il trattamento di prima linea nel paziente con mutazione egfr vanesa gregorc thoracic oncology and...

Il trattamento di prima linea nel paziente con mutazione EGFR

Vanesa Gregorc Thoracic Oncology and Melanoma area coordinator

IRCCS Ospedale San RaffaeleMilano

Who should be tested for EGFR mutations?

• Non-squamous NSCLC• NSCLC NOS• Adenosquamous NSCLC• Squamous cell carcinoma if

– Low smoking exposure– Young age

Smoking exposure and EGFR mutations

Pham et al, JCO 2006

Pack-year %EGFR+

0-15

>=16 0-10

30-51

At half of LCMC sites, multiplexed testing for all mutations is now routine practice in their pathology departments

(ASCO 2011)

- 16 US cancer centers

- Test 10 driver mutations in 1000 lung adenocarcinomas

Lung Cancer Consortium Mutation

EGFR mutations

Sequist et al, JCO 2007

Test EGFR su DNA circolante

Douillard et al, Br J Cancer 2013

Quale EGFR-TKI in EGFR mutati? Indicazioni AIFA

GefitinibIndicato in qualunque linea in EGFR mutati

ErlotinibIndicato in I linea negli EGFR mutati;

II-III linea indipendentemente da EGFR

AfatinibIndicato in I linea negli EGFR mutati

1st line: EGFR-TKIs vs CTAuthor Study N (EGFR

mut. +)EGFR-TKI Median PFS*

(months)PFS* HR

Mok IPASS 261 Gefitinib 9.8 vs. 6.4 0.48

Lee First-SIGNAL 42 Gefitinib 8.4 vs. 6.7 0.54

Mitsudomi WJTOG 3405 177 Gefitinib 9.2 vs. 6.3 0.49

Maemondo NEJGSG002 228 Gefitinib 10.8 vs. 5.4 0.30

Zhou OPTIMAL 154 Erlotinib 13.1 vs. 4.6 0.16

Rosell EURTAC 175 Erlotinib 9.7 vs. 5.2 0.37

Yang LUX-Lung 3 345 Afatinib 11.1 vs. 6.9 0.58

Wu LUX-Lung 6 364 Afatinib 11.0 vs 5.6 0.28

Shi CONVINCE 296 Icotinib NA NA

*Primary endpoint

MTE12: Therapy for Driver Mutation Positive Advanced NSCLC – Federico Cappuzzo

PFS with TKIs better for del19 than L858R

Lee et al. JCO 2015

Del19 HR: 0.24 L858R HR: 0.48

p for interaction < 0.001

PFS

Lancet Oncology, Feb 2015

Del19Common Mutations

LUX-Lung 3: OS in Common Mutations and Del19 in Asian and Whole Population

Time (months)

203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0149 148 141 135 126 121 106 98 91 81 77 67 47 41 29 9 1 075 70 66 61 57 51 45 42 40 37 31 27 20 17 10 5 1 0

AfatinibCis/Pem

No. of patients

AfatinibCis/Pem

Time (months)

Estim

ated

OS

prob

abili

ty

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

1.0

0.8

0.6

0.4

0.2

0

112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 057 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 082 81 78 75 70 68 59 56 52 45 43 37 27 24 18 6 1 041 40 37 33 31 26 22 20 18 17 15 11 7 5 1 1 0 0

AfatinibPem/Cis

No. of patients

AfatinibCis/Pem

Afatinib (All)

Afatinib (Asian)

Cis/Pem (All)

Cis/Pem (Asian)

Time (months)

Estim

ated

OS

prob

abili

ty

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Afatinib (All)

Afatinib (Asian)

Cis/Pem (All)

Cis/Pem (Asian)

PFS in overall population

LUX-Lung 3

(All)

LUX-Lung 3(Asian population)

Afatinib n=112

Cis/Pem

n=57

Afatinib n=82

Cis/Pemn=41

Median, months

33.3 21.1 33.3 22.9

HR (95%CI) P value

0.54 (0.36–0.79), P=0.0015

0.57 (0.36–0.90)P=0.0153

PFS in overall population

LUX-Lung 3

(All)

LUX-Lung 3(Asian population)

Afatinib n=203

Cis/Pem

n=104

Afatinib n=149

Cis/Pem n=75

Median, months

31.6 28.2 31.7 29.1

HR (95%CI) P value

0.78 (0.58–1.06)P=0.1090

0.82 (0.57–1.17)P=0.2771

Sequist et al. CMSTO 2014. Oral presentation. Abstract 3341.

Kato T et al., ISPOR 2015; PCN40

HR for OS in del19

HR for OS in L858R

75%

53%

52%

Adapted from West, ASCO 2014

Crossover from CT to TKI

95%

76%

Kato T et al., ISPOR 2015; PCN40

HR for OS in L858R

Outcome in caso di mutazioni non comuni

Yang et al, WCLC 2013

Survey (n = 562, 10 countries):first-line choice in EGFR mutated

Spicer et al, ELCC 2015

OPEN Questions:EGFR-TKI and OBD vs MTD,

side effects, dosage, drug interaction, drug reductions

Skin Rash:Gefitinib: 49-85%Erlotinib: 73-79%Afatinib: 80-89%

Stomatitis:Erlonib: 13%

Gefitinib: 9-40%Afatinib: 50-72%

Paronichia:Erlonib: 4%

Gefitinib: 13-32%Afatinib: 32-56%

Anorexia:Afatinib: 10-20%Gefitinib: 14-44%

Erlotinib: 31%

Fatigue:Afatinib: 10-17%Gefitinib: 10-39%Erlotinib: 5-57%

Modified from Landi L , Expert Opin Pharmacother 2014

Diarrhoea:Erlonib: 25-57%

Gefitinib: 34-54%Afatinib: 88-95%

Vomiting:Erlonib: 1%

Afatinib: 9-17% Gefitinib: 12-19%Transaminitis:

Erlotinib: 6%Afatinib: 11%

Gefitinib: 40-60%

Afatinib Plasma Levels in Patients Who Dose Reduced and Those Who Remained on Afatinib 40 mg

• Dose reduction was more likely in patients with higher plasma concentrations

• Geometric mean plasma concentrations

– 24.4 ng/mL after dose reduction to 30 mg ≥4 days previously (n=38)

– 23.7 ng/mL in patients who remained on 40 mg (n=126)

23

: patients who remained on 40 mg until C3V1 (n=126); , patients who dose reduced to 30 mg before C3V1 (n=38; only 10 of these patients had valid trough concentrations on 40 mg afatinib at C2V1 [the rest had either no PK sampling due to dose interruption, were already on 30 mg afatinib or were excluded due to invalid sampling])

140

120

100

80

60

40

20

0

Trou

gh p

lasm

a co

ncen

trati

ons

(ng/

mL)

C3V1 (Day 43)

40 mg(n=126)

30 mg(n=38)

C2V1 (Day 22)

40 mg(n=122)

40 mg(n=10)

Individual data with median and 25th/75th percentiles

10th/90th percentiles

Datapoints outside percentiles

Yang et al. ASCO 2015 #8073

PFS in Patients Who Had or Had Not Dose Reductions Within the First 6 Months

Median PFS was similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily

24

No. at risk<40 mg in first 6 months≥40 mg for first 6 months

105124

8793

7576

5862

4136

2624

1516

64

21

00

Time (months)

1.0

0.6

0.4

0.2

0

Estim

ated

PFS

pro

babi

lity

0 3 6 9 12 15 18 21 24 27

0.8

CI, confidence interval; HR, hazard ratioYang et al. ASCO 2015 #8073

PFS in overall population

<40 mg in first 6 months≥40 mg in first 6 months

Pharmacokinetic parameters for EGFR TKI

Parameter Reversible EGFR - TKI Irreversible EGFR - TKI

Gefitinib Erlotinib Afatinib DacomitinibUsual starting dose

(mg/day) 250 150 (100) 40 (50/30/20) 45

T max (h) 3-7 4 2-5 ≈ 6Vol distr. (L) 1700 232 2870 2600

Protein binding (%) ≈ 90 ≈ 95 ≈ 95 97-98

t ½ (h) 48 -72 36 37 72Metabolism Extensive Extensive Minimal Extensive

Renal excretion 4% 9% < 5% 3%Accumulation 1.5 to ≈4 fold 1.5 to ≈5.4fold 2 to 3 fold ≈ 6 fold

Gastric PH effect Reduces abs Reduce abs Not known Reduces absFood effect Not relevant AUC 34-66% AUC 39% Not relevant

Drug interaction CYP CYP P-gp transp Potent CYP 2D6 sub

Afatinib è indicato  nel trattamento di pazienti adulti naïve agli inibitori tirosinchinasici del recettore del fattore di crescita dell’epidermide (EGFR-TKI) con carcinoma polmonare non a piccole cellule (NSCLC)

localmente avanzato o metastatico con mutazione(i) attivante(i) l’EGFR.Adapted from S. Peters et al. Cancer Treatments review 40(2014) 917-926

OPEN Questions:

Direct comparisons?

• Patients with– Advanced lung adenocarcinoma– Documented common EGFR mutations (del19 or L858R)– First line (no prior treatment)

• N = 264

Afatinib 40 mg

Randomization

Gefitinib 250 mg

Primary endpoint: PFS and disease control rate at 12 months

ClinicalTrials.gov. NCT01466660.

LUX Lung 7: phase IIb trial of afatinib vs gefitinib

• Patients with– Advanced NSCLC– Documented common EGFR mutations (del19 or L858R ± T790M)– First line (no prior treatment)

• N = 440

Dacomitinib 45 mg

Randomization

Gefitinib 250 mg

Primary endpoint: PFS

ClinicalTrials.gov. NCT01774721

ARCHER 1050: phase III trial of dacomitinib vs gefitinib

OPEN Questions:EGFR-TKIS clinical strategy?

Del19/L858R: first line TKI and post progression treatment

Gefitinib, erlotinib AZD9291, Rociletinib

Afatinib

PFS (months)

9-11 8-9

10-13

?

T790M+(60%)

?

Del19/L858R: first line TKI and post progression treatment

AZD9291, Rociletinib

PFS (months)

?

?

Randomized trials of 3rd vs 1st generation TKI in 1L are ongoing

OPEN Questions:T790M in TKI-naïve patients

EURTAC: PFS according to T790M and treatment

Costa et al. Clinical Cancer Research 2014

9.7 months

6.0 months

T790M detected in 65.2% of patient

T790M in TKI-naïve patients

• 20 T790M TKI-naïve patients (2% of EGFR-mutant tumors)– 16/20 concurrent L858R– 4/20 concurrent exon 19 deletion

Yu et al. Ann Oncol 2014

PFS under TKIs inT790M+ patients

Yu et al. Ann Oncol 2014

AfatinibDacomitinib

GefitinibErlotinib

EGFRm EGFRm

T790M

T790M

WtWt

1x

10x

100x

Rel

ativ

e IC

50

Adapted from Oxnard

Irreversible TKIs and T790M: small therapeutic window

Ideal T790M inhibitor

EGFRm

T790M

Wt

OPEN Questions:EGFR-TKIS resistanceEGFR-Tkis & future?

A001L858R

A006Ex 19 del

A014L858R

A021L858R

A017L858R

A027Ex 19 del

A022Ex 20 ins

A028L858R

TP53EGFR EGFR

PTENMAP3K19

TP53EGFR

ARID1BTP53EGFR

TP53EGFR EGFR EGFR EGFR

Private

Shared

Trunk

100

No

of

mu

tati

on

s

50

EGFR mutations are early events

Tan, WLCC 2015

ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO European Cancer Congress, September

2015

Infiammation+/-IMMS

angiogenesis

Future perspectivesNeed for a deepened understanding of mechanisms of primary resistance to TKIs in EGFR mutated patients•Mutation-based mechanisms:

• De novo T790M• PIK3CA mutations (2%)• PTEN loss (5%)

•Microenvironment mediated cancer progression:• Angiogenesis: VEGFR, FGFR (nintedanib, ramucirumab)• Paracrine signalling: HGF (ficlatuzumab)• Immune escape: PD-1/PDL-1 (immunotherapy)

Erlotinib +/-ramucirumab

Ongoing studies

RELAY (NCT02411448)Erlotinib in Combination with Ramucirumab or Placebo in PreviouslyUntreated Patients with EGFR Mutation-Positive Metastatic NSCLC

PROSE study: VeriStrat proteomic algorithm as a prognostic and predictive test

VeriStrat proteomic classifier is prognostic for OS and PFS•OS: HR Poor vs Good 2.50 [95% CI 1.88–3.31]; p<0.0001•PFS: HR Poor vs Good 1.75 [95% CI 1.34–2.29]; p<0.0001

43

• Good classification group had no significant OS difference between treatment arms: HR Erl vs CT 1.06 [95% CI 0.77–1.46], p=0.714.

• Poor classification group had significantly shorter OS on erlotinib than on chemotherapy: HR Erl vs CT 1.72 [95% CI 1.08–2.74], p=0.022.

Gregorc et al. Lancet Oncol.2014 Jun;15(7):713-21

44Mok et al. Ann Oncol. 2012;23(Suppl 9):ix391:Abstract 1198PMok et al. Ann Oncol, 25 (Suppl. 4) (2014), pp. 58–84 (Abstract 205P)

Good

Poor

Phase II study of Ficlatuzumab+Gefitinib vs Gefitinib+placeboVeriStrat retrospective analysis

Erlotinib +/-Ficlatuzumab

Ongoing studies

RELAY (NCT02411448)Erlotinib in Combination with Ramucirumab or Placebo in PreviouslyUntreated Patients with EGFR Mutation-Positive Metastatic NSCLC

FOCAL (NCT02318368)Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib

in Subjects with Previously Untreated Metastatic, EGFR-mutated NSCLC and BDX004 Positive Label

AZD9291 +/-MEDI4736

Ongoing studies

RELAY (NCT02411448)Erlotinib in Combination with Ramucirumab or Placebo in PreviouslyUntreated Patients with EGFR Mutation-Positive Metastatic NSCLC

CAURAL (NCT02454933)Phase III Study of AZD9291 in Combination with MEDI4736 (anti PD-L1

mAb)versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic EGFR T790M positive NSCLC who have received Prior EGFR

TKIs

FOCAL (NCT02318368)Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib

in Subjects with Previously Untreated Metastatic, EGFR-mutated NSCLC and BDX004 Positive Label

AfatinibGefitinib/Erlotinib

L858R Gefitinib/Erlotinib/Afatinib Or CT followed by EGFR-TKis

Uncommon EGFRm

Afatinib/Erlotinib/Gefitinib

-Drug interaction-Patient compliance

(ECOG PS, age, education..)

-Liver function

EGFR-mutant NSCLC

Del 19

 Database Center NetDatabase NSCLC NavigatorDatabase Clinical Trial ongoing

Forum di discussioneLink a siti utili

www.lucenetwork.it

alessandro.urbani@programmaergo.com