Nsclc slide deck

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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.

+

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)


+

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.


+First-line Large-Scale Comparative Studies of Gefitinib in NSCLC

2010 2012 2008 2004 2009


+

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)


+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)


+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


+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


+Secondary End Points: PFS & OS

Progression-Free Survival (PFS) Overall Survival (OS)


+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


+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


+

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.

+

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

Health & Medicine

Nsclc slide deck