Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MD Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center.

Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat?

Vincent A Miller, MDThoracic Oncology Service

Memorial Sloan-Kettering Cancer Center

Consultant

ArQule, Boehringer Ingelheim Pharmaceuticals Inc, Genentech BioOncology, Lilly USA LLC, OSI Pharmaceuticals Inc, Sanofi

Grant/ResearchBoehringer Ingelheim Pharmaceuticals Inc, Lilly USA LLC, Sanofi

Disclosure Slide

Background

• Patients with CML and GIST have a high rate of response to treatment with imatinib.

• These patients commonly acquire resistance after an initial response.

• There are a small number of conserved changes in the BCR-ABL tyrosine kinase domain which confer resistance in vivo.

• Other patients with acquired resistance have amplification of the BCR-ABL gene.

• Virtually all patients with response to gefitinib or erlotinib eventually have progression of disease.

21M 23M 25M

Pre-rx 4M 19M

bx

Acquired Resistance to TKI

Clinical Definition of Acquired Resistance to EGFR TKIs in Lung Adenocarcinoma

• Prior treatment with single agent TKI• Either:

– EGFR ex 19 del, L858R, G719X, L861Q– PR or CR with TKI or SD lasting ≥6 months

• PD by RECIST or WHO in previous 30 days• No therapy after TKI before start of new agent• “Washout” after stopping TKI not >5 half-lives of the

TKI (14 days for gefitinib or erlotinib)• Obtain baseline scan on day 1

Jackman J Clin Oncol 2009

Treatment RR (%) Reference

EGFR TKI + everolimus 0 Riely et al CCR ‘07

Everolimus 2 Soria et al Ann Oncol ‘09

Neratinib 3 Sequist et al JCO ‘10

IPI-504 4 Sequist et al JCO ‘10

Erlotinib + cetuximab 0 Janjigian et al CCR ‘11

Dasatinib/erlotinib + dasatinib 0/0 Johnson et al JTO in press

XL647 4 Miller et al PASCO ‘08

PF00299804 5 Campbell et al PASCO ‘10

PF00299804 15* (only 2 pts w/ EGFR mt) Park et al PASCO ‘10

Erlotinib + XL184 8 (only 1 pt w/ EGFR mt) Wakelee et al PASCO ‘10

Afatinib/placebo 7/0.5 Miller et al PESMO ‘10

* The number of patients enrolled into the trial with AR to EGFR TKIs was low.

Trials to Overcome Acquired Resistance

T790M in Acquired Resistance

• Acquired exon 20 mutation found in >50% of pts with acquired resistance to TKI

• Increases relative affinity of mutant EGFR for ATP, may also cause steric hindrance

• Less commonly detected in CNS, thought to be due to poor CNS penetrance of TKI

Overall Survival from Start of TKI100

80

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000 5050 100100 150150

Survival of TKI_OS: Survival proportionsSurvival of TKI_OS: Survival proportions

HR 0.46, p = 0.006HR 0.46, p = 0.006

Median OS T790M-positive = 47 monthsMedian OS T790M-negative = 26 monthsMedian OS T790M-positive = 47 monthsMedian OS T790M-negative = 26 months

TKI_OSTKI_OS

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Courtesy of VA Miller. Courtesy of VA Miller.

Survival from Progressive Disease100

80

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0

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000 2020 6060 8080

Survival of PPS: Survival proportionsSurvival of PPS: Survival proportions

HR 0.59, p = 0.057HR 0.59, p = 0.057

Post-PD survival T790M-positive = 22 monthsPost-PD survival T790M-negative = 14 monthsPost-PD survival T790M-positive = 22 monthsPost-PD survival T790M-negative = 14 months

PPSPPS

Per

cen

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surv

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PPS_t790M

PPS_neg

PPS_t790M

PPS_neg

Courtesy of VA Miller. Courtesy of VA Miller.

4040

T790M as a Biomarker

T790M-typeresistance

– Longer survival– Later metastases– Indolent growth

– Sensitivity to 2nd-line EGFR inhibitors?

Non-T790M-typeresistance

– Poorer survival– Earlier metastases– More aggressive?

– Needs mechanisms better elucidated and alternate therapies?

EGFR - Cys773

HER2 - Cys805

Solca F et al. 17th EORTC-NCI-AACR Symposium on “Molecular Targets and Cancer Therapeutics” Philadelphia, PA, USA, November 14 – 18, 2005.

N

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Afatinib (BIBW 2992) — Irreversible Dual EGFR/HER2 Inhibitor• Anilino quinazoline derivative • Activity versus T790M (100 nM)• Binds covalently to Cys773 of the EGFR and Cys805 of HER2

LUX-Lung 1: Trial Design

Randomization 2:1(Double blind)

Oral afatinib 50 mg once daily plus BSC

Oral placebo once daily plus BSC

Primary endpoint: Overall survival (OS)

Secondary: PFS, RECIST response, QoL (LC13 & C30), safety

• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter• Exploratory biomarkers:

Archival tissue testing for EGFR mutations (optional; central lab)Serum EGFR mutational analysis (all patients)

• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter• Exploratory biomarkers:

Archival tissue testing for EGFR mutations (optional; central lab)Serum EGFR mutational analysis (all patients)

Patients with:• Adenocarcinoma of the lung • Stage IIIB/IV • Progressed after one or two lines of chemotherapy (incl one platinum-based regimen)

and ≥12 weeks of treatment with erlotinib or gefitinib• ECOG 0–2

N = 585

PFS by Independent Review

Placebo, PFS events = 133, median = 1.1 months (95% CI: 0.95-1.68)

Afatinib, PFS events = 275, median = 3.3 months (95% CI: 2.79-4.40)Hazard ratio (95% CI) = 0.38 (0.306, 0.475)Log-rank test p-value <0.0001

PFS time since randomization (months)

Est

imat

ed P

FS

pro

babi

lity

Number at riskNumber at risk

195195 26 26 4 4 2 2390390 152 152 65 65 16 16 9 9 3 3195195 26 26 4 4 2 2390390 152 152 65 65 16 16 9 9 3 3

00 33 66 99 1212 1515 1818

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.

Primary Analysis: Overall Survival

Placebo, deaths = 114 (58.5%), median = 11.96 months (95% CI: 10.15-14.26)Afatinib, deaths = 244 (62.6%), median = 10.78 months (95% CI: 9.95-11.99)Hazard ratio (afatinib vs placebo) = 1.077 (0.862, 1.346)Log-rank test p-value (one-sided) = 0.7428

Time to death since randomization (months)

Est

imat

ed s

urvi

val p

roba

bilit

y

Number at riskNumber at risk

195195 169169 142142 112 112 65 65 33 33 18 18 5 5390390 344344 283 283 217 217 122 122 69 69 32 32 12 12

00 33 66 99 1212 1515 2424

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

1818 2121

Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.

Drug L858R L858R + T790M T790M

Remove dox Response (6) Response (9) Response (5)

Placebo No response (3) No response (6) No response (2)

Erlotinib Response (12) No response (6) No response (5)

Pemetrexed n/a No response (4) n/a

Paclitaxel n/a No response (5) n/a

Cetuximab Response (6) No response (7) No response (2)

Erloti/cetux n/a No response (4) n/a

BIBW 2992 Response (4) No response (6) n/a

BIBW/cetux n/a Response! (8) n/a

(number in parentheses = number of mice treated and assessed)

Summary – HOPP Lab Animal Studies

Hypothesis

We hypothesized that the combination of afatinib and cetuximab would overcome acquired resistance to erlotinib or gefitinib in patients with non-small cell lung cancer (NSCLC)

Methods: Study Design• Phase Ib, open-label, multicenter trial in the US and the

Netherlands • Primary objective: Maximum tolerated dose (MTD) and

recommended Phase II dose (RPIID) for afatinib and cetuximab in patients with acquired resistance to erlotinib and gefitinib

• Primary endpoint:– Occurrence of dose-limiting toxicity (DLT)

• Secondary endpoints include:– Safety as assessed by National Cancer Institute (NCI) Common

Terminology Criteria for Adverse Events (CTCAE) grading system

– Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed at weeks 4, 8 and 12, and every 8 weeks thereafter

Methods

• Definitions of DLTs (CTCAE V3):• Grade ≥2 decrease in cardiac left ventricular function• Grade ≥2 diarrhea lasting for ≥7days, despite anti-diarrheal

therapy• Grade ≥3 rash or nausea/vomiting despite medical management• Grade ≥3 fatigue lasting for ≥7 days• Grade 3 or 4 hypomagnesemia with clinically significant

sequelae• All other toxicities of CTCAE Grade ≥3 (except alopecia and

allergic reaction) leading to an interruption of afatinib/cetuximab for ≥14 days until recovery

Expansion cohort part

MTD cohort expandedup to 80 EGFR mutation-

possible patients:40 T790M-positive and

40 T790M-negative

NSCLC withEGFR mutation

AND

Stable disease(SD) ≥6 months on erlotinib/gefitinib

OR

Partial orcomplete responseto erlotinib/gefitinib

Diseaseprogression

Stop erlotinib/gefitinib for≥72 hours

Dose escalation schema 3-6 patients per cohort

Afatinib PO daily + escalating doses of

intravenous (IV) cetuximab q 2 weeks

Dose levels starting at: afatinib 40 mg +

cetuximab 250 mg/m2

Predefined maximum dose: afatinib 40 mg +

cetuximab 500 mg/m2

Study Schema

1 EGFR G719X, exon 19 deletion, L858R, L861Q mandated in MTD expansion cohort

Patient EligibilityInclusion criteria:• Pathologically confirmed NSCLC • Presence of EGFR drug-sensitizing

mutations1 or RECIST response, or SD ≥6 months

• Systemic progression of disease on continuous treatment with erlotinib or gefitinib within 30 days

• No systemic therapy between cessation of gefitinib/erlotinib and initiation of the study treatment

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

• Age ≥18 years

Exclusion criteria:

• Prior treatment with EGFR targeting antibodies

• Prior severe infusion reaction to a monoclonal antibody

• Patients with disease progression only in the central nervous system

• Symptomatic brain metastases

Patient Characteristics

Afatinib 40 mg

TotalCetuximab250 mg/m2

Cetuximab500 mg/m2

n (%) 4 (8) 47 (92) 51

Median age, years (range) 63 (49–76) 61 (41–82) 61 (41–82)

Women, n (%) 1 (25) 36 (77) 37 (73)

Ethnicity: White/Black/Asian/American Indian, % 75/0/25/0 83/4/13/0 82/4/14/0

Baseline ECOG 0/1/2, % 25/75/0 21/75/4 22/75/4

Median time on erlotinib/gefitinib, months 10 25 24

Prior chemotherapy, n (%) 3 (75) 36 (77) 39 (77)

T790M-positive*, n (%) — 27 (57) 27 (53)

T790M-negative*, n (%) 2 (50) 15 (32) 17 (33)

EGFR deletion 19, n (%) 2 (50) 27 (58) 29 (57)

EGFR L858R, n (%) 1 (25) 17 (36) 18 (35)

Unknown/other, n (%) 2 (50) 5 (11) 7 (14)

* Ongoing trial – T790M status not available in all patients

• Dose cohorts tested in the dose escalation:– Afatinib 40 mg + 250 mg/m2 cetuximab (n = 4)– Afatinib 40 mg + 500 mg/m2 cetuximab (n = 6)– No DLT occurred in cycle 1 (28 days)

• Pre-defined MTD = RPIID:– Afatinib 40 mg daily + cetuximab 500 mg/m2

• 47 patients have been enrolled in the MTD expansion cohort to date out of 80 planned

– 12 (26%) patients discontinued due to progression of disease

– Six (13%) patients discontinued due to toxicity

Results

Afatinib + Cetuximab at MTD: Responses by Mutation

T790M+ T790M- No mutation Uninformative70605040302010

0-10-20-30-40-50-60-70-80-90

-1000 4 8 12 16 20 24 28 32 36 40 44 48

Patient index sorted by maximum % decrease

Max

imum

per

cent

age

decr

ease

fr

om b

asel

ine

(%)

With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.

T790Mpositive

T790Mnegative

T790M unknown

No EGFR mutation Total

Total treated 27 15 3 2 47

Evaluable for efficacy* 26 14 3 2 45

Best response n (%)

Any PR 13 (50) 8 (57) 2 (67) — 23 (51)

Confirmed PR 9 (35) 7 (50) 2 (67) — 18 (40)

SD 11 (42) 5 (36) 1 (33) — 19 (42)

Clinical response (any PR + SD)

24 (92) 13 (93) 3 (100) 2 (100) 42 (93)

Progression of disease 2 (8) 1 (7) — — 3 (7)

* Two patients were not evaluable for efficacy

Afatinib + Cetuximab at MTDResponses by Mutation

Jackman J Clin Oncol 2009

Case Presentation

• Middle-aged female diagnosed with Stage III-A lung adenocarcinoma in 2004

• 10 pack-yr smoker, no symptoms• Treated with chemotherapy, lobectomy and adjuvant

RT followed by adjuvant erlotinib• May 2007 isolated bone met, treated with

bisphosphonate, analgesics• May 2008 XRT L hip• June 2008 renal metastasis

Case Presentation

• Erlotinib continued• February 2009 clinical trial with dasatinib – POD• May 2009 pemetrexed added and then bevacizumab

added – initial response then POD in October 2010• KPS 60-70%• Left hip pain, nausea, malignant pleural effusion,

nausea, hematuria• Opiates, oxygen required

Case Presentation (cont’d)

• Commenced afatinib and cetuximab• Nausea resolved; weight gain• Opiates stopped, no need for wheelchair or cane• Hematuria absent• KPS 80%• Tox – Grade 1 rash, xerosis, paronychia

9/14/10 10/11/10

What Causes Non-T790M Resistance?

• 47 of 93 patients (51%) had tissue available for MET FISH– 9 patient specimens failed testing

• 4 of 38 patients (11%) had MET:CEP7 ratio >2– 1 pt with high level amplification + T790M– 2 of 3 pts with low level amplification had T790M

• Is FISH the optimal way to test for MET amplification?

ARQ 197-209: Study DesignRandomized, placebo-controlled, double-blind clinical trial

RANDOMIZE

Erlotinib 150 mg PO QD+ placebo

28-day cycle

Erlotinib 150 mg PO QD+ placebo

28-day cycle

Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID

28-day cycle

Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID

28-day cycle

Endpoints • 1° PFS• 2° ORR, OS• Subset analyses• Crossover: ORR

NSCLC• Inoperable locally

adv/metastatic dz• ≥1 prior chemo

(no prior EGFR TKI)

• 33 sites in 6 countries

• Study accrual over 11 months (10/08-9/09)

• Randomization stratified by prognostic factors incl sex, age, smoking, histology, performance status, prior therapy and best response, and geography (US vs ex-US)

PD

With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.

ARQ 197-209: Progression-Free Survival (ITT Population)

5020 300 10 40

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Time from randomization (weeks)

Erlotinib + ARQ 197 16.1 wks(n = 84)

Erlotinib + placebo 9.7 wks(n = 83)

* Cox regression model

• PFS also measured by independent radiographic review: - median 15.6 vs 8.4 wks- unadjusted/adjusted HR = 0.74/0.51

• HR = 0.81 (95% CI: 0.57, 1.15); p = 0.24• Adjusted HR = 0.68 (95% CI: 0.47, 0.98); p < 0.05*


ARQ 197-209: Overall Survival (ITT Population)

• HR = 0.88 (95% CI: 0.60, 1.3); p = 0.50• Adjusted HR = 0.88 (95% CI: 0.6, 1.3); p = 0.52*

Erlotinib + ARQ 197: 36.6 wks(n = 84)

Erlotinib + placebo: 29.4 wks(n = 83)

0 10 20 30 50 7040 60

Survival time (weeks)

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* Cox regression model


MetMAb Is an Anti-Met Monovalent Antibody That Inhibits HGF-Mediated Activation

• Rationale for targeting Met:

– Met is amplified, mutated, overexpressed in many tumors

– Met expression is associated with a worse prognosis in many cancers including NSCLC

– Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations

• MetMAb:

– One-armed format designed to prevent HGF-mediated stimulation of pathway

– Preclinical activity across multiple tumor models

HGFHGF HGFHGF

MetMetMetMet

MetMAbMetMAb

Growth, migration, survival

Growth, migration, survival

No activity

No activity

With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.

OAM4558g Study Design: Global, Double-Blind, Placebo-Controlled, Phase II Study

Arm AErlotinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w)

Addition of MetMAb*

PD

* If eligible

Co-primary objectives:

• PFS in “MET High” patients

• PFS in overall ITT population

Other key objectives:

• OS in “MET High” patients

• OS in overall ITT patients

• Overall response rate

• Safety/tolerability

Key eligibility:

• Stage IIIB/IV NSCLC

• 2nd/3rd-line NSCLC

• Tissue required

• PS 0-2

RANDOMIZATION

1:1n = 128

n = 64

n = 64

n = 23

- Enrollment from 3/2009 to 3/2010- Data cut-off: June 8, 2010

Arm BErlotinib (150 qd-oral) +placebo (IV q3w)


Stratification factors:

• Tobacco history

• Performance status

• Histology

PFS, HR = 0.56 OS, HR = 0.55

MetMAb + erlotinib improves both PFS and OS in MET high NSCLC patients


Pro

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

Time to Progression (weeks)

Median PFS (wk)Hazard ratiop-value# Events

6.4 12.4

25 19

0.560.0547

30

35

30

35

18

22

18

22

5

9

5

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3

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3

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Overall Survival (months)

Median OS (mo)Hazard ratiop-value# Events

7.4 7.7

20 13

0.550.1113

30

35

30

35

17

26

17

26

9

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3

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Erlotinib +Placebo(n = 30)

Erlotinib + placeboErlotinib + placebo


Erlotinib +MetMAb(n = 35)

Erlotinib + MetMAbErlotinib + MetMAb


Number at Risk: Number at Risk:

PFS and OS: MET High Population Erlotinib +Placebo(n = 30)


PFS and OS: MET Low PopulationPFS, HR = 2.01 OS, HR = 3.02

MET low NSCLC patients do worse with MetMAb + erlotinib


Pro

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ion

Fre

e 1.0

0.8

0.6

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0.2

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

Time to Progression (weeks)

11.4 6.0

20 23

2.010.0354

Number at Risk:

29

27

29

27

22

15

22

15

9

5

9

5

6

1

6

1

2

0

2

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2

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1.0

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0 3 6 9 12 15

Overall Survival (months)

9.2 5.5

9 14

3.020.0212

Number at Risk:

29

27

29

27

23

12

23

12

9

3

9

3

3

0

3

0

0

0

0

0

0

0

0

0







Median PFS (wk)Hazard ratiop-value# Events

Median OS (mo)Hazard ratiop-value# Events



Approach to Therapy of Acquired Resistance to EGFR TKIs• Rebiopsy the patient

– T790M prognostic and possibly predictive biomarker

– Rare transformation to small cell phenotype• Continue an EGFR TKI• “Second generation” EGFR/ErbB2 TKIs• Rational combination strategies

– BIBW 2992 + cetuximab– HSP-90 inhibitor + chemo or EGFR-TKI– Add MET inhibitor - best diagnostic unclear

Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MD Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center.

Documents

survival of tki

resistance slide

acquired resistance

months tki

t790m os

survival of pps

t790m pps

sanofi disclosure slide