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EVOLVING STRATEGIES IN THE PERSONALIZED TREATMENT OF NON-SMALL CELL LUNG CANCER (NSCLC)
Best Supportive Care
Single-agent platinum
Doublets
Histology-directed care
Biomarker-directed care?
+Histological Sub-Types of Lung Cancer
Lung Cancer
Small Cell Lung Cancer
Non-Small Cell Lung Cancer
(NSCLC)
Adenocarcinoma Squamous Cell Carcinoma
Large Cell Carcinoma
40%
25-30%
10-15%
20%
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other
Sub-Types of Lung Cancer Sub-Types of NSCLC
American Cancer Society database. http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed October 8, 2014.
+Molecular Subsets of NSCLC Defined by Driver Mutations
Driver Mutations in NSCLC Oncogene Frequency (%)
AKT1 1 ALK 3-7
BRAF 1-3 EGFR 10-35 HER2 2-4 KRAS 15-25 MEK1 1 NRAS 1
PIK3CA 1-3 RET 1-2
ROS1 1 Lovly, C., L. Horn, W. Pao. 2014. Molecular Profiling of Lung Cancer. My Cancer Genome. http://www.mycancergenome.org/content/disease/lung-cancer. Accessed October 6, 2014.
AKT1 ALK BRAF
EGFR HER2
KRAS
MEK1 NRAS
PIK3CA RET
ROS1
Unknown
AKT=AK strain transforming; ALK=The anaplastic lymphoma kinase; BRAF=B-rapidly accelerated fibrosarcoma; EGFR=epidermal growth factor receptor; HER=human epidermal growth factor receptor, KRAS, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MEK=mitogen-activated protein kinase kinase; NRAS=neuroblastomas RAS; PIK3CA=phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; RET=rearranged during transfection; ROS=reactive oxygen species.
+Mechanism of Action of EGFR Tyrosine Kinase Inhibitors (TKIs)
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.
Figure adapted from Araki T, Yashima H, Shimizu K, et al. Clin Med Insights Oncol. 2012;6:407–421.
ATP=adenosine triphosphate; ERK=Extracellular signal-regulated kinases; mTOR=mammalian target of rapamycin; MAPK=mitogen-activated protein kinase.
+Transition from Empiric to Targeted Therapy of NSCLC
“Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib”1
“EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy”2
“Mutations of the Epidermal Growth factor Receptor Gene Predict Prolonged Survival After Gefitinib Treatment in Patients with Non-Small-Cell Lung Cancer With Postoperative Recurrenc”3
1. Lynch et al. New Eng J Med. 2004;350:2129- 2139. 2. Paez et al. Science. 2004;304:1497-1500. 3. Mitsudomi T et al. J Clin Oncol. 2005;2513-2520.
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Gefitinib (IRESSA™)
First approved in Japan in 2002
In 2009, the European Commission granted marketing authorisation for gefitinib for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR-TK across all lines of therapy
Gefitinib is currently approved for the treatment of first-line EGFR mutation-positive advanced NSCLC patients in 64 countries (excluding US)
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.
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GEFITINIB CLINICAL TRIALS: A Brief History
+Second- or Third-Line Comparative Studies of Gefitinib in NSCLC
2008 2010 2012 2006 2003 2005
Note: *Time to treatment failure. ORR=overall response rate; PFS=progression-free survival; OS=overall survival; NA=not available; BSC=best supportive care; IDEAL=Iressa Dose Evaluation in Advanced Lung Cancer; ISEL=Iressa Survival Evaluation in Lung Cancer; INTEREST=Iressa Non-small cell lung cancer Trial Evaluating Response and Survival against Taxotere; ISTANA=Iressa as Second-line Therapy in Advanced NSCLC-KoreA.
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.
+First-line Large-Scale Comparative Studies of Gefitinib in NSCLC
2010 2012 2008 2004 2009
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.
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IMPROVED BIOMARKER ANALYSIS AND MOLECULAR DIAGNOSTICS IN NSCLC
Data From Phase-IV, Open-label, Single-Arm Study of First-Line Gefitinib in Caucasian EGFR Mutation-Positive Patients With NSCLC (NCT01203917)
+First-Line Gefitinib in Caucasian EGFR Mutation-Positive NSCLC
Gefitinib 250 mg/day
Patients • Caucasian
patients with EGFR mutation-positive, locally advanced or metastatic NSCLC
• Patients with EGFR mutation conferring resistance to TKIs were excluded from the study
Primary • Objective Response Rate (ORR)
(investigator assessment)
Secondary • Progression-free survival (PFS) • Disease control rate (DCR) • Overall Survival (OS) • Safety and tolerability • Correlation between clinical
characteristics and baseline tumor EGFR mutation status
Exploratory Biomarker Objective I • Utility of surrogate samples
(plasma) using circulating-free tumor DNA (cfDNA) for EGFR mutation analysis
Endpoints
+Patient Disposition
Screeneda
n=1060
Patients eligible for treatment based on
EGFR mutation-positive status
n=118
Treatment startedb n=107
Eligible by EGFR mutation status n=106c (89.8%)d
Discontinued treatment
n=58 (54.2%)e
Discontinued study
n=36 (33.6%)e
Status at data cutoff On gefitinib n=49
(45.8%)e
Off gefitinib n=58 (54.2%)e
aAll screened patients. Used to calculate the correlation between clinical characteristics and tumor. EGFR mutation status and the comparison of EGFR mutation status between tumor DNA and plasma-derived circulating free DNA. bOne patient of EGFR mutation-positive-ineligible status was treated in error and included in the evaluable-for-safety population. A total of 107 patients therefore started study treatment. cFull analysis set population. Used to summarize efficacy data, and for the comparison of EGFR mutation status in plasma and tumor samples. dNumber of patients with EGFR mutation-positive tumors (n=118) used as the denominator for the percentage calculation. eNumber of patients started on treatment (n=107) used as the denominator for the percentage calculation
Patients ineligible for treatment based on EGFR mutation status
n=942 Exploratory biomarker analyses Baseline tumour samples n = 1033 (97.5%) EGFR mutation status determined n = 859 (81.0%) EGFR mutation-positive n = 118 (11.1%) Baseline plasma 1 samples n = 803 (75.8%) EGFR mutation status determined n = 784 (74.0%) EGFR mutation-positive n = 82 (7.7%)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Key Patient Demographic and Baseline Characteristics Characteristic FAS (N=106)
Median age, years (range) 65 (35 – 82)
Age group, years, N (%)
≥ 18 to < 65 ≥ 65 to < 75 ≥ 75
52 (49.1) 28 (26.4) 26 (24.5)
Gender, n (%)
Male Female
31 (29.2) 75 (70.8)
Race, n (%)
Caucasian Black/ African-American
106 (100.0) 0 (0.0)
Histology, n (%)
Adenocarcinoma (NOS) Adenocarcinoma bronchiolo-alveolar Adenosquamous carcinoma Large-cell carcinoma (NOS) Other/missing
92 (86.8) 10 (9.4) 2 (1.9) 1 (0.9) 1 (0.9)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Key Patient Demographic and Baseline Characteristics (cont’d) Characteristic FAS (N=106)
Performance status, n (%)
0 1 2 Other/Missing
48 (45.3) 51 (48.1) 7 (6.6) 0 (0.0)
Smoking status, n (%)
Never Current Former Missing
68 (64.2) 6 (5.7) 32 (30.2) 0 (0.0)
Prior treatment, n (%)
Radiotherapy Chemotherapy
14 (13.2) 10 (9.4)
EGFR mutation subtype, n (%)
Exon 19 deletions L858R L861Q G719X (G719S/A/C)
69 (65.1) 33 (31.1) 2 (1.9) 2 (1.9)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Primary End point: ORR
Category FAS (N=106) (n)
Objective responders
(n)
ORR (%) 95% Cl
Total response
106 74 69.8 60.5 – 77.7
CR 2 - 1.9 -
PR 72 - 67.9 -
Age
≤ 65 years > 65 years
55 51
36 38
65.5 74.5
52.3 – 76.7 61.1 – 84.5
Sex
Male Female
31 75
22 52
71.0 69.3
53.4 – 83.9 58.2 – 78.6
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Primary End point: ORR (cont’d)
Category FAS
(N=106) (n)
Objective responders (n) ORR (%) 95% Cl
Performance status
0-1 ≥ 2
99 7
69 5
69.7 71.4
60.0 – 77.9 29.0 – 96.3
Smoking status
Never Ever
68 38
50 24
73.5 63.2
62.0 – 82.6 47.3 – 76.6
EGFR mutation type
Exon 19 deletion L858R L861Q G719X (G719S/A/C)
69 33 2 2
50 21 1 2
72.5 63.6 NC NC
61.0 – 81.6 46.6 – 77.8 NC – NC NC - NC
Histology
Adenocarcinoma Non-adencocarcinoma
103 3
72 2
69.9 NC
60.5 – 77.9 NC - NC
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Secondary End Points: PFS & OS
Progression-Free Survival (PFS) Overall Survival (OS)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Exploratory Biomarker Objective I Data
Tumor and plasma 1 – screened patients evaluable for both samples (N=652)
Plasma 1 EGFR mutation status (n)
Positive Negative Total
Adjusted baseline tumor EGFR mutation status, n
Positive Negative Total
69 1 70
36 546 582
105 547 652
Exon 19 deletions L858R L858R and
T790M Negative Total
Exon 19 deletions
48 0 0 23 71
L858R 0 21 0 12 33
L858R and T790M
0 0 0 1 1
Negative 0 1 0 546 547
Total 48 22 0 582 652
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
+Conclusions From the Phase IV Study
Gefitinib is effective as a first-line therapy in patients with EGFR mutation-positive NSCLC, irrespective of ethnicity or clinical characteristics
Plasma is a suitable substitute for mutation analysis when tumor tissue is unavailable as EGFR mutation status can be accurately assessed using cfDNA
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.
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ACQUIRED RESISTANCE TO EGFR TKIS Approaches to Management
+Acquired Resistance to EGFR TKIs
16%
63%
5%
3% 13%
Others EGFR T790M
MET Amplification SCLC Transformation
HER2 Amplification
EGFR T790M point mutation in exon 20 is the most frequent mechanism of acquired resistance1
Progressive Disease Sub-Type Influences Clinical Practice
1. Yu HA et al. Clin Cancer Res. 2013;19:2240–2247. 2. Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.
CNS=central nervous system; PD= progressive disease.
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Switch Therapy (Chemotherapy or
second-generation TKI)
Systemic-PD
Approaches to Manage Acquired Resistance to TKIs
Add Therapy to TKI Chemotherapy ? Another targeted agent?
Continue Same TKI Alone (Post PD to “slow progression”)
Re-biopsy
RECIST Response
Subsequent systemic PD
Advanced NSCLC With
Oncogene-Driven Cancer
Targeted TKI
EGFR mutation ALK fusion
Remission Baseline Multiple PD Lesions
Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.
RECIST=Response Evaluation Criteria In Solid Tumors.
+Approaches to Manage Acquired Resistance to TKIs (cont’d)
Oligo-PD
Remission Baseline Solitary New Lesion
Remission Baseline Brain-Only PD
CNS-PD (Sanctuary)
+Treatment of Brain Metastasis With Gefitinib
Study Treatment ORR Median PFS OS
Ma et al1
(N=21)
40 Gy/20 fractions/ 4 weeks whole-brain
radiotherapy and gefitinib 250 mg once
daily
81% (95% CI;
58%–95%)
10.0 mos (95% CI; 7.5–12.5)
13.0 mos (95% CI; 8.2–17.8)
Park et al2
(N=28)
Erlotinib or gefitinib after systemic
treatment NA NA
15.9 mos (95% CI; 7.2–24.6)
Fan et al3
(N=210)
Chemotherapy + Localized Treatment NA NA
9 mos (P=0.002)
EGFR TKI + localized treatment NA NA
12 mos (P=0.002)
Luchi et al4
(N=41) Gefitinib alone without
radiation 87.8% 14.5 mos 21.9
months
1. Ma S et al. Lung Cancer. 2009;65:198–203. 2. Park SJ et al. Lung Cancer. 2012;77:556–560.
3. Fan Y et al. Onco Targets Ther. 2013;6:1789–1803. 4. Luchi T et al. Lung Cancer. 2013;82: 282–287.
+Summary
Gefitinib is effective as a first-line therapy in patients with EGFR mutation-positive NSCLC
Results from clinical trials are awaited for the use of gefitinib in combination with chemotherapy in patients with NSCLC who have acquired resistance to gefitinib
While gefitinib has demonstrated efficacy in brain metastases, large-scale randomized clinical trials are needed to confirm its efficacy
Improved tumor molecular characterizations on small amounts of tumor material or using CfDNA will allow personalized and evidence-based treatment for advanced NSCLC