First Line Therapy in EGFR Mutant Advanced/Metastatic NSCLC

Selecting First-line Therapy in the “EGFR Mutant”

Advanced/Metastatic NSCLCEmad Shash MBBCh., MSc., MD.Medical Oncology Department

National Cancer Institute, Cairo University

How to Hit a Target? The art of “Precision” Medicine

NSCLC Pathology: From Traditional View to more sub-molecular categorization

Evolution Of Knowledge

The EGFR Signal Transduction Pathway

Salomon, et al. Crit Rev Oncol Hematol 1995

Tyrosine kinase


EGFR Sub-Mutations in NSCLC

9%exon 20variants

3%codon 719

variants2%

othervariants

40%L858R

substitution

46%exon 19

deletions

Herbst RS, et al. N Engl J Med. 2008.Sequist LV, et al. J Clin Oncol. 2007.


Advanced NSCLC: Evolution of Treatment

2000 - 2006 2006 - 2009 2010 2011 – 2017……..

EGFR mutation

ALK rearrangement

K-ras mutation

B-raf, HER2 mutation

ROS1, RET

Immunotherapy

Non-Squamous

Squamous

Targeting an Oncogenic Driver

EGFR mutation

Non-Squamous

Squamous

Non-Squamous

Squamous

NSCLC

Targeting EGFRTreating according histologyNSCLC

Adeno LCC-NOS SCC SCLC

EGFR mutants ALK ROS/RET

HER2

BRAF KRAS

KRAS

Changes in the Therapeutic Landscape of Stage IV Lung Cancer: 2017

More individualization of therapy?

How’s The Story Began?Can we get rid of chemotherapy administration?

Adapted from Shash E et al. J Thorac Dis 2011.

Setting up the ground in Unselected population: Previously Treated

Study EGFR TKI Used Phase Population OS Remark

ISEL Gefitinib VS Placebo

III Previously Treated

5.6 vs 5.1 months (p value = 0.087)

Negative Trial

BR 21 Eroltinib VS Placebo

III Previously Treated

6.7 vs 4.7 months (p value < 0.001)

Positive Trial

Lessons Learnt & Identification of Subgroups that might benefit more

Study Subgroup analysis Results

ISEL Never Smokers 8.9 vs 6.1 months (p value = 0.012)

ISEL Asian Ethnicity 9.5 vs 5.5 months (p value = 0.01)

BR 21 Females, non-smokers & Adenocarcinoma

Confirmed ISEL Subgroup analysis

More gaining evidence that those patients with EGFR Mutations yielded better RR, PFS & OS

Moving Forward with Selected population Trial Designs!Optimizing therapy for “EGFR Mutant” patients

Mok TS, et al. N Engl J Med. 2009.

IPASS: First-line Gefitinib vs Paclitaxel/ Carboplatin in Stage IIIB/IV NSCLC

• Open-label phase III trial

• Primary endpoint: PFS• Secondary endpoints: OS, ORR, quality of life, symptom reduction, safety

• Study conducted in Asian countries

Previously untreated pts with stage IIIB/IV NSCLC,

adenocarcinoma, never or ex-light smokers, WHO PS

0-2(N = 1217)

Up to six 3-wk cycles

Gefitinib 250 mg/day PO(n = 609)

Paclitaxel 200 mg/m2 IV on Day 1 +Carboplatin AUC 5-6 mg/mL/min IV on Day 1

(n = 608)

Gefitinib vs Paclitaxel/Carboplatin in Advanced NSCLC: PFS by EGFR Status

• PFS: gefitinib superior to carboplatin/paclitaxel in ITT population• HR for progression/death: 0.74 (95% CI: 0.65-0.85; P < .001)

• EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel

Mok TS, et al. N Engl J Med. 2009.

EGFR Mutation Positive

HR: 0.48 (95% CI: 0.36-0.64; P < .001)

Prob

abili

ty o

f PFS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

EGFR Mutation Negative

HR: 2.85 (95% CI: 2.05-3.98; P < .001)

Prob

abili

ty o

f PFS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

GefitinibPac/carbo

GefitinibPac/carbo

EURTAC: Erlotinib vs Chemo in EGFR Mutation–Positive, Stage IIIB/IV NSCLC

• Primary endpoint: PFS (interim analysis planned at 88 events)• Secondary endpoints: ORR, OS, location of progression, safety, EGFR-mutation analysis, QoL

Pts with no prior chemotherapy, stage

IIIB/IV NSCLC, mutated EGFR,* ECOG PS 0-2

(N = 174†)

PD

PD

Erlotinib 150 mg/day(n = 86)

Platinum Doublet‡

Q3W x 4 cycles(n = 87)

Stratified by mutation type,* ECOG PS (0 vs 1 vs 2)

*Exon 19 deletion or exon 21 L858R mutation. †1227 pts screened; 174 pts with mutated EGFR enrolled; 1 pt withdrawn. ‡Cisplatin 75 mg/m2 Day 1/docetaxel 75 mg/m2 Day 1; cisplatin 75 mg/m2 Day 1/ gemcitabine 1250 mg/m2 Days 1, 8; carboplatin AUC = 6 Day 1/docetaxel 75 mg/m2 Day 1; carboplatin AUC = 5 Day 1/gemcitabine 1000 mg/m2 Days 1, 8.

Rosell R, et al. Lancet Oncol. 2012.

Randomized, open-label phase III trial

PFS in ITT Population

Prob

abili

ty o

f PS

Erl (n = 86)Chemotherapy (n = 87)HR: 0.37 (95% CI: 0.25-0.54;log-rank P < .0001)

Mos0 3 6 9 12 15 18 21 24 27 30 33

Pts at Risk, nErl 86 63 54 32 21 17 9 7 4 2 2 0 Chemo 87 49 20 8 5 4 3 1 0 0 0 0

1.0

0.8

0.6

0.4

0.2

09.75.2

Rosell R, et al. Lancet Oncol. 2012;13:239-246.

First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLC

Study Treatment N Median PFS, Mos Median OS, Mos

Maemondo[1] Gefitinib vs carboplatin/paclitaxel 230 10.8 vs 5.4

(P < .001)30.5 vs 23.6

(P = .31)

Mitsudomi[2,3] Gefitinib vscisplatin/docetaxel 172 9.2 vs 6.3

(P < .0001)35.5 vs 38.8(HR: 1.19)

OPTIMAL[4,5] Erlotinib vscarboplatin/gemcitabine 165 13.1 vs 4.6

(P < .0001)22.8 vs 27.2(HR: 1.19)

EURTAC[6] Erlotinib vsplatinum-based chemotherapy 174 9.7 vs 5.2

(P < .0001)19.3 vs 19.5

(P = .87)

LUX-Lung 3[7,8] Afatanib vscisplatin/pemetrexed 345 11.1 vs 6.9

(P = .001)28.2 vs 28.2

(P = .39)

LUX-Lung 6[8,9] Afatinib vs cisplatin/gemcitabine 364 11.0 vs 5.6(P < .0001)

23.1 vs 23.5 (P = .61)

1 Maemondo M, et al. N Engl J Med. 2010. 2Mitsudomi T, et al. Lancet Oncol. 2010. 3Mitsudomi T, et al. ASCO 2012.4 Zhou C, et al. Lancet Oncol. 2011. 5Zhou C, et al. Ann Oncol. 2015. 6Rosell R, et al. Lancet Oncol. 2012. 7Sequist LV, et

al. J Clin Oncol. 2013. 8Yang JC, et al. Lancet Oncol. 2015. 9Wu YL, et al. Lancet Oncol. 2014.

Lee CK, et al. J Natl Cancer Inst. 2013.

Favors EGFR TKI Favors Chemo

Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS

StudyHR

(95% CI)HR

(95% CI)

EGFRmut (first-line therapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUX LUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal

0.37 (0.25-0.54)0.54 (0.27-1.10)1.08 (0.24-4.90)0.55 (0.19-1.60)0.48 (0.36-0.64)0.58 (0.43-0.78)0.32 (0.24-0.44)0.16 (0.11-0.26)0.59 (0.21-1.67)0.90 (0.39-2.06)0.49 (0.20-1.20)0.52 (0.38-0.72)0.43 (0.38-0.49)

Lee CK, et al. J Natl Cancer Inst. 2013.

Favors EGFR TKI Favors Chemo

First-line EGFR TKI Studies: Improved QoL

StudyHR

(95% CI)HR

(95% CI)

EGFRmut (first-line therapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUX LUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal

0.37 (0.25-0.54)0.54 (0.27-1.10)1.08 (0.24-4.90)0.55 (0.19-1.60)0.48 (0.36-0.64)0.58 (0.43-0.78)0.32 (0.24-0.44)0.16 (0.11-0.26)0.59 (0.21-1.67)0.90 (0.39-2.06)0.49 (0.20-1.20)0.52 (0.38-0.72)0.43 (0.38-0.49)

Patients & Clinicians would like to see SURVIVAL GAIN!!The advancement of Diagnosis Knowledge & Drug Development: Can they yield better results?

2nd Generation

TKIs

3rd Generation TKIs

1ST Generation

TKIs

3 Generations of EGFR TKIs

Physician's Dilemma

One difference is how they bind to the EGFR protein Receptor

Another Difference is their therapeutic window

Gefitinib

EGFRm

T790M

Wt

Afatinib Osimertinib

EGFRm EGFRm

T790M

T790M

Wt

Wt

1x

10x

100xR

elat

ive

IC50

Li D, et al. Oncogene. 2008. Ranson M, et al. WCLC 2013. Moyer JD, et al. Cancer Res. 1997. Kancha RK, et al. Clin Cancer Res. 2009.

Erlotinib

T790M

EGFRm

Wt

2nd Generation: LUX-Lung clinical trials and eligibility

*EGFR mutations detected by TheraScreen EGFR29 test:

• Common: 19 deletions in exon 19 and L858R in exon 21• Uncommon: 3 insertions in exon 20, L861Q, T790M, G719S, G719A and G719C, S768I

Treatment

Line of treatment

Mutation test

LUX-Lung 2Phase II

N=129

Afatinib

First- and second-line

(after chemo)

Direct sequencing

(central)

LUX-Lung 3Phase III

N=345

Afatinib vs. Pemetrexed/

cisplatin

First-line (Global)

EGFR29* (central)

LUX-Lung 6Phase III

N=364

Afatinib vs. Gemcitabine/

cisplatin

First-line (Asian)

EGFR29* (central)

2

LUX-Lung 2: High Response of EGFR-Mutated, TKI-Naive NSCLC to Afatinib

• Phase II: 61% (79/129) pts achieved ORR (2 CR; 77 PR) regardless of type of EGFR mutation

Yang JC, et al. Lancet Oncol. 2012.

Measurable Tumor at Time of Best ResponseM

axim

um D

ecre

ase

From

Bas

elin

e(%

)

50

20

0

-30

-50

-100200 40 60 80 100

Pt

Sequist et al. J Clin Oncol. 2013

LUX-Lung 3 Study Design

Randomization 2:1 Stratified by:

EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian)

Afatinib 40 mg/day†Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2

i.v. q21 days, up to 6 cycles

Primary endpoint: PFS (RECIST 1.1, independent review)‡

Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO§, safety, PK

Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)

EGFR mutation in tumor(central lab testing; Therascreen EGFR29* RGQ PCR)

*EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AE.‡Tumor assessments: q6 weeks until Week 48 and q12 weeks thereafter until progression/start of new therapy. §Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and q3 weeks until progression or new anti-cancer therapy.

Del l9/L858R mutations

AFATINIB– Superior first-line PFS vs pemetrexed/ cisplatin in common mutations (del 19/L858R)

• 53% reduction in relative risk of death or tumour progression in patients with common mutations (HR 0.47; P<0.001)

• In ITT population, median PFS was 11.1 and 6.9 months for AFATINIB and pemetrexed/ cisplatin, respectively (HR: 0.58; 95% CI, 0.43-0.78; P<0.001)

PFS by independent review (primary endpoint)Preplanned subgroup analysis

PFS

rate

(%)

0.2

0.4

0.6

0.8

1.0

0.0

Time (months)

0 3 6 9 18 2112 15 24 27

Hazard ratio 0.47(95% CI, 0.34-0.65)P<0.001

AFATINIB® (n=204)Pemetrexed/cisplatin (n=104)

13.6months

6.9months

Sequist et al. J Clin Oncol. 2013

Del 19 mutations

AFATINIB– Over 1 year extended OS vs pemetrexed/cisplatin in subgroup of del19 patients

Hazard ratio 0.54(95% CI, 0.36-0.79)P=0.0015

AFATINIB (n=112)Pemetrexed/cisplatin (n=57)

• 46% reduction in relative risk of death in del 19 patients (HR 0.54; P=0.0015)• OS in ITT population (N=345) was 28.2 and 28.2 months for AFATINIB vs

pemetrexed/cisplatin, respectively (HR 0.88; P=0.39)

Overall survival (secondary endpoint)Preplanned subgroup analysis

Estim

ated

OS

prob

abili

ty

0.2

0.4

0.6

0.8

1.0

0.0

Time of overall survival (months)

0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42 48 51

33.3months

21.1months

>12months increase

median OS


LUX-Lung 31,2 / LUX-Lung 62,3, %Afatinib LL3 (n=229) / LL6 (n =239 ) Cis/Pem (n=111) / Cis/Gem (n=113)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Rash/acnea 89.1 / 80.8 16.2 / 14.2 0.0 / 0.4 6.3 / 8.8 0 0Diarrhoea 95.2 / 88.3 14.4 / 5.4 0 15.3 / 10.6 0 0Paronychia/nail effecta 56.8 / 33.9 11.4 / 0.0 0 0 / 0 0 0Stomatitis/mucositisa 72.1 / 51.9 8.3 / 5.4 0.4 / 0.0 15.3 / 5.3 0.9 / 0.0 0Decreased appetite 20.5 / 10.0 3.1 / 1.3 0 53.2 / 40.7 2.7 / 1.8 0Vomiting 17.0 / 9.6 3.1 / 0.8 0 42.3 / 80.5 2.7 / 15.9 0.0 / 3.5Fatiguea 17.5 / 10.0 1.3 / 0.4 0 46.8 / 36.3 12.6 / 0.9 0Nausea 17.9 / 7.5 0.9 / 0.0 0 65.8 / 75.2 3.6 / 7.1 0.0 /0.9Dry skin/pruritusb 29.3 / 10.9 0.4 / 0.4 0 1.8 / 0.0 0 0Neutropenia 0.9 / 2.1 0.4 / 0.4 0 31.5 / 54.0 15.3 / 17.7 2.7 / 8.8Anaemia 3.1 / 5.4 0.4 / 0.4 0 27.9 / 27.4 4.5 / 7.1 1.8 / 1.8Leukopenia 1.7 / 3.3 0.0 / 0.4 0 18.9 / 51.3 8.1 / 13.3 0.0 / 1.8ALT increase 7.4 / 20.1 0.0 / 1.7 0 2.7 / 15.9 0.0 / 1.8 0.0 / 0.9AST increase 5.2 / 15.1 0.0 / 0.4 0 1.8 / 10.6 0.0 / 1.8 0

Most Frequent Treatment-Related Adverse Events (>20% Difference Between Treatment Arms)

aGrouped term for closely related AEs.bIn LUX-Lung 3, the incidence for dry skin and pruritus were reported separately as 29.3% and 18.8%, respectively, for all grades and 0.4% each for grade ≥3 in afatinib arm. ALT = alanine aminotransferase; AST = aspartate aminotransferase.

1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Data on file. Boehringer Ingelheim; 3. Wu et al. Lancet Oncol. 2014;15:213.

2nd Generation EGFR TKI activity in Uncommon Mutations “Explored analysis”

Patients with uncommon mutations treated with afatinib

n=23 n=26 n=26

Del19n=408

L858Rn=330

Uncommonn=100

LUX-Lung 2Phase II

N=129

n=52

n=54

n=23

LUX-Lung 3Phase III

N=345

n=170

n=138

n=37

LUX-Lung 6Phase III

N=364

n=186

n=138

n=40

Uncommonn=75

LUX-Lung 2+3+6: Afatinib in NSCLC Pts With Uncommon EGFR Mutations

• Combined post hoc, ITT analysis of data on pts with uncommon EGFR mutations (n = 100) prospectively collected from the LUX-Lung 2, 3, and 6 trials

• Afatinib: n = 75; chemotherapy: n = 25

• Pts with uncommon EGFR mutations given afatinib categorized into 3 cohorts


Cohort n Uncommon Mutations

Group 1 38Point mutations or duplications in exons 18-21 (L861Q, G719S, G719A, G719C, S768I, rare others) alone or in combination with each other

Group 2 14 De novo T790M mutations in exon 20 alone or in combination with other mutations

Group 3 23 Exon 20 insertions

Tumour shrinkage in patients with uncommon mutations

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

Max

imum

cha

nge

from

bas

elin

e (%

) Exon 20 insertions (n=23)

De novo T790M (n=14):T790M alone(*), T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X

Other (n=38):L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R, S768I, L861P, P848L, R776H+L858R, L861Q+Del19, K739_1744dup6

Independent review (n=67†)

*

**


Are 2nd Generation Agents Superior to 1st Generation Agents?Time for Head-To-Head Comparison

Park K et al. Lancet Oncol 2016

LUX- LUNG 7

• Treatment beyond progression allowed if deemed beneficial by investigator• RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until

Week 64, and every 12 weeks thereafter

• Stage IIIB/IV adenocarcinoma of the lung

• EGFR mutation (Del19 and/or L858R) in the tumour tissue*

• No prior treatment for advanced/metastatic disease

• ECOG PS 0/1

Afatinib 40 mg once daily†

Gefitinib 250 mg once daily

Primary endpoints: PFS (independent) TTF OS

Secondary endpoints:ORRTime to response Duration of responseDuration of disease controlTumor shrinkageHRQoLSafety

*Central or local test†Dose modification to 50, 30, 20 mg permitted in line with prescribing information

Stratified by •Mutation type (Del19/L858R) •Brain metastases (present/absent)

1:1N=319

Baseline Characteristics

Afatinib 160, N (%)

Gefitinib159, N (%)

Median age, years (range) 63 (30–86) 63 (32–89)

Gender, % Female/Male 57/43 67/33

Race, % AsianNon-Asian

59 41

5545

Brain metastases*, % 16 16

Smoking status, %Never smoked

Light ex-smokerCurrent/other ex-smoker

661321

671221

Baseline ECOG, % 01

3268

3070

NSCLC stage, % IIIBIV

595

298

EGFR mutation, % Del19L858R

5842

5842


PFS by Independent Review

No. at risk:Afatinib 160 142 112 94 67 47 34 27 21 13 6 3 1 0 0Gefitinib 159 132 106 83 52 22 14 9 7 5 3 3 1 1 0

1.0

0.8

0.6

0.4

0.2

00

Time of progression free survival (months)

Estim

ated

PFS

pro

babi

lity

Afatinib GefitinibMedian, mo 11.0 10.9

HR (95% CI)P-value

0.73 (0.57-0.95)0.0165

27%

18%

15%8%

3 6 9 12 15 18 21 24 27 30 33 36 39 42

P=0.0176

P=0.0184

AfatinibGefitinib


PFS for Subgroups by Independent Review

Total 319 0.732 (0.566, 0.947)EGFR mutation

L858R 1330.708 (0.475, 1.055)

Del19 1860.764 (0.549, 1.063)

Brain metastasesAbsent 268

0.739 (0.560, 0.976)Present 51

0.764 (0.405, 1.439)Baseline ECOG score

0 980.892 (0.542, 1.469)

1 2210.705 (0.524, 0.948)

GenderMale 122

0.876 (0.585, 1.312)Female 197

0.653 (0.469, 0.910)Age group

<65 years 1770.681 (0.479, 0.968)

≥65 years 1420.845 (0.585, 1.221)

Race groupNon-Asian 137

0.717 (0.487, 1.056)Asian 182

0.756 (0.539, 1.060)Smoking history

Never smoked 2120.801 (0.584, 1.097)

<15 pack years + stopped >1 year before 401.094 (0.559, 2.140)

Other current or ex-smokers 670.477 (0.270, 0.845)

1/16 1/4 1 4 16

Favours Afatinib Favours Gefitinib

Factors Number of Patients Hazard Ratio (95% CI)


Deepening of Response!!Does it matters??

Tumor Shrinkage by Independent Review

A(n)

G(n)

≥20% increase 1 4

0–<20% increase 6 6

0–<30% decrease 27 41

≥30–<50% decr. 50 46

≥50% decrease 65 54

AfatinibGefitinib

Based on maximum percentage decrease from baseline in the sum of target lesion diameters. A=Afatinib G=Gefitinib


Time to Treatment Failure

No. at risk:Afatinib 160 148 133 113 91 68 56 48 40 25 18 9 5 0 0Gefitinib 159 144 120 103 74 59 43 30 21 11 6 6 2 2 0

Time to treatment failure (months)

Estim

ated

pro

babi

lity

of b

eing

free

of

trea

tmen

t fai

lure

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

25%

5%

P=0.0029

15%

13%

P=0.0067

AfatinibGefitinib

Afatinib Gefitinib

Median, mo 13.7 11.5

HR (95% CI)P-value

0.73 (0.58-0.92)0.0073

TTF = time from randomization to treatment discontinuation for any reason


TTF by Subgroups

Total 319 0.728 (0.576, 0.920)EGFR mutation

L858R 1330.748 (0.525, 1.065)

Del19 1860.729 (0.535, 0.994)

Brain metastasesAbsent 268

0.687 (0.533, 0.886)Present 51

1.135 (0.635, 2.026)Baseline ECOG score

0 980.784 (0.515, 1.195)

1 2210.724 (0.547, 0.957)

GenderMale 122

0.729 (0.499, 1.066)Female 197

0.746 (0.554, 1.006)Age group

<65 years 1770.606 (0.443, 0.831)

≥65 years 1420.902 (0.633, 1.286)

Race groupNon-Asian 137

0.660 (0.459, 0.949)Asian 182

0.817 (0.603, 1.108)Smoking history

Never smoked 2120.752 (0.566, 0.998)

<15 pack years + stopped >1 year before 401.192 (0.621, 2.288)

Other current or ex-smokers 670.567 (0.334, 0.963)

Factors Number of patients Hazard Ratio (95% CI)

1/16 1/4 1 4 16

Favours Afatinib Favours Gefitinib


Objective Response and Disease Control Rate by Independent Review

P = 0.0083

Afatinib112/160

Gefitinib89/159

0%

20%

40%

60%

80%

ORR

70%

Afatinib GefitinibMedian DoR , months (95% CI)

10.1 (7.8, 11.1)

8.4 (7.4 – 10.9)

Disease control rate (N) 91.3% (146) 87.4% (139)

56%


Toxicity of EGFR TKIs in NSCLC

EGFR TKI Study

Treatment-Related AEs, %

Diarrhea Rash Paronychia Stomatitis

Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4

Gefitinib Mitsudomi Maemondo

4738

1.10.9

7275

2.35.3

27NR

1.22.6

1911

00

Erlotinib OPTIMAL EURTAC

2144

15

4856

212

3NR

0NR

10NR

1NR

Afatinib LUX-Lung 3 LUX-Lung 6

8081

14.45.4

7265

16.214.6

4532

11.40

6345

8.75.4

Burotto M, et al. Oncologist. 2015.

• Gefitinib and erlotinib have comparable toxicity• Afatinib associated with more associated toxicity than gefitinib or erlotinib

Can 3rd Generation EGFR TKIs offer much improvement in 1st Line Setting?The Future will tell

AURA: Osimertinib Efficacy by EGFR T790M Status

• Phase I/II trial for pts with EGFR-positive NSCLC with progression after previous treatment with EGFR TKIs

Median PFS: 2.8 mos Median PFS: 9.6 mos

Jänne PA, et al. N Engl J Med. 2015.

1.00.90.80.70.60.50.40.30.20.1

0

Prob

abili

ty o

f PFS T790M positive

T790M negative

Mos0 3 6 9 12

Response Rates of EGFR T790M–Positive Cohorts to Osimertinib

• DCR (CR, PR, or SD): 90% (95% CI: 84-94); activity in LM

Jänne PA, et al. New Engl J Med. 2015. Yang, J C-H, et al. ASCO 2016.

n = 127 20 mg 40 mg 80 mg 160 mg 240 mg Total

n 10 32 61 41 13 157

ORR, % (95% CI) 50(19-81)

59(41-76)

66(52-77)

51(35-67)

54(25-81)

59(51-66)

*Imputed values for pts who died within 14 wks (98 days) of start of treatment and had no evaluable target lesion assessments. DStudy discontinuation. T790M mutation determined by central test.

40 mg 80 mg160 mg240 mg

20 mg

-100-90-80-70-60-50-40-30-20-10

01020304050

DD*D*

DDDD

DD DD D

DDD

DDD

DD

D DD DD D DD DD

D D D D D DDD D D D D DDD

D D DD D DD

D

D D

D

D

D

Best % Change From Baseline in Target Lesion

Osimertinib FDA approved (November 2015) for advanced EGFR T790M–positive NSCLC after PD on prior EGFR TKI

Mok T. et al. N Engl J Med 2017

AURA 3: Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer

Third-Generation EGFR TKIs

Agent N RR, % T790M-

RR, % T790M+ PFS, mos Toxicity

Osimertinib[1] 253 21 61 ~ 8.2 DiarrheaRociletinib[2,3] 130 29

(17)59

(45)13.1(6.1)

Hyperglycemia

Olmutinib[4] 62 NR 55 NR Dyspnea/rashEGF816[5] 53 60 NR RashASP8273[6] 47 ~ 33 61 NR Hyponatremia/

diarrhea

1. Jänne PA, et al. N Engl J Med. 2015. 2. Sequist LV, et al. N Engl J Med. 2015. 3. Sequist LV, et al. N Engl J Med. 2016.

4. Park K, et al. ASCO 2015. 5. Tan DS, et al. ASCO 2015..

6. Goto Y, et al. ASCO 2015.

AURA: AZD9291 in Previously Untreated Advanced NSCLC

Predefined expansion

cohorts

Sequential cohorts of pt with previously untreated LA/

metastatic NSCLC with confirmed EGFR mutation, WHO

PS 0-1

Cohort 5 (240 mg) T790M+

Cohort 4 (160 mg)(n = 30)

T790M+/-

Cohort 3 (80 mg)(n = 30) T790M+/-

Cohort 2 (40 mg) T790M+/-

Cohort 1 (20 mg) T790M+

Ramalingam SS, et al. ASCO 2015

AZD9291 Dosing

AURA: Pt Population

Characteristic 80 mg(n = 30)

160 mg(n = 30)

Total(N = 60)

Female, % 67 83 75Median age, yrs (range) 63 (40-77) 65 (38-91) 64 (38-91)EGFR mutation type,* % Exon 19 del L858R Other†

304723

433323

374023

T790M status,* % Positive Negative Unknown

137017

38313

87715

Ramalingam SS, et al. ASCO 2015

*Determined by central testing.†Other includes other EGFR mutations, no mutation, or unknown result.

-70-50-30-10

AURA: Tumor Response and PFS

Outcome 80 mg(n = 30)

160 mg(n = 30)

Total(N = 60)

Maximum DoR, mos 13.8* 9.7*

PFS, % (95% CI) 3 mos 6 mos 9 mos 12 mos

90 (72-97)83 (64-93)83 (64-93)73 (51-87)

97 (79-100)90 (72-97)78 (57-89)

NC

93 (83-97)87 (75-93)81 (68-89)72 (55-64)

Ramalingam SS, et al. ASCO 2015.

*Ongoing.

5040302010

0-20-40-60-80-90

-100

80 mg160 mg

Best

Per

cent

age

Chan

ge

From

Bas

elin

e in

Tar

get

Lesi

on

Individual Patients

D

DDD D D DD

D DD*

clinicalTrials.gov

Third-Generation EGFR TKIs

Stewart EL, et al. Transl Lung Cancer Res. 2015;4:67-81.Chan BA, et al. Transl Lung Cancer Res. 2015;4:36-54.

EGFR Mutations: Context To Memorize• Found in approximately 10% to 30% of pts with NSCLC

• More common in never smokers, adenocarcinomas, females, Asians

• Associated with response to first-, second-, and third-generation TKIs

• Predominantly located in EGFR exons 18-21 • 85% of EGFR mutations are either deletions in exon 19 or a single-point mutation in exon 21

(L858R)

• The specific EGFR mutation identified is important• There are sensitive mutations, primary resistance mutations (often exon 20), and acquired

resistance mutations (T790M)

Summary of First-line EGFR TKIs in EGFR- Mutated NSCLC

• 1st Generation & 2nd Generation TKIs improve PFS and QoL

• Afatinib PFS superior to first-generation EGFR TKIs

• Afatinib Showed OS in preplanned Subgroup (Further confirmations are warranted)

• Afatinib showed activity in both Common & Uncommon Mutations

• 3rd generation TKIs in 1st line setting may offer additional hope for patients (All EGFR population & those with Specific Mutations)

• Choice of a specific EGFR TKI should consider toxicities and pt preferences

Choose Confidently for Your Patient!

Thank You

First Line Therapy in EGFR Mutant Advanced/Metastatic NSCLC

Health & Medicine

Transcript of First Line Therapy in EGFR Mutant Advanced/Metastatic NSCLC