Management of NSCLC

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
David R. Gandara, MD
Professor of Clinical Medicine University of California Davis Cancer Center Davis, California
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Faculty Disclosure
David R. Gandara, MD, has disclosed that he has received research grants from Bristol-Myers Squibb, Genentech, ImClone, Eli Lilly and Company, Merck, and Novartis; served as consultant for Amgen, Array, AstraZeneca, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, ImClone, Merck, Novartis, Response Genetics, and sanofiaventis.

Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers
Histology
Maintenance
Predictive Biomarkers
Factors are interlinking and not independent
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male smoker, squamous
KRAS Mt
In 2012:
Most oncologists would agree that these patients have very different malignancies Most oncologists would agree that these patients should receive different therapy


Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male smoker, squamous 39-yr-old female never-smoker, adenoca EGFR Mt
KRAS Mt
In 2012:


Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male smoker, squamous 39-yr-old female never-smoker, adenoca EGFR Mt
KRAS Mt 54-yr-old male never-smoker, adenoca ALK fusion In 2012:


Nonsquamous Histology
Molecular Marker Status: EGFR Mutation Positive, ALK Fusion Negative
Your Treatment Recommendations Age , Yrs Zubrod PS Smoking History Primary Patient Desire: Response and Survival Primary Patient Desire: QoL and Low Risk for AEs
Therapy Choices Targeted therapy T0. No targeted therapy T1. Bevacizumab T2. Cetuximab T3. Erlotinib T4. Crizotinib Platinum P0. No platinum P1. Cisplatin P2. Carboplatin Nonplatinum chemotherapy C1. Paclitaxel C2. Docetaxel C3. Gemcitabine C4. Vinorelbine C5. Pemetrexed C6. Etoposide
First line*
Younger than 70 Younger than 70 Younger than 70 Younger than 70 70 or older 70 or older 70 or older 70 or older 0, 1 Never/former light T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0
Maintenance
T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0
First line*
Maintenance
0, 1
Former heavy/current
Never/former light
0, 1
Never/former light
0, 1
Never/former light
*Assume standard risk patient (no hemoptysis, no brain mets, no severe comorbidities that would alter decision making). Assume patient has had a PR to first-line therapy and now has a PS of 0 and is asymptomatic.
CCO survey. 2012.

Algorithm for Therapy of Advanced-Stage NSCLC: 2009

Proposed Treatment Algorithm EGFR mutation positive
Molecular
Good PS
Clinical (PS)
POOR PS
Erlotinib Bevacizumab eligible
Nonsquamous
Histologic
Bevacizumab ineligible Platinum/pemetrexed (or other*)
Squamous
Single-agent chemotherapy
Clinical
First line
Platinum/gemcitabine (or other*)
Platinum/pemetrexed (or other*) bevacizumab
Maintenance
End of first-line chemotherapy Bevacizumab or erlotinib or pemetrexed Pemetrexed or erlotinib
Erlotinib
Based on previous therapy
Progression
Chemotherapy by algorithm Based on previous therapy Based on previous therapy Based on previous therapy
Second line
*Docetaxel, paclitaxel, vinorelbine. Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012

Advanced-Stage NSCLC & PS 0-1
EGFR mutation positive ELM4-ALK positive EFGR mutation and ALK negative and nonsquamous histology EFGR mutation and ALK negative and squamous histology
Bevacizumab appropriate Erlotinib or gefitinib first line Consider crizotinib first or second line Consider carboplatin/paclitaxel + bevacizumab or cisplatin/pemetrexed bevacizumab
Bevacizumab inappropriate Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine cetuximab
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.


Advanced-Stage NSCLC & PS 0-1
Molecular
Erlotinib or gefitinib first line Consider crizotinib first or second line
Bevacizumab appropriate
Bevacizumab Histology: Clinical inappropriate Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine cetuximab
Consider carboplatin/paclitaxel + bevacizumab or cisplatin/pemetrexed bevacizumab
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Histology
Maintenance Therapy

Hypothesis: Treatment of NSCLC Should Be Histology Based

Observation: Differential efficacy of pemetrexed in squamous vs nonsquamous subtypes of NSCLC
JMDB: Pemetrexed/cisplatin vs gemcitabine/cisplatin in first-line therapy of advanced NSCLC[1]
JMEI: Pemetrexed vs docetaxel in second-line therapy of advanced NSCLC[2]

JMEN: Pemetrexed vs placebo as maintenance therapy of NSCLC[3]
1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. 2. Otani S, et al. Gan To Kagaku Ryoho. 2012;39:59-62. 3. Greenhalgh J, et al. Health Technol Assess. 2010;14(suppl 2):33-39.

JMDB Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC

No difference in overall PFS or survival between study arms
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Survival Probability CP CG CP vs CG Median (95% CI) 10.3 (9.8-11.2) 10.3 (9.6-10.9) Adjusted HR (95% CI) 0.94 (0.84-1.05)
6 12 18 24 Survival Time (Mos) in All Patients
30
Cis/Pem improves survival over CG in non-SCCA (HR: 0.81; P = .005)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Survival Probability
Median (95% CI) 11.8 (10.4-13.2) CP 10.4 (9.6-11.2) CG CP vs CG Adjusted HR (95% CI) 0.81 (0.70-0.94)
6 12 18 24 Survival Time (Mos) in All Patients With Nonsquamous Histology
30
Cis/Gem improves survival over CP in SCCA (HR: 1.23; P = .05)

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Survival Probability
CP CG CP vs CG
Median (95% CI) 9.4 (8.4-10.2) 10.8 (9.5-12.1) Adjusted HR (95% CI) 1.23 (1.00-1.51)
6 12 18 24 Survival Time (Mos) in All Patients
30

SWOG Database Analysis of Taxane/VincaBased Therapy in Adv NSCLC by Histology

N = 741 S9806, S0003, and CDDP/vin arm of S9308 No difference in any efficacy outcome by histology
OS Histology Adeno N (%) 424 (57) Median, Mos 8.5 Adjusted HR* 1.00 (referent) Median, Mos 4.3 PFS Adjusted HR* 1.00 (referent)
SCCA
Large cell NSCLC, NOS
128 (17)
82 (11) 107 (14)
8.4
7.9 9.6
0.987 (P = .89)
0.974 (P = .83) 0.971 (P = .79)
4.5
4.2 5.0
0.986 (P = .89)
1.03 (P = .81) 0.87 (P = .20)
*HR from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex. HR for SCCA vs all others combined, OS: 0.995 (95% CI: 0.82-1.21; P = .96). HR for SCCA vs all others combined, PFS: 1.01 (95% CI: 0.83-1.22; P = .94) Chansky K, et al. IASLC WCLC 2009. Abstract B2.7

Histology Not a Predictor of Survival From Antimicrotubule or Gem.-Based Therapy

1.0
All Patients (N = 607)

Adeno Other Large cell Squamous
1.0
VC Patients (n = 201)
Proportion Surviving
0.6 0.4 0.2 0 0 6 12 18 24 OS (Mos) 30 36
0.8
0.8
0.6 0.4 0.2 0 0 6 12
18 24 OS (Mos)
30
36
1.0 0.8 0.6 0.4 0.2 0 0
PC Patients (n = 201)
1.0 0.8 0.6 0.4 0.2 0
GC Patients (n = 205)
12
18 24 OS (Mos)
30
36
12
18 24 OS (Mos)
30
36
Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.

Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted Therapy)

Histologic subtyping groups tumors based on microscopic pattern recognition by a pathologist (using 1800s technology)
At best, histology = crude molecular selection
Van LeeuwenHoek
Molecular Profiling

Thymidylate Synthase Expression in Lung Cancer
TS
SCLC: highest TS Squamous: high TS Adeno: low TS
Bhattacharjee A, et al. Proc Natl Acad Sci U S A. 2001;98:13790-13795.

TS mRNA Results by Histology (N = 1671): Squamous vs Adenocarcinoma

14 12 10 8 6 4 2 0 AC Biomarker TS Median Range SCCA NSCLC: Total (N = 1671) 2.71 0.14-68.0 NSCLC: SCCA (n = 316) 4.1 0.14-59.3 NSCLC: AC (n = 649) 2.5 0.39-68.0 SCCA vs AC P Value < .001* *MannWhitney test TS (Reference < 2.33 for Pemetrexed) NSCLC: total NSCLC: adenoca NSCLC: SCCA % Below Reference Level 41.3 45.7 25.9
Gandara DR, et al. ASCO 2010. Abstract. 7513.
TS

Histology
Maintenance Therapy
Factors are Interlinking and not independent

Maintenance Therapy Terminology: A Rose by Any Other Name?

Same agent A until PD or toxicity Platinum-based doublet chemotherapy: 4 cycles of induction eg, cisplatin + agent A Continuation maintenance
Different agent C until PD or toxicity Switch maintenance

Summary of Switch Maintenance Trials

Agent/Control Arm Fidias[1] Ciuleanu[2] Cappuzzo[3] Miller[4] Docetaxel Delayed docetaxel Pemetrexed Placebo Erlotinib Placebo Erlotinib + bevacizumab Placebo + bevacizumab Erlotinib Observation Gefitinib Placebo N 309 663 889 768 PFS 5.7 mos HR: 0.63 2.7 mos P = .001 4.0 mos HR: 0.50 2.6 mos P < .0001 12.3 wks HR: 0.71 11.1 wks P < .0001 4.8 mos HR: 0.72 3.8 mos P = .001 Salvage Treatment, % 63 67 72 55.5 12.3 9.7 13.4 10.6 12.0 11.0 15.9 13.9 OS HR: 0.80 P = .085 HR: 0.79 P = .012 HR: 0.81 P = .0088 HR: 0.90 P = .2686
Perol[5] Zhang[6]
310 296
2.9 mos HR: 0.82 1.9 mos P = .002 4.8 mos HR: 0.42 2.6 mos P < .0001
81.9 58.8
NA NA 18.7 16.9
HR: .91 HR: .84 P = .2608
1. Fidias P, et al. J Clin Oncol. 2010;28:5116-5123. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA, et al. ASCO 2009. Abstract LBA8002. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Zhang L, et al. ASCO 2011. Abstract LBA7511.

Continuation Maintenance Trials

Study Brodowicz[1] Yr 2006 Induction Therapy Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4 Maintenance Therapy Gemcitabine 1250 mg/m2 on Days 1,8 BSC Median PFS, Mos 6.6 Median OS, Mos 13.0 Main Grade 3/4 Toxicities Maintenance Gem: ANC 14.9%, Plts 1.7%; blood transfusion: 20% gemcitabine vs 6.3% BSC ANC: 15% chemo, 2% BSC; Plts: 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Fatigue: 4.2% pem, 0.6% BSC; Anemia: 4.5%, 0.6% BSC; ANC: 3.6% pem, 0 BSC
5.0 (P < .001) 7.4 7.7 (P = .575) 3.8 1.9 (P < .0001) 4.1 2.8 (P = .00006)
11.0
Belani[2]
2010
Gemcitabine 1000 mg/m2 on Days 1, 8 + carboplatin AUC 5 on Day 1 x 4 Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4
Gemcitabine 1000 mg/m2 on Days 1,8 BSC
8.0 9.3 (P = .838) NR NR
Perol[3]
2010
Gemcitabine 1000 mg/m2 on Days 1,8 BSC
Paz Ares[4]
2011
Pemetrexed 500 mg/m2 on Day 1 + cisplatin 75 mg/m2 on Days 1 x 4
Pemetrexed 500 mg/m2 on Day 1 BSC
NR NR
1. Brodowicz T, et al. Lung Cancer. 2006;52:155-163. 2. Belani CP, et al. ASCO 2010. Abstract 7506. 3. Perol M, et al. ASCO 2010. Abstract 7507. 4. Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.

PARAMOUNT: Continuation Pemetrexed Maintenance

Independently Reviewed PFS From Maintenance 1.0 Survival Probability 0.8 Pem + BSC Placebo + BSC Pemetrexed: median 3.9 mos (3.0-4.2) Placebo: median 2.6 mos (2.2-2.9) Log-rank P = .0002 Unadjusted HR: 0.64 (0.51-0.81)
0.6
0.4 0.2
0
0 3 6 Mos
Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.
12
15

Maintenance Therapy: Options After Platinum-Based Therapy With Non-PD

Watch & Wait vs Maintenance/ Consolidation/Sequencing Who decided that 4 cycles of therapy is optimal? 4 (~ 6) cycles chemo stop Watch and wait
R
Continue same chemo
Continuation maintenance
Options: bevacizumab, cetuximab, pemetrexed 4 (~ 6) cycles chemo stop Watch and wait Switch maintenance Watch and wait
R
Different chemo or another drug 4 (~ 6) cycles chemo Stop Options: docetaxel, pemetrexed, erlotinib/gefitinib
R
Different chemo or another drug
Gandara DR. Best of ASCO 2011.
Early second-line therapy

Issues to Consider Regarding Maintenance Therapy

The big question about maintenance therapy is WHO to treat and WHEN to treat How do these trials relate to the patients I am treating in my office? If 6 cycles of platinum chemotherapy are given, are the maintenance data still relevant?
If a patient achieves no response (SD) and remains symptomatic, is subsequent therapy maintenance or early second-line therapy?
If a patient achieves response and becomes asymptomatic, is maintenance therapy always better than watch and wait? What about the underlying molecular profile of the individual patient? In the emerging era of personalized therapy, these decisions should be made on an individual basis: One size does not fit all
Gandara DR. Best of ASCO 2011.

Histology
Maintenance

Histology Maintenance Therapy
Looking Forward to 2015: Moving From Empiric to Individualized From One Size Fits All to Tailored and Individualized Therapy

Transition From Empiric to Tailored and Individualized Cancer Therapy

Empiric therapy Tailored and individualized therapy
Patient characteristics Relevant literature Physician experience
Availability of adequate tumor tissue for molecular profiling Predictive biomarkers Account for interpatient tumor heterogeneity
Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.


Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 39-yr-old female Never-Smoker, Adenoca EGFR Mt

Your Treatment Recommendations Age (years) Zubrod PS Smoking History Primary patient desire: Response and Survival Primary patient desire: QOL and Low-Risk for AEs
Therapy choices Targeted therapy T0. No targeted therapy T1. Bevacizumab T2. Cetuximab T3. Erlotinib T4. Crizotinib Platinum P0. No platinum P1. Cisplatin P2. Carboplatin Non-platinum chemotherapy C1. Paclitaxel C2. Docetaxel C3. Gemcitabine C4. Vinorelbine C5. Pemetrexed C6. Etoposide
First line*
< 70 0,1 Never/Former Light T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0 T0 P0 C0
Maintenance**
First line*
Maintenance**
< 70
0,1
Former Heavy/Current
< 70
Never/Former Light
< 70
70
0,1
Never/Former Light
70
0,1
70
Never/Former Light
70
*Assume standard risk patient (no hemoptysis, no brain mets, no severe co-morbidities that would alter decision-making) **Assume patient has had a partial response to first-line therapy and now has a performance score of 0 and is asymptomatic
CCO survey. 2012.

First line*
Maintenance**
First line*
Maintenance**
< 70
0,1
< 70
Never/Former Light
< 70
70
0,1
Never/Former Light
70
0,1
70
Never/Former Light
70
CCO survey. 2012.

EGFR Mutations and Responsiveness to Gefitinib in NSCLC

Patient No. 1 2 3 Sex Age at Beginning of Gefitinib Therapy, Yr 70 66 64 Pathological Type BAC BAC Adeno Previous Regimens, n 3 0 2 Smoking Status Never Never Never Duration of Therapy, Mos 15.6 > 14.0 9.6 OS, Mos EGFR Mutation Yes Yes Yes Response F M M 18.8 > 14.0 12.9 Major; improved lung lesions Major; improved bilateral lung lesions Partial; improved lung lesions and soft-tissue mass Minor; improved pleural disease Partial; improved liver lesions Major; improved lung lesions Partial; improved liver and lung lesions Partial; improved liver lesions Partial; improved lung nodules
4 5 6 7
F F M F
81 45 32 62
Adeno Adeno BAC Adeno
1 2 3 1
Former Never Never Former
> 13.3 > 14.7 > 7.8 > 4.3
> 21.4 > 14.7 > 7.8 > 4.3
Yes Yes Yes Yes
8 9
F F
58 42
Adeno BAC
1 2
Former Never
11.7 > 33.5
17.9 > 33.5
Yes No
Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139.

EGFR TKIs vs Chemotherapy as First-line Therapy

Trial/Patient Group N Selected by Clinical Factors I-PASS[1] East Asian, light/nonsmoker, adeno Korean, nonsmoker, adeno Japan, EGFR mutant Japan, EGFR mutant 261 10.7 6.0 0.35 (0.23-0.52) 0.613 (0.31-1.22) 0.35 (0.25-0.50) 0.48 (0.33-0.71) 21.6 21.9 Gefitinib Erlotinib Median PFS, Mos Chemo HR (95% CI) OS, Mos Gefitinib Erlotinib Chemo
First-SIGNAL[2]
42
8.4
6.7
30.6
26.5
Selected by Molecular Parameter NEJ002[3] WJTOG3405[4] 194 172 10.4 9.2 5.5 6.3 28.0 30.9 23.6 NR
OPTIMAL[5]
Spain[6]
China, EGFR mutant

Spain, EGFR mutant
154
217
13.1
14.0
4.6
0.16 (0.1-0.26)
NR
27.0
NR
1. Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874. 2. Lee JS, et al. WCLC 2009. Abstract PRS.4. 3. Maemondo M, et al. N Engl J Med. 2010;362: 2380-2388. 4. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 5. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 6. Rosell R, et al. N Engl J Med. 361:958-967.

IPASS: Importance of EGFR Mutation on Patient OutcomeGefitinib vs Chemo

Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia, Philippines, Hong Kong, and Singapore
Patients Chemo naive 18 yrs of age or older Adenocarcinoma histology Never or ex-light smokers* Life expectancy 12 wks WHO PS 0-2 Measurable stage IIIB/IV disease Primary Endpoint PFS (noninferiority)
Gefitinib
Secondary Endpoints Objective response rate OS Quality of life Disease-related symptoms Safety and tolerability
Carboplatin + Paclitaxel
Exploratory Biomarkers EGFR mutation EGFR gene copy number EGFR protein expression
94% never-smokers; ~ 80% female

Mok TS, et al. N Engl J Med. 2009;361:947-957.

IPASS: PFS in EGFR MutationPositive and Negative Patients

EGFR Mutation Positive
1.0 Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129) HR: 0.48 (95% CI: 0.36-0.64; P < .0001) Gefitinib events , n (%) 97 (73.5) C/P events, n (%) 111 (86.0) 1.0
EGFR Mutation Negative

Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85) HR: 2.85 (95% CI: 2.05-3.98; P < .0001) Gefitinib events, n (%) 88 (96.7) C/P events, n (%) 70 (82.4)
Probability of PFS
0.6 0.4 0.2 0 0 4 8
Probability of PFS
0.8
0.8
0.6 0.4 0.2 0
12 Mos
16
20
24
12 Mos
16
20
24
Treatment by subgroup interaction test, P < .0001 Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy Front-line EGFR TKI should be restricted to EGFR mutationpositive patients
Mok TS, et al. N Engl J Med. 2009;361:947-957.

BR.21 (Erlotinib vs Placebo): OS

1.00
Survival Distribution Function
0.75
0.50 4.7 mos 0.25 Erlotinib Placebo 0 0 6
BR.21 results not explained by EGFR mutation alone BR.21 survival primarily the results of increased SD and increased disease control rate This represents largely a cytostatic effect in patients with EGFR wild-type cancers This disease control rate effect may also be true for cetuximab in NSCLC (FLEX and S0342 trials)
6.7 mos
HR: 0.73 (95% CI: 0.61-0.86*; P < .001)
12 Mos
18
24
30
*From Cox regression model. From 2-sided log-rank test. Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

Cytotoxic vs Cytostatic Effects of EGFR TKIs (Erlotinib) in NSCLC

Cytotoxic effects (apoptosis) primarily seen in EGFR Mt+ cancers (objective response) Cytostatic effects (growth arrest) predominate in EGFR wild-type cancers (RECIST SD; disease control rate)
30 25 Percent Apoptosis 20 15 10 5 0 A549 H1666 H3255
Control Gefitinib
Gandara DR ,et al. Clin Lung Cancer. 2009;10:148-150. Gandara DR ,et al. J Thoracic Oncol. 2010;5:1933-1938. Jnne PA ,et al. Clin Cancer Res. 2006;12:4416s-4420s.


Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
54-yr-old male never-smoker, adenoca ALK fusion

Molecular Marker Status: EGFR Mutation Negative, ALK Fusion Positive
First line
Maintenance**
First line
Maintenance*
< 70
0,1
< 70
Never/Former Light
< 70
70
0,1
Never/Former Light
70
0,1
70
Never/Former Light
70
CCO survey. 2012.

EML4-ALK Translocations in NSCLC
1 EML4 EML4-ALK variant 1 1 ALK
HELP 496
WD
981 EML4-ALK frequency: ~ 4% (64/1709) Primarily in adenocarcinoma More common in younger patients More common in never-smokers (~ 20%)
Basic
496
1059
1620
1058
Kinase
TM
Soda M, et al. Nature. 2007;448:561-566.

ALK-Positive NSCLC and Impact of ALK Inhibition

ALK Rearrangement in NSCLC
Rarely overlaps with EGFR and KRAS mutations Clinical testing
Break-apart FISH assay (FDA-approved test) IHC RT-PCR
Shaw AT, et al. ASCO 2011. Abstract 7507.
Activity of ALK Inhibitor Crizotinib in Patients With Advanced ALK-FISH Positive NSCLC (N = 82)


Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC) 65-yr-old male smoker, squamous KRAS Mt

Squamous Histology
Molecular Marker Status: EGFR Mutation Negative, ALK Fusion Negative
First line
Maintenance*
First line
Maintenance*
< 70
0,1
< 70
Never/Former Light
< 70
70
0,1
Never/Former Light
70
0,1
70
Never/Former Light
70
CCO survey. 2012.


Advanced-Stage NSCLC and PS 0-1
Bevacizumab appropriate Erlotinib or gefitinib first line Consider crizotinib first or second line Consider carboplatin/paclitaxel + bevacizumab Or cisplatin/pemetrexed Bevacizumab
Bevacizumab inappropriate Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine cetuximab

FLEX: Chemotherapy Cetuximab in First-line Therapy of Advanced NSCLC

Cetuximab + Cisplatin + Vinorelbine (n = 550) Stage IIIB or IV EGFR positive R Cisplatin + Vinorelbine (n = 550)
Eligibility criteria: EGFR-expressing, advanced-stage NSCLC; no previous CT Primary endpoint: median OS (845 events needed) Secondary endpoints: survival rate (1 and 2 yrs), PFS rate (6 and 12 mos), response rate, safety, QoL Sample size: 1100 in 170 centers in EU, Latin America, Asia
Survival
Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.

FLEX: Response and OS by IHC Score

FLEX: Response Rate by EGFR Expression Levels (IHC Score)
Low EGFR Expression (< 200), n = 776 (69%) High EGFR Expression (200), n = 345 (31%)
Predictive Value of High EGFR for Survival Benefit With CT + Cetuximab
Low EGFR
HR: 0.99 (95% CI: 0.84-1.16) OS (%)
High EGFR
HR: 0.73 (95% CI: 0.58-0.93)
44.4 29.6 32.6 28.1
100 80 60 40 20 0 0
Mos
P = .36
Treatment interaction test P = .040
P = .002
Interaction P = .044
12 18 24 Mos
30
CT + cetuximab CT
OByrne et al. JPO 20120, 12 (suppl), S558 (LBOAI)
CT + cetuximab CT

FLEX Survival: High EGFR Expression Squamous Cell Carcinoma (N = 144)

100
Survival Median, Mos 1 Yr, % CT + cetuximab CT 11.2 8.9 44 25
80
OS (%)
60
HR: 0.62 (95% CI: 0.43-0.88)

40
20
0 0 Pts at Risk, n CT + cetuximab 75 CT 69 6 52 42 12 Mos 32 17 19 7 10 2 0 0 18 24 30

S0819: Chemotherapy Cetuximab and Predictive Biomarker Validation EGFR FISH

Stratify
Marker + Marker testing Marker -
Randomize
Chemo Chemo/Cetux Chemo Chemo/Cetux
M+ M+ MM-
Chemotherapy: Paclitaxel/Carboplatin Primary endpoints: OS for entire study PFS for EGFR FISH Integrated: EGFR IHC score
ClinicalTrials.gov. NCT00946712. PI: R. Herbst

Potential Druggable Molecular Targets?

Lung Cancer Molecular Consortium Lung Adenocarcinomas
No Mutation Detected
AKT1 NRAS MEK1 MET AMP HER2 PIK3CA 2% BRAF 2% Double Mutants 3%
Emerging Druggable Targets in NSCLC-Squamous Subtype

Gene FGFR1 FGFR2 PIK3CA PTEN CCND1 CDKN2A PDGFRA EGFR MCL1 BRAF DDR2 ERBB2 Event Type Amplification Mutation Mutation Mutation deletion Amplification Deletion/mutation Amplification mutation Amplification Amplification Mutation Mutation Amplification Frequency, % 20-25 5 9 18 8 45 9 10 10 3 4 2
KRAS 22% EGFR 17%
EML4-ALK 7%
Mutations found in 54% (280/516)
Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

Moving Toward 2015: CASTLE Network

CAS TLE Biospecimens CASTLE
Core Biopsy
Network Plasma RNA/DNA

RNA DNA
Serum
ResponseDXTM
Submissions
VeriStrat
Submission
ERCC1 gene expression RRM1 gene expression KRAS mutation analysis EGFR amplification TS expression
EGFR-TKI: a) candidate or b) contraindicated
Biorepository
Biorepository
clinical
Genomics/Proteomics/Clinical Outcomes
research
ALCMI (Addario Lung Cancer Medical Institute)

Lung Cancer Therapy: 2012 Looking Forward to 2015

We are making progress
Histology Maintenance therapy Predictive biomarkers
Reality: the transition to rationally selected and personalized therapy is challenging

In every challenge, there are opportunities We must take advantage of each of these opportunities if we are to advance the care and cure of patients with lung cancer
Progress requires continuing change

Culture change
Requirement for more tumor tissue (molecular profiling) Ungroup NSCLC into individual patients (personalized therapy)
Go Online for More CCO Coverage of Advanced Lung Cancer!

Interactive Decision Support Tool: With just a few clicks through pulldown menus, this Interactive Decision Support Tool allows users to enter their patients specific characteristics along with the treatment options they would likely choose and then provides expert insight from 5 lung cancer experts regarding optimal choices for first-line and maintenance therapy for advanced NSCLC.

Management of NSCLC

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Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

This program is supported by educational grants from

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

About These Slides

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Factors are interlinking and not independent

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

KRAS Mt 54-yr-old male never-smoker, adenoca ALK fusion In 2012:

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

CCO survey. 2012.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Algorithm for Therapy of Advanced-Stage NSCLC: 2009

Erlotinib Bevacizumab eligible

Platinum/pemetrexed (or other*) bevacizumab

End of first-line chemotherapy Bevacizumab or erlotinib or pemetrexed Pemetrexed or erlotinib

Based on previous therapy

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012

Consider carboplatin/paclitaxel + bevacizumab or cisplatin/pemetrexed bevacizumab

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Factors are interlinking and not independent

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Hypothesis: Treatment of NSCLC Should Be Histology Based

JMEI: Pemetrexed vs docetaxel in second-line therapy of advanced NSCLC[2]

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

JMDB Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC

6 12 18 24 Survival Time (Mos) in All Patients

Cis/Pem improves survival over CG in non-SCCA (HR: 0.81; P = .005)

6 12 18 24 Survival Time (Mos) in All Patients With Nonsquamous Histology

Cis/Gem improves survival over CP in SCCA (HR: 1.23; P = .05)

6 12 18 24 Survival Time (Mos) in All Patients

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

SWOG Database Analysis of Taxane/VincaBased Therapy in Adv NSCLC by Histology

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Histology Not a Predictor of Survival From Antimicrotubule or Gem.-Based Therapy

All Patients (N = 607)

0.6 0.4 0.2 0 0 6 12 18 24 OS (Mos) 30 36

1.0 0.8 0.6 0.4 0.2 0 0

1.0 0.8 0.6 0.4 0.2 0

Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted Therapy)

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Thymidylate Synthase Expression in Lung Cancer

Bhattacharjee A, et al. Proc Natl Acad Sci U S A. 2001;98:13790-13795.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

TS mRNA Results by Histology (N = 1671): Squamous vs Adenocarcinoma

Gandara DR, et al. ASCO 2010. Abstract. 7513.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

Factors are Interlinking and not independent

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Therapeutic Decision Making in Advanced NSCLC: A 2012 Perspective