Best of ASCO 2014:Highlights in Metastatic Non-Small Cell Lung Cancer

Howard (Jack) West, MD@JackWestMDSwedish Cancer InstituteSeattle, WA

Best of ASCO 2014Seattle, WA

Learning Objectives

•Determine whether evidence on necitumumab and ramucirumab for broad NSCLC populations are sufficient to modify current treatment standards

•Evaluate treatment options of crizotinib and ceritinib for ALK-positive advanced NSCLC

•Compare utility of various EGFR TKI-based options as first line treatment of advanced EGFR mutation-positive NSCLC

•Recognize efficacy of both AZD9291 and CO1686 in treating acquired resistance to EGFR TKIs (*T790M-positive)

Novel Agents in Broad (Molecularly Unselected)Advanced NSCLC Populations

SQUIRE: Chemotherapy +/- Necitumumab for First Line Adv Squamous NSCLC

Adv squamousNSCLC

Treatment-naïve

N = 1093

RANDOMIZE

Cisplatin/Gemcitabine+ Necitumumabup to 6 cycles

Primary endpoint: OS

• Necitumumab (Neci) (IMC-11F8) is a human IgG1 anti-EGFR monoclonal antibody

Cisplatin/Gemcitabineup to 6 cycles

Maintenance neci until

progression

Cisplatin 75 mg/m2 IV day 1 q21 daysGemcitabine 1250 mg/m2 IV days 1, 8 q21 days

Necitumumab 800 mg/kg IV days 1, 8 q21 days

Thatcher, A#8008

SQUIRE: Efficacy of Necitumumab

Overall Survival (ITT)Progression-Free Survival (ITT)

Thatcher, A#8008

Chemo/Neci(N = 545)

Chemo alone(N = 548)

P

ORR (CR + PR) 31.2% 28.8% 0.400

DCR (CR + PR +SD) 81.8% 77.0% 0.043*

*Cochran-Mantel-Haenszel test (stratified)

SQUIRE: Toxicity of Necitumumab

Thatcher, A#8008

SQUIRE: FLEX Redux? (Re-FLEX?)SQUIRE FLEX

• Extremely similar agent; extremely similar results – cetuximab has had negligible impact on NSCLC management

• Highlights distinction between statistical & clinical significance

Pirker, Lancet 2009Thatcher, A#8008

REVEL: Docetaxel +/- Ramucirumab as Second Line Therapy for Adv NSCLC

Adv NSCLC(any histology)

Prior platinum-based chemo

Prior bev allowed

N = 1253

RANDOMIZE

Docetaxel 75 mg/m2 +Ramucirumab 10 mg/kg

IV Q21 days

Docetaxel 75 mg/m2 +Placebo

IV Q21 daysPrimary endpoint: OS

Treat until PD or prohibitive

toxicity

• Ramucirumab (RAM) is a human IgG1 monoclonal antibody, specifically binding to the extracellular domain of VEGFR-2

• Approved in previously treated gastric cancer

Perol, A#LBA-8006

REVEL: Efficacy of Ramucirumab

Overall Survival (ITT)Progression-Free Survival (ITT)

RAM + DOC(N = 628)

PL + DOC(N = 625)

P

ORR (CR + PR) 22.9% 13.6% <0.001

DCR (CR + PR +SD) 64.0% 52.6% <0.001

REVEL: Toxicity (Adverse Events in >20% of Patients or >5% Higher w/RAM

Half Empty or Half Full?

• 1.4 mo increase in OS isn’t much

• Cost: about $7K/treatment

• But options improving OS >2nd line are very limited, especially for squamous NSCLC

Optimistic oncologist perspective

• Whether adding new agent with some increased toxicity and additional significant cost is “worth it” for 1.4 mo improvement in median OS is your judgment

• Not a clear change in standard of care

(Not Very) Old and NewAgents for ALK-Positive

Advanced NSCLC

PROFILE 1014: First-Line Crizotinib vs. Chemo in ALK-Positive Adv NSCLC

• Crizotinib has significant activity, RR 60-65%, in previously treated ALK+ NSCLC, & PFS 7.7 mo vs. 3.0 months compared with 2nd line chemo (Shaw, ESMO 2012, A#2862)

• Though largely presumed to be superior to first line chemo in ALK-positive NSCLC, this hasn’t been prospectively demonstrated

Advanced NSCLC ALK+No Prior Rx

N= 343

RAND

Crizotinib

Cisplatin/Pemetrexed or Carboplatin/Pemetrexed

Primary endpoint: PFS

1: 1

Mok, A#8002

First-Line Crizotinib vs. Chemo: Progression-Free Survival

Mok, A#8002

Responses, Crizotinib vs. Chemo

74%

45%

Mok, A#8002

Criz Chemo

ORR 74% 45%

Resp Dur (wks) 49 23

Common AEs of Any Cause in ≥25% of PatientsWith ≥5% Difference Between Groupsa

Crizotinib (n=171), n (%) Chemotherapy (n=169), n (%)b

Any grade Grade 3/4 Any grade Grade 3/4

Higher frequency (≥5% absolute difference) in crizotinib arm

Vision disorderc 122 (71) 1 (1) 24 (14) 0

Diarrhea 105 (61) 4 (2) 29 (17) 1 (1)

Edemac 83 (49) 1 (1) 22 (13) 1 (1)

Vomiting 78 (46) 3 (2) 68 (40) 6 (4)

Constipation 74 (43) 3 (2) 53 (31) 0

Elevated transaminasesc 61 (36) 24 (14) 22 (13) 4 (2)

Upper respiratory infectionc 55 (32) 0 21 (12) 1 (1)

Abdominal painc 45 (26) 0 20 (12) 0

Dysgeusia 45 (26) 0 11 (7) 0

Higher frequency (≥5% absolute difference) in chemotherapy arm

Nausea 95 (56) 2 (1) 103 (61) 3 (2)

Decreased appetite 51 (30) 4 (2) 59 (35) 1 (1)

Fatigue 49 (29) 5 (3) 65 (38) 4 (2)

Neutropeniac 36 (21) 19 (11) 51 (30) 26 (15)

Asthenia 22 (13) 0 42 (25) 2 (1)

Anemiac 15 (9) 0 54 (32) 15 (9)

aNot adjusted for differential treatment duration; bbefore crossover to crizotinib; cclustered term

● Permanent treatment discontinuations due to treatment-related AEs: 5% in crizotinib arm; 8% in chemotherapy armb

● No grade 5 AEs reported to be related to treatment; 1 patient in chemotherapy arm had grade 5 pneumonitis after crossover to crizotinib, considered to be treatment-related

Ceritinib: New Treatment Option for ALK-Positive NSCLC

Kim, A#8003

FDA Approved April, 2014

Cost: $13,500/mo

###

Dose Expansion Cohort, 750 mg/day: Best Percentage Change from Baseline

NSCLC with prior ALKi NSCLC ALKi naïve

Cha

nge

from

bas

elin

e in

sum

of

long

est

diam

ete

rs (

%)

*Patients with measurable disease at baseline and at least 1 post baseline assessment without unknown response for target lesion or overall response

N=228*

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#PFS event

Kim, A#8003

Activity of Ceritinib in ALK+ NSCLC

Endpoint Criz-Naïve (N = 83)

Criz-Refractory(N = 163)

Response Rate 66% 55%

12-mo Prog-Free Survival 61% 28%

Median Time from Dx to Ceritinib

8.1 mo 21.2 mo

Disease Control, Brain Mets 70% 75%

• Modestly higher RR, longer responses in crizotinib-naïve patients

Kim, A#8003

Toxicity Challenges with Ceritinib

• Greater than with crizotinib• Dose reduction – 59% (!)

– Increased ALT/AST, nausea, diarrhea, vomiting

• Discontinuation due to adverse effects – 10%– Pneumonia, ILD/pneumonitis, decreased appetite

• Oncologists need to know to dose-reduce early– 750 mg daily may be more than needed

Kim, A#8003

Timing of Ceritinib?

Presented by: H. Jack West

• Approval is for crizotinib-refractory and crizotinib-intolerant patients with ALK rearrangement

• Should it be used earlier?

ALK+No Prior Rx

N= 348

RAND

Ceritinib

Cisplatin/Pemetrexed or Carboplatin/PemetrexedPrimary endpoint: PFS

Trial in development

ALK+No Prior Rx

RAND Ceritinib

Crizotinib

Primary endpoint: OS

Trial we need

Ceritinib

Chemo or MD choice

Assessing Options for First Line Treatment of

EGFR Mutation-Positive Advanced NSCLC

LUX Lung-3, LUX Lung-6 Trials

EGFR Mut’n PosAdvanced NSCLC

No Prior RxN= 345Global

RAND

Afatinib 40 mg PO dailyuntil progression

Cisplatin/Pemetrexed Q21dup to 6 cycles

Primary endpoint: PFS

Sequist, JCO 2013LUX Lung-3

RAND

Afatinib 40 mg PO dailyuntil progression

Cisplatin d1, Gemcitabine d1,8 q21dup to 6 cycles

Wu, Lancet 2014EGFR Mut’n Pos

Advanced NSCLCNo Prior Rx

N= 364Asia

Primary endpoint: PFS

LUX Lung-6

2:1

2:1

OS Analysis: LUX-Lung 3, LUX-Lung 6 (Del 19 and L858R only)

Yang, A#8004

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed O

S p

roba

bilit

y

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months)

203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0

104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0

Afatinib

Pem/Cis

No of patients

LUX-Lung 3 Afatinib

n=203Pem/Cis n=104

Median, months 31.57 28.16

HR (95%CI), p-value

0.78 (0.58–1.06), p=0.1090

LUX-Lung 6 Afatinib

n=216Gem/Cis

n=108

Median,months 23.6 23.5

HR (95%CI), p-value

0.83 (0.62–1.09), p=0.1756

1.0

0.8

0.6

0.4

0.2

0E

stim

ated

OS

pro

babi

lity

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (months)

216 214 202 190 172 158 141 118 104 93 80 51 19 9 1 0

108 101 93 87 81 70 61 55 49 36 30 17 8 3 0 0

Afatinib

Gem/Cis

No of patients

Combined OS Analysis: LUX-Lung 3, LUX-Lung 6 (Del 19 and L858R only)

Yang, A#8004

Combined OS Analysis: LUX-Lung 3, LUX-Lung 6 by Mutation Subtype

Yang, A#8004

Differences in Efficacy of Gefitinib/ Erlotinib: Exon 19 Del vs. L858R

OSPFS

Jackman, Clin Cancer Res, 2006

Riely, Clin Cancer Res, 2006

OS

Treatment after Progression on First Line Therapy (Del 19 and L858R only)

LUX-Lung 3 LUX-Lung 6

Afatinib (n=203)

Pem/Cis (n=104)

Afatinib (n=216)

Gem/Cis (n=108)

Discontinued treatment, n (%) 184 (100) 104 (100) 194 (100) 108 (100)

Subsequent systemic therapy, n (%)† 144 (78) 88 (85) 123 (63) 70 (65)

Chemotherapy, n (%) 131 (71) 49 (47) 114 (59) 29 (27)

EGFR TKI therapy, n (%)

ErlotinibGefitinib AfatinibAZD9291DacomitinibIcotinibEGFR TKI combinations

81 (44)

61 (33)28 (15)

2 (1)2 (1)

––

5 (3)

78 (75)

46 (42)44 (42)

7 (7)1 (1)1 (1)

–9 (9)

50 (26)

21 (11)19 (10)

–––

11 (6)5 (3)

61 (56)

22 (20)39 (36)

–––

3 (3)3 (3)

Other systemic therapy±, n (%) 5 (3) 2 (2) 3 (2) 4 (4)

Radiotherapy, n (%) 32 (17) 21 (20) 4 (2) 0 (0)

†Collection of data on subsequent therapies still ongoing. ± include investigational agents, monoclonal antibodies, non-EGFR targeting protein kinase inhibitors etc

Yang, A#8004

Treatment after Progression on First Line by Country’s Reimbursement*

Countries with universal reimbursement policies**

Countries without universal reimbursement

policies***

Afatinib (n=144)

Chemo (n=75)

Afatinib(n=275)

Chemo(n=137)

Discontinued treatment, n (%) 127 (100) 75 (100) 251 (100) 137 (100)

Subsequent systemic therapy, n (%) 112 (88) 69 (92) 158 (63) 89 (65)

Chemotherapy, n (%) 103 (81) 35 (47) 142 (57) 43 (31)

EGFR TKI, n (%) 76 (60) 68 (91) 55 (22) 71 (52)

Other, n (%) 5 (4) 2 (3) 3 (1) 4 (3)

Radiotherapy, n (%) 27 (22) 18 (24) 9 (4) 3 (2)

*Determined by presence or absence of a national reimbursement policy in effect throughout the period of trial conduct:

**Main countries contributing : Japan, Taiwan, Korea, Germany, France, Australia, UK, Belgium

***Main countries contributing : China, Thailand, Russia, the Philippines, Malaysia

Yang, A#8004

Impact of subsequent EGFR TKIs on OS: exploratory analyses by category of EGFR TKI reimbursement policy in country of residence*

Population % received TKI after 1st line chemo

HR (95% CI)Common

mutations

HR (95% CI)Del19

HR (95% CI) L858R

Combined LL3/6 population (n=631)

66% 0.81 (0.66–0.99)

0.59(0.45–0.77)

1.25(0.92–1.71)

Countries with universal reimbursement policies**(n=219)

91% 0.71(0.49–1.02)

0.50(0.31–0.81)

1.14(0.64–2.03)

Countries without universal reimbursement policies***(n=412)

52% 0.85 (0.66–1.08)

0.59(0.42–0.82)

1.32(0.91–1.92)

Japan (n=77)

100% 0.57 (0.29–1.12)

0.34(0.13–0.87)

1.13(0.40–3.21)

*Determined by presence or absence of a national reimbursement policy in effect throughout the period of trial conduct:

**Main countries contributing : Japan, Taiwan, Korea, Germany, France, Australia, UK, Belgium, Ireland

***Main countries contributing : China, Thailand, Russia, the Philippines, Malaysia

Yang, A#8004

Is OS with Afatinib in LUX-Lung 3/6 Superior to That of Other EGFR TKIs?

Med

OS

(m

o)

WJTOG2 EURTAC3 OPTIMAL4 LUX-Lung 35

NEJGSG1

Gefitinib Erlotinib Afatinib1) Maemondo et al. N Engl J Med. 2010;362:2380; 2) Mitsudomi et al. Lancet Oncol. 2010;11:121; 3) Rosell et al. Lancet Oncol. 2012;13:239; 4) Zhou et al. Lancet Oncol. 2011;12:735; 5) Yang et al. Proc ASCO 2014: A#8004

N=230 N=177Terminated early, after Interim analysis?

N=174 N=165 N=345 N=364

LUX-Lung 65

EGFR TKI Chemo

Multiple Shots on Goal

• No survival difference for overall ITT population

• No survival difference for LUX-Lung trials individually

• Statistical significance is function of magnitude of difference & population size

• Pooling two trials and eliminating rare mutations statistical significance

• Still, OS benefit for Del19 pts is robust, impressive

Relevant Comparison for Afatinibin 2014 is to Other EGFR TKIs

• Is timing of EGFR TKI critical re: crossover?– L858R population showed PFS benefit but reversal w/OS– Sequence of therapy may be relevant

• Would other EGFR TKIs show OS benefit if > 700 pts enrolled & results divided by mut’n subtype?

EGFR Mut+N = 316

(Asia)

RAND Afatinib daily

Gefitinib daily

Completed July, 2013Primary endpoint: OS

LUX-Lung 7

• Toxicity assessment will also be critical

Or is optimal therapy now an EGFR TKI/bevacizumab

combination?

Subsets Demonstrate Benefit with Bev Added to 2nd Line Erlotinib (BeTa)

Herbst, Lancet 2011

Erlotinib +/- Bevacizumab as Maintenance Therapy (ATLAS): Clinical Subgroups

Johnson, JCO 2013

EGFR Regulates VEGF in EGFR Mutant Cell Lines

Courtesy of Heymach et al.; manuscript in preparation

0

500

1000

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ell)

EGF(60ng/ml) - - + + - - + + - - + + - - + +Erlotinib(1mM) - + - + - + - + - + - + - + - +

A549 (wt)

HCC827 (mut)

H3255 (mut)

H1975 (mut)

wild-type mutant Mutant + T790M

• EGFR mutant NSCLC cell lines express higher levels of VEGF

• VEGF expression is reduced with EGFR inhibitors

Erlotinib/Bevacizumab vs. Erlotinib for EGFR Mutation-Positive Adv NSCLC

Adv NSCLCEGFR Mut’n (exon 19/21)

Treatment-naïveN = 154

RAND

Erlotinib 150 mg/day+ bevacizumab 15 mg/kg IV Q21 daysuntil progression or prohibitive toxicity

Primary endpoint: PFSErlotinib 150 mg/days

until progression or prohibitive toxicity

EB E P

ORR (CR/PR) 69% 64% ns

DCR (CR/PR/SD) 99% 88% 0.018

Kato, A#8005

JO25587 PFS in Context of Other Trialsin EGFR Mutation-Positive NSCLC

1. Rosell et al. Lancet Oncol. 2012;13:239; 11. Zhou et al. Lancet Oncol. 2011;12:735; 3. Sequist et al. J Clin Oncol. 2013;31:3327; 4. Wu et al. Lancet Oncol. 2014;15:213; 5. Kato, Proc ASCO 2014, A#8005

MedPFS (mo)

EURTAC1 OPTIMAL2 JO25587-Erlotinib5

JO25587-Erloti/Bev5

LUX-Lung-33

LUX-Lung-64

Erlotinib +/- Bevacizumab:PFS by EGFR mutation type

EB group E group

Median (months) 18.0 10.3HR 0.41

(95% CI: 0.24–0.72)

EB

E

E

EB

Number at risk

0

1.0

0

40

40 E

EB

Number at risk

EB

E

1.0

00

35

37

Time (months)

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

38 33 2739 36 29 24 12 5 219 8 2 0

29 22 1235 26 16 9 5 1 09 3 0 0

Time (months)

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

31 27 2233 28 24 14 8 3 211 5 2 0

28 17 1231 18 13 12 7 4 19 7 2 0

0.2

0.4

0.6

0.8

PF

S p

rob

ab

ility

PF

S p

rob

ab

ility

0.2

0.4

0.6

0.8

Exon 19 deletion Exon 21 L858R

EB group E group

Median (months) 13.9 7.1

HR 0.67 (95% CI: 0.38–1.18)

Kato, A#8005

Toxicity Issues with Erlotinib/Bevacizumab on JO25587

• No unforeseen toxicities or Rx-related deaths• Grade >3 toxicity 91% vs. 53% (esp. HTN, proteinuria)

• 41% discontinued bevacizumab for adverse effects– Primarily proteinuria (15%) or hemorrhagic (12%)

• Bevacizumab discontinuation rate 10-15% in BeTa, ATLAS trials

• Difference?– Greater toxicity in Japanese population?– Greater toxicity in EGFR mutation-positive?– Longer duration of therapy higher risk of ADRs

Cost Considerations with Erlotinib/Bev Combination

Cost/Month($USD)

$6,300

$16,700

Erlotinib Erlotinib/Bevacizumab

Addition of bevacizumab increases cost of first line treatment by ~$120,000 for 16 treatments (acquisition cost alone)

Is Erlotinib/Bevacizumab the New Standard of Care for EGFR Mut+?

• Kato: median PFS 16.0 vs. 9.7 mo, HR 0.54

(ECOG 4599: median PFS 6.2 vs. 4.5 mo, HR 0.66)• My preferred regimen moving forward • Threshold for clinical confidence ≠ threshold for coverage• Confirmatory trial needed? Outside of Japan? OS diff?• Will it be covered?

EGFR Mut+N = 118 N Amer

RAND

Erlotinib daily

Erlotinib daily &Bevacizumab q3wk

Ongoing (slowly)

Primary endpoint: PFS

ACCRU Trial

PI – T. Stinchcombe

Breaking the Impasse for EGFR Mutation-Positive Patients

with Acquired Resistance

Acquired Resistance: AZD9291 and CO-1686

• The vast majority of patients with an activating EGFR mutation who respond well to initial EGFR TKI therapy demonstrate progression several months to years later

• T790M mutation detected in approximately 60% of patients with acquired resistance

• AZD9291 and CO1686 are mutant selective, irreversible inhibitors of EGFR with significant anti-tumor activity in preclinical tumor models with both EGFR TKI-sensitizing and T790M resistance mutations with greater wild-type sparing than first generation EGFR TKIs

Best percentage change from baseline in target lesion: all evaluable patients, escalation and expansion (N=205)

Jänne, A#8009

AZD9291: Response rate* in overall population( T790M+ and T790M-)

• First patient dosed Mar 6, 2013• Longest response >9 months ongoing at time of data cutoff• ORR* = 53% (109/205; 95% CI 46%, 60%); no difference in ORR by race• Overall disease control rate (CR+PR+SD) = 83% (171/205; 95% CI 78%, 88%)

20 mg 40 mg 80 mg 160 mg 240 mg

N (205) 20 57 61 55 12

ORR 55% 44% 54% 58% 67%

*Includes confirmed responses and responses awaiting confirmation; #represents imputed values. Population: all dosed patients with a baseline RECIST assessment and an evaluable response (CR, PR, SD, or PD), N=205 (from 232 dosed patients, 27 patients with a current non-evaluable response are not included). CI, confidence interval; CR, confirmed complete response; ORR, overall response rate; PD, progressive disease; PR, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease

40

20

0

-20

-40

-60

-80

-100

Complete response

#######

Partial response*

Non-response

Jänne, A#8009

AZD9291: Response rate* in T790M+ (central test)

• ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC• Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%)

20 mg 40 mg 80 mg 160 mg 240 mg

N (107) 10 29 34 28 6

ORR 50% 62% 68% 64% 83%

Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B

*Includes confirmed responses and responses awaiting confirmation; #represents imputed valuesPopulation: all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD), N=107 (from 120 T790M+ patients; 13 patients with a current non-evaluable response are not included). D, discontinued; QD, once daily

Best percentage change from baseline in target lesion: T790M+ evaluable patients, expansion cohorts only (N=107)

40 mg QD

80 mg QD

160 mg QD

240 mg QD

20 mg QD

40

20

-20

-40

-60

-80

-1000

# #D D

D D

D

D DD D

D D

D DD D

DD D

D D

D DD

• ORR* = 22% (11/50; 95% Cl 12%, 36%) in patients with EGFR T790M- NSCLC• Overall disease control rate (CR+PR+SD) = 56% (28/50; 95% CI 41%, 70%)

20 mg 40 mg 80 mg 160 mg

N (50) 3 17 17 13

ORR 67% 12% 24% 23%

*Includes confirmed responses and responses awaiting confirmation; #represents imputed valuesPopulation: all dosed centrally confirmed T790M- patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD), N=50 (from 56 T790M- patients; six patients with a current non-evaluable response are not included)

40 mg QD

80 mg QD

160 mg QD

20 mg QD

# # # #D D D D

40

20

-20

-40

-60

-80

-1000

D

DD

D DD

D

D D DD D D D D D D D

D D DD

DD

AZD9291: Response rate* in T790M- (central test)

Jänne, A#8009

T790M+ T790M-

68/105 43/6925/36

11/50 3/28

8/22

Response rate* according to T790M (central test) status: immediate prior EGFR-TKI,# yes vs no

*Includes confirmed responses and responses awaiting confirmation; #TKI therapy is defined as being immediately prior if TKI was the last regimen taken prior to the study, with no subsequent therapy. Population: all dosed centrally confirmed T790M+ and T790M- patients with a baseline RECIST assessment and an evaluable response, T790M+ N=105 (from 107 T790M+ patients with response data; two patients not included as subgroup missing), T790M- N=50

Jänne, A#8009

AZD9291: Progression-free survival by T790M (central test) status

0 6 12 18 24 30 36 42Study week

Pro

bab

ilit

y o

f p

rog

ress

ion

-fre

e su

rviv

al T790M+ (95% CI)

T790M- (95% CI)

Dots indicate censored observations, shaded area represents 95% CIs; progression events that do not occur within 14 weeks of the last evaluable assessment (or first dose) are censored. Population: all dosed centrally confirmed T790M+ and T790M- patients, N=170 (115 T790M+, 55 T790M-; six patients for whom start date is not yet known are not included)

0

1.0

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Patients at riskT790M+T790M-

11555

9633

7821

5615

217

60

10

Jänne, A#8009

Jänne, A#8009

AZD9291: Toxicity Summary

• No clear maximum-tolerated dose up to 240 mg/d– No clear correlation of toxicity with dose– 80 mg/d selected as optimal for therapeutic index

• At 80 mg/d dose:– Diarrhea in 20%– Rash in 27%– Interstitial lung disease in 3%– Hyperglycemia 1%

CO-1686: Best Response in Phase I and Early Phase II Cohort Patients

Sequist, A#8010

CO-1686: Progression-Free Survival

Sequist, A#8010

Sequist, A#8010

CO-1686: Toxicity Profile

Current/Future Development of Third Generation EGFR TKIs

• AZD9291– AURA: Ph 2 expansion in T790M+– AURA 2: Confirmatory Ph 2 in T790M+– AURA 3: Ph 3 2nd line vs. chemo in T790M+

• CO-1686– TIGER X: expansion of 2nd line or later in T790M+– TIGER 1: Ph 2/3 1st line vs. erlotinib

(no T790M+ requirement)– TIGER 2: Ph 2 after 1 prior EGFR TKI in T790M+– TIGER 3: Ph 2 vs. chemo in T790M+

Summary of Third Generation EGFR TKIs in Acquired Resistance

• BOTH agents have impressive efficacy and are granted breakthrough designation by FDA – Foot race to clinic

• Toxicity differences:– AZD9291: rash & diarrhea (<erlotinib), ILD in minority– CO-1686: hyperglycemia, mild diarrhea, nausea, rare

QTc prolongation

• Though some potential toxicity concerns in both, anticipated benefit >> risk

• For both agents, focus is on T790M+ patients

Closing Thoughts/Summary

No absolute rule for the amount of evidence required to change practice

• Big effects don’t require big trials • Crizotinib was justifiably approved based

on phase I/II trial with >50% RR– Ceritinib similarly approved despite relatively small

numbers, but large effect

• EGFR TKI therapies became clear first line standard of care despite absence of OS benefit– Different standard for adding bevacizumab?

• Conversely, is an intervention clinically significant if the trial needs >1000 patients to demonstrate statistical significance?

In 2014, Cost/Value of Therapy is a Factor in Cancer Care

• Reality is that cost matters, especially as new drugs have eclipsed the prior $10,000/mo barrier

• It is appropriate to expect a semblance of value and not merely p < 0.05

• We need to discuss value openly and not just have it bias our clinical judgment

• Cost is limiting our ability to deliver best treatment

Optimal Rx ($$$$)

Cost/practical limits

Drug deliveryto needy patients

Take Home Messages for Advanced NSCLC Management from ASCO 2014

• Necitumumab: Re-FLEX?; not enough benefit vs. toxicity• Ramicirumab for 2nd line: Maybe; is 1.4 mo med OS diff

worth cost?; improving OS is hard, esp in squam NSCLC• Crizotinib >> chemo first line (RR & PFS) in ALK+ • Ceritinib highly active for criz-naïve or criz-resistant ALK+

(RR & PFS), & CNS activity, but toxicity challenging• Afatinib OS benefit specific to Del 19; Unique to afatinib?

– Major differences between Del 19 and L858R populations

• Bevacizumab significantly improved PFS w/erlotinib for EGFR mut’n pos-NSCLC

• AZD9291 and CO-1686 both very active in EGFR T790M+ acquired resistance after prior 1st gen EGFR TKI