Overview of Lung Cancer

Overview of Lung Cancer

:Perspectives from Cancer Genotype

Ji-Youn Han, MD, PhD.

Center for Lung Cancer

National Cancer Center

Histologic classification of lung cancer

Platinum-based doublets (3^rd generation)

Response rate 20-30%

Median time to progression 3-4 months

Median overall survival 8-10 months

Therapeutic plateau reached with chemotherapy in NSCLC

Lung Cancer: high incidence & high mortality

주요 암의 5년 생존율 추이 : 전체

How many genes are altered in a typical solid tumor?

30-80

~10 100-200

Vogelstein 2010 AACR

EGFR as an anti-cancer target

Tumor type EGFR expression

Head & neck cancer 80-95%

NSCLC 40-80%

Breast cancer 14-91%

Colon cancer 25-77%

Ovarian cancer 35-70%

Pancreatic cancer 30-50%

1980s 1990s

1^st generation EGFR-TKIs

Phase II results of gefitinib

in previously treated advanced NSCLC (2002)

18 19

9 12

0 5 10 15 20 25 30

Response rate, %

500 mg 250 mg

Vertical bars represent 95% CI.

500 mg 250 mg

IDEAL 1 – Japan and Europe 2^nd or 3^rd line setting

(n=210) IDEAL 2 – USA

3^rd-linesetting (n=216)

Kris JAMA 2003;290:2149-58 Fukuoka JCO 2003;21:2237

Japan & US approvals of Gefitinib

•

Japan – full approval granted July 2002

Indication: Inoperable or recurrent non small cell lung cancer.

•

US – accelerated approval granted May 2003

IRESSA is indicated as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.

The effectiveness of IRESSA is based on objective response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

•

US – Phase III for full regulatory approval (ISEL: OS superiority vs placebo)

Group Responses P Study

Women vs. Men 19% vs. 3% 0.001 IDEAL 2

Japanese vs.

Caucasian 28% vs. 10% 0.0023 IDEAL 1

Adenocarcinoma vs.

Others 13% vs. 4% 0.046 IDEAL 2

Non-smoker vs.

Former/current 36% vs. 8% <0.001 MSKCC

Subpopulations & response to gefitinib in NSCLC

1Fukuoka et al, JCO 2003; ²Kris et al, JAMA 2003; ³Miller et al, JCO 2004

R

•

Primary endpoint: overall survival (OS)

•

Secondary endpoints: progression-free survival (PFS), response rate (RR), safety, quality of life (QoL), duration of response

Previously treated (failure of 1–2 previous

chemo-regimens) stage IIIB/IV NSCLC with PS 0–3

(n=1692)

Gefitinib 250mg/day (n=1129)

Placebo (n=563)

Thatcher et al. Lancet 2005;366:1527

Iressa Survival Evaluation Lung Cancer (ISEL)

R

BR.21

•

Primary endpoint: overall survival (OS)

•

Secondary endpoints: progression-free survival (PFS), response rate (RR), safety, quality of life (QoL), duration of response

Previously treated (failure of 1–2 previous

chemo-regimens) stage IIIB/IV NSCLC with PS 0–3

(n=731)

Erlotinib 150mg/day (n=488)

Placebo (n=243)

Shepherd F, et al. N Engl J Med 2005;353:123–32

2

1

Phase III results of Gefitinib & Erlotinib in previously treated advanced NSCLC

0.40 0.60 0.80 1.00 1.25 HR and 95% CI

Survival ORR

9% vs. 1%

8% vs. 1%

BR21 ISEL

Trial EGFR-TKI

Erlotinib Gefitinib

731 1692 Patients

Favours active agent Favours placebo (HR=0.89 [95% CI: 0.77-1.02])

(HR=0.70 [95% CI: 0.58-0.85])

Timeline of EGFR-targeting in NSCLC

2002 2003 2004 2005

Iressa approval in Japan

Iressa approval

in US

Final ISEL results shows no survival benefit

with Iressa

Tarceva approval

in US

AstraZeneca restricts Iressa use in US to those previously

taking Iressa with demonstrated benefit

Sharma et al. Nature Reviews Cancer 2007; 7, 169–181

Why gefitinib failed in the United States ?

Survival & response rates by subgroup

analysis (ISEL)

Thatcher et al. Lancet 2005;366:1527

EGFR mutations in NSCLC (2004)

Nat Rev Cancer 2007;7:16-181

Mutations associated with drug sensitivity

Mutations associated with drug resistance

Gazdar AF et al. Trends Mol Med 2004;10:481

Wild type Mutant form

Effects of EGFR-TK domain mutations on the ATP-binding cleft

• Enhanced kinase activity

• Increased sensitivity to TKI

EGFR mutations in NSCLC

Somatic mutation in EGFR-TK domain

More common in never- or light-smokers

30-40% of Asians 10-15% of Caucasians

Oncogenic in NIH3T3 cells & mice

Exquisite sensitivity to EGFR-TKIs

Oncogenic addiction

Prospective non-randomized studies of NSCLC with EGFR mutations treated with EGFR-TKIs

Author # screened EGFR mutations Agent RR (%) PFS (M)

First-line

Inoue 99 16 Gefitinib 75 9.7

Paz-Ares 1047 43 Erlotinib 82 13.3

Tamura 118 32 Gefitinib 75 11.5

Asahina 82 16 Gefitinib 79 8.9

Sequist 98 31 Gefitinib 55 11.4

Kim 147 45 Gefitinib 53 13.2

Second-line

Sutani 107 23 Gefitinib 74 9.4

First - & second or more-line

Rosell 2015 350 (16.6%)-217Tx Erlotinib 71 14

Kim et al. Lung Cancer 2010, Rosell et al. NEJM 2009;361:958

Iressa Pan-Asia Study (IPASS)

Carboplatin (AUC 5 or 6) /

paclitaxel (200 mg / m²)

3 weekly^# 1:1 randomization

• Chemo-naïve

• Age ≥18 years

• Adenocarcinoma

• Never or

ex-light smokers

• Life expectancy

≥12 weeks

• WHO PS 0-2

• Measurable stage IIIB / IV

Primary

• Progression-free survival (non-inferiority)

Secondary

• Objective response rate

• Overall survival

• Quality of life

• Disease-related symptoms

• Safety and tolerability Exploratory

• Biomarkers

─ EGFR mutation

─ EGFR-gene-copy number

─ EGFR protein expression End points

Randomization period: March 2006 – October 2007

Mok et al. NEJM 2009

Gefitinib (250 mg / day)

** Cross-over permitted

Mok et al. NEJM 2009

Comparison of PFS by EGFR mutation status

Phase III trials comparing gefitinib versus chemotherapy as first-line therapy in EGFR mutant NSCLC

Study N TKI Chemo Primary endpoint

NEJ002

G719X X19 L858R L861Q

198 Gefitinib TC PFS

WJTOG3405 X19 L858R 172 Gefitinib DP PFS

OPTIMAL X19

L858R 152 Erlotinib GC PFS

EURTARC X19

L858R 146 Erlotinib Platinum

+G or D PFS

T: paclitaxel, C: carboplatin, G: gemcitabine, D: docetaxel, P: cisplatin

First-line EGFR-TKI vs. Chemo in EGFR mutant NSCLC

NEJ002 (N=228) WJTOG3405 (N=172) OPTIMAL (N=165) EURTAC (n=174)

Gefitinib (n=114)

PC (n=114)

Gefitinib (n=86)

DP (n=86)

Erlotinib (n=83)

GC (n=82)

Erlotinib (n=86)

Chemo (n=88)

ORR (%) 74 31 62 32 83 36 58 15

P<.001 P<.0001 P<.0001

Median

PFS (M) 10.4 5.5 9.2 6.3 13.1 4.6 9.7 5.2

HR=0.30 (95% CI:0.22-0.41)

P<.001

HR=0.489 (95% CI: 0.34-0.71)

P<.0001

HR=0.16 (95% CI: 0.10-0.26)

P<.0001

HR=0.37 (05% CI: 0.25-0.54)

P<.0001 Median

OS (M) 30.5 23.6 35.5 38.8 22.7 28.9 19.3 19.5

EGFR mutations identified in NSCLC

Quinazoline EGFR Inhibitors discovered

Gefitinib approved for EGFR-M NSCLC

2009 1990s 2004 2005

Gandi & Janne Clin Cancer Res 2012

Gefitinib FDA approval was withdrawn Erlotinib approved

for NSCLC

Timeline of EGFR-targeting in NSCLC

EGFR mutation screening

Irreversible EGFR-TKIs: 2

generation EGFR-TKIs

Yun CH et al. PNAS 2008;105:2070 Suda K et al. JTO 2009; 4:1-4

Agent Type EGFR

IC₅₀ (nM)

HER2 IC₅₀ (nM)

Other targets Gefitinib Reversible 1-3 1830 NA Erlotinib Reversible 1 512 NA Afatinib Irreversible 0.5 14 HER-4 Neratinib Irreversible 92 59 HER-4 Dacomitinib Irreversible 6 46 HER-4

Theoretical advantages of 2^nd-generation irreversible EGFR-TKIs

 Higher affinity for EGFR-TKI domain

 Irreversible TK blockade

 More complete EGFR signaling blockade by inhibiting HER2 or HER4

 Modest in-vitro activity to T790M mutation

Irreversible EGFR-TKIs in clinical trials

HKI-272 (EGFR+HER2) RR 3% in TKI-resistant pts Intriguing response in G719X

(Sequist, JCO 2010)

XL647 (EGFR, HER2, VEGF) RR 2% in TKI-resistant pts

(Pennell, Chicago Lung 2008)

BIBW2992 (EGFR+HER2) RR 7% in TKI-resistant pts

2M PFS advantage (3.3 vs.1.1M)

(Miller, ESMO 2010)

PF299804 (EGFR+HER2+HER4) RR 7% in TKI-resistant pts

(Janne, ASCO 2009)

Afatinib in EGFR mutant NSCLC: LUX Lung-3

Response rate: Afatinib vs. PemCis

PFS: Afatinib vs. PemCis

Toxicity: Afatinib vs. PemCis

Afatinib PemCis

AE leading to discontinuation 23 (10%) 16 (14%) Drug-related AE leading to

discontinuation 18 (8%) 13 (12%)

EML4-ALK fusion gene

Natural history of ALK-positive NSCLC



3-7% of NSCLC



Adenocarcinoma

: acinar, papillary, cribriform, mucin-producing, signet-ring cell



Never or light smoking status



Younger: median 51 years



Minimal overlap with other oncogenic driver mutations



Excess of hepatic mets & pleural/pericardial effusion at presentation

Fluorescence In Situ Hybridization (FISH)

FISH characteristics Criteria for positivity

Number of cells counted At least 50 cells

% of positive signals > 15%

Distance between 5’ (green) & 3’ (red) signals Greater than 2 signal diameter separation Presence of single 3’ ALK signal only (single red) Yes

Presence of single 5’ ALK signal only (green only) No

Camidge DR et al. Clin Cancer Res 2010;16:5581-5590

Ignatius Ou SH. 2011;5:471

Diagnosis of ALK-rearranged NSCLC

Treatment of ALK-rearranged NSCLC

Sasaki T & Janne PA: Clin Cancer Res 2011;17:7213-7218

ALK-TKI

Crizotinib

Crizotinib efficacy in ALK-rearranged NSCLC

• Camidge DR, et al. J Clin Oncol 2011; 29 Suppl: Abstract 2501

• Crino L et al. J Clin Oncol 2011;29 Suppl: abstract 7514

Efficacy A8081001 (n=119) PROFILE 1005 (n=136)

ORR (CR+PR) [95% CI]

61% (2%+59%) [52-70%]

50% (1%+49%) [42-59%]

Duration of response (range) 11.2 (0.96-17.9) M 9.8 (1.5-9.8) M

Median PFS (95% CI) 10 M (8-15M) Median OS

OS rate at 12M

Not reached yet 81%

Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer

NEJM 2013

EGFR Timeline

EGFR mutations identified in NSCLC

Quinazoline EGFR Inhibitors discovered

Erlotinib approved for NSCLC

Gefitinib approved for NSCLC

2009 1990s 2004 2005

Crizotinib developed

Responses seen in ALK+NSCLC Treated on phase I study of crizotinib

EML4-ALK discovered in NSCLC

Crizotinib approved for ALK+-NSCLC

2011 2005 2007 2009

ALK Timeline

Gandi & Janne Clin Cancer Res 2012

Cost of Cancer Drugs: What Price for What Benefit?

•

Simple measures of efficacy could be based on the amount of time a new drug prolongs life.

•

If survival is prolonged by more than 6 months and/or by more than one- third of the patient’s life expectancy (eg, 12–18+ months or 30–40+

months), this would be considered extremely effective and would put the drug price in a higher range—for example, over $50,000 per year, but not more than $75,000.

•

A drug that prolongs survival by 3 to 6 months and/or by 25% to 33% of life expectancy (eg, 12–16 months or 30–37 months) would be

considered beneficial and priced modestly—perhaps between $30,000 to 50,000 per year.

•

Finally drugs that demonstrate “statistically significant survival benefits”

of 2 months or less and less than 25% prolongation of life expectancy

would be considered to have minimal efficacy and priced below $30,000

a year.

2

generation ALK inhibitors in under investigation

Crizotinib AP26113 LDK378 CH5424802

ALK IC₅₀ 24nM 0.62nM 0.15nM 1.9nM

Other targets C-Met EGFR T790M

ROS-1 IGF1R -

ORR

(crizotinib-naïve)

60.8%

(n=143)

50%

(n=4)

60%

(n=35)

93.5%

(n=46) ORR

(crizotinib-resistant)

75%

(n=16)

57%

(n=79)

2nd Generation ALK Inhibitors (NSCLC)

• Very Difficult to Beat Xalkori on Response Rate

• Penetration of the Blood Brain Barrier & Increased Potency Could Lead to Better Efficacy

• Xalkori should be beatable front-line, not on ORR but PFS.

Xalkori ^TM (Crizotinib)

성분 함량

흰색 또는 연한 노란색의 분말이 든 흰색/분홍색의 경질캡슐

• ALK-positive locally advanced or metastatic NSCLC

• Based on response rate

• Selective ATP competitive RTK-inhibitor (ALK, c-Met, RON)

• 2011년 12월 29일

한국: ALK-양성 국소 진행성 또는 전이성 비소세포폐암의 치료 성상

효능 효과

작용 기전

허가

Crizotinib: Absorption

 Peak plasma time: median 4 to 6 hours (following a single dose of crizotinib)

 Steady state: within 15 days (repeated 250mg twice a day)

 Bioavailability: mean 43% (range: 32% to 66%) following a single dose

 The solubility of crizotinib decreases with increasing pH & its bioavailability may be reduced with coadministration with drugs that elevate gastric pH.

 XALKORI can be administered with or without food

 A high-fat meal reduced crizotinib AUC and C_max by approximately 14%.

 Poorly penetrate blood-brain barrier

Crizotinib: common side effects (25%)

 Vision problems (62-64%)

These problems usually happen within 2 weeks of starting XALKORI

 flashes of light

 blurred vision

 light hurting eyes

 new or increased floaters

 nausea (53-57%)

 diarrhea (43-49%)

 vomiting (40-45%)

 hands and feet swelling (28-38%)

 constipation (27-38%)

 Grade 3-4 adverse reactions in at least 4% of patients in both studies

: ALT increased & neutropenia

Dose modification: hematologic toxicities

CTCAE Grade XALKORI Dosing

Grade 3 Withhold until recovery to Grade ≤ 2, then resume at the same dose schedule

Grade 4

Withhold until recovery to Grade ≤ 2, then resume at 200 mg twice daily

In case of recurrence, withhold until recovery to Grade ≤ 2, then resume at 250 mg once daily.

Permanently discontinue in case of Grade 4 recurrence.

Hematologic toxicities except lymphopenia

(unless associated with clinical events, e.g., opportunistic infections)

Dose modification: non-hematologic toxicities

CTCAE Grade XALKORI Dosing

Grade 3 or 4 ALT or AST elevation

with Grade ≤ 1 total bilirubin (TB) Withhold until recovery to Grade ≤ 1 or baseline, then resume at 200 mg twice daily^a

Grade 2, 3 or 4 ALT or AST elevation

with concurrent Grade 2, 3 or 4 TB elevation

(in the absence of cholestasis or hemolysis) Permanently discontinue Any Grade pneumonitis^b Permanently discontinue

Grade 3 QTc prolongation Withhold until recovery to Grade ≤ 1, then resume at 200 mg twice daily^a Grade 4 QTc prolongation Permanently discontinue

a In case of recurrence, withhold until recovery to Grade ≤ 1, then resume at 250 mg once daily.

Permanently discontinue in case of further Grade 3 or 4 recurrence.

b Not attributable to NSCLC progression, other pulmonary disease, infection, or radiation effect.

Complex renal cysts

 Crizotinib 치료받은 환자 중 8명(1% 미만)에서 복합성 신낭종이 보고됨 [아시아인 환자 6명(2%미만)]

 치료를 시작한 이후 2-8개월 이내에 보고

 8명 중 2명의 환자에서 진단 당시 옆구리 통증

 어떤 환자에서도 뇨분석 이상이나, 신장애가 보고되지는 않았음

 종양 재평가 시 및 옆구리 통증이 나타나는 경우에 신낭종에 대한 방사선 촬영 모니터링(예. CT, MRI 등)을 수행해야 함

 신낭종으로 진단된 환자는 신기능 검사와 영상검사를 사용한 모니터링을 고려해야 함

Case 1 (Female/57 세)

NSCLC (ADC) stage IV: 2010.4.14 Dx 1) Gemcitabine+cisplatin X 2: PD

2) 2010.06.25: PF-02341066(Crizotinib)

After C4: Lt renal cortical cyst

Baseline

Liver cystic lesion (C6)

Left kidney subcapsular lesion (C6) Tract seeding after aspiration (C10)

Multiseptated cyst (C10)

Hold Crizotinib

Alimta C2

Clizotinib C10

Hold Crizotinib

Alimta C6

Clizotinib C10

Hold Crizotinib

Alimta C6

Clizotinib C10

Xanthogranulomatous perinephritis

ROS1

Bergethon K et al. JCO 2012;30:863-870

 1.7% (18/1,073)

 Younger

 Never-smoker

 Adenocarcinoma

 Asians

 Good response to crizotinib

Actionable targets in lung adenocarcinomas

1999 2004 2012

Actionable targets in squamous cell lung cancer

1999 2004-2010 2012

100%

unknown

100%

unknown

Summary: 1 ^st line therapy



Testing for EGFR mutation & ALK rearrangements is critical before initiating 1

-line treatment in advanced NSCLC.



Strive to ensure enough cellular material is collected during the initial biopsy for molecular analysis.



Platinum-based chemotherapy is still the standard therapy for

pan-negative NSCLC.

First-line treatment for pan-negative (EGFR/ALK/ROS1 negative) NSCLC

Questions.

What is your preferred non-protocol first-line regimen for patients with pan-negative lung adenocarcinoma ?

1) Pemetrexed + Cisplatin (or Carboplatin) 2) Gemcitabine+ Cisplatin (or Carboplatin)

3) Platinum-based chemotherapy + Bevacizumab

4) Erlotinib

Pem/Cis vs Gem/Cis in 1

line NSCLC: Survival by histology

Nonsquamous histology

Squamous histology

Scagliotti, et al. J Clin Oncol 2008;26:3543

Months

Months

The treatment-by-histology interaction analysis (P=0.001)

Question

A patient with advanced lung adenocarcinoma receives 4 cycles of cisplatin/pemetrexed and has had a partial response on CT scan.

He has tolerated therapy well but has a grade 1 peripheral neuropathy and grade 2 anemia. ECOG PS of 1

At this point, you would recommend:

1) 2 more cycles of cisplatin/pemetrexed

2) Continuation maintenance with single-agent pemetrexed 3) Switch maintenance with erlotinib

4) Switch maintenance with docetaxel

5) Observation with close follow-up, implementing second-line treatment upon progression

Maintenance chemotherapy

Continuous maintenance therapy with pemetrexed (PRAMOUNT)

Therapy at PD

58% (PEM 4%) 58%

Switch maintenance therapy

Trial Year

induction Maintenance

Therapy at progression

PFS OS (M)

Tx No Tx No Median P Median P

SATURN 2010 Platinum

-based X 4 1949

Erlotinib 438 55% 12.3 wk

<.001

12.0

.01

Placebo 451 64%

(EGFR-TKI 16%) 11.1 wk 11.0

JMEN 2009 Platinum

-based X 4 745

PEM 441 51% 4.0 mo

<.001

13.4

.01

Placebo 222 67%

(PEM 19%) 2.0 mo 10.6

Fidias 2009 GCb X 4 566

Docetaxel 153 NR 5.7 mo

<.001

12.3

.09 Observation 156 Docetaxel 63% 2.7 mo 9.7

Factors predicting benefit from maintenance chemotherapy

Factors Examples

Response to 1^st-line therapy

JMEN: CR/PR-OS HR 0.81, SD-OS HR 0.68 SATURN: CR/PR-OS HR 0.94, SD-OS HR 0.72

PARAMOUNT: CR/PR-PFS HR 0.48 (95% CI, 0.34-0.67), SD-PFS HR 0.74 (95% CI, 0.53-1.04)

PS ECOG PS of 0 or 1

Likelihood of

therapy at PD Fidias: OS was similar in immediate vs. delayed docetaxel

Histology

SATURN: Adenocarcinoma-OS HR 0.77 (95% CI, 0.61-0.97) SQCC-OS HR 0.86 (95% CI, 0.68-1.10)

JMEN: PFS & OS benefits were confined to nonSQ histology Molecular

characteristics

The clinical benefit of EGFR-TKI was greatest in EGFR-mutant NSCLC.

ATLAS trial: KRAS wild-PFS HR 0.67 (0.49-0.9), KRAS mutant-PFS HR 0.93 (0.55-1.56)

PointBreak study AVAPERL

PARAMOUNT

PARAMOUT POINTBREAK AVAPERL PRONOUNCE

PEM+CP PEM

PEM+CP Placebo

PEM+CB+A PEM+A

Pac+CB+A A

PEM+CP+A PEM+A

PEM+CP+A A

PEM+CB PEM

PEM+CB+A PEM+A Median

PFS (M) 4.1 2.8 6.0 5.6 7.4 3.7 4.4 5.5

P <.001 .012 <.001 .610

Median OS (M) (maintenance

group)

13.9 (16.9)

11.0 (14.0)

12.6 (17.7)

13.4

(15.7) 17.1 13.2 10.5 11.7

P .019 .949 .29 .615

Continuous maintenance therapy

Survival from maintenance randomization (ITT)

PEM, pemetrexed; CP, cisplatin; CB, carboplatin; A, Avastin (bevacizumab); Pac, paclitaxel; NR: not reached

Second-line treatment for pan-negative (EGFR/ALK/ROS1 negative) NSCLC

Questions.

What is your preferred non-protocol 2nd-line regimen for patients with pan-negative NSCLC ?

1) EGFR-TKI

2) Chemotherapy

TAILOR Study Design

Garassino MC, et al. J Clin Oncol. 2012;30. Abstract LBA7501.

Stratification: Minimization approach

• Center

• Recurrent/progressive disease

• Prior chemotherapy regimen (pemetrexed vs. gemcitabine vs. vinorelbine)

• ECOG PS (0-1 vs. 2)

• Adequacy of tissue sample (optimal vs. suboptimal)

• Advanced/

recurrent

• Prior platinum -based doublet

• EGFR wild type

• KRAS wild type

• ECOG PS 0-2

R

Docetaxel

75 mg/m² IV d 1, 21 or 35 mg/m² IV d 1, 8, 15,

28

Erlotinib 150 mg oral daily

CROSS- OVER

NOT ALLOWED

TAILOR: PFS in Intent-to-Treat Group

Garassino MC, et al. J Clin Oncol. 2012;30. Abstract LBA7501.

Docetaxel (n=94)

Erlotinib

(n=92) P

CR 4.3% 0

0.002

PR 9.6% 2.2%

SD 27.6% 20.6%

PD 58.5% 77.2%

RR

(CR+PR) 13.9% 2.2% 0.004

DCR

(CR+PR+SD) 41.5% 22.8% 0.007

DELTA: Docetaxel vs. Erlotinib

Okano et al. 2013 ASCO.

Stratification: Minimization approach

• Gender

• PS

• Histology

• Institution

• Advanced NSCLC

• Prior 1-2 regimens

• ECOG PS 0-2

• EGFR M test

R

Docetaxel

60 mg/m² IV Q 3 wks

Erlotinib 150 mg

oral daily

Docetaxel (n=85)

Erlotinib

(n=106) P

CR 0 0

PR 20.0% 5.6%

SD 50.6% 47.2%

PD 29.4% 47.2%

RR

(CR+PR) 20.0% 5.6% 0.003

DCR

(CR+PR+SD) 52.8% 70.6% 0.017

DELTA: PFS in Intent-to-Treat Group

EGFR-wild type lung adenocarcinomas are heterogeneous!

Summary

 First-line EGFR-TKI Therapy & for patients with EGFR mutations

 Particular sensitive to EGFR-TKIs: higher RR & longer PFS

 Improved toxicity profile & QOL of EGFR-TKIs compared to chemotherapy 2^nd generation EGFR-TKI?

 Chemotherapy is better for EGFR wild type NSCLC in any setting

 EGFR wild type NSCLCs are not homogenous (ALK, ROS-1, RET, KRAS, etc)

 Test for other potentially actionable genetic alterations

 Both continuation & switch maintenance chemotherapy have demonstrated

favorable toxicity profile, prolongation of PFS, & -in some instance, an OS benefit.

 There are still considerable controversies in maintenance therapy

 Economic consideration

 Additional toxicity with maintenance therapy

 In the absence of clear-cut survival advantage or differential improvement in symptoms, it may difficult to justify extending therapy instead of delaying.