Repeat Biopsies and the Potential Value of Biologically-Informed Acquired Resistance Therapy

Lecia V. Sequist, MD, MPH

Associate Professor of Medicine, Harvard Medical School

Mary B. Saltonstall Endowed Chair in Oncology, Massachusetts General Hospital

“The magic of EGFR inhibitors”

The promise of genotype-directed therapy

Treatment B

Treatment CTreatment D

Treatment A

The Concept of Oncogene Addiction

EGFR

PI3K P42/44

MAPK

Jak/Stat

gefitinib

Apoptosis

EGFR-Addicted

PTEN

IGFR

K-Ras

PI3K MAPK Jak/Stat

EGFR

Non-addicted case

• EGFR mutant cancers are “simple”-one RTK controls all downstream signaling.

Dec 2010 TKImax response

Acquired Resistance

Feb 2010Diagnosis

July 2011Acq. resist

Repeat Biopsy

Clinical Information

Biopsy

Routine and Molecular Pathology

Targeted Therapy

Repeat Biopsies: EGFR mutants with AR to gefitinib, erlotinib

8

Sequist et al Sci Transl Med 2011

Specific TKI

Target Alteration

RTK mutation or amplification

PI3KERKSTAT

P PP PP P

Two General Classes of TKI Resistance

Receptor TK

PI3KERKSTAT

Sensitive/TKI-naïve

RTK2

Receptor TK

PI3KERKSTAT

RTK1

P

RTK2

P

Bypass Tracks

?

Slide courtesy of Alice Shaw

Sci Transl Med; March 2011

• 37 consecutive samples with paired pre- and post- AR tissue

• Comparative analyses for:

– Histology with IHC

– SNaPshot (most common mutations in 13 genes)

– FISH for EGFR and MET amplification

T790M 52%alone 42%

with EGFR amp 10%

No identified AR mechanism26%

BRAF 2%

MET amp 5%SCLC 8% with EGFR amp 1% alone 4% with PI3K 3%

Updated MGH cohort: EGFR mutants with AR, n=106

EGFR Amp 15% with T790M 10% alone 4% with SCLC 1%

PI3K 5% with SCLC3% alone 2%

Waxing/waning resistance in response to TKI selective pressure

Sequist et al, Sci Transl Med 2011

Waxing/waning resistance in response to TKI selective pressure

Sequist et al, Sci Transl Med 2011

Adenocarcinoma

High-grade neuroendocrine carcinoma

EGFR transformed to SCLC is responsive to SCLC chemo

Patient received carboplatin, etoposide and erlotinib

T790M Most common mechanism of resistance

to EGFR TKIs (50-68%) May have a better prognosis than non-

T790M mechanisms (Oxnard, CCR 2010)

0

20

40

60

80

100

120

gefitinib

HKI-272

EKB-569

Drug concentration (M)

0 .02 .2 2 20

Rel

ati

ve

cel

l vi

abil

ity

(%)

P-AKT

P-MAPK

Total EGFR

P-EGFR

Total AKT

Total MAPK

untreated

0.001

0.01

0.1

1 10

gefitinib (M)

untreated

0.001

0.01

0.1

1 10

HKI-272 (M)

NCI-H1975 (L858R and T790M)

Overcoming T790M: Irreversible TKIs

Kwak, PNAS 102:7665, 2005

• Neratinib (HKI-272)

– RR 2%, PFS 15 weeks in TKI-resistant patients (Sequist, JCO 2010)

• Afatinib (BIBW-2992)

– RR 7%, PFS ~13 weeks in TKI-resistant pts (Miller, Lan Onc ‘12)

• Dacomitinib (PF-299804)

– RR 7% in TKI-resistant patients (Janne, ASCO ’09)

….novel T790M-specific TKIs are entering clinical trials

– CO-1686

– AP26113

Irreversible TKIs (Pan-HER Inhibitors): Not highly effective for T790M

www.esmo2012.org

Afatinib + cetuximab at MTD: Responses by T790M mutation

5040302010

0–10–20–30–40–50–60–70–80–90

–100–110

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100Patient index sorted by maximum % decrease

Max

imum

per

cent

age

de

cre

ase

from

ba

selin

e (%

)

T790M+ T790M– EGFR wt Uninformative for T790M

www.esmo2012.org

PFS at MTD

Number at riskAfatinib + cetuximab

MTD: Afatinib 40 mg daily + cetuximab 500 mg/m2 every 2 weeks

Est

imat

ed P

FS

4 pr

obab

ility

1.0

0.8

0.6

0.4

0.2

0.0

Time from treatment start (months)0 3 6 9 12 15 18

Median

Afatinib + cetuximab 4.7

96 59 32 12 5 3 0

MTD = maximum tolerated dose; PSF4 = progression-free survival at 4 months.

AUY922 (Hsp90): best CT response: EGFR-mutant patients (n=25†/35)

EGFR-mutant (n=35)

ORR (any PR) 7 (20%)‡

DCR (CR/PR or SD) 20 (57%)

PFS (18 weeks [95% CI]), % 35.2 (18.7, 52.2)

*Confirmed responses; †Patients with at least one post-baseline scan;‡Including one PR not confirmed.

* * * **

-100

-80

-60

-40

-20

0

20

40

60

80

100

Best

% c

hang

e in

targ

et le

sion

s

*

Felip, et al. ESMO ‘12

EGFR

HGF

MET

TKI Resistance via MET Amplification

Engelman et al., Science 2007: 316; 1040.

1/30/08 3/31/08

Pre-Rx ‘08 Resistant ‘09

Proof of principle: 63 year old man with an EGFR mutant lung cancer

erlotinib

Developed Resistance

Rx on clinical trial

2/25/09

Met Inhibitors in Clinical Trials

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

showed PFS benefit of combo but wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Sequist, JCO 2011)

Met-mab Randomized phase II of erlotinib +/- MET-Mab in TKI-naïve paitents

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

Crizotinib: We know it works in MET amp patients, but we don’t know about

EGFR mutant,TKI resistant pts with MET amp

Treatment of MET amp pt with Crizotinib

Jan 2012 March 2012

Clinical Strategies for Patients in the Clinic

1. Repeat biopsies whenever possible

2. Clinical trials whenever possible

3. Treatment beyond progression and local therapy for local

progression

4. Continuing TKI beyond with other therapies

Treatment Beyond Progression: appealing if PD is slow

Oxnard, et al ASCO’12

Summary and Future Directions

• Genotype-directed therapy paradigm has revolutionized NSCLC

landscape

• Treatment of resistance has proven complicated

• Repeat biopsies of patients with AR will continue to greatly

supplement lab-based research

• Prevention may be a potent strategy, especially since pre-

disposition toward certain mechanisms may be identifiable. Need

more ideal combination regimens

• Need to develop less-invasive ways of assessing tumor genotype

Acknowledgments

MGH Cancer Center Jeff Engelman Alice Shaw Daniel Haber Becca Heist Jerry Azzoli Jennifer Temel Inga Lennes Justin Gainor Panos Fidias Rachel Rosovsky Mike Lanuti Subba Digumarthy Michele Myers Marguerite Parkman Emily Howe

MGH Pathology John Iafrate Mari Mino-Kenudson Dora Dias-Santagata Vicente Morales

Yale Tom Lynch Scott Gettinger Sarah Goldberg Katie Politi

Engelman Lab Tony Faber Matt Niederest Elizabeth Lockerman

Vanderbilt William Pao Kadaoki Ohashi

Funding Uniting Against Lung Cancer NIH/NCI (R21CA156000) MGH Thoracic Oncology MGH Pathology

Stanford Joel Neal

UCSF Belinda Waltman

Germans Trias i Pujol, Barcelona Teresa Moran

Haber/Toner Lab Shyamala Maheswaran Shannon Stott John Walsh James Sullivan Mike Rothenberg