healing or
bleeding
complications
Incidence: among patients requiring surgery Wait for complete healing of surgical incision and
within 60 d of B + C 15% vs C 4%
at least 28 d after surgery before starting
B therapy
Hemorrhage
Incidence Gr 3–5 bleeding: B + C 5.2% vs B
3.8% vs C 0.7%
Incidence epistaxis (nosebleeds): B + C
35% vs C 10%
Epistaxis usually mild, use standard first aid
techniques
Patients with recent hemoptysis should not
receive B therapy
AT = arterial thromboembolic; B = bevacizumab; C = chemotherapy.
Sources: www.avastin.com/avastin/nurseFaqPro4.m
Avastin (bevacizumab) prescribing information. Available at:
http//www.gene.com/gene/products/information/oncology/avastin/insert.jsp
56
Blood Pressure Diary
Courtesy of Michelle Purdom, RN, BSN
57
Management of Bortezomib-Associated
Side Effects
Side Effect
Scope
Symptoms and Management
Peripheral
neuropathy
Incidence of new cases: 36%
Gr 3, 7%
Monitor patients for symptoms: burning sensation, hyperesthesia,
hypoesthesia, paresthesia, discomfort, neuropathic pain
New and worsening neuropathy: depending on severity consider
recommended changes in dose and schedule
Before initiating therapy, carefully consider risk/benefits of
bortezomib treatment for patients with pre-existing neuropathy
Asthenia
(fatigue,
malaise,
weakness)
Incidence: bortezomib 61% (Gr
3/4, 12%) vs dexamethasone
45% (Gr 3/4, 6%)
Educate patients about caution in operating cars and other
machinery because of potential for fatigue, dizziness, syncope,
hypotension, diplopia, blurred vision
Educate patients about avoiding dehydration and seeking medical
advice if experience dizziness, light-headedness, or fainting spells
GI toxicities
Incidence Gr 3 bortezomib 18% Most common GI toxicities: nausea, diarrhea, constipation,
vs dexamethasone 6% (Gr 4
vomiting, and anorexia
rare in both groups)
Hypotension
Incidence: bortezomib 11% vs
dexamethasone 2%
Velcade (bortezomib) prescribing information.
May need to adjust doses of antihypertensive medications
58
Management of Cetuximab-Associated
Side Effects
Side Effect
Scope
Symptoms and Management
Infusion reactions
Incidence of severe
reactions: 2%–4%
Incidence of Gr 1–2
reactions: 16%–19%
Symptoms of severe (potentially fatal) reactions: rapid onset of airway
obstruction (bronchospasm, stridor, hoarseness), urticaria,
hypertension, and/or cardiac arrest
Symptoms of Gr 1–2 reactions: chills, fever, dyspnea on 1st day of
initial dosing
Severe reactions: immediate and permanent cetuximab treatment
discontinuation
Mild/moderate reactions: slow infusion rate, use antihistamines (eg,
diphenhydramine) in subsequent doses
Cardiopulmonary
arrest
Incidence of arrest
and/or sudden death:
cetuximab + radiation
therapy 2% vs 0% for
radiation therapy
Use with caution in patients with coronary heart disease, congestive
heart failure, and arrhythmias
Closely monitor serum electrolytes (including magnesium, potassium,
calcium) during and after cetuximab therapy
Dermatologic
toxicity
Incidence in CRC: 89%
of all treated patients,
severe in 11%
Signs: acneform rash, skin drying and fissuring
Monitor for development of inflammatory and infectious sequelae;
consider topical and/or oral antibiotics
Severe acneform rash: institute dose modifications
Topical corticosteroids not recommended
www.erbitux.com
59
Management of Erlotinib-Associated
Side Effects
Side Effect
Rash
Diarrhea
Interstitial
lung disease
(ILD)
www.tarceva.com.
Scope
Symptoms and Management
Overall incidence of rash: erlotinib
75% vs placebo 17%
Incidence of Gr 3 rash with erlotinib:
8%
Incidence of severe diarrhea: 6%
Take erlotinib at the same time each day between
meals (one hour before or two hours after eating).
Pts with severe skin reactions may need dose
reductions or interruptions
Educate patients to seek prompt medical attention
for severe or persistent diarrhea
Usually managed with loperamide
Use dose reductions or interruptions in patients
who are dehydrated or have unresponsive severe
diarrhea
Overall incidence of ILD-like events: Interrupt treatment for acute onset or progression
0.7%
of unexplained pulmonary symptoms
Most cases in lung cancer patients If ILD confirmed, discontinue treatment
associated with confounding factors Educate patients to seek prompt medical attention
for onset or worsening of unexplained shortness of
breath or cough
60
Management of Gefitinib-Associated
Side Effects
Side Effect
Interstitial lung
disease (ILD)
Eye toxicity
Scope
Overall incidence: 1% of
gefitinib-treated patients (1/3
of these cases were fatal)
Symptoms and Management
Symptoms: acute onset of dyspnea, sometimes
with cough or low-grade fever, often quickly
worsening and requiring hospitalization
Interrupt treatment in patients with acute onset
or worsening of pulmonary symptoms (dyspnea,
cough, fever)
Discontinue gefitinib treatment if ILD confirmed
Low incidence of eye pain and Consider therapy interruption until symptoms
corneal erosion/ulcer,
resolved and removal of aberrant eyelash (if
sometimes with aberrant
present)
eyelash growth
Most common gefitinib-associated adverse events: diarrhea, rash, acne, dry skin, nausea, vomiting
www.iressa.com
61
Example of
Typical
Rash Induced by
EGFR Inhibitors
Courtesy of Michelle Purdom, RN, BSN
62
EGFR Rash
Courtesy of Michelle Purdom, RN, BSN
63
Management of Sunitinib-Associated
Side Effects
Side Effect
Scope
Symptoms and Management
GI events
Most common: diarrhea, nausea,
stomatitis, dyspepsia, vomiting
Supportive care with antiemetic or antidiarrhea medications
Left ventricular
dysfunction
Incidence: sunitinib 11% vs placebo 3%
Some patients recovered without intervention
Possible interventions: dose reduction, use of antihypertensive or
diuretic
Carefully monitor patients for signs and symptoms of congestive
heart failure
Hemorrhage
Incidence of bleeding: sunitinib 18% vs
placebo 17%
Fatal pulmonary hemorrhage occurred in 2
patients in a sunitinib NSCLC clinical trial
Epistaxis most common hemorrhagic adverse event
Hypertension
Incidence: sunitinib 15% (Gr 3, 4%) vs
placebo 11% (Gr 3, 0)
No Gr 4
Monitor and treat with standard hypertensive
If severe, suspend sunitinib treatment until hypertension is
controlled
Skin toxicity
Skin discoloration: occurs in 1/3 of pts
Attributed to yellow drug color
Advise patients of potential occurrence
Other possible dermatologic effects: dryness, thickness or cracking
of skin, blister or rash on palms of hand and soles of feet
www.sutent.com
64
Management of Sorafenib-Associated
Side Effects
Side Effect
Scope
Dermatologic
Hand-foot skin reaction (35%)
and rash (38%) most common
adverse event
Usually Gr 1-2, appear during
1st 6 weeks of treatment
Hypertension
Incidence: sorafenib 16.9% vs
placebo 1.8%
Usually mild to moderate and
occurs early in treatment
Hemorrhage
Incidence: sorafenib 15.3%
(Gr 3, 2%; no Gr 4) vs placebo
8.2% (Gr 3, 1.3%; Gr 4 0.2%)
Cardiac ischemia Incidence: sorafenib 2.9% vs
and/or infarction placebo 0.4%
www. nexavar.com
Symptoms and Management
Topical therapies for symptomatic relief
Temporary treatment interruption or dose
modifications
Severe or persistent cases may require treatment
discontinuation
BP should be monitored weekly for 1st 6 weeks of
sorafenib therapy
Manage with standard antihypertensive therapy
Temporary treatment interruption or dose
modifications
Treatment discontinuation rare
If bleeding necessitates medical intervention,
consider permanently discontinuing sorafenib
Consider temporary or permanent treatment
discontinuation
65
Pharmacoeconomics of Cancer
Management and Role/Implications of
Targeted Therapies in
Managed Care Setting
Cohen M, et al. Am J Manag Care. 2006;12:524.
66
Targeted Therapies and Managed Care




New therapies need evidence of effectiveness
and safety
Impact on quality of life
Net impact on total cost of care
Concept of value differs among patients,
providers, health plans, and employers
Cohen M, et al. Am J Manag Care. 2006;12:524.
67
Biotechnology Pipeline
Condition
AIDS/HIV infections/related conditions
Autoimmune disorders
Blood disorders
Cancer/related conditions
Cardiovascular disease
Eye conditions
Diabetes/related conditions
Digestive disorders
Genetic disorders
Growth disorder
Infectious disease
Neurologic disorders
Other conditions not specified here
Respiratory disorders
Skin disorders
Transplantation
Number of Agents
17
26
2
154
19
5
10
11
9
3
43
16
17
14
7
3
2004 Survey. Medicines in Development: Biotechnology. Available at: http://www.phrma.org/files/Biotech%20survey.pdf.
Accessed February 15, 2006.
68
Growth Drivers for Biologics
Key contributors from managed care perspective include
 Increased availability of targets for biologic agents
 Increased use of approved drugs
 Increased approval of biotechnology drugs for more
common conditions
 Expanded indications for approved drugs
Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
69
Reasons for Off-Label Use of Biologics

Small population size and/or assessed cost of clinical trials may
discourage marketers from seeking formal FDA approval

Potential of newer therapies for better efficacy and outcomes

Proven safety and efficacy in other disease states

Potential for increased quality of life

Thought leader advocacy/patient demand

Better understanding of disease pathways, particularly immunemodulating diseases
Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
70
Managed Care’s Concerns Regarding
Off-Label Use of Biologics







Safety/efficacy questions
Differing dosing and administration
Potential for inappropriate care
Potential for cost increase
Paucity of data
Lack of uniform guidelines/best
practices
Legal/ethical issues
Cohen M, et al. Am J Manag Care. 2006;12:524-537. Reprinted with permission.
71
Recommendations for Managing
Expanded Indications






Scan the pipeline to become aware of impending drug
launches
Increase education for P&T committees
Define a process and clear criteria
Develop and/or augment treatment guidelines for
expanded indications
Increase case management/disease management
Strive for innovative management strategies that
contain cost and maintain access
Cohen M, et al. Am J Manag Care. 2006;12:524.
72
Continued Challenges for
Managed Care Organizations



Expanding indications for FDA-approved drugs present unique
challenges for MCOs.
– This translates into added expenditures for MCOs because of increased
frequency of administration and/or longer duration of therapy
– For patients, may result in higher copays and more restrictive access
management strategies, particularly the use of prior authorization
Maintain focus on potential of agents for reduction in disease progression and
disability rather than solely on patient copays and aggressive management
strategies
– Shift focus on cost to clinical decision making through evidence-based
medicine
Adequately plan for agents with multiple indications
– Need more definitive criteria for evaluating expanded indications and
potential for cost savings
Cohen M, et al. Am J Manag Care. 2006;12:524.
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Nursing Implications
The nurse should help the patient understand
importance of prior insurance authorization due
to the high cost of biopharmaceuticals
 The nurse should assist the patient as a liaison
with the hospital business office/MCO by
initiating the process early and often
 Emotional support

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Summary


Expanding indications and off-label applications of FDA-approved
targeted therapies present unique challenges
– MCOs face added expenses
– Patients face higher co-pays and more restrictive access
– Clinicians need to expand their knowledge base and skill sets
Nurses have an important role in providing
– Professional care
– Toxicity management and side effect education
– Assistance in navigating the preauthorization process
– Emotional support
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Keeping Pace with Targeted Therapies in Lung Cancer
Highlights from the ASCO 2006 Annual Meeting
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