west xcenda molec testing sf oct 2011 revised final

Molecular Markers and Testing Strategies in Advanced Non-Small Cell Lung Cancer

Howard (Jack) West, MD Swedish Cancer Institute

Seattle, WA

Challenging Cases in Breast & Lung Cancer

San Francisco, CA October 22, 2011

Why do molecular testing?

•  To improve clinical outcomes – Give best treatment first (timing of EGFR TKI Rx) – To provide access to agent (crizotinib for ALK-

positive) – To identify subsets who might benefit from targeted

therapy (cetuximab?) •  To facilitate clinical research

– May improve patient outcomes – Better understanding of molecular oncology

IPASS: Gefitinib vs. Carbo/Paclitaxel as First Line Rx in Asian Never- or Light Ex-Smokers

Mok, NEJM 2009

Carbo/Paclitaxel IV every 3 weeks Advanced NSCLC

No Prior Systemic Therapy

Never-/Light Former Smoker

N = 1217

R A N D Gefitinib 250 mg/day

•  Primary Endpoint: Progr-Free Survival (PFS) •  Biomarker analysis

IPASS: Objective Response Rate by EGFR Mutation Status

Gefitinib Carboplatin / paclitaxel

EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p=0.0001

EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p=0.0013

Overall response rate (%)

(n=132) (n=129) (n=91) (n=85)

Odds ratio >1 implies greater chance of response on gefitinib

71.2%

47.3%

1.1%

23.5%

Mok, NEJM 2009

IPASS Study: OS

Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.

Overall Population 1.0

0.8

0.6

0.4

0.2

0 Prob

abili

ty o

f Sur

viva

l

0 52 4 8 12 16 20 24 28 32 36 40 44 48 Time Since Random Assignment (Mos)

HR: 0.90 (95% CI: 0.79-1.02; P = .109)

Gefitinib (n = 609) Carboplatin/paclitaxel (n = 608)

EGFR Mutation Negative 1.0

0.8

0.6

0.4

0.2

0 Prob

abili

ty o

f Sur

viva

l


HR: 1.18 (95% CI: 0.86-1.63; P = .309)


EGFR Mutation Positive 1.0

0.8

0.6

0.4

0.2

0 Prob

abili

ty o

f Sur

viva

l


HR: 1.00 (95% CI: 0.76-1.33; P = .990)


IPASS Study: PFS by EGFR Status

•  EGFR mutation status most predictive, EGFR gene amplification also significantly predictive, but less

Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.

Prevalence of EGFR Mutations

Phenotype of NSCLC Patient Prevalence of EGFR Mutation

All 10% to15%

Caucasian never-smokers ~35%

Asian never-smokers ~65%

Jackman DM et al. ASCO 2008 Annual Meeting. Abstract 8035.

MSKCC Continuum of Tobacco Exposure and EGFR Mutations

•  Looking for exon 19 or 21 mutations in tumors from 265 pts with detailed smoking history

Pham, JCO 2006

Prevalence of EGFR Mutations by Smoking Status: Lung AdenoCa at MSKCC

•  Testing for exon 19 or 21 mutation in 2142 adenocarcinomas at MSKCC

•  Rate: EGFR mut’ns seen in 52% of never-smokers, 15% of former smokers, and 6% of current smokers

D’Angelo, J Clin Oncol 2011

Prospective Trials of EGFR TKIs vs. Chemo in EGFR Mutation (Exons 19, 21) Population

Trial N Rx RR PFS (mo) OS (mo)

TKI Chemo TKI Chemo TKI Chemo

MaemondoNEJ002 230 Gefitinib vs.

Carbo/Pac 74% 31% 10.8 5.4 30.5 23.6

MistudomiWJTOG3405 172 Gefitinib vs.

Cis/Doce 62% 32% 9.2 6.3 30.9 N.R.

Zhao OPTIMAL 165 Erlotinib vs.

Carbo/Gem 83% 36% 13.1 4.6 N.R. N.R.

Rosell EURTAC 174 Erlotinib vs.

Plat Doublet 58% 15% 9.4 5.2 N.R. N.R.

Maemondo, NEJM 2010; Mistudomi, Lancet Oncol 2010; OPTIMAL, Lancet Oncol 2011; Rosell, ASCO 2011

TORCH Study: Chemo Erlotinib vs. Erlotinib Chemo

Gridelli, ASCO 2010, #7508

Advanced NSCLC No clinical or

molecular selection N = 760,

closed by DSMB

Cis/Gemcitabine x 6 cycles

R A N D Erlotinib 150 mg/d

Cis/Gemcitabine x 6 cycles

Erlotinib 150 mg/d

Order of therapy matters: get best treatment in at first opportunity

Standard arm

Experimental arm

TORCH Study: Efficacy Analysis

Gridelli C, et al. ASCO 2010. Abstract 7508.

Efficacy Outcome Erlotinib → Chemo

(n = 380)

Chemo → Erlotinib (n = 380)

HR (95% CI)

P Value

Median OS, mos 7.7 10.9 1.40 (1.13-1.73) .002

Median PFS,* mos 2.2 5.7 Not reported Objective response,† %  With first-line treatment

• CR • PR  With second-line treatment • CR • PR

18

< 1 9

1 9

32

1 27

< 1 6

Not reported

*Assessment of first-line treatment only. †Intent-to-treat population.

KRAS Mutations and Resistance to EGFR Inhibitors

Trial N Agent RR OS

Wild Type Mutant Wild Type Mutant

INTEREST 275 Gefitinib 10% 0% 7.5 mos 7.8 mos

Jackman 116 Gefitinib or erlotinib 5% 0% 11.8 mos 13 mos

Massarelli 70 Gefitinib or erlotinib 10% 0% 9.4 mos 5 mos

Shepherd 206 Erlotinib 10.2% 5% 7.5 mos 3.7 mos

Miller* 101 Erlotinib 32% 0% 21 mos 13 mos

Douillard. ASCO. 2008 (abstr 8001); Jackman. ASCO. 2008 (abstr 8035); Massarelli. Clin Cancer Res. 2007;13:2890; Shepherd. ASCO. 2007 (abstr 7571); Miller. J Clin Oncol. 2008;26:1472.

*Patients with BAC.

Waterfall Plot of Response on Erlotinib in Advanced BAC, with Molecular Correlates

•  Most but not all of the best responders carry EGFR mutations •  Many with minor response and even some with PR have neither EGFR

mutation nor EGFR gene amplification •  Several KRAS mutation patients have stable disease or even minor responses

(which very likely correlate with modest clinical benefit) •  Selecting on basis of EGFR mutations or FISH positivity would filter out many

beneficiaries; selecting by KRAS would also eliminate many w/SD or MR Miller, JCO 2008

INTEREST Trial: A Wide Range of Very Unhelpful Molecular Markers

Douillard, JCO 2010

Worldwide trial, second line docetaxel vs. gefitinib, N = 1466 OS DFS

EML4-ALK Translocations in NSCLC

EML4-ALK frequency: ~4% (64/1709)

Primarily adenoCa, minimal or no smoking history

Soda et al., Nature 448: 561-566, 2007

Bang, ASCO 2010 #2 (Plenary), then NEJM

Pre-Treatment After 2 cycles PF-02341066

48 yo Female Never Smoker with Stage IV NSCLC Positive for EML4-ALK

77% of Patients with ALK-positive NSCLC Remain on Crizotinib Treatment

0 3 6 9 12 15 18 21 Treatment duration (months)

N=82; red bars represent discontinued patients

Indi

vidu

al p

atie

nts

•  Duration of treatment (median: 5.7 months)

0–3 mo 13 pts >3–6 mo 29 pts >6–9 mo 24 pts >9–12 mo 9 pts >12–18 mo 4 pts >18 mo 3 pts

•  Reasons for discontinuation –  Related AEs 1 –  Non-related AEs 1 –  Unrelated death 2 –  Other 2 –  Progression 13

The Majority of ALK-Positive Patients are Never-Smokers

ALK-Positive

Never smoker

Light smoker

Smoker

Shaw et al. ASCO 2010

Mutation Status By Smoking History Caucasians

ALK EGFR WT/WT

≤10 pack-years (N=255)

>10 pack-years (N=232)

18% 2%

Shaw et al. ASCO 2010

Mutation Status By Smoking History Asians

Never-smokers (N=127)

Ever-smokers (N=82)

8%

1.2%

EGFR KRAS ALK WT/WT/WT

Wong et al., Cancer 2009;115:1723-33.

Mutation Status in Asian Never-Smokers

N=52

Sun et al. JCO 2010;28:4616-20

•  Primary end point: OS

•  Secondary end points: PFS, RR, QOL, safety

•  Stratification •  – ECOG PS: 0/1 vs. 2 •  – Stage: IIIB (wet) vs. IV

Pirker et al, Lancet 2010

FLEX: Study Design

Cis d1/Vin d1,8 Adv NSCLC EGFR IHC 1 + No prior Rx

No brain mets (N = 1,125)

R A N D

Cis d1/Vin d1,8 + weekly cetuximab

Pirker, Lancet 2010

Ove

rall

surv

ival

(%)

ITT (n=1125) Median OS 1-year survival

▬ CT + cetuximab (n=557) 11.3 mo 47%

▬ CT (n=568)

10.1 mo 42%

HR=0.871 [95% CI 0.762–0.996]; p=0.044

Months

O‘Byrne, Lancet Oncol 2011

EGFR Expression in FLEX Study

Parameter Low EGFR Expression High EGFR Expression

CT CT + Cetuximab CT CT + Cetuximab

Median OS (months) 10.3 9.8 9.6 12.0

FLEX High EGFR IHC, by Histology

Adenocarcinoma (N = 135) Squamous (N = 144)

NCCN Guidelines (October, 2011)

Caveat: NCCN expertise: cancer treatment, independent of cost NCCN non-expertise: health care economics/value of Rx

•  Patients with non-squamous advanced NSCLC should be tested for EGFR mutation and ALK rearrangement

•  Treatment in this setting should be guided by results of this testing

ASCO Guidelines (Sept, 2011) Re: EGFR inhibitors

•  Most patients should not receive EGFR TKI as part of 1st line treatment

•  For those with EGFR mut’n, EGFR TKI alone may be recommended

•  For patients receiving cis/vinorelbine, cetuximab may be added

ASCO Guidelines (Sept, 2011) Re: Molecular Testing

•  ASCO recognizes that most patients with NSCLC may not have any special molecular tests…these molecular tests remain investigational, and selecting treatment based on molecular tests has not been shown to improve a patients’s overall length of live.

•  Therefore, ASCO does not recommend using any routine molecular analysis of tumor tissue to guide treatment decisions at this time. For patients with an EGFR mutation, erlotinib or gefitinib may be the best first-line therapy, but may also work well as a second or third-line treatment.

•  Larger tissue samples recommended when performing Bx, to facilitate future research and maximize eligibility in trials.

My Conclusions: Clinical Management Decisions

•  EGFR TKIs – EGFR TKI shouldn’t be 1st line Rx in unselected pts. –  If you know EGFR mut’n +, I’d give earlier >> later –  Importantly, EGFR wild type doesn’t mean no benefit

from EGFR TKI in maintenance or later •  ALK positivity is KEY to access to crizotinib

major benefit •  EGFR IHC possibly very helpful in selecting for

cetuximab

Setting the Balance: Where Do You Fit on the Spectrum?

Never-smoker, adeno Test 12%, find 40%

Test enriched population

Adeno (any smoking Hx) Test 45%, find 90%

Adeno (any) + non-squam light smokers, Test 67%, find 95%

All non-squamous adv NSCLC Test 75%, find 97%

Test everyone to miss NOBODY

All advanced NSCLC Test 100%, find 100%

$5K/pos test

$60K/pos test (All numbers approximate)

My Conclusions: Who To Test?

•  Selective vs. everything for everyone? –  I favor a selective approach based on histology &

smoking status, not (yet) testing for all patients •  Remember fallibility of histology assignment

– EGFR mut’n pts can still get comparable benefit as maintenance or 2nd line

– Stronger argument for ALK testing (pos = access) – This is a clinical judgment, with ASCO and NCCN

endorsing different conclusions – The only wrong answer is a dogmatic one

west xcenda molec testing sf oct 2011 revised final

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