Targeted Therapies for Advanced NSCLC - ceconcepts.com Therapy for...Targeted Therapies for Advanced NSCLC. Current Clinical Developments . Friday, June 3, 2016. Supported by an independent

Targeted Therapies for Advanced NSCLC

Current Clinical Developments Friday, June 3, 2016

Supported by an independent educational grant from AstraZeneca

Not an official event of the 2016 ASCO Annual Meeting

Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation

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• This slide deck in its original and unaltered format is for educational purposes and is current as of Friday, June 3, 2016. The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter.

• These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies or strategies described in this educational activity.

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1. Review the molecular pathology of lung cancer and examine its relevance for clinical practice.

2. Outline the safety and efficacy of first-line therapies for advanced NSCLC, including first generation EGFR and ALK inhibitors.

3. Evaluate treatment approaches used to overcome EGFR and ALK resistance in advanced NSCLC, including the safety and efficacy of second- and third-line therapies and recommended molecular testing.

4. Appraise emerging concepts with EGFR TKIs and ALK inhibitors, including their role in adjuvant therapy, combination therapies, and other evolving data.

Learning Objectives

Firstline Therapy for EGFR Mutant and ALK Rearranged NSCLC

Tom Stinchcombe, MD Associate ProfessorThoracic Oncology ProgramSchool of MedicineUniversity of North Carolina at Chapel HillChapel Hill, NC

• Consultant for ARIAD and Boehringer Ingelheim

• Receives Grant/Research Support from Genentech

Disclosures

Topics

• Currently available EGFR TKIs

• Treatment beyond disease progression

• EGFR TKI combinations

• ALK TKI available for first-line use: current options

Hidalgo M, et al. J Clin Oncol. 2001; Ranson M, et al. J Clin Oncol. 2002; Li D, et al. Oncogene. 2008; Kuan FC, et al. Br J Cancer. 2015; Cross DA, et al. Cancer Discov. 2014; Greig L. Drugs. 2016.

NSCLCCurrently Available EGFR TKIs

TKIsReversible

vsirreversible

EGFRm EGFRwt

HER2 [ErbB2] and

ErbB4 binding

T790Mbinding

Gefitinib,Erlotinib Reversible + + - -

Afatinib Irreversible + + + +

Osimertinib Irreversible + - - ++

Yang JC, et al. Lancet Oncol. 2015.

LUX-Lung 3 and 6 Phase III Trials Afatinib vs Cisplatin-Based Chemotherapy

• Stage IIIB/IV adenocarcinoma of the lung• Presence of EGFR mutation in the tumor tissue*• No prior treatment with chemotherapy for advanced/metastatic

disease or EGFR inhibitors• ECOG PS 0 or 1

Randomization

Afatinib40 mg orally once daily

Primary endpoint: PFS (independent review)Secondary end points: ORR, DCR, OS, PRO, safety

2:1

LUX-Lung 3 Cisplatin + pemetrexed

up to 6 cycles

LUX-Lung 6Cisplatin + gemcitabine

up to 6 cycles

*EGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I

Stratification by EGFR mutation type: Del19/L858R/other and by race (LUX-Lung 3 only): Asian/non-Asian


LUX-Lung 3 and 6 Phase III Trials Combined OS Analysis

AfatinibN=419

Chemo N=212

Median, months 27.3 24.3

HR (95%CI), P-value

0.81 (0.66–0.99), .0374

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

Prob

abili

ty

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

419 411 390 371 343 320 284 251 225 201 181 141 77 58 33 9 1 0212 199 185 173 162 141 124 110 101 83 70 52 34 23 10 5 1 0

AfatinibChemo

No. of patients

Common Mutations (n=631)


LUX-Lung 3 and 6 Phase III Trials OS Analysis by Mutation Type

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

prob

abili

ty

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

Time (months)

1.0

0.8

0.6

0.4

0.2

0Es

timat

ed O

S pr

obab

ility

Time (months)

AfatinibChemo

No of patients

93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0AfatinibChemo

No of patients

Del19Afatinib N=236

Chemo N=119

Median, months 31.7 20.7

HR (95%CI) P-value

0.59 (0.45–0.77), .0001

L858RAfatinibN=183

Chemo N=93

Median,months 22.1 26.9

HR (95%CI) P-value

1.25 (0.92–1.71) .16

236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0

119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0

183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0

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

Park K, et al. Lancet Oncol. 2016.

LUX-Lung 7 Phase IIb Trial Afatinib vs Gefitinib

Randomization

1:1

Afatinib 40 mg once daily(N=160)

Gefitinib 250 mg once daily(N=159)

• Stage IIIB/IV adenocarcinoma of the lung • EGFR mutation (Del19 and/or L858R) in the tumor tissue* • No prior treatment for advanced/metastatic disease• ECOG PS 0/1

Primary endpoints: PFS (independent review), TTF, OSSecondary endpoints: ORR, time to and duration of response, duration of

disease control, tumor shrinkage, HRQoL, safety

Stratified by mutation type (Del19 vs L858R)and presence of brain metastases (yes vs no)

Treatment beyond progression allowed if deemed beneficial by investigator

LUX-Lung 7 Phase IIb Trial PFS by Independent Review

Afatinib N=160

GefitinibN=159

Median PFS (months) 11 10.9

HR (95%CI), P-value

0.73 (0.57–0.95), .0165


*P=.0176; †P=.0184

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42

27%*

18%†

15% 8%

160 142 112 94 67 47 34 27 21 13 6 3 1 0AfatinibGefitinib 159 132 106 83 52 22 14 9 7 5 3 3 1 1

00

Estim

ated

PFS

pro

babi

lity

Time (months)


LUX-Lung 7 Phase IIb Trial ORR and DCR

Efficacy Parameter Afatinib (N=160)

Gefitinib (N=159) P

ORR 70% 56% .0083(OR=1.87)

DCR 91% 87% .24(OR=1.55)

ORR Exon 19 (N=186) 73% 66%

ORR Exon 21 L858R (N=133) 66% 42%

DCR=disease control rate; OR=odds ratio; ORR=overall response rate.


LUX-Lung 7 Phase IIb Trial Select Drug-Related AEs

AE category Gr 1-2 Gr 3 Gr 4 Gr 1-2 Gr 3 Gr 4 Diarrhea 78% 12% 1% 60% 1%

Rash/acne 79% 9% 78% 3%

Stomatitis 60% 4% 24%

Paronychia 54% 2% 16% 1%

Fatigue 15% 6% 14%

Nausea 15% 1% 14%

Vomiting 11% 3% 1%

AST/ALT increased 10% 16% 8% 1%

ILD 0% 1% 1% 1%

Afatinib Gefitinib

Drug-related AE leading to dose reduction: afatinib 39% doses reduced to 30 mg daily, 13% reduced to 20 mg

AE = Adverse Event

Treatment Beyond Disease Progression

Park K, et al. JAMA Oncol. 2016.

ASPIRATION Phase II Trial Post-Progression Erlotinib

EGFR mutant NSCLCStage 4 diseasePS 0-2(N=207)

Erlotinib 150 mg

daily

Disease progression with symptomatic progression, rapid

progression, worsening PS, or life threatening complications

93 continued erlotinib

(54%)

78 discontinued erlotinib(46%)

70 patients with PFS 2 event

14 still on erlotinib9 patients withdrew

Primary end-point: • First PFS event (PFS1)

Secondary end-points:• Second PFS event

(PFS2), ORR, OS DCR

Park K, et al. JAMA Oncol. 2016.

ASPIRATION Phase II Trial Results of Erlotinib Continuation

Median PFS1: 11.0 (95% CI, 9.2-11.0)93 patients continuing erlotinibMedian PFS2: 14.1 (95% CI, 12.2-15.9)Difference in median: 3.1 months

Patients continuing erlotinib: Patient characteristics (P<0.05):More likely to have recurrent disease at baseline, ECOG PS 0 or 1 at PFS1 Treatment characteristics (P<0.05):Longer PFS1, improved depth of response, longer time from median time from BOR to PFS10 10 20 30 40

0

0.2

0.4

0.6

0.8

1.0

Time, mo

Prog

ress

ion-

Free

Sur

viva

l Pro

babi

lity

PFS1PFS2

No. at riskPFS1 93 52 10 0 0PFS2 93 70 27 9 0


LUX-Lung 7 Phase IIb Trial Treatment Beyond Disease Progression

• Allowed treatment beyond progression at the discretion of the investigator

• Results− Afatinib 35% (N=56) continued beyond investigator

assessed disease progression: median 2.7 months (95% CI, 1.94-4.3)

− Gefitinib 30% (N=47) continued beyond investigator assessed disease progression: median 2.0 months (95% CI, 1.5-3.0)

EGFR TKI Combination Trials for First-line Therapy

Seto T, et al. Lancet Oncol. 2014.

JO25567 Phase II TrialErlotinib +/- Bevacizumab

• Stage IIIB/IV NSCLC• EGFR exon 19 deletion

or exon 21 L858R• No brain metastases

Erlotinib 150 mg daily (N=75)

Erlotinib 150 mg daily +bevacizumab 15 mg/kg every 3 weeks (N=75)Primary end-point: PFS by IRC

Secondary end-points: OS, ORR,DCR, QoL


JO25567 Phase II Trial PFS by Independent Review

1.0

00

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 0E

EBNumber at risk

Time (months)4 8 122 6 10 14 18 22 2616 20 24 28

0.2

0.4

0.6

0.8

PFS

prob

abili

ty

9.7 16.0

EBE

*log-rank test, two-sided

EB E

Median, months 16 9.7

HR P-value*

0.54 (95% Cl, 0.36–0.79) .0374


JO25567 Phase II Trial Efficacy Data

Efficacy Parameter Erlotinib Erlotinib + Bevacizumab P-value (HR)

ORR 64% 69% .4951

DCR 88% 99% .0177

PFS 9.7 months 16.0 months .0015 (0.54)

PFS exon 19 (N=80) 10.3 months 18.0 months .0011 (0.41)

PFS exon 21 L858R(N=72) 7.1 months 13.9 months .1653 (0.67)


JO25567 Phase II Trial Safety Data

Adverse event Grade 3 Grade 4 Grade 3 Grade 4Rash 25% 0% 19% 0%

Diarrhea 1% 0% 1% 0%

Paronychia 3% 0% 4% 0%

Dry skin 3% 0% 0% 0%

Stomatitis 1% 0% 3% 0%

Liver tests 7% 1% 9% 9%

Hypertension 60% 0% 8% 0%

Hemorrhagic event 3% 0% 0% 0%

Proteinuria 8% 0% 0% 0%

Erlotinib + Bevacizumab (N=75)

Erlotinib(N=77)

Stahel RA, et al. ECC. 2015.

BELIEF Phase II Trial Firstline Erlotinib/Bevacizumab

Patient cohort Number of patients ORR Median PFS (months)Intent-to-treat 109 76% 13.8 (95% CI, 10.3-21.3)

T790M positive 37 70% 16.0 (95% CI, 13.1-NE)

T790M negative 72 79% 10.5 (95% CI, 9.2-16.2)

• Stage IIIB/IV• Exon deletion 19

or exon 21 L858R

Erlotinib 150 mg daily + bevacizumab 15 mg/kg

every 3 weeks

• Primary end-points: PFS in pretreatment T790M+ and T790M-

• T790M mutations centrally tested using TaqMan assay in presence of PNA

Ichihara E, et al. J Thorac Oncol. 2015.

1001 Phase II TrialFirstline Gefitinib/Bevacizumab

Efficacy parameter Results

ORR 73.8% (95% CI, 58-86.1)

Median PFS 14.4 (95% CI, 10.1-19.2)

1-year PFS 56.7% (95% CI, 39.9-70.5)

Exon 19 (N=24) vs L858R (N=16) 18.0 vs 9.4 months, P=.006

• Stage IIIB/IV • Exon 19 deletion

or exon 21 L858R

Gefitinib 250 mg daily + bevacizumab

15 mg/kg every 3 weeks (N=42)

Primary end-point:

1-year PFS rate

Janjigian YY, et al. Cancer Discov. 2014.

Dual EGFR InhibitionPhase Ib Trial: Afatinib + Cetuximab

• Prior erlotinib or gefitinib within 30 days

• EGFR mutation required in MTD cohort

• T790M+ and T790M− patients enrolled

Afatinib 40 mg daily and

cetuximab500 mg/m2 every

2 weeks(N=126)

Janjigian YY, et al. Cancer Discov. 2014.

Afatinib + CetuximabEfficacy and Safety Data

Cohort ORR PFSExpansion cohort (N=126) 29% 4.7 months

T790M+ (N=71) 32% (95% CI, 21.8-44.5) 4.8 months

T790M– (N=53) 25% (95% CI, 13.8-38.3) 4.6 months

Adverse event All Grades Grade 3 Grade 4Rash 90% 20% 0%

Diarrhea 71% 6% 0%

Nail effects 57% 0% 0%

Stomatitis 56% 1% 0%

Fatigue 47% 2% 1%

Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02438722.

SWOG S1403 Phase II/III TrialAfatinib +/- Cetuximab

• EGFR mutant NSCLC

• Stage 4 disease• PS of 0-2

Afatinib 40 mg daily

Afatinib 40 mg daily and cetuximab

500 mg/m2 every 2 weeks

Primary objectives:Phase 2: PFS to determine if trial shouldcontinue to phase 3Phase 3: OSSecondary objectives:ORR, safety, treatment failure and time to discontinuation

First-line Therapy for ALKRearranged NSCLC

PROFILE 1014 Phase III StudyFirstline Crizotinib vs Chemotherapy

Solomon BJ, et al. N Engl J Med. 2014.

Key Entry Criteria● ALK-positive by

central FISH testing● Locally advanced,

recurrent, or metastatic non-squamous NSCLC

● No prior systemic treatment for advanced disease

● ECOG PS 0−2● Measurable disease● Stable treated brain

metastases allowed

Crizotinib250 mg twice daily

PO, continuous Dosing (N=172)

Pemetrexed 500 mg/m2

+ cisplatin 75 mg/m2

or carboplatin AUC 5–6 every 3 weeks

for ≤6 cycles(N=171)

Endpoints

● Primary– PFS (RECIST 1.1,

independent radiologic review [IRR])

● Secondary– ORR– OS– Safety – Patient-reported

outcomes (EORTC QLQ-C30, LC13)

RANDOMIZE

Crossover to crizotinib permitted after progression

PFS

prob

abili

ty (%

)

100

80

60

40

20

00 5 10 15 20 25 30 35

Time (months)172 120 65 38 19 7 1 0171 105 36 12 2 1 0 0

No. at riskCrizotinibChemotherapy

PROFILE 1014 Phase III StudyPFS as Assessed by IRC

Solomon BJ, et al. N Engl J Med. 2014.

CrizotinibChemotherapy

CrizotinibN=172

Chemo N=172

Events, n (%) 100 (58) 137 (80)

Median, months 10.9 7

HR (95%CI) 0.45 (0.35–0.60)

ORR 74% 45%

P-value <.0001

J-ALEX Phase III Study Alectinib vs Crizotinib

• ALK + NSCLC• ALK treatment naive • ALK positive by

central testing• PS 0-2

Crizotinib 250 mg po twice daily

Alectinib 300 mg po BID

Primary end-point: PFS by IRRSecondary end-point:OS, ORR, CNS progression, HRQoL

JAPIC Clinical Trials Information. Available at: http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132316.

J-ALEX Phase III Study Alectinib vs Crizotinib

• ALK + NSCLC• ALK treatment naive • ALK positive by

central testing• PS 0-2

Crizotinib 250 mg po twice daily

Alectinib 300 mg po BID

Primary end-point: PFS by IRRSecondary end-point:OS, ORR, CNS progression, HRQoL

JAPIC Clinical Trials Information. Available at: http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132316.

Closed by IDMC at preplanned interim analysis after207 patients enrolled since primary end-point of PFS met

Nokihara et al Abstract 9008: Oral abstract sessionMonday June 6th 9:45-12:45

Arie Crown Theater

Conclusions

• Erlotinib, gefitinib, and afatinib are all options in the first-line setting.

• Combination trials reveal promising activity • Continuing therapy beyond disease

progression is an option for select patients.−Most likely delays a change in therapy by 2-3

months • Crizotinib is the standard for ALK+ NSCLC,

but I eagerly await Monday’s presentation.

Thank you!Please visit us at: www.ceconcepts.com

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Targeted Therapies for Advanced NSCLC - ceconcepts.com Therapy for...Targeted Therapies for Advanced NSCLC. Current Clinical Developments . Friday, June 3, 2016. Supported by an independent