Acquired resistance to EGFR TKIs in Lung Cancer (NSCLC)

How Do We Manage Acquired Resistance to EGFR TKI Therapy?

Howard (Jack) West, MDSwedish Cancer Institute

Seattle, WA

Challenging Cases in Breast & Lung Cancer

Las Vegas, NVApril 21, 2012

Why Do We See Acquired Resistance?

T790M Mutation

• Most common mechanism of resistance to EGFR TKIs (50-68%)

• May have a better prognosis than non-T790M mechanisms: 19 vs. 12 mo post-progression, Oxnard, CCR 2010N = 93

• T790M more likely to show progression in lungs/pleura

• Non-T790M more likely to progress distantly, & worse PS

Rapid acceleration of disease progression resulting in hospitalization and/or death after discontinuation of gefitinib or erlotinib and before initiation of study drug (up to ~1/4 of pts in MSKCC series (Chaft, CCR, 2011)Last day of TKI Off EGFR TKI Resumed TKI

Day 0 Day 21 Day 42

From Riely, CCR 2007

Rapid Progression with Discontinuation of EGFR TKI after Prolonged PFS

For Cancers with a Known Driver Mutation, ContinuingInhibition of that Target is Beneficial after Progression

• Progression of CML on imatinib increase dose, or dasatinib, or nilotinib lead to consistent response

• Solid tumor example: HER2+ breast cancer

Minckwitz, JCO 2009

Brakes may not be as good, but better than no brakes

Such Patients Often Show Slow, Modest Progression

No change in therapy may be needed initially

Combining Systemic and Local Targeted Therapies: Radiation (or Surgery) to Isolated Area of Progression

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Freedom from Locoregional Recurrence after Chest RT

EGFR mutation

EGFR wild type

Mak, ASCO 2010, A#7016

Survival after RT to 1-2 sites of metastatic disease (Lung Ca)

Kahn, Radiotherapy & Oncology, 2006 Perhaps extend the idea of the “precocious metastasis” to

“precocious recurrence”

Overcoming T790M: Irreversible TKIs

Irreversible TKIs in Clinical Trials

• HKI-272 (EGFR + Her2)• RR 2% in TKI-resistant patients

• Intriguing responses in G719X patients (Sequist, JCO 2010)

• XL-647 (EGFR, Her2, VEGF)• RR 2% in TKI-resistant patients (Pennell, Chicago Lung ’08)

• PF-299804 (EGFR + Her2)• RR 7% in TKI-resistant patients (Janne, ASCO ’09)

• BIBW-2992 (EGFR + Her2)• RR 7% in TKI-resistant pts, 2 mo PFS increase (Miller, ESMO’10)

• Interesting ongoing study combining afatinib and cetuximab based on a mouse model that was successfully treated w/ this combo

LUX Lung 1

• Does Afatinib work in patients with acquired resistance to first generation EGFR TKI?

Randomization2 : 1

Oral BIBW 2992 50 mg once daily plus best supportive care

Oral placebo once daily plus best supportive care

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

Primary endpoint: Overall survival (OS)

Secondary: PFS, RECIST response, QoL, safety

LUX Lung 1: Efficacy

Progression-Free Survival Overall Survival

Miller, ESMO 2010

Implication of LUX Lung1

• Lack of OS– OS of 11.9 months in Placebo group

• Suggestive evidence of efficacy: – RR at 13.3% and PFS (HR 0.38)

• Relationship to T790M not known• Future implication

– Biomarker selection – Combination with cetuximab

Expansion cohort part4

MTD cohort expanded up to 80 EGFR mutation-positive patients:40 T790M-positive and 40 T790M-negative

1 EGFR G719X, exon 19 deletion, L858R, L861Q 2Progression of disease (RECIST v1.1) on continuous

treatment with erlotinib or gefitinib within the last 30 days.

3Amended from original 14 days interval4Acquisition of tumor tissue after the emergence of

acquired resistance was mandated

Dose escalation schema3-6 patients per cohort

afatinib p.o. daily + escalating doses ofcetuximab IV q 2 weeks

Dose levels starting at:afatinib 40 mg +cetuximab 250 mg/m2

Predefined maximum dose:afatinib 40mg + cetuximab 500 mg/m2

NSCLC w/ EGFR mut’n1

andSD 6 mo on erlotinib/gefitinib

orCR or PRto erlotinib/gefitinib

Jangigian & Pao, ASCO 2011, #7525

Afatinib/Cetuximab in EGFR TKI-Resistant NSCLC

PD2

Stop EGFR TKIFor ≥ 72 hours3

Afatinib + Cetuximab at MTD:Responses by EGFR Mutation

40% confirmed response rate and a clinical benefit rate of 90% Jangigian & Pao, ASCO 2011, #7525

Afatinib + Cetuximab: Insights & Future Directions

• Remarkable efficacy seen in EGFR TKI-resistant tumors– Requires further validation

• Activity not specific to common T790M mutant

• Need to further define biology and refine patient population for phase III trial

MET Overexpression

Met Inhibitors in Clinical Trials

• ARQ-197, specific MET inhibitor– Randomized phase II of erlotinib +/- ARQ-197 in TKI-naïve patients

showed some benefit of combo but wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Schiller, ASCO 2010)

• Met-Mab – Randomized phase II of erlotinib +/- MET-Mab in TKI-naïve pts

showed benefit of combo, but again wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Spigel , ASCO 2011

• XL-184, MET + RET + VEGF– Randomized phase II of erlotinib +/- XL-184 in TKI-resistant patients,

completed but not reported yet

• PF-02341066: – Still in early phase studies

MetMAb is an anti-Met Monovalent Antibody that Inhibits HGF-MediatedActivation

Rationale for targeting Met:

• Met is amplified, mutated, overexpressed or uniquely activated in many tumors

• Met expression is associated with 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

MetMAb

Met

HGF HGF

Met

GrowthMigrationSurvival

Noactivity

HGF: Hepatocyte growth factor

Spigel, ASCO 2011, #75051

Randomized Phase II: Erlotinib + MetMAbor Placebo in 2nd/3rd line NSCLC

Stage IIIB/IV NSCLC2nd/3rd lineTissue requiredPS 0–2Stratification factors: •Tobacco history •Performance status •Histology

N = 137

N = 69

Co-primary objectives:• PFS in ‘Met Diagnostic

positive’ patients (est. 50%)• PFS in overall ITT population

Other key objectives:• OS in ‘Met Diagnostic positive’

patients• OS in overall ITT patients • Overall response rate• Safety/tolerability

PD

add MetMAbMust be eligible to be treated with MetMAb

Spiegel, ASCO 2011, #7505

Erlotinib 150 mg PO dailyMetMAb 150 mg/kg IV Q3wkR

AND Erlotinib 150 mg PO daily

Placebo IV Q3wkN = 68

N = 27

Met Dx Negative

Development of Met IHC for Use as a Companion Diagnostic

• Technical metrics– Tissue was obtained from 100% of patients.– 93% of patients had adequate tissue for evaluation of Met by IHC

• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories

• Met diagnostic status was assessed after randomization and prior to unblinding– ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity

Negative (0) Weak (1+)

Moderate (2+) Strong (3+)

Met Dx Negative

Met Dx Positive

MET IHC score

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52% patients enrolled were ‘Met Diagnostic Positive’


Erlotinib + MetMAb or Placebo in 2nd/3rd line NSCLC: Safety

Met Diagnostic Positive Met Diagnostic Positive Met Diagnostic NegativeMet Diagnostic Negative

No.of patients (%)No.of patients (%)Placebo + erlotinibPlacebo + erlotinib

(n=31)(n=31)MetMAb + erlotinibMetMAb + erlotinib

(n=35)(n=35)Placebo + erlotinibPlacebo + erlotinib

(n=31)(n=31)

MetMAb +MetMAb +erlotiniberlotinib(n=31)(n=31)

Any adverse eventAny adverse event 31 (100)31 (100) 35 (100)35 (100) 31 (100)31 (100) 31 (100)31 (100)

Grade ≥3 adverse Grade ≥3 adverse eventevent 17 (54.8)17 (54.8) 20 (57.1)20 (57.1) 13 (41.9)13 (41.9) 17 (54.8)17 (54.8)

Serious adverse Serious adverse eventevent 11 (35.5)11 (35.5) 15 (42.9)15 (42.9) 9 (29.0)9 (29.0) 13 (41.9)13 (41.9)

Adverse events Adverse events leading to leading to treatment treatment discontinuationdiscontinuation

2 (6.5)2 (6.5) 8 (22.9)8 (22.9) 0 (0)0 (0) 2 (6.5)2 (6.5)

Adverse events Adverse events leading to deathleading to death 4 (12.9)4 (12.9) 1 (2.9)1 (2.9) 0 (0)0 (0) 3 (9.7)3 (9.7)


Note: + = censored value.

Erlotinib + MetMAb or Placebo: Efficacy in ITT Population

Time to progression (months)

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Placebo +erlotinib

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MetMAb +erlotinib

8.90.80

(0.50–1.3)0.3434

Median (mo)HR(95% CI)Log-rank p-valueNo. of events

Overall survival (months)

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MetMAb +erlotinib

2.21.09

(0.73–1.62)0.6948


Note: + = censored value.

PFS: HR=1.09 OS: HR=0.8

Control arm was consistent with previous studies in a similar population (Br21 PFS 2.2 mo, OS 6.7 mo, ORR 8.9%)


Erlotinib + MetMAb or Placebo: Efficacyin Met Diagnostic Positive NSCLC Patients

Time to progression (months)

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Placebo +erlotinib

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MetMAb +erlotinib

12.60.37

(0.19–0.72)0.002

16


Overall survival (months)

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(0.28–0.99)0.042

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The addition of MetMAb to erlotinib doubled the progression free survivaland nearly tripled the overall survival in this population

PFS: HR=0.53 OS: HR=0.37


ARQ-197: c-MET Receptor Tyrosine Kinase

• Implicated in tumor cell migration, invasion, proliferation, and angio-

genesis1

• Only known high-affinity receptor for hepatocyte growth factor (HGF)1

1. Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:404–102. Cappuzzo F et al. JCO 2009;27:1667–743. Engelman JA et al. Science 2007;316:1039–434. Bean J et al. PNAS 2007;104:20932–7

• c-MET amplification associated with:• Poor prognosis in NSCLC2

• Resistance to EGFR TKIs3,4

Rand Phase II: Erlotinib + Tivantinib (ARQ-197) or Placebo in Prev Treated Adv NSCLC

Inop Loc Adv/Met NSCLC>1 prior line of RxNo prior EGFR TKIPS 0–2Stratification factors: sex, age, ECOG PS, smoking status, histology, prior Rx, best response, & geography (U.S. vs. ex-U.S.)

N = 167

N = 84

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

PD

add ARQ-197

Sequist, JCO 2011

Erlotinib 150 mg PO dailyARQ-197 360 mg PO BIDR

AND Erlotinib 150 mg PO daily

Placebo PO BIDN = 83

N = 21

Erlotinib + Tivantinib or Placebo: Efficacy (ITT Population)

Sequist, JCO 2011

Erlotinib + Tivantinib or Placebo: PFS & OS in Non-Squamous NSCLC Patients

Sequist, JCO 2011

Erlotinib + Tivantinib or Placebo: Time to New Metastatic Lesions (ITT & Non-Squamous)

Sequist, JCO 2011

5.02.0

Erlotinib + Tivantinib or Placebo: PFS in Histologic and Molecular Subgroups

ARQ197/erlotinib

Placebo/ erlotinib

Unadjusted HR (95% CI)N Median PFS (95% CI, weeks)

Squamous Cell 26 / 24 13.7 (8.0‒18.1) 8.4 (7.9‒21.0)

Non-Squamous Cell 58 / 59 18.9 (15.0‒31.1) 9.7 (8.0‒16.0)

c-MET FISH >4 19 / 18 15.4 (8.1‒24.4) 15.3 (7.1‒16.3)

c-MET FISH >5 8 / 11 24.1 (16.3‒NE) 15.6 (7.9‒31.4)

EGFR mutant 6 / 11 24.1 (8.0‒32.1) 21.0 (8.1‒36.0)

EGFR wt 51 / 48 13.7 (8.1‒18.1) 8.1 (7.9‒9.9)

KRAS mutant 10 / 5 9.7 (7.9‒NE) 4.3 (1.1‒8.0)

KRAS wt 49 / 45 15.4 (8.1‒18.1) 9.9 (8.0‒16.0)

1.00

Favors ARQ 197/Erlotinib

Favors Erlotinib/placebo

HR=0.70

HR=0.18

0.5 1.5

HR=1.01

HR=1.23

HR=0.45

HR=0.71

HR=1.05

HR=0.71

Schiller, ASCO 2010

2 PR22 PR2

34 Crossover Patients

23 Evaluable for Response1

1 Baseline + ≥1 post-baseline scan.Reasons for non-evaluable incl:- Clinical progression (n=4)- Active but haven’t received 1st post-progression scan (n=2)- Death (n=1)- Dosing delay (n=1)- Withdrew consent (n=1)- Investigator decision (n=1)

9 SD39 SD3

12 PD12 PD

2 Pt # 24:EGFR INDKRAS WT

c-MET > 4

Pt # 58:EGFR MUTKRAS WTc-MET > 5

3 3‒18+ weeks

Erlotinib + Tivantinib or Placebo: Crossover Patients

Schiller, ASCO 2010

Research Efforts for Acquired Resistance to EGFR TKIs

• Afatinib/cetuximab looks very promising• Unexpectedly, not correlated with T790M• Phase III trial in development

• MetMAb phase II trial encouraging in subset• Benefit appears limited to high Met expression (detrimental in low Met expression)• Phase III trial in development

• Tivantinib phase II trial favorable, esp in non-squamous• Phase III trial now ongoing• Possibly particularly helpful for KRAS mut’n positive

• Increasing interest in post-PD biopsies, though not yet useful outside of trial setting

Acquired Resistance to EGFR TKIs:Practical Principles for the Clinic

• Patients can respond to EGFR TKI with rechallenge, especially after long interval off of EGFR TKI (breaks onc rule of “you can never go back”

• ?Consider local therapy to solitary area of PD

• Some patients will have a rebound rapid progression after being taken off of an EGFR TKI• Heterogeneous populations of cancer cells• Is it better to continue the EGFR TKI and add an

agent/regimen, or to stop it and potentially restart it later??• I favor continuing EGFR TKI when PD < PR, but not

when PD is very clear• No comparison and no good data to address this

Acquired resistance to EGFR TKIs in Lung Cancer (NSCLC)

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