cco metastatic nsclc slides

Non-Small-Cell Lung Cancer: Transformations in the Care of Metastatic Disease

This program is supported by educational grants from Celgene Corporation and Lilly.

clinicaloptions.com/oncologyTransformations in the Care of Metastatic Disease

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Core Faculty

Corey J. Langer, MD, FACPDirector, Thoracic OncologyAbramson Cancer CenterProfessor of MedicineHematology-Oncology DivisionUniversity of PennsylvaniaPhiladelphia, Pennsylvania

Heather Wakelee, MDAssociate Professor of Medicine, OncologyDepartment of Medicine/OncologyStanford UniversityStanford, California


Faculty Disclosures

Corey J. Langer, MD, FACP, has disclosed that he has received funds for research support from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Nektar, OSI, and Pfizer and consulting fees from Abbott, Abraxis, Amgen, AstraZeneca, Bayer/Onyx, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Caris Dx, Celgene, Clarient, Genentech, ImClone, Lilly, Morphotek, Novartis, Pfizer, sanofi-aventis, Synta, and Vertex and served on a DSMC for Amgen, Agennix, Lilly, and Synta.

Heather Wakelee, MD, has disclosed that she has received consulting fees from Peregrine and funds for research support (paid to Stanford) from AstraZeneca, Bristol-Myers Squibb, Celgene, Clovis, Exelixis, Genentech/Roche, Lilly, Novartis, Pfizer, Regeneron, and Xcovery.

Individualizing Therapy for Advanced/Metastatic NSCLC


Adeno LCC-NOS SqCC SCLC

EGFR mutants ALK ROS/RET

HER2

BRAF KRAS

KRAS

Changes in the Therapeutic Landscape of Stage IV Lung Cancer


Tissue sent to pathology

Morphologic analysis

IHC, special stains

Tumor genotyping

Tumor biomarkers

Paradigm Shift in Pathology . . .


NSCLC Biopsy: Key Factors Adequate tissue for molecular analysis is critical to best

select first-line NSCLC therapy

Determination of EGFR mutation and ALK translocation status is indicated

– Should other genes be evaluated? ROS1, KRAS, BRAF, HER2, others

Rebiopsy at time of progression helpful in determining resistance mechanisms

Bone biopsy less ideal due to decalcification and degradation of DNA

Liquid biopsies in development


Circulating Tumor DNA Tumors continually shed DNA into the circulation

ctDNA analysis (liquid biopsy or blood sample)

– Can identify both genetic and epigenetic aberrations

– Can provide the genetic landscape of all cancerous lesions (primary and metastases)

– Opportunity to systematically track genomic evolution

– Potential utility in inaccessible lesions and bone-only tumor

Crowley E, et al. Nat Rev Clin Oncol. 2013;10:472-484.

Tumor Histology


Histology in Management of Advanced- Stage Non-Oncogene–Driven NSCLC What is the current treatment

algorithm in the absence of a known and targetable oncogenic driver?

Is NSCLC histologic subtype prognostic (ie, portends pt outcome independent of therapeutic intervention)?

Is NSCLC histologic subtype predictive of differential benefit from available therapies?

Large Cell

Squamous

Adenocarcinoma


Pathologic Assessment of Histology Helps Determine Optimal Treatment Histology still guides the therapeutic choice for the vast

majority of pts

Classify pts as squamous or nonsquamous

Adenocarcinomas are TTF1 positive (70% to 90%) and generally negative for p63 (70%) and p40 (97%)[1-4]

Squamous cells are typically p63 (or p40) positive and TTF1 negative[1-4]

All pts who do not have bona fide squamous NSCLC should be considered nonsquamous

1. Di Loreto C, et al. J Clin Pathol. 1997;50:30-32. 2. Fabbro D, et al. Eur J Cancer. 1996;32A:512-517. 3. Rekhtman N, et al. Mod Pathol. 2011;24:1348-1359. 4. Bishop JA, et al. Mod Pathol. 2012;25:405-415.


Histologic Subtypes of NSCLC: US

Wahbah M, et al. Ann Diagn Pathol. 2007;11:89-96.American Cancer Society database.

Decreasing Incidence of Squamous Cell Subtype Over Time

85% of lung cancers are NSCLC

AdenocarcinomaSquamous cell carcinomaLarge cell carcinomaOther or not otherwise specified

40%20%

10% to 15%

25% to 30%

AdenocarcinomaSquamous cellLarge cell

454035302520151050

Can

cer I

ncid

ence

(%)

Yr of Diagnosis (3-Yr Moving Average)

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

Tumor Molecular Profile


Frequency of Driver Abnormalities in NSCLC, %

AKT1 1

ALK 3-7

BRAF 1-3

EGFR 10-35

HER2 2-4

KRAS 15-25

MEK1 1

NRAS 1

PIK3CA 1-3

RET 1-2

ROS1 1

BRAFHER2

MEK1

AKT1

ALK

PIK3CA

NRAS

ROS1RET

www.mycancergenome.org.

Molecular Subsets of Lung Cancer Defined by Driver Abnormalities*

UnknownKRAS

EGFR

*Double mutations are rare (< 3%)


Selection for Molecular Testing in NSCLC All pts with an adenocarcinoma

component should be tested Pure SCC diagnosis is appropriate for

EGFR mutation and ALK testing in some clinical settings[1]

– Young, never, or light smoker

– Poor quality/small sample

– East Asian ethnicity (EGFR mut testing)

Primary tumors and metastatic lesions are equally suitable for testing[1]

– Discordance between mut status primary tumor and metastases uncommon for EGFR mut and ALK translocation (in previously untreated pts)[3]

If sensitizing EGFR mutation or ALK is unknown, consider ROS1 testing[4]

1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859. 2. D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070. 5. Yatabe Y, et al. J Clin Oncol. 2011;29:2972-2977. 4. NCCN. Lung cancer. v5.2015.

Pack-Yrs[2] EGFR Mutation, % 95% CI

Never 52 48-56

1-5 34 25-43

6-10 34 26-44

11-15 18 11-26

16-25 11 7-16

26-50 8 6-11

51-75 9 5-13

> 75 4 2-8


Molecular Testing Guideline: EGFR and ALK Pts SHOULD NOT be treated with first-line EGFR and

ALK inhibitors based on clinical characteristics alone

– If one uses clinical characteristics alone, EGFR inhibitors will be inappropriately given first line to 40% to 60% of pts

Pts SHOULD NOT be offered or denied testing based on clinical characteristics alone

Pathologic sample preparations using heavy metal fixatives or acidic solutions compromise molecular testing[1]

– eg, avoid bone biopsy for molecular testing due to decalcifying solutions, which denature the DNA

1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859.

Selecting Therapy Based on Tumor Histology


1.0

0.8

0.6

0.4

0.2

0

Cis/Gem vs Cis/Pem in Advanced NSCLC: OS by Histology

Mos

Surv

ival

Pro

babi

lity

SquamousNonsquamous

Mos

Surv

ival

Pro

babi

lity

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

C/PC/G

C/P vs C/G

Median Survival11.8 mos10.4 mosAdjusted HR: 0.81(95% CI: 0.70-0.94)

C/PC/G

C/P vs C/G

Median Survival9.4 mos10.8 mosAdjusted HR: 1.23(95% CI: 1.00-1.51)

1.0

0.8

0.6

0.4

0.2

0300 6 12 18 24 300 6 12 18 24


Carbo/Albumin-Bound Paclitaxel vs Carbo/Paclitaxel in Advanced NSCLC

Phase IIIPrimary endpoint: ORRSecondary endpoints: PFS, OS, safety

Pts with stage IIIb/IV NSCLC, ECOG PS

0-1, no previous chemotherapy for metastatic disease

(N = 1050)

Nab-Paclitaxel 100 mg/m2 on Days 1, 8, 15 +Carboplatin AUC 6 on Day 1

No premedication

Paclitaxel 200 mg/m2 on Day 1 +Carboplatin AUC 6 on Day 1

Premedication: dexamethasone, antihistamines

Stratified by stage (IIIb vs IV), age (< 70 yrs vs > 70 yrs), sex,

histology (squamous vs nonsquamous), geographic region

21-day cycles

Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.


P = .005RRR: 1.3133%

25%

Intent to Treat

Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Carbo/Nab-Paclitaxel vs Carbo/Paclitaxel in Advanced NSCLC: Responses*

Carboplatin/albumin-bound-paclitaxelCarboplatin/paclitaxel

Res

pons

e R

ate

(%)

P < .001RRR: 1.680

P = .808RRR: 1.034

41%

26%24% 25%

0

10

20

30

40

50

Squamous† Nonsquamous†

229 221 292 310

*Independent radiological review. †Not a prespecified endpoint. Interaction P value for histology = .036

521 531n =


Bevacizumab-Containing Regimens in Advanced Nonsquamous NSCLCOutcome E4599[1]

(N = 878)AVAiL[2,3]

(N = 1043; P values vs placebo)JO19907[4]

(N = 180)PCB PC CGB

(7.5 mg/kg)CGB

(15 mg/kg)Placebo +

CGPCB Placebo

+ PCORR, % 35 15 37.8 34.6 21.6 60.7 31.0

P < .001 P < .0001 P = .0002 P = .001

HR for PFS 0.66P < .001

0.75P = .0003

0.85P = .046

0.61P = .009

Median PFS, mos 6.2 4.5 6.7 6.5 6.1 6.9 5.9

HR for OS 0.79P = .003

0.93P = NS

1.03P = NS

0.99P = .95

Median OS, mos 12.3 10.3 13.6 13.4 13.1 22.8 23.4

1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234.3. Reck M, et al. Ann Oncol. 2010;21:1804-1809. 4. Niho S, et al. Lung Cancer. 2012;362-367.


Maintenance Therapy for Pts With Nonprogressive Disease*

Pts with at least SD after 4 cycles

of CT, PS 0-1

Continuation Maintenance

Observation

Switch Maintenance

Observation

Early 2nd-line Therapy

Observation

Bevacizumab, cetuximab, or pemetrexed (cat 1)

Bevacizumab + pemetrexed

Gemcitabine (2B)

Category 2B:Docetaxel,Pemetrexed,Erlotinib,Gefitinib

NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.

Options:

*After initial platinum-based chemotherapy.


NSCLC Maintenance Therapy: Advantages and Disadvantages

Advantages

Maintains disease control

Improves PFS

Improves OS

Maintains quality of life

Opportunity to treat more pts

Pts support maintenance therapy

Disadvantages

Induction regimens of 4 vs 6 cycles may achieve the same improvement in PFS

Careful follow-up reveals more pts available for second-line therapy than initially estimated by early reports

Cumulative toxicity with Grade 3/4 AEs in 30% to 40% of pts

Cost

Lack of reliable predictive biomarkers


Second-line (or Third-line) Therapy for Advanced NSCLC (Non-Oncogene Driven) Commonly used options

– Docetaxel ± ramucirumab

– Pemetrexed

– Erlotinib

– Gemcitabine

– Nivolumab

Multiple investigational options

Adapted from NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.


100

80

60

40

20

0

REVEL: Docetaxel ± VEGFR2 Antibody Ramucirumab in 2nd-Line NSCLC

First study in the second-line setting to show an OS advantage for the addition of a “targeted” agent to docetaxel compared with docetaxel alone

First and only study of angiogenesis inhibition in advanced NSCLC to show a benefit in a squamous cell cancer cohort

Overall Survival Phase III Study

Ram + Doc

Pl + Doc

P Value

ORR,%(95% CI)

22.9(19.7-26.4)

13.6(11.0-16.5)

< .001

Median PFS, mos(95% CI)

4.5 (4.2-5.4)

3.0 (2.8-3.9)

HR: 0.72

< .0001

Perol M, et al. ASCO 2014. Abstract LBA8006^.

0 3 6 9 12 15 18 21 24 27 30 33 36Survival Time (Mos)

OS

(%)

Ram + Doc 10.5 (9.5-11.2) 31.8%Pl + Doc 9.1 (8.4-10.0) 27.0%Ram + Doc vs Pl + Doc:Stratified HR: 0.857 (95% CI: 0.751-0.979)Stratified log-rank P = .0235

Median (95% Cl) Censoring Rate

Ram + DocPl + Doc

Selecting Therapy Based on Tumor Molecular Profile


Activity of Crizotinib in Pts With ROS1 Fusions: Best Overall Response

Shaw AT, et al. N Engl J Med. 2014;371:1963-1971.

ORR: 72%

100

80

60

40

20

0

-20

-40

-60

-80

-100

Cha

nge

From

Bas

elin

e (%

)

PDSDPRCR


Targeted Therapy Focuses on Driver Gene Alterations: “Oncogenic Addiction”

Gefitinib[1,2] Erlotinib[3,4] Afatinib[5,6] Crizotinib[7-9]

Activity EGFR EGFR EGFR(ErbB family) ALK, ROS1, MET

Target EGFR EGFR EGFR ALK

RR, % 60-80 50-80 ~ 60 ~ 60

PFS, mos 10-11 10-14 ~ 11 ~ 10

TRD, % 1~2 1~2 1.7 < 1

EGFR mutants ALK ROS/RET

1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334. 6. Wu YL, et al. Lancel Oncol. 2014;15:213-222. 7. Camidge DR, et al. Lancet Oncol 2012;10:1011-1019. 8. Kim DW, et al. ASCO 2012. Abstract 7533. 9. Shaw AT, et al. N Engl J Med 2013;368:2385-2394.


Johnson B, et al. ASCO 2013. Abstract 8019.

Lung Cancer Mutation Consortium: OS by Mutation and Treatment

Driver mutation + targeted therapy (n = 313; median OS: 3.5 yrs)Driver mutation + no targeted therapy (n = 265; median OS: 2.4 yrs)No driver mutation (n = 361; median OS: 2.1 yrs)

100

80

60

40

20

0

OS

(%)

0 1 2 3 4 5Yrs

Targeted therapy vs no targeted therapy; P < .0001

EGFR Mutation


Paclitaxel 200 mg/m2/

Carboplatin AUC 5 or 6‡

Gefitinib†

250 mg/day

*Never smokers (< 100 cigarettes in lifetime) or light ex-smokers(stopped 15 yrs ago and smoked 10-pack yrs).†Carboplatin/paclitaxel was offered to gefitinib pts upon progression.‡Limited to a maximum of 6 cycles.

Pts Chemo naive Aged ≥ 18 yrs Adenocarcinoma

histology Never or light ex-

smokers* Life expectancy

≥ 12 wks PS 0-2 Measurable stage

IIIB/IV disease

EndpointsPrimary PFS (noninferiority) Secondary ORR OS Quality of life Disease-related symptoms Safety and tolerability

Exploratory Biomarkers

– EGFR mutation

– EGFR gene copy number

– EGFR expression

Mok TS, et al. N Engl J Med. 2009;361:947-957. Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.

IPASS: First-line Gefitinib vs Paclitaxel/ Carboplatin


IPASS: PFS by EGFR Mutation Status Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)

PFS: gefitinib superior to carboplatin/paclitaxel in ITT population

EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel

Mok TS, et al. N Engl J Med. 2009;361:947-957.

EGFR Mutation Positive

HR: 0.48 (95% CI: 0.36-0.64; P < .001)

Prob

abili

ty o

f PFS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

EGFR Mutation Negative

HR: 2.85 (95% CI: 2.05-3.98; P < .001)

Prob

abili

ty o

f PF

S

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

GefitinibPac/carbo

GefitinibPac/carbo


Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605

Favors EGFR TKI Favors Chemo

Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS

StudyHR

(95% CI)HR

(95% CI)

EGFRmut (first-line therapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUX LUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal

0.37 (0.25-0.54)0.54 (0.27-1.10)1.08 (0.24-4.90)0.55 (0.19-1.60)0.48 (0.36-0.64)0.58 (0.43-0.78)0.32 (0.24-0.44)0.16 (0.11-0.26)0.59 (0.21-1.67)0.90 (0.39-2.06)0.49 (0.20-1.20)0.52 (0.38-0.72)0.43 (0.38-0.49)


Phase II Study: Erlotinib ± Bevacizumab in Advanced NSCLC With EGFR Mutations

Open-label study

Primary endpoint: PFS (independent review; RECIST)

Secondary endpoints: OS, tumor response; QoL, safety

Seto T, et al. Lancet Oncol. 2014;15:1236-1244. Kato T, et al. ASCO 2014. Abstract 8005.

Pts with chemo-naive, nonsquamous

NSCLC and EGFR mutations (del 19, L858R), no brain

mets(N = 154)

Treat until disease

progression

Erlotinib 150 mg QD +Bevacizumab 15 mg/kg q3w

(n = 77)

Erlotinib 150 mg QD(n = 77)


75 72 69 64 60 53 49 38 30 20 13 8 4 4 077 66 57 44 39 29 24 21 18 12 10 5 2 1 0

00

1.0

EEBPts at Risk, n Mos

4 8 122 6 10 14 18 22 2616 20 24 28

0.2

0.4

0.6

0.8

Prob

abili

ty o

f PFS

9.7 16.0

EBE

Seto T, et al. Lancet Oncol. 2014;15:1236-1244. Kato T, et al. ASCO 2014. Abstract 8005.

Erlotinib ± Bevacizumab in Advanced NSCLC With EGFR Mutations: PFS

.0015


LUX-Lung 3+6: OS by del(19) and L858R Mutation Status

Yang JCH, et al. Lancet Oncol. 2015;16:141-151.

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

Prob

abili

ty

0 6 12 18 24 30 36 42 48Mos

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

Prob

abili

ty

Mos0 6 12 18 24 30 36 42 48

Del(19)Afatinib (n = 236)

Chemo (n = 119)

Median, mos 31.7 20.7 HR (95% CI) 0.59 (0.45-0.77)

P = .0001

L858RAfatinib (n = 183)

Chemo (n = 93)

Median, mos 22.1 26.9 HR (95% CI) 1.25 (0.92-1.71)

P = .1600


EGFR Inhibitor–Associated Skin Rash: ManagementPreventive Recommended Not Recommended Comments

TopicalHydrocortisone 1% cream with

moisturizer, sunscreen twice daily Pimecrolimus 1% cream Tazarotene 0.05% cream Sunscreen as single agent

Systemic Minocycline 100 mg/day Doxycycline 100 mg BID

Tetracycline 500 mg BID Doxycycline is preferred in pts

with renal impairment;

minocycline is less photosensitizing

Treatment Recommended Not Recommended Comments

Topical Alclometasone 0.05% cream Fluocinonide 0.05% cream BID Clindamycin 1%

Vitamin K1 cream

Systemic Doxycycline 100 mg BID Minocycline 100 mg/day Isotretinoin at low doses

(20-30 mg/day)

Acitretin Photosensitizing agents

Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.


Oligo-PD

Systemic-PD

CNS-PD(Sanctuary)

Acquired Resistance to Targeted TKIs: PD Subtype Influences Clinical Practice

Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.

RemissionBaseline Multiple PD Lesions

TherapyContinuedTherapy

RemissionBaseline “Solitary” New Lesions


Complete RemissionBaseline


Brain-Only PD

InadequateCNS penetration?

Drug


Acquired Resistance in NSCLC: Studies Comparing EGFR TKIs

Pts activating EGFR TK mutResistance to first-line gefitinib,

No prior chemo(planned N = 287)[1]

Cisplatin/Pemetrexed

Cisplatin/Pemetrexed + ongoing Gefitinib Primary endpoint: PFS

PIs: Tony Mok, Jean-Charles Soria

Stage IV NSCLCActivating EGFR TK mutation,

Resistance to first-line erlotinib,PS 0/1

(planned N = 120)[2]

Cisplatin or Carboplatin + Pemetrexed, ongoing Erlotinib

Cisplatin or Carboplatin + Pemetrexed

Primary endpoint: PFS PI: Leora Horn Erlotinib retreatment

after progression

Stratified by EGFR mutation (exons 19

vs 21), TTP on EGFR TKIs (< vs > 1 yr), PS (0 vs 1)

1. ClinicalTrials.gov. NCT01544179. 2. ClinicalTrials.gov. NCT01928160.


IMPRESS: Cis/Pem ± Gefitinib in Stage IIIb/IV NSCLC w/EGFR Mutations and PD

Primary endpoint: PFS Secondary endpoints: OS, ORR, DCR, safety/tolerability, QoL Exploratory endpoints: biomarkers Randomization did not include stratification factors; analyses adjusted for

age (< vs ≥ 65 yrs) and prior gefitinib response (SD vs PR/CR)

Pts with stage IIIb/IV NSCLC, EGFR

mutations, chemo naive, response ≥ 4 mos with first-line

gefitinib, PD < 4 wks prior to randomization

(N = 265)

Cisplatin 75 mg/m2 +Pemetrexed 500 mg/m2 (≤ 6 cycles) +

Gefitinib 250 mg(n = 133)

Cisplatin 75 mg/m2 +Pemetrexed 500 mg/m2 (≤ 6 cycles) +

Placebo 250 mg(n = 132)

Mok T, et al. ESMO 2014. Abstract LBA2_PR.

Phase III trial


Gefitinib (n = 133)

Placebo (n = 132)

Median PFS, mos 5.4 5.4

Events, n (%) 98 (73.7) 107 (81.1)

HR: 0.86 (95% CI: 0.65-1.13; P = .273)

Gefitinib (n = 133)Placebo (n = 132)

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10 12 14

Prob

abili

ty o

f PFS

Time of Randomization (Mos)Pts at Risk, n Gefitinib Placebo

133132

110100

8885

4039

2517

125

64

00

HR < 1 implies lower risk of progression with gefitinib

Med OS: 14.8 mos (G) vs 17.2 mos (P)HR: 1.62 (P = .029) but 33% of events

IMPRESS: Cis/Pem ± Gefitinib in Stage IIIb/IV NSCLC w/EGFR Mutations: PFS

Mok T, et al. ESMO 2014. Abstract LBA2_PR.


Observed Resistance Mechanisms

N = 37

T790M (total) + EGFR amp + beta-catenin + APC

21421

MET amplification 2

PIK3CA 3

SCLC transformation 5

Epithelial-mesenchymal transition

2

No changes identified 8

Sequist LV, et al. Sci Trans Med. 2011;3:75ra26.

Repeat Biopsies for Pts With NSCLC and Acquired Resistance to EGFR inhibitors

T790M(49%)

Unknownmechanism

(30%)

WithEGFRamp

METamp(5%)

PIK3CA(5%)

SCLCtransformation(14%)


Third Generation EGFR TKIs

EGFR TKI N ORR* T790M-

ORR T790M+

PFS Toxicity

Rociletinib (CO-1686)[1]

256 37% 53% ~8.0 mos Hyperglycemia

AZD9291[2] 253 21% 61% ~8.2 mos(9.6 mos T790+,2.8 mos T790-)

Diarrhea

HM61713[3] 34/62 12%(300 mg)

55%(800 mg)

NR Dyspnea/rash

EGF816X[4] 53 - 60% NR Rash

ASP8273[5] 47 ~33% 61% NR Hyponatremia/diarrhea

1. Sequist LV, et al. ASCO 2015. Abstract 8001. 2. Jänne PA, et al. New Engl J Med. 2015;372:1689-1699. 3. Park K, et al. ASCO 2015. Abstract 8084. 4. Tan DSW, et al. ASCO 2015. Abstract 8013. 5. Goto Y, et al. ASCO 2015. Abstract 8014.

*T790M- subgroups are very small pt populationsMultiple other agents in early development

ALK Translocation


Tumor Responses to ALK Inhibitor Crizotinib in ALK+ Lung Cancer Most pts on study had already had ≥ 2 lines of previous therapy

Objective response rate: 60.8%

Median PFS: 9.7 mos (95% CI: 7.7-12.8)

Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019.

Crizotinib in ALK-Positive NSCLC (N = 143)

100806040200

-20-40-60-80

-100

Cha

nge

From

Bas

elin

e (%

) PDSDPRCR


Crizotinib(n = 173)

Chemotherapy(n = 174)

Events, n (%) 100 (58) 127 (73)

Median, mos 7.7 3.0

HR (95% CI) 0.49 (0.37-0.64)

P value < .0001

Prob

abili

ty o

f Sur

viva

l With

out

Prog

ress

ion

(%)

100

80

60

40

20

00 5 10 15 20

25 MosPts at Risk, nCrizotinib

Chemotherapy


Crizotinib vs Standard Chemotherapy in ALK+ NSCLC (PROFILE 1007): PFS in 2nd or 3rd Line

173174

9349

3815

114

21

00


Outcome PROFILE 1001[1]

(N = 143)PROFILE 1005[2]

(N = 259)PROFILE 1007[3]

(N = 173)Best overall response, n (%) CR 3 (2) 4 (2) 1 (1) PR 84 (59) 151 (58) 112 (65) SD 31 (22)* 69 (27) 32 (18) PD NR 19 (7) 11 (6)

Objective response rate, % (95% CI) 60.8 (52.3-68.9) 59.8 (53.6-65.9) 65 (58-72)

Median duration of response, wks (95% CI)

49.1 (39.3-75.4) 45.6 (35.3-53.6) 32.1 (2.1-72.4)†

Median duration of treatment, wks (range)

43.1 (0.1-138.6) N/A 15.9 (2.9-73.4)

Median PFS, mos (95% CI) 9.7 (7.7-12.8) 8.1 (6.8-9.7) 7.7 (6.0-8.8)

Crizotinib in ALK-Positive NSCLC: Efficacy

1. Camidge DR, et al. Lancet Oncol. 2012;10:1011-1019. 2. Kim DW, et al. ASCO 2012. Abstract 7533. 3. Shaw AT, et al. N Engl J Med. 2013;368:2385-2394

*At Wk 8.†Range.


PROFILE 1014: Crizotinib vs Pemetrexed/ Platinum in Advanced Untreated NSCLC

Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177. Mok T, et al. ASCO 2014. Abstract 8002.

100

80

60

40

0

20

0 5 10 15 20 25 30 35

PFS

(%)

Crizotinib(n = 171)

Chemotherapy(n = 169)

HR (95% CI) P Value

ORR, % 74 45 < .001

mPFS, mos 10.9 7.0 0.45 (0.35-0.60) < .001

Adv ALK-pos nonsquamous

NSCLC not previously

treated(N = 343)

Crizotinib 250 mg BID

Pemetrexed + Cisplatin orCarboplatin

q3w x 6 cycles

Primary endpoint: PFS


Ceritinib in ALK+ NSCLC: Best % Change From Baseline in Target LesionsOther second-generation ALK inhibitors in development:

CH5424802 (alectinib)

AP26113

X-396

ASP3026

GSK 1838705

CEP-28122


ORR (CR + PR): 58%Prior crizotinib: 56% Crizotinib naive: 62%

100

80

60

40

20

0

-20

-40

-60

-80

-100Pts

Prior crizotinib treatment

No prior crizotinib treatment

Disease progression or death

Bes

t Cha

nge

From

Bas

elin

e (%

)


Phase I ASCEND-1: Ceritinib in ALK-Positive NSCLC Treatment (N = 246): 750 mg/day

(MTD from dose-escalation phase)

Antitumor activity independent of prior ALK inhibitor treatment

Most common grade 3/4 AEs: increased ALT (29.8%) and AST (9.8%)

Most common AEs (all grades): diarrhea (86.7%), nausea (82.7%), vomiting (61.6%)

ALK inhibitor treated (n = 163)ALK inhibitor naive (n = 83)All (n = 246)

0 6 12 18 24 30 36

100

80

60

40

0

20

Felipe E, et al. ESMO 2014. Abstract 1295P.

PFS

(%)

Mos

Median PFS: 18.40 mos

Median PFS: 9.03 mosMedian PFS: 6.93 mos


Alectinib in Pts With ALK-Positive NSCLC: Results

ORR: 93.5% (95% CI: 82.1-98.6); CR: 19.6%; PR: 73.9%; SD: 2.2%

Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10.

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35

Mos

PFS

Median PFS: 27.7 mos(95% CI: 26.9-NR) 1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35

Mos

OS

2-yr OS rate: 79%(95% CI: 63% to 89%)


AP26113 Antitumor Activity in ALK+ NSCLC Pts

72% (41/57) objective response rate (95% CI: 59% to 83%)

100% (6/6) crizotinib-naïve responded (incl. 1 CR)

– Average time to response: 9.2 wks (± 3.22 wks)

69% (35/51) post-crizotinib responded (95% CI: 54% to 81%)

– Response duration: 1.6-14.7 mos (ongoing)

– Average time to response: 9.3 wks (± 3.72 wks)

– Median PFS: 10.9 mos

Gettinger S, et al. ASCO 2014. Abstract 8047.

*Received prior crizotinib and ceritinib. †TKI naïve: 5/6 pts had best target lesion response data entered at time of analysis.

40

20

0

-20

-40

-60

-80

-100

Bes

t Cha

nge

From

Bas

elin

e in

Tar

get L

esio

n (%

)

††

†*

††

*

Best overall response: PDSD

PRCR

Immunotherapies


PD-1 Inhibitor Nivolumab in Pts With Progressive Squamous NSCLC

Stage IIIB/IV squamous NSCLC

≥ 2 prior systemic therapies

ECOG PS 0-1 (N = 140 screened)

Nivolumab 3 mg/kg IV q2w until PD or

unacceptable toxicity (n = 117)

Primary: Confirmed ORR

(IRC assessed)

Secondary: Confirmed ORR (investigator

assessed)

Exploratory: Safety and tolerability PFS/OS PD-L1 expression and efficacy

Endpoints

Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.

Phase II study


Nivolumab in Pts With Squamous NSCLC: Clinical Activity

Be aware of immune-related adverse events and quickly initiate therapy with steroids in recommended cases

Outcome Measures IRC Assessed

ORR, % (n; 95% CI) 15 (17; 9-22)

Disease control rate, % (n) 40 (47)

Median DOR, mos (range) NR (2+ to 12+)

Ongoing responders, % (n) 76 (13)

Median time to response, mos (range) 3 (2-9)

PFS rate at 1 yr, % (95% CI) 20 (13-29)

Median PFS, mos (95% CI) 2 (2-3)

Median OS, mos 8.2

OS at 1 yr , % 41

Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.

Immune-Related AE, %

Any Grade Grade 3/4

Skin 15 2

Gastrointestinal 10 3

Endocrine 6 1

Pneumonitis 5 3

Renal dysfunction

3 0

Hepatic 1 0


CheckMate 017: Nivolumab vs Docetaxel in Previously Treated Squamous NSCLC Open-label, randomized phase III trial

Primary endpoint: OS

Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL

Spigel DR, et al. ASCO 2015. Abstract 8009.

Pts with stage IIIB/IV squamous NSCLC and ECOG

PS 0-1 with failure of 1 previous platinum doublet

chemotherapy (N = 272)

Nivolumab 3 mg/kg IV q2w(n = 135)

Docetaxel 75 mg/m2 IV q3w(n = 137)

Until disease progression or unacceptable

toxicity

Stratified by previous paclitaxel therapy (yes vs no) and region


CheckMate 017: Nivolumab Significantly Improved OS and PFS vs DocetaxelEfficacy Outcome Nivolumab

(n = 135)Docetaxel (n = 137) HR (95% CI) P Value

Median OS, mos 9.2 6.0 0.59 (0.44-0.79) .00025

Median PFS, mos 3.5 2.8 0.62 (0.47-0.81) .0004

ORR, % CR PR

SDPDUnevaluable

201

19294110

909343522

.0083

Median time to response, mos 2.2 2.1

Median duration of response, mos NR 8.4

Ongoing response, % 63 33

Spigel DR, et al. ASCO 2015. Abstract 8009.


CheckMate 057: Nivolumab vs Docetaxel in Advanced Nonsquamous Cell NSCLC

Primary endpoints: OSSecondary endpoints: PFS, ORR, QoL, PD-LI protein expression

Key eligibility criteria

≥ 18 yrs of age

Stage IIIB/IV nonsquamous NSCLC

Prior platinum-containing chemotherapy (2nd-line) required: additional TKI therapy allowed (3rd-line)

Pt may have received continuous or switch maintenance with pemetrexed, erlotinib, or bevacizumab post platinum-containing chemotherapy

ECOG PS ≤1

No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 or other antibody targeting T-cell costimulation or checkpoint pathways

ClinicalTrials.gov. NCT01673867.


CheckMate 057: Increased Efficacy of Nivo vs Docetaxel in Nonsquamous NSCLCEfficacy Outcome Nivolumab

(n = 292)Docetaxel (n = 290) HR (95% CI) P Value

Median OS, mos 12.2 9.4 0.73 (0.59-0.89) .0015

Median PFS, mos 2.3 4.2 0.92 (0.77-1.11) .3932

ORR, %CRPRSDPDUnevaluable

191

18254411

12< 112422916

1.72 (1.1-2.6)* .0246

Median time to response, mos 2.1 2.6

Median duration of response, mos 17.2 5.6

Ongoing response, % 52 14

*Odds ratio (95% CI).

Paz-Ares L, et al. ASCO 2015. Abstract LBA109.


KEYNOTE 001: Pembrolizumab as Initial Therapy in Pts With Advanced NSCLC

Objectives Evaluate safety, tolerability, and clinical activity of pembrolizumab, a PD-1–blocking antibody Evaluate correlation between clinical activity of pembrolizumab and PD-L1 expression

Response assessment Primary measure: RECIST v1.1 per independent central review Secondary measure: immune-related response criteria per investigator assessment

*First 11 pts randomized to 2 mg/kg q3w and 10 mg/kg q3w (until protocol Amendment 07) and could have a sensitizing EGFR mutation or ALK rearrangement.

Mandatory biopsy within 60 days of first dose

Pembrolizumab 10 mg/kg q3w

Pembrolizumab 10 mg/kg q2w

PD

PD

R1:1*

Treatment-naive, stage IV NSCLC ECOG PS 0-1 EGFR negative* No ALK rearrangement* PD-L1 positive (≥ 1% staining) No systemic steroid No autoimmune disease No or stable brain mets

Balmanoukian AS, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 2.

Phase I trial (N = 45)


KEYNOTE-001 Study: Survival

Treatment naive– Median PFS: 27 wks (95% CI: 14-45)– 24-wk PFS: 51%

Previously treated– Median PFS: 10 wks (95% CI: 9.1-15.3)– 24-wk PFS: 26%

Treatment naive– Median OS: NR (95% CI: NE-NE)– 6-month OS: 86%

Previously treated– Median OS: 8.2 mos (95% CI: 7.3-NR)– 6-month OS: 59%

0 8 16 24 32 40 48

100

80

60

40

20

0

PFS

(%)

WksPts at Risk, nTreatment naive

Previously treated45

21739

1592581

1133

413

22

00

Treatment naivePreviously treated

OS

(%)

Mos45

21738

1461333

78

2477

41192

20

00

Treatment naivePreviously treated

OSPFS (RECIST v1.1, Central Review)

Garon E, et al. ESMO 2014. Abstract LBA43.

100

80

60

40

20

00 2 4 6 8 10 12 14


KEYNOTE-010 (NCT01905657)PD-L1+ advanced NSCLC*PD following platinum doublet chemotherapy

Pembro2 mg/kg

q3w

Pembro10 mg/kg

q3w

R1:1:1

N = 920

Docetaxel

KEYNOTE-024 (NCT02142738)Strongly PD-L1+ advanced NSCLC*No prior therapy

Pembro200 mg

q3w

Platinum-based chemo

R1:1

N = 300

KEYNOTE-042 (NCT02220894)PD-L1+ advanced NSCLC*No prior therapy

Pembro200 mg

q3w

Platinum-based chemo

R1:1

N = 1240

Primary endpoints: OS, PFS Primary endpoint: PFS Primary endpoint: OS

Ongoing Studies of Pembrolizumab in NSCLC

Garon EB, et al. ESMO 2014. Abstract LBA43.*As assessed using the clinical trial assay and the 22C3 antibody.


POPLAR: Atezolizumab (MPDL3280A) Efficacy Increased With Higher PD-L1 Expression

PFS and ORR: similar trends in outcome for atezolizumab vs docetaxel based on PD-L1 expression‒ Median PFS in ITT population: 2.8 vs 3.4 mos (HR: 0.98)‒ Median PFS in TC3 or IC3 population: 7.8 vs 3.9 mos (HR: 0.57)‒ ORR in ITT population: 15% vs 15%‒ ORR in TC3 or IC3 population: 38% vs 13%

Interim data based on minimum of 10 mos of follow-up

Interim Median OS Outcomes, mos

Atezolizumab(n = 144)

Docetaxel (n = 143) HR (95% CI) P Value

ITT population (N = 287) 11.4 9.5 0.77 (0.55-1.06) .11

Subgroups based on PD-L1 expression*TC0 and IC0 (n = 92)TC1/2/3 or IC1/2/3 (n = 195)TC2/3 or IC2/3 (n = 105)TC3 or IC3 (n = 47)

9.7NR13.0NR

9.79.17.4

11.1

1.12 (0.64-1.93)0.63 (0.42-0.94)0.56 (0.33-0.94)0.46 (0.19-1.09)

.70.024.026.070

Spira AI, et al. ASCO 2015. Abstract 8010.

*PD-L1 expression measured by SP142 IHC assay (low expression – TC0/IC0, high expression - TC3/IC3).


Select Anti–PD-L1 Immunotherapy Trials in Locally Advanced or Metastatic NSCLCTrial N Design Key Eligibility CriteriaBirch (phase II) 635 MPDL3280A PD-L1+ tumorFir (phase II)* 128 MPDL3280A PD-L1+ tumor

Poplar (phase II)* 287 MPDL3280A vs docetaxel

Failure of plt-based CT

Oak 1100 MPDL3280A vs docetaxel

Failure of plt-based CT or combined modality therapy

Pacific 702 MEDI4736 vs placebo Stage III, ≥ 2 cycles plt-based CT + RT

Arctic (planned)MEDI4736 ±

tremelimumabvs SOC CT

*Enrollment is complete.

ClinicalTrials.gov.


Summary Histology still guides the therapeutic choice for the vast majority

of pts

Molecular testing is standard of care for pts with stage IV non-small-cell lung cancer and adenocarcinoma component

Ramucirumab, nivolumab new options for treatment

Important to factor pt age and PS as well as optimal management of treatment-related adverse effects

Most pts relapse or are refractory to existing therapies; promising agents under investigation include immunotherapies and small-molecule inhibitors of EGFR and VEGFR pathways

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