Targeted therapies in lung cancer - what are the limits? D. Ross Camidge, MD PhD Director, Thoracic Oncology Clinical Program University of Colorado Halifax,

Targeted therapies in lung Targeted therapies in lung cancer cancer - what are the - what are the

limits?limits?D. Ross Camidge, MD PhDD. Ross Camidge, MD PhD

Director, Thoracic Oncology Clinical Director, Thoracic Oncology Clinical ProgramProgram

University of ColoradoUniversity of Colorado

Halifax, Nova Scotia, 21st October 2011

Disclosures (DRC)Disclosures (DRC)• Employment or leadership Position: NoneEmployment or leadership Position: None• Advisory Role: Ad Hoc Advisory Boards/Consultations (most recent Advisory Role: Ad Hoc Advisory Boards/Consultations (most recent

contact last 3 years):contact last 3 years):– 2011: Ariad, Array Biopharma, AstraZeneca, Aveo, Boehringer Ingelheim, Chugai, 2011: Ariad, Array Biopharma, AstraZeneca, Aveo, Boehringer Ingelheim, Chugai,

Clovis, Novartis, SyntaClovis, Novartis, Synta– 2010: Millenium, Pfizer2010: Millenium, Pfizer– 2009: Imclone, OSI2009: Imclone, OSI

• Stock Ownership: NoneStock Ownership: None• Honoraria: Seminar/Talks to Industry (most recent contact last 3 years). Honoraria: Seminar/Talks to Industry (most recent contact last 3 years).

– 2011: Ariad, Array Biopharma, Pfizer2011: Ariad, Array Biopharma, Pfizer– 2009: Imclone, Boehringer Ingelheim,2009: Imclone, Boehringer Ingelheim,

• Speakers Bureau/Talks for Industry: NoneSpeakers Bureau/Talks for Industry: None• Research Funding:Research Funding:

– 2010: Eli-Lilly (Translational)2010: Eli-Lilly (Translational)– 2008: Onyx/Merck (IIT)2008: Onyx/Merck (IIT)

• Expert Testimony: NoneExpert Testimony: None• Other Remuneration: NoneOther Remuneration: None

Negative phase III trials of new agents in NSCLC 2000-2010

Compound Mechanism of action N° trials N End point

Gefitinib EGFR TKI 8 5975 OS

Erlotinib EGFR TKI 4 3661 OS

Afatinib EGFR/HER2 TKI 1 585 OS

Cetuximab EGFR antibody 1 676 PFS

Prinomastat Matrix metalloprotease inhibitor 2 1048 OS

Rebimastat Matrix metalloprotease inhibitor 1 774 OS

PF-676Toll-like receptor 9-activating

oligodeoxynucleotide 2 1667 OS

AprinocarsenProtein kinase C-alpha antisense

oligonucleotide 2 1286 OS

Bexarotene Retinoid X receptor activator 2 1235 OS

Lonafarnib Farnesyl-transferase inhibitor 1 675 OS

Figitumumab IGF-1R antibody 1 681 OS

Celecoxib Cox2 inhibitor 1 561 OS

IL-2 Cytokine 1 241 OS

Total 27 19 065

Slide courtesy of JC Soria

NSCLCMarker

A

NSCLCMarker

B

Drug A

Drug B

Targeted therapies?

BR.21 (Shepherd et al, 2005):

Erlotinib vs. placebo in 2nd/3rd lineunselected NSCLC

PFS: 2.2 vs 1.8 Months(.4 months difference i.e. < 2 weeks)P<0.001

Spanish Lung Cancer Group (Rosell et al, 2009):

Erlotinib in 1st/2nd lineEGFR mutant selected NSCLC

PFS: 14 months

EGFR mutant selected NSCLC

Unselected NSCLC

Ou et al, JTO 2010Rapid and dramatic tumor response in ALK+ NSCLC to crizotinib

Best Percent Change from Best Percent Change from Baseline in Baseline in Target Lesions Target Lesions

% D

ecre

ase

or

incr

ease

fro

m b

ase

lin

e

Progressive disease

Stable disease

Partial response

Complete response

100

80

60

40

20

0

–20

–40

–60

–80

–100

Objective response details(all evaluable patients)

N=116

ORR (95% CI) 61% (52, 70)

Median response duration 48 weeks

Median time to response 8 weeks

Disease control rate at 8, 16 weeks 79%, 67%

Camidge et al, ASCO 2011

Potential predictive biomarkers Potential predictive biomarkers (both categorical and continuous (both categorical and continuous variables)variables)• TumorTumor

– MutationsMutations– Gene rearrangementsGene rearrangements– Gene copy numberGene copy number– Protein expression/expression levelProtein expression/expression level– Transcript(s) levelsTranscript(s) levels

• HostHost– Immune systemImmune system– VasculatureVasculature– Endocrine environmentEndocrine environment

Personalized medicine in Personalized medicine in oncologyoncology

Unselected largepopulation, modestoverall benefit

Selected small population, large benefit

From a drug-perspective, the From a drug-perspective, the limits will only be partly set by limits will only be partly set by the targetsthe targets

KinaseKinasess Protein-Protein-

ProteinProteinInteractionsInteractions

ImmuneImmuneEffectorsEffectors

NucleiNucleiccAcidAcid

Beyond chemoTranscriptional repressors (e.g. YM155)SiRNAMiRNAGene therapy •Challenges set by the methods of drug delivery

•But required - given the challenge of most oncogenic changes being loss of function …

Most of the limits are far more Most of the limits are far more immediate and more ‘obvious’immediate and more ‘obvious’• There are no common cancersThere are no common cancers

– The practical implications of heterogeneityThe practical implications of heterogeneity– The financial consequences of heterogeneityThe financial consequences of heterogeneity

• Today’s miracles aren’t curing anyoneToday’s miracles aren’t curing anyone– The brain is a special placeThe brain is a special place– Addressing molecular Addressing molecular

mechanisms of resistancemechanisms of resistance– Darwinian oncologyDarwinian oncology

The elephant(s) in the room

1. There are no common 1. There are no common cancerscancers

516 analyzed cases: Incidence of Oncogenic Drivers

Mutation found in 54% (280/516) ofTumors: 97% mutually exclusive

Kris et al, ASCO 2011

1.1 The practical implications 1.1 The practical implications of heterogeneity in clinical of heterogeneity in clinical researchresearch

Origin of lung cancer patients (green circles) who participated in crizotinib clinical trials at the University of Colorado (red circle) (62% from Colorado, 36% from other US States, 2% International (Johannesburg, South Africa; not shown)).

Have mutation, will travelHave mutation, will travel

Camidge et al., Camidge et al., J Thoracic Oncol. J Thoracic Oncol. (2011)(2011)

Table 2: Multivariate analysisTable 2: Multivariate analysis

ParameterParameter HRHR 95% CI95% CIP value P value

(Chi squared)(Chi squared)Molecular status Molecular status (vs. triple negative)(vs. triple negative) ALKALK++ 0.360.36 0.17-0.730.17-0.73 0.0051*0.0051* EGFR EGFR mutantmutant 1.01.0 0.49-2.040.49-2.04 0.99830.9983 KRAS KRAS mutantmutant 0.550.55 0.28-1.10.28-1.1 0.09520.0952Line of therapy Line of therapy 1.571.57 1.07-2.311.07-2.31 0.0221*0.0221*Age at diagnosisAge at diagnosis 1.01.0 0.98-1.020.98-1.02 0.79180.7918Smoking status Smoking status (vs. non-smokers)(vs. non-smokers) 1.061.06 0.63-1.760.63-1.76 0.83680.8368Histology Histology (vs. adenocarcinoma)(vs. adenocarcinoma) Adeno-squamousAdeno-squamous 0.460.46 0.1-2.060.1-2.06 0.30930.3093 Large cellLarge cell 15.115.1 3.8-59.933.8-59.93 0.0001*0.0001* SquamousSquamous 6.076.07 0.73-50.660.73-50.66 0.09580.0958

Type of therapy Type of therapy (vs. pemetrexed monotherapy)(vs. pemetrexed monotherapy)

Non-platinum combinationNon-platinum combination 0.50.5 0.25-1.00.25-1.0 0.04940.0494

Platinum combinationPlatinum combination 0.850.85 0.44-1.630.44-1.63 0.61820.6182SexSex 1.591.59 0.96-2.640.96-2.64 0.07460.0746

* P values <0.05* P values <0.05

PFS by molecular status on pemetrexed-PFS by molecular status on pemetrexed-based therapybased therapy

Ongoing randomized trials of crizotinib Ongoing randomized trials of crizotinib in in ALKALK+ NSCLC+ NSCLC

PROFILE 1007 (N=318)PROFILE 1007 (N=318)

● ALK-FISH positiveALK-FISH positive

● 1 prior chemotherapy 1 prior chemotherapy (platinum-based)(platinum-based)


● ALK-FISH positiveALK-FISH positive

● 1 prior chemotherapy 1 prior chemotherapy (platinum-based)(platinum-based)

RRAANNDDOOMMIIZZEE

RRAANNDDOOMMIIZZEE

Crizotinib 250 mg BID (n=159)Crizotinib 250 mg BID (n=159)[continuous][continuous]


pemetrexed pemetrexed 500 mg/m500 mg/m22 orordocetaxel 75 mg/mdocetaxel 75 mg/m22 (n=159) (n=159)

infused on day 1 of a 21-day cycleinfused on day 1 of a 21-day cycle

pemetrexed pemetrexed 500 mg/m500 mg/m22 orordocetaxel 75 mg/mdocetaxel 75 mg/m22 (n=159) (n=159)



● ALK-FISH positiveALK-FISH positive, non-, non-squamous NSCLCsquamous NSCLC

● No prior treatment for advanced No prior treatment for advanced diseasedisease


● ALK-FISH positiveALK-FISH positive, non-, non-squamous NSCLCsquamous NSCLC

● No prior treatment for advanced No prior treatment for advanced diseasedisease

RRAANNDDOOMMIIZZEE

RRAANNDDOOMMIIZZEE



pemetrexed/cisplatin orpemetrexed/cisplatin orpemetrexed/carboplatin (n=167)pemetrexed/carboplatin (n=167)


pemetrexed/cisplatin orpemetrexed/cisplatin orpemetrexed/carboplatin (n=167)pemetrexed/carboplatin (n=167)


Crossover on PDCrossover on PDCrossover on PDCrossover on PD

Tumor samples available from negative phase III trials of chemo vs new agent or chemo +/- new agent in NSCLC?

Compound Mechanism of action N° trials N End point

Gefitinib EGFR TKI 8 5975 OS

Erlotinib EGFR TKI 4 3661 OS

Afatinib EGFR/HER2 TKI 1 585 OS

Cetuximab EGFR antibody 1 676 PFS

Prinomastat Matrix metalloprotease inhibitor 2 1048 OS

Rebimastat Matrix metalloprotease inhibitor 1 774 OS

PF-676Toll-like receptor 9-activating

oligodeoxynucleotide 2 1667 OS

AprinocarsenProtein kinase C-alpha antisense

oligonucleotide 2 1286 OS

Bexarotene Retinoid X receptor activator 2 1235 OS

Lonafarnib Farnesyl-transferase inhibitor 1 675 OS

Figitumumab IGF-1R antibody 1 681 OS

Celecoxib Cox2 inhibitor 1 561 OS

IL-2 Cytokine 1 241 OS

Total 27 19 065

1.2 The financial 1.2 The financial consequences of consequences of heterogeneityheterogeneity

KRAS MtNSCLC

BRAF MtNSCLC

Every cancer is an orphan?

Orphan disease status:US = Prevalence <200,000 casesEU = Prevalence <5/10,000 population

20% lung adenocarcinomas < 20,000 cases/year

1% lung adenocarcinomas <1000 cases/year

When low biomarker frequency, cost of screening test dominates over cost of drug in cost effectiveness analysis. Lower screening test cost (red line ($500/person) vs blue line ($1,500/person screened)) shifts this inflexion point further to the left.

Flat line if screening cost = $0/person

Atherley and Camidge, Submitted

You can’t change the benefit from the drug in the marker positive population, soto be more cost effective either:

1. Reduce cost of drug

2. Reduce price of screening test per person positive

3. Screen more enriched populations

The ‘savings’ and ‘cost’ of The ‘savings’ and ‘cost’ of enrichment policiesenrichment policiesScreening Criteria Predicted

proportion of ALK positives

Percentage of total initial population

screened

Predicted number of ALK+ cases

found per 1000 Initial NSCLC cases

Predicted number of ALK+ cases

missed per 1000 Initial NSCLC cases

Advanced NSCLC 1.6% 100% 16 0

Advanced stage adenocarcinoma

3.7% 39% 14 2

Advanced stage adenocarcinoma /Never smokers

13.7% 5.80% 8 8

Advanced stage adenocarcinoma /Never smokers /EGFR and KRAS

wildtype

35.9% 2.00% 7 9

Atherley and Camidge, Submitted

2. Today’s miracles aren’t 2. Today’s miracles aren’t curing anyonecuring anyone

Is there a median PFS ceiling in Is there a median PFS ceiling in targeted therapy for oncogene targeted therapy for oncogene addicted NSCLC?addicted NSCLC?Study PFS to specific inhibitor in marker

positive population

EGFR mutant NSCLC with EGFR inhibitor

Spanish Lung Cancer Group (erlotinib) 14 months

EURTAC (erlotinib) 9.7 months

OPTIMAL (erlotinib) 13.1 months

IPASS (gefitinib) 9.5 months

NEJ 002 (gefitinib) 10.8 months

WJTOG 3405 (gefitinib) 9.2 months

ALK rearranged NSCLC with ALK inhibitor

1001 (crizotinib) 10 months

Potential mechanisms of ‘acquired’ Potential mechanisms of ‘acquired’ resistance:resistance:

• Fail to deliver drug to targetFail to deliver drug to target– E.g. Non complianceE.g. Non compliance– E.g. PK sanctuary sites (e.g. E.g. PK sanctuary sites (e.g. CNSCNS))

• Alter targetAlter target– E.g. Gate-keeper or conformational change E.g. Gate-keeper or conformational change

mutations in drug targetmutations in drug target• Bypass targetBypass target

– E.g. Develop second oncogenic driversE.g. Develop second oncogenic drivers– E.g. Downregulate effector pathwaysE.g. Downregulate effector pathways

2.1 The brain is a special 2.1 The brain is a special placeplace

Grommes et al, Neuro-Oncology 2011

EGFR MT disease: CNS progressionEGFR MT disease: CNS progression

Grommes et al, Neuro-Oncology 2011

1500 mg erlotinib weekly (high dose intermittent)

44% ORR

Median CNS PFS 2.7 months (range: 0.8-14.5 m)

ALK progression within brainALK progression within brain

Costa et al, JCO 2011

•29 y/o male with ALK+ NSCLC•Systemic (body) control but brain progression

•Blood and cerebrospinal fluid(CSF) sampling 5 hours after taking 250mg crizotinib

•CSF:plasma ratio = 0.0026 (i.e. <0.3% gets into brain) ?too low to work on ALK

•Caveats: One patient, blood brain ‘barrierness’ may vary, ‘free’ drug may differ

Who needs new targets? The brain in Who needs new targets? The brain in clinical trialsclinical trials

Status of extra-CNS disease

Status of CNS disease Overall plan

Stable/responding Progressing Log PFS for CNS, treat with local CNS Rx, continue drug and log extra-CNS PFS timepoint when occurs

Progressing Stable/responding Log PFS for extra-CNS, if able to give local systemic therapy then continue drug until CNS progresses, if systemic therapy has to change or stop then censor CNS

Progressing Progressing Log PFS both CNS and extra-CNS, no specific trial follow up, ongoing drug at investigator discretion

1. Only first progression considered.2. OS follow may continue in any scenario3. Mandates baseline and routine CNS surveillance on study

2.2 Addressing molecular 2.2 Addressing molecular mechanisms of resistancemechanisms of resistance

EGFR Mutant:EGFR Mutant:acquired acquired resistance resistance mechanismsmechanisms

Sequist et al, Science Translational Medicine2011

Natural selection of resistant clones while most disease still controlled by crizotinib

Natural selection of resistant clones while most disease still controlled by crizotinib

Baseline: July 2009 Crizotinib response:Sept 2009 November 2009

April 2010: New right adrenal -SBRT & crizotinib continues

August 2010: New LN – More SBRT & crizotinib

October 2010: New LN – More SBRT & crizotinib

Drugs for AR: Rapid Deployment Drugs for AR: Rapid Deployment Forces vs. Armies of Occupation?Forces vs. Armies of Occupation?

• Adding in/replacing with each new drug at Adding in/replacing with each new drug at time of AR?time of AR?

• Or combine up front?Or combine up front?

• Tolerability of new drug(s)?Tolerability of new drug(s)?

Afatinib + cetuximab at MTD.Responses by mutation

40% confirmed response rate and a clinical benefit rate of 90%Appears independent of T790M status as assessed in study

N = 45

Abstract 7525ASCO 2011

2.3 Darwinian Oncology2.3 Darwinian Oncology

Number of CTCs (micropost) and frequency of different alleles (L858R/Del/T790M)relative to control, alters with treatment and parallels radiographic response (Top panels – [X] = low frequency allele) (Bottom panels –number of amplification cycles for detection – left to right panel at different points in treatment)

Maheswaran et al, NEJM 2008

Pt 9 T790M present [low levels] inCTCs– still ‘responds’to reversible TKIs as T790M is not an all/none event

Diversity pre-exists(?hard-wired) In patients who manifested MET gene amp as mechanism of

acquired resistance, rare amplified cells were seen pre-EGFR TKI treatment

Turke et al, Cancer Cell 2010

Why is the TKI naïve molecular Why is the TKI naïve molecular status as it is?status as it is?

• Why don’t T790M and MET amplified EGFR Why don’t T790M and MET amplified EGFR mutants dominate prior to EGFR TKI?mutants dominate prior to EGFR TKI?– Easier to develop the basic model?Easier to develop the basic model?– T790M and/or MET plus EGFR MT have T790M and/or MET plus EGFR MT have

some some disadvantagedisadvantage in the absence of a in the absence of a specific selection pressure?specific selection pressure?

Changes in Unidimensional CT Measurements (RECIST) Changes in Unidimensional CT Measurements (RECIST) After Discontinuation and Re-Introduction of EGFR TKIAfter Discontinuation and Re-Introduction of EGFR TKI

-30%

0%

20%

50%

EGFR TKIstop re-start

3 weeks 3 weeks

Ch

an

ge

fro

m b

ase

line

Riely et al ‘07

Re-emergence of partial EGFR TKI sensitivity during time off EGFR TKI therapy (relaxation of

specific selection pressure)

Known L858R07/07 2nd line erlotinib (PR)03/09 PD (new MET amp)Sunitinib +/- pemetrexed trialuntil PD in 04/2010

PD on chemo (MET amp)

04/2010 Minor response to erlotinibrechallengePD in 08/2010

Minor short-lived responseto erlotinib rechallenge

CMF09048 Sample: N09-633 A2Received – 3/12/09 Reported – 3/18/09Mean MET= 13.07; sd= 4.51Mean CEP7= 3.17; sd= 1.74Ratio MET/CEP7 = 4.13L858R EGFR mutation

CMF10009 Sample: S10-208 A1Received – 1/12/10 Reported – 1/15/10Mean MET= 9.24; sd= 5.17Mean CEP7= 4.20; sd= 1.41Ratio MET/CEP7 = 2.20L858R EGFR mutation

Gem/Carbo(PR)

ConsolidativeSBRT

= 1 month

XRT to bone met

Erlotinib(PR)

PD pleura/lung/bones

Pem/Sut trial(PR)

Doc (PD)Gem (PR)Clinical trial (EGFR/MET) ongoing

05/2006

12/2010

10 months off erlotinib selection pressure

Biston betularia(morpha typica)

1848 – carbonaria morph first described

By 1895 – 98%carbonaria

Natural selection, secondary to industrial soot blackening the environment, would not have been obvious if all local insects, rather than just the peppered moth, had been studied together as a single group.

Changes in Unidimensional CT Measurements (RECIST) Changes in Unidimensional CT Measurements (RECIST) After Discontinuation and Re-Introduction of EGFR TKIAfter Discontinuation and Re-Introduction of EGFR TKI

-30%

0%

20%

50%

EGFR TKIstop re-start

3 weeks 3 weeks

Ch

an

ge

fro

m b

ase

line

Riely et al ‘07

Drug sensitive cells survive drug

‘Sleeper’ cell? Therapy

Relaxation of dark blue specific

selection pressure

Sleeper cellsor unstable variants(blue can generate white and vice versa)?

‘UnstableVariants’?

Therapy


selection pressure

Stem cell? Therapy


selection pressure

Repopulationfrom universalprogenitorrepeating selectionprocess again?

PC-9 EGFR exon 19 del NSCLC cell lineSensitive to reversible EGFR TKI0.3% of starting population survive(drug tolerant persisters – largely quiescent) – that can be expandedFrom quiescent state over time (drug tolerant expanded persisters).No loss of mutation, no T790M, no MET

9 days 33 days

Sharma et al, Cell 2010

Panel E: DTPs grown without erlotinib for 9 doublingsreacquire drug sensitivityPanel F: DTEPs require ~30 passages to reacquiresame drug sensitivity

Drug tolerant persisters

Sharma et al, Cell 2010

Among multiple combinations withErlotinib, only HDAC inhibitors andan IGF1R inhibtor (AEW541) preventedemergence of DTEPs

HDACI then erlotinib did not preventDTEP Eemergence – HDACI must be present at time of selection pressureas DTPs continuously generated

Combine targeted therapy in selected populationwith additional therapy directed to purge cancer of its reservoir of resistance?

Clinical outcome: Response duration? PFS? (assessing pattern of failure)

The Limits:The Limits:

• Making non-chemo nucleic acid targeted therapies Making non-chemo nucleic acid targeted therapies deliverable and addressing loss of function driversdeliverable and addressing loss of function drivers

More immediately…More immediately…• Addressing heterogeneity:Addressing heterogeneity:

– In trial design and interpretationIn trial design and interpretation– In the financial aspects of developing new treatmentsIn the financial aspects of developing new treatments

• Giving the CNS credit for being differentGiving the CNS credit for being different• Optimally monitoring, defining and treating Optimally monitoring, defining and treating

acquired resistanceacquired resistance• Addressing the existence of ‘reservoirs of Addressing the existence of ‘reservoirs of

resistance’resistance’

The End of the Beginning…

Contact: D. Ross Camidge MD, [email protected]

University of ColoradoUniversity of ColoradoThoracic Oncology ProgramThoracic Oncology ProgramPositions now available for outstanding:Positions now available for outstanding: Senior Clinical FellowsSenior Clinical FellowsPost-Doctoral ScientistsPost-Doctoral Scientists

Acquired resistance (AR) Acquired resistance (AR) monitoringmonitoring

• Most appropriate imaging? PET or not?Most appropriate imaging? PET or not?• Molecular follow-up? Quantitation issuesMolecular follow-up? Quantitation issues

Maheswaran et al, NEJM 2008

Documents

Targeted therapies in lung cancer - what are the limits? D. Ross Camidge, MD PhD Director, Thoracic Oncology Clinical Program University of Colorado Halifax,