Prolonging the Chemotherapy-free Period in EGFRM+ NSCLC · 2020-05-28 · Prolonging the Chemotherapy-free Period in EGFRM+ NSCLC Pr. Nicolas Girard Thorax Institut Curie-Montsouris,

Prolonging the Chemotherapy-free Period in EGFRM+ NSCLC

Pr. Nicolas GirardThorax Institut Curie-Montsouris, Paris, France

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019

2

Disclosures


• Personal financial interests: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hoffmann La Roche, Merck Sharp & Dohme, Novartis, Pfizer, Takeda

• Institutional financial interests: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hoffmann La Roche, Merck Sharp & Dohme, Novartis, Pfizer, Takeda

• Nonfinancial interests: Former VP of International Thymic Malignancy Interest Group, Executive Board of French Thoracic Cancer Intergroup, Secretary of the Oncology Group of the French Speaking Respiratory Medicine Society, Associated Coordinator of RYTHMIC

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Introduction• Progress in the treatment of EGFRM+ NSCLC allows for several

treatment lines, leading to prolonged survival1,2

• Choosing a treatment strategy that delays disease progression while maintaining quality of life is a key objective in the treatment of EGFRM+ NSCLC3

• Remaining chemotherapy-free might help patients and physicians achieve these goals4

What factors should be considered when choosing the best treatment sequence?

1. Hirsch et al. Lancet. 2017;389:299; 2. Planchard et al. Ann Oncol. 2018;29(suppl 4):iv192; 3. Polanski J et al. Onco Targets Ther. 2016;9:1023; 4. Sasaki H, et al. Int J Clin Oncol. 2017;22:793.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019EGFRM = epidermal growth factor receptor mutation; NSCLC = non−small cell lung cancer.

4

Choosing the Sequence in EGFR-Mutant NSCLC

TKIs replaced chemotherapy as standard-of-care 1L treatment

Evidence #1

Not all TKIs are equal

Evidence #2

Monitoring of tumour biology drives treatment sequencing

Evidence #3Evidence #4

Evidence #5

Girard. Future Oncol. 2018;14:1117.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 20191L = first-line.

Sequence makessurvival

Optimisation of treatmentsequences

5



Evidence #1


Evidence #2



Evidence #5





6

First- and Second-Generation EGFR TKIs Are Standard in the 1L Treatment of NSCLC Harbouring Common EGFR Mutations

Better PFS vs Platinum-Based Chemotherapy

aPFS not reported for common mutations only.PFS = progression-free survival.

1. Rosell et al. Lancet Oncol. 2012;13:239; 2. Wu et al. Ann Oncol. 2015;26:1883; 3. Zhou et al. Lancet Oncol. 2011;12:735; 4. Fukuoka et al. J Clin Oncol. 2011;29:2866; 5. Maemondo et al. N Engl J Med. 2010;362:2380; 6. Mitsudomi et al. Lancet Oncol. 2010;11:121; 7. Mok et al. N Engl J Med. 2009;361:947; 8. Sequist et al. J Clin Oncol. 2013;31:3327; 9. Wu et al. Lancet Oncol. 2014;15:213.


*

*9.7

11

13.1

9.2

10.8

9.5

13.6

11

5.2 5.54.6

6.35.4

6.36.9

5.6

0

2

4

6

8

10

12

14

16

EURTAC ENSURE OPTIMAL WJTOG NEJ002 IPASS LL3 LL6 EURTAC ENSURE OPTIMAL WJTOG NEJ002 IPASS LL3 LL6

Mon

ths

a

Gefitiniba,4-7Erlotinib1-3 Afatinib8,9 Platinum-Based Chemotherapy

a

7



Evidence #1


Evidence #2



Evidence #5





8

2nd-generation TKI

3rd-generation TKI

K Kinase domain

Activity range

• Reversible binding to wild-type and mutant EGFR• Inactive on T790M mutant

• Irreversible covalent binding to EGFR, ErbB2, and ErbB4 to inhibit all ErbB family signalling

• Broader activity to overcome EGFR TKI-resistant mutations

EGFR inhibition

ErbB family blockade

EGFR mutant-specific inhibitor

1st-generation TKI Activity rangeErlotinibGefitinib

AfatinibDacomitinib

Osimertinib

Wild-type EGFR

Intrinsic mutant EGFR

Acquired T790M EGFR

K K K K K KK

ErbB heterodimers(eg, HER2: ErbB3)

Activity• Irreversible covalent binding to mutant EGFR• Specificity for EGFR T790M mutant; EGFR

wild-type sparing

range

First-, Second-, and Third-Generation EGFR TKIs Are Not Equal: Activity Against EGFR Mutations

DrugMetabolised byCYP Enzymes

Possible Drug-Drug

Interactions

Erlotinib Yes Yes

Gefitinib Yes Yes

Afatinib No Limited

Dacomitinib Yes Yes

Osimertinib Yes Yes

1. Girard. Future Oncol. 2018;14:1117; 2. Cross et al. Cancer Discov. 2014;4:1046; 3. Li et al. Oncogene. 2008;27:4702; 4. Peters et al. Cancer Treat Rev. 2014;40:917; 5. TAGRISSO [package insert]; 2017.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019CYP = cytochrome P450; HER2 = HER2 = human epidermal growth factor receptor 2.

9

LUX-Lung 7: afatinib vs gefitinib as 1L treatment of patients with EGFR mutation-positive NSCLC: a phase 2B, open-label, randomised, controlled trial

First- and Second-Generation EGFR TKIs Are Not Equal: LUX-Lung 7

Afatinib(n=160)

Gefitinib(n=159)

Median, mo 11.0 10.9

HR (95% CI)P value

0.74 (0.57-0.95)0.0178

PFS

(%)

100

80

60

40

20

0

Time (mo)0 3 6 9 12 15 18 21 24 27 30 33 26 39 42 45 48 51

160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0

AfatinibGefitinib

27%

16%

16% 8%

73% 75%

69%

56%

66%

42%

0%

20%

40%

60%

80%

Res

pons

e R

ate

GefitinibAfatinib

P=0.002 P=0.150 P=0.003

No. at risk

17% 9% 27%

Corral et al. Ann Oncol. 2017;28(suppl 2):ii28.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019CI = confidence interval; HR = hazard ratio.

Total Del19 L858R

10

ARCHER 1050: Dacomitinib vs gefitinib as 1L treatment of patients with EGFR mutation-positive NSCLC: a phase 3, double-blind, randomised trial (excluding CNS metastases)

First- and Second-Generation EGFR TKIs Are Not Equal: ARCHER 1050

Daco (n=227) Gef (n=225)

Events, n (%) 136 (59.9%) 179 (79.6%)

Median PFS (95% Cl) 14.7 (11.1-16.6) 9.2 (9.1-11.0)

HR (95% Cl) 0.59 (0.47-0.74)P<0.0001

Phase 3, randomised, open-label study to evaluate dacomitinib as an alternative 1L treatment for patients with advanced NSCLC with an EGFR-activating mutation

PFS: Blinded Independent Review (ITT Population)

Dacomitinib225227

0 42363024181260

0.2

0.4

0.6

0.8

1.0

155154

69106

3473

720

16

00

00

Prob

abili

ty o

f PFS

Time (mo)

++ Censored

PFS rate30.6% vs 9.6%

Gefitinib

No. at risk

• Advanced NSCLC with EGFR-activating mutation(s)

• No prior systematic treatment of advanced NSCLC

• No CNS metastasis• No prior EGFR TKI or

other TKI• ECOG PS 0, 1

Dacomitinib45 mg PO QD

(n=227)

Gefitinib250 mg PO QD

(n=225)

Primary endpointPFS by blinded

independent review• ≥256 PFS events• PFS HR ≤0.667

(50%↑)• 90% power• 1-sided ɑ=0.025• mPFS: 14.3 vs

9.5 months

R 1:1(N=452)

1. ClinicalTrials gov. https://clinicaltrials.gov/ct2/show/NCT01774721. Accessed April 1, 2019; 2. Mok et al. J Clin Oncol. 2017;35(suppl 18):LBA9007; 3. Wu et al. Lancet Oncol. 2017;18:1454.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group performance status; ITT = intent-to-treat; mPFS = median progression-free survival; PO = orally; QD = once daily; R = randomised.

11

FLAURA: Osimertinib vs erlotinib or gefitinib as 1L treatment of patients withEGFR mutation-positive NSCLC: a phase 3, double-blind, randomised trial

First- and Third-Generation EGFR TKIs Are Not Equal: FLAURA

Primary Endpoint: PFS (by Investigator Assessment)

Data cutoff 12 Jun 2017. Tick marks indicate censored data. For statistical significance, P value of less than 0.0015, determined by O’Brien Planning approach, was required.Soria et al. N Engl J Med. 2018;378:113.


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First-, Second-, and Third-Generation EGFR TKIs Are Not Equal: Safety

LUX-Lung 71,2 ARCHER 10503 FLAURA4

Afatinib (n=160)

Gefitinib (n=159)

Dacomitinib (n=227)

Gefitinib (n=225)

Osimertinib (n=279)

First-gen TKI(n=277)

Treatment discontinuation rate 6% 6% 10% 7% 10% 14%

Most commongrade ≥3 AEs

Diarrhoea, 12%Rash/acne, 9%

Liver enzymeelevation, 9%

Rash/acne, 3%

Acne, 14%Diarrhoea, 8%

Paronychia, 7%

Liver enzyme elevation, 12%Dyspnoea, 3%

Diarrhoea, 2%Decreased

appetite, 2%

Rash/acne, 7%Liver enzyme

elevation, 12%

Second- or Third-Generation TKIs vs First-Generation TKIs

• Dose reduction of afatinib in LUX-Lung 7 reduced drug-related AEs without compromising efficacy5

1. Park et al. Lancet Oncol. 2016;17:577; 2. Paz-Ares et al. Ann Oncol. 2017;28:270; 3. Wu et al. Lancet Oncol. 2017;18:1454; 4. Soria et al. N Engl J Med. 2018;378:113; 5. Hirsh et al. J Clin Oncol. 2016;34(suppl 15):9046.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019AE = adverse event.

13



Evidence #1


Evidence #2



Evidence #5





14

• 155 EGFR-mutantNSCLC acquired resistance after TKI

• Molecular analyses on rebiopsy specimen

Molecular Mechanisms of Acquired Resistance to First- and Second-Generation EGFR TKIs

Yu et al. Clin Cancer Res. 2013;19:2240.

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019MET = mesenchymal-epithelial transition.

15

Proposed Algorithm for Use of Plasma Genotyping for EGFR T790M

Acquired resistanceto EGFR TKI

All patients undergo biopsy, FDA-approved FFPE assay for T790M

T790M+

T790M–

3rd-gen EGFR TKI

Chemotherapy

Acquired resistanceto EGFR TKI

FDA-approved plasma assay for T790M and sensitising mutations

T790M+

T790M–

Skip biopsy, start 3rd-gen EGFR TKI

Biopsy, FDA-approvedFFPE assay for T790M

T790M+

T790M–

3rd-gen EGFR TKI

Chemotherapy

A

B

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019FDA = US Food and Drug Administration; FFPE = formalin-fixed, paraffin-embedded.


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Biopsy or Plasma May Be Used to Determine EGFR T790M Status

Technique Sensitivity Optimal Application

Ther

ascr

een:

T79

0M D

etec

ted

>7%

Sanger sequencing1 >10% Tumour tissue

ctDNA will bedetected in thisrange

Pyrosequencing1 10% Tumour tissue

COLD-PCR and Pyro2 2% Tumour tissue

NGS1 2% Tumour tissue

Q-PCR1 1% Tumour tissue

ARMS1 0.10% Tumour tissue

COBAS, Therascreen3,4

(adapted for cDNA) 0.1% ctDNA

ddPCR5 0.01% ctDNA

1. Diaz and Bardelli. J Clin Oncol. 2014;32:579; 2. Milbury et al. Expert Rev Mol Diagn. 2011;11:159; 3. Kim et al. BioMed Res Int. 2018;2018:7392419; 4. How Kit et al. Hum Mutat. 2013;34:1568; 5. Oxnard et al. Clin Cancer Res. 2014;20:1698.


Adapted from Diaz and Bardelli.1ARMS = amplification-refractory mutation system; cDNA = complementary deoxyribonucleic acid; COLD-PCR = coamplification at lower denaturation temperature-polymerase chain reaction; ctDNA = circulating tumour DNA; ddPCR = Droplet Digital™ PCR; NGS = next-generation sequencing; Q-PCR = quantitative PCR.

17

Osimertinib Standard of Care for T790M+ Acquired Resistance to First- and Second-Generation EGFR TKIs: AURA3

Mok et al. N Engl J Med. 2017;376:629.

No. at riskOsimertinib 279 240 162 88 50 13 0Platinum/Pem 140 93 44 17 7 1 0

Osimertinib Platinum/Pem

Median PFS (mo)(95% Cl) 10.1 (8.3-12.3) 4.4 (4.2-5.6)

No. of Patients 279 140

BICR: PFS 11.0 months

Prob

abili

ty o

f PFS

Time (mo)0 3 6 9 12 15 18

0

0.2

0.4

0.6

0.8

1.0

HR for disease progression or death, 0.30 (95% CI, 0.23-0.41)

P<0.001

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019BICR = blinded independent central review.

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T790M+

≥50% of Patients Can Benefit From Sequential Therapy

1. Yang et al. J Clin Oncol. 2017;35:1288; 2 Wu et al. Oncotarget. 2016;7:10684;. 3. Hochmair et al. Target Oncol. 2019;14:75; 4. Tanaka et al. J Clin Oncol. 2018;36(suppl 15):e21173; 5. Sequist et al. Ann Oncol. 2017;28(suppl_2):ii28; 6. Yang et al. Lancet Oncol. 2015;16:141; 7. Jenkins et al. J Thorac Oncol. 2017;12:1247.

T790M+

2L

50%-70% of patients develop a T790M on afatinib1-4

The likelihood is even higher in patients with Del19 disease: ≈75%7

~80% of patients treated with afatinib 1L will receive a 2L therapy (depending on reimbursement system)5,6

≥50% of patients can benefit from a sequencing strategy

Benefit From Sequencing

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 20192L = second line.

19

Molecular Mechanisms of Acquired Resistance to 1L Osimertinib

1. Ramalingam et al. Ann Oncol. 2018;29(suppl 8). 2. Rudin. ESMO 2018. Discussant of Abstract LBA50.

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Treatment Sequence After Osimertinib Relies on a Chemotherapy-Based Regimen for the Vast Majority of Patients

2L Osimertinib After T790M-Driven Resistance to First-/Second-Generation

EGFR TKIs

1L Osimertinib vs First-Generation TKI

1. Mok et al. N Engl J Med. 2017;376:629; 2. Planchard et al. Clin Cancer Res. 2019 Jan 18. doi: 10.1158/1078-0432.CCR-18-3325. [Epub ahead of print]

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019FST = follistatin; PD-1 = programmed cell death protein 1; PD-l! = programmed death ligand 1.

Ongoing osimertinib treatment at time of data cut-off (n=166)Discontinued treatment (n=113)• Objective disease progression (n=77)• Adverse event (n=18)• Subject decision (n=9)• Other (n=8)• Severe protocol non-compliance (n=1)

Anti-cancer treatment post-discontinuation of osimeritinib (n=67)• Platinum-containing chemotherapy regimen (n=48)• Non-platinum-containing chemotherapy regimen (n=18)• Radiotherapy (n=17)• EGFR-TKI (n=9)• EGFR-TKI + non PD-1/PD-L1 (n=6)• PD-1/PD-L1 (n=4)

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Evidence #1


Evidence #2



Evidence #5





22

Treatment Sequences in EGFR-Mutant NSCLC After 1L EGFR TKI

T790M+ Osimertinib

T790M- Chemotherapy

Osimertinib Chemotherapy

First-/Second-Generation

TKI

Except if molecular target

Other

Chemotherapy

MET/HER2 inhibitor


TKI rechallenge?Chemotherapy?Immunotherapy



23


T790M+ Osimertinib

T790M- Chemotherapy


First-/second-generation

TKI


Other

Chemotherapy

MET/HER2 inhibitor





24

#1: OS of Patients With EGFR+ NSCLC Increased Even With Limited Access to Subsequent Osimertinib

1. Yang et al. Lancet Oncol. 2015;16:141. 2. Soria et al. N Engl J Med. 2018;378:113.

LUX-Lung 31a

No. at risk: Afatinib 203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0Cis/Pem 104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0

Estim

ated

OS

(Pro

babi

lity)

aFew patients in the LUX-Lung 3 trial were treated subsequently with osimertinib.NC = not calculable. ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019

0.0120 3 6 15 18 27 30 33

0.2

0.4

0.6

0.8

1.0

9 21 24 36 39 42 45 48 51

Time of OS (mo)

AfatinibCis/Pem

31.6 mo

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#2: Overall Survival May Not Reflect Actual Duration of EGFR TKI Treatment

1. Park et al. JAMA Oncol. 2016;2:305; 2. Mok et al. N Engl J Med. 2017;376:629.

Afatinib/Gefitinib: LUX-Lung 71 Osimertinib: AURA 32

• 35% of patients with afatinib• 30% of patients with gefitinib• Median duration

− 2.7 mo with afatinib− 2.0 mo with gefitinib

• 64% of patients• Median duration of 4.1 mo

Allocated to osimertinib (n=279) (intent-to-treat)• Received allocated treatment (n=279) (safety analysis set)• Did not receive allocated treatment (n=0)

Ongoing osimertinib treatment at time of data cutoff (n=166)Discontinued treatment (n=113)• Objective disease progression (n=77)• Adverse event (n=18)• Subject decision (n=9)• Other (n=8)• Severe protocol noncompliance (n=1)

Discontinued treatment (n=140)• Disease progression (n=111)• Worsening of underlying cancer

disease (n=3)• Adverse event (n=18)• Noncompliant with protocol (n=1)• Lost to follow-up (n=1)• Refused to continue taking trial

medication (n=4)• Other reasons (n=3)

Assigned to afatinib (n=160)Treated (n=160)

149 Discontinued treatment (n=149)• Disease progression (n=119)• Worsening of underlying cancer

disease (n=3)• Adverse event (n=17)• Noncompliant with protocol (n=1)• Lost to follow-up (n=0)• Refused to continue taking trial

medication (n=3)• Other reasons (n=5)

Assigned to gefitinib (n=159)Treated (n=159)


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T790M+ Osimertinib

T790M- Chemotherapy


First-/second-generation

TKI


Other

Chemotherapy

MET/HER2 inhibitor





27

#3: Prolonged Duration of EGFR TKI Treatment With Afatinib Followed By Osimertinib

1. Hochmair M et al. Future Oncol. 2018;14:2861. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03370770. Accessed March 31, 2019.


GioTag: Real-world studya on sequential therapy in patients with EGFR mutation–positive advanced NSCLC

Time on Treatmentb for the Sequence Afatinib-Osimertinib Survival Rates (From Start of Afatinib)

a RCTs are designed to assess the efficacy and safety of study drugs under well-defined conditions and in selected patient populations. In contrast, real-world studies include everyday patients with characteristics which might preclude their participation in a RCT. Real-world studies are complementary to RCTs, and explore patient outcomes in populations more representative of clinical practice than perspective clinical trials. Real-world studies are essential for capturing clinically relevant data at the point of care, and providing clinically meaningful insights which can be applied to patient care.

bTime on treatment defined from the start of 1L treatment until the end of 2L treatment or death date by any cause.RCT = randomised controlled trial.

No. at riskAfa-Osi 204 204 179 150 106 43 25 14 3 1 1

Time (months)0 12 30 42 48 606 2418 36 54

48% are still on treatment

Trea

tmen

t pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0

Afatinib followed by osimertinib (N=204)

Events 106

Median time (mo), 90% CI 27.6(25.9-31.3)

Time (months)

00 12 30 42 48 606 2418 36 54

No. at riskECOG 0-1 153 153 148 136 100 50 28 14 4 1 1

84%

Surv

ival

pro

babi

lity

(%)

100

80

60

40

20

ECOG 0-1 (n=153)

2-year survival rate 83.9%

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#4: FLAURA Data are Challenged When Looking at the Treatment Sequences

Planchard et al. Clin Cancer Res. 2019 Jan 18. doi: 10.1158/1078-0432.CCR-18-3325. [Epub ahead of print]

FLAURA Postprogression Endpoints PFS2

0.0120 3 6 15 18 27

0.2

0.4

0.6

0.8

1.0

9 21 24

Time From Randomisation (mo)

Prob

abili

ty o

f PFS

No. at risk:Osimertinib 223279 272 262 188 100 0242 37 11Erlotinib orGefitinib

194277 260 244 147 72 0211 26 9

Median PFS2, mo (95% CI)

Study treatment (1L) 1st subsequent therapy (2L)

PFS

PFS2RAN

DO

MIS

ATIO

N 1 23 3

Osimertinib NC (23.7, NC)Erlotinib or 20.0 (18.2, NC)GefitinibHR 0.58 (95% CI 0.44, 0.78) P<0.001

ELCC 2019 Congress, Geneva, Switzerland, 10-13 April 2019PFS2 = second progression-free survival.

29

Ongoing Studies Evaluating Sequencing Strategies for EGFR TKIsAPPLE: randomised, open-label, phase 2 study evaluating the

strategy for sequencing gefitinib and osimertinib1AFAOSI: phase 2, single-arm, Japanese study evaluating

the strategy for intercalating osimertinib and afatinib2

Osimertinib Afatinib Osimertinib Afatinib ….

1 cycle (8 wk × 2)

Osimertinib until

RECIST PD

Osimertinib until

RECIST PD

Advanced NSCLC Common

mEGFRTreatment-Naïve

PS 0-2 Stable BM

Stratification: • Del19 versus

L858R• Initial T790M +/-• BM +/-

R1:1:1

Osimertinib until RECIST PD

n=156

ARM A

ARM B

Gefitiniba until cfDNA PD (T790M+)

ARM C Gefitiniba

Until RECIST PD

Rebiopsy at RECIST PD

(optional)


(optional)


(optional)

Primary Endpoint: PFS rate at 18 months

1. Remon et al. Clin Lung Cancer. 2017;18:583; 2. NIPH Clinical Trails Search. https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs051180009 Accessed April 10 2019.


(cfDNA using COBAS every 4 weeks and CT scan of the brain-thorax-abdomen every 8 weeks all arms)aIn case of RECIST progression without T790M+, patients will be switched BM = bone marrow; cfDNA = circulating free DNA; ICT = induction chemotherapy.

• This study has been fully recruited

https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs051180009

30



Evidence #1


Evidence #2



Evidence #5





31

CNS disease and progressionClinicalfactors

How to Optimise Sequence?


32

FLAURA: No Difference of Benefit in Patients With or Without CNS Metastases

Soria et al. N Engl J Med. 2018;378:113.

No stratification. No systematic imaging.

CNS progression events occurred in 17 (6%) vs 42 (15%) patients receiving osimertinib vs erlotinib or gefitinib (all patients)

With Known CNS Metastases (n=116) Without CNS metastases (n=440)

Osimertinib Erlotinib or Gefitinib

Median PFS (95% CI), mo 19.1 (15.2, 23.5) 10.9 (9.6, 12.3)

No. at risk:Osimertinib 3253 51 40 22 9 037 4 1

Erlotinib or Gefitinib 2463 57 40 13 6 024 2 1

Osimertinib Erlotinib or Gefitinib

Median PFS (95% CI), mo 15.2 (12.1, 24.4) 9.6 (7.0, 12.4)

0.0120 3 6 15 18 27

0.2

0.4

0.6

0.8

1.0

9 21 24


Prob

abili

ty o

f PFS

HR 0.47 (95% CI 0.30, 0.74); P=0.0009

0.0120 3 6 15 18 27

0.2

0.4

0.6

0.8

1.0

9 21 24


Prob

abili

ty o

f PFS

146226 211 193 117 62 0173 22 383214 182 157 65 31 0119 8 1

HR 0.36 (95% CI 0.36, 0.59); P<0.0001


33

How to Optimise Sequence

CNS disease and progression

Optimisationof treatments

AntiangiogenicsChemotherapy

Clinicalfactors


34

How to Optimise Sequence

CNS disease and progression

Optimisationof treatments

AntiangiogenicsChemotherapy

Understandingof biology Resistance mechanisms to sequencing vs osimertinib

Clinicalfactors


35

Multimodal Heterogeneity of EGFR+ NSCLC Along Treatment Sequence

1. Lee et al. J Clin Oncol. 2017;35:3065; 2. Blakely et al. Nat Genet. 2017;49:1693.

• Longitudinal and volumetric history along sequence1

• Spatial history along sequence2


36

Hypothetical Changes in Clonal Composition Over Time Following Treatment With Sequential EGFR TKIs

Third-generation EGFR TKI (eg, osimertinib)


?

First-generation EGFR TKI (eg, erlotinib,

gefitinib)

Second-generation EGFR TKI (eg, afatinib,

dacomitinib)


Adapted from Kohsaka et al. Future Oncol. 2019;15:637.


Met amplification

Other mutation

EGFR common (Del19/L858R) mutation

Minor mutation

Compound mutation

EGFR T790M mutation

37



Evidence #1


Evidence #2



Evidence #5





38

• Blakely et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 2017;49:1693

• ClinicalTrials gov. ARCHER1050: A Study of Dacomitinib vs. Gefitinib in 1st-Line Treatment Of Advanced NSCLC. (ARCHER1050). https://clinicaltrials.gov/ct2/show/NCT01774721. Accessed April 1, 2019

• ClinicalTrials.gov. Afatinib Osimertinib Sequencing NIS. https://clinicaltrials.gov/ct2/show/NCT03370770. Accessed March 31, 2019.

• Corral et al. Afatinib versus gefitinibin patients with EGFR mutation-positive (EGFRm+) NSCLC: updated overall survival data from the Phase IIbtrial LUX-Lung 7. Ann Oncol. 2017;28(suppl 2):ii28.

• Cross et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046

• Diaz and Bardelli. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32:579

• Fukuoka et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).J Clin Oncol. 2011;29:2866

• Furuya et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. J Clin Oncol. 2018;36(suppl):9006.

• Girard. Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when? Future Oncol. 2018;14:1117.

• Hirsch et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389:299

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