challenges/management of oncogene dependent...

Challenges/Management of Oncogene Dependent NSCLC

Odd Terje Brustugun, MD PhD

Dept of Oncology, Norwegian Radium Hospital

Oslo, Norway

Disclosures

Grants/research support:AstraZeneca, GlaxoSmithKline, Roche/Genentech

Speaker/advisor honoraria, travel support:AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche, SanofiAventis,

Brustugun, Dresden Nov 2015

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1997 1999 2001 2003 2005 2007 2009 2011 2013

Perc

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1, 2 and 5 year survival, lung cancer Norway

F 1y

F 2y

F 5y

M 1y

M 2y

M 5y

Cancer Registry of Norway 2015


SCC AC

SCLC LCC

Moleculartesting

Current standard


Different genes are mutated in lung adenocarcinoma and lung squamous cell carcinoma

RTK/Ras/Raf pathway in lung adenocarcinoma:

KRAS, EGFR, NF1, BRAF, MET, ERBB2, RIT1, RAF1

Common squamous cell cancer genes including NFE2L2, FAT1, NOTCH1 in lung SqCC

Meyerson, WCLC 2015

Campbell et al., submitted


Adenocarcinomas in 2015

TCGA, Nature, 2014: Alice Berger, William Lee

75% potentially druggable

3 main subtypes?Skoulidis F, # 3224


2015 updateBrustugun, Dresden Nov 2015

Today/yesterday

EGFR ALK KRASBRAF PIK3CA EtcTissue

Tissue (blood?)

EGFR

ALK

KRAS

BRAF

PIK3CA

Etc

NGS

Tomorrow/already today

Less amount of tissue (DNA), faster turnaround, cheaper?


ORAL06.07 - A. Kostenko

Multiple vs single molecular testing• Workload & turnaround time (10 days for 4 genes vs 12 days for 14 genes (Koenig K et al., J Thorac Oncol. 2015))• Tissue suitability (10 ng per gene vs 50 ng for NGS panel)• Patient benefit (risk: multiple biopsies required)• Quality of testing and interpretation of results• Cost (risk: multiplication of single test costs)


Presentation Number: Presentation Title – Philip C. Mack, Ph.D

Raf

Mek

Erk1/2

p90RSK

Adaptor

PI3K

PDK1

AKT

PTEN

RAS

MEKK1

MKK7

JNK

RAC

PAK

MKK3,6

p38JNK

PAT

HW

AY

FKH

mTOR

p70S6K

CREB

GSK3

ATF2Jun

MSK2

115

EGFR: 123HER2 ins: 9

Fusions:ALK: 6RET: 9

26

5

NF-1

65(22 are truncating)

Plasma NGS in 978NSCLC cases –

Liquid biopsies

32

3

RTK mutations, fusions and MEK pathway alterations were almost completely mutually exclusive

MET amp: 18MET E14sk: 8

14In blood we trust?

Worth considering when tissue is unavailable

Sequential testing


+Mereletinib (AZD9291)RociletinibEGF816BI 1482694

+AlectinibBrigatinibLorlatiniband others


EGFR


1st gen EGFR-TKIAny difference?


A randomized controlled trial of erlotinib versus gefitinib in advanced non-small-cell lung cancer

harboring EGFR exon 19 or 21 mutations (CTONG0901)

Jin-Ji Yang, Qing Zhou, Hong-Hong Yan, Xu-Chao Zhang, Hua-Jun Chen, Hai-Yan Tu, Zhen Wang, Chong-Rui Xu, Jian Su, Yi-Sheng Huang, Bin-Chao Wang, Ben-Yuan Jiang, Xiao-Yan Bai, Wen-Zhao Zhong, Xue-Ning Yang, Yi-Long Wu*.

Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences. No.106, Zhongshan 2nd Rd, Guangzhou, Postal code:510080, People’s Republic of China.

*Correspondence: [email protected]

Presentation Number: Presentation Title – Presenting AuthorBrustugun, Dresden Nov 2015

A B

C D

E was not superior to G in PFS and OS.

E19 was superior to E21 in OS.E19 was not superior to E21 in PFS.


3rd generation EGFR TKI


First-line cohort objectiveSafety and tolerability of AZD9291 (80 mg or 160 mg orally) as first-line therapy for patients with EGFRm positive NSCLC

AURA Phase I dose escalation / expansion global study design

Data cut-off August 1, 2015Data from cohorts in grayed out boxes are not included in the analyses reported hereILD, interstitial lung disease

Key inclusion criteria:• Locally advanced or metastatic NSCLC

• No prior therapy for advanced disease

• Measurable disease

• Patients must have EGFRm positive tumor status from a local test

Key exclusion criteria:• Prior history of ILD

• Symptomatic brain metastases

Esca

latio

n

Enrollment into first-line cohorts by local and / or central (cobas™ EGFR

Mutation Test) identification of EGFR-TKI-sensitizing mutation

Cohort 120 mg

Negative

Cohort 240 mg

Cohort 5240 mg

Rolling six design

Cytology

Tablet

Negative

Cohort 3 80 mg

Negative

Cohort 4 160 mg

Positive Positive PositivePositive Positive

Biopsy Biopsy

T790M cohorts

First-line EGFRm80 mg

First-line EGFRm160 mg

Expa

nsio

n

Ramalingam et al, WCLC 2015Brustugun, Dresden Nov 2015

Tumor response in AZD9291 first-line cohorts by dose

Population: evaluable for response, data cut-off August 1, 2015; RECIST 1.1, programmatically calculated from investigator-recorded tumor measurementCI, confidence interval; D, discontinued

80 mgN=30

160 mgN=30

TotalN=60

Confirmed objective response rate 67% (95% CI 47, 83)

83% (95% CI 65, 94)

75% (95% CI 62, 85)

Disease control rate 93% (95% CI, 78, 99)

100% (95% CI 88, 100)

97% (95% CI 89, 100)

Best objective responseComplete responsePartial responseStable diseaseProgressive disease

02082

2*2350

2*43132

DD

DD D

DDDDD

D

80 mg

160 mg

DD

D

100

807060

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2010

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DD

Best percentage change in target lesion size – all patients

-90

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DoR and PFS in AZD9291 first-line cohorts (investigator assessed)

80 mg N=30

160 mgN=30

TotalN=60

Median PFS,‡ months (95% CI)

NC (12.3, NC) Maturity: 40%



Maximum PFS, months 19.2+ 13.8+ 19.2+

Remaining alive and progression-free,† % (95% CI)

9 months12 months

83 (64, 93)75 (55, 87)

80 (60, 90)69 (48, 82)

81 (69, 89)72 (58, 82)

Population: all dosed patients, data cut-off August 1, 2015Progression events that do not occur within 14 weeks of the last evaluable assessment (of first dose) are censored*Duration of response is the time from first documentation of response until date of progression or death or last evaluable RECIST assessment for patients who do not progress; †Calculated using the Kaplan-Meier technique; ‡Progression-free survival is the time from date of first dosing until the date of objective disease progression or deathDoR, duration of response; NC, not calculable; PFS, progression-free survival

80 mg N=20

160 mgN=25

TotalN=45

Median DoR,* months (95% CI)

13.6 (11.1, NC) Maturity: 35%

NC (9.7, NC)Maturity: 28%


Maximum DoR, months 18.0+ 12.6+ 18.0+

Remaining in response,†% (95% CI)

9 months12 months

89 (64, 97)76 (46, 90)

78 (56, 90)69 (45, 84)

83 (68, 92)71 (53, 83)

Progression-free survivalDuration of response1.0

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1512630Month

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Number of patients at risk:

AZD9291 80 mg

30 26 23

9 18

AZD9291 160 mg

80 mg 22 19 12 3

30 29 27160 mg 23 17 0 0

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20 20 17

9 18

AZD9291 160 mg

14 10 5 0

25 25 21 18 8 0 0

Number of patients at month:

80 mg

160 mg

Censored observation





AURA2: Phase II, open-label, single-arm study

*The EGFR T790M mutation status of the patient’s tumor was prospectively determined by the designated central laboratory using the cobas™ EGFR Mutation Test (Roche Molecular Systems) by biopsy taken after

confirmation of disease progression on the most recent treatment regimenBICR, blinded independent central review; EGFR, epidermal growth factor receptor; EGFRm, EGFR-TKI-sensitizing mutation; NSCLC, non-small cell lung cancer; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors; TKI, tyrosine kinase inhibitor; WHO, World Health Organization

Primary objectiveTo investigate the efficacy of AZD9291 by assessment of ORR (RECIST 1.1 BICR)

Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved

EGFR-TKI

Central T790M mutation testing* of biopsy sample

collected following confirmed disease progression

T790M positive(n=210)

T790M negative

AZD9291 80 mg once daily

Not eligible for enrollment

Key inclusion criteria• Aged ≥18 (≥20 in Japan)

• Confirmation of tumor EGFR mutation associated with EGFR-TKI • At least one lesion suitable for accurate repeated measurements• WHO performance status 0 or 1• Acceptable organ function• Stable brain metastases allowed

Mitsudomi et al, WCLC 2015Brustugun, Dresden Nov 2015

NOTE: Investigator-assessed ORR was also 71% (95% CI 64, 77)Data cut-off: May 1, 2015. Population: evaluable for response set (n=199). *Represents imputed values: if it is known that the patient has died, has new lesions or progression of non-target lesions, has withdrawn due to disease progression, and has no evaluable target lesion (before or at progression) assessments, best change will be imputed as 20%; †ORR defined as the number (%) of patients with at least one visit response of complete response or partial response that was confirmed at least 4 weeks later; ‡Response required confirmation after 4 weeks; §Stable disease ≥6 weeks included the RECIST visit window (±7 days) CI, confidence interval; DCR, disease control rate (complete response + partial response + stable disease)

Tumor response by independent central review

Confirmed objective response Total

ORR† 71% (95% CI 64, 77)

Complete response,‡ n (%)Partial response,‡ n (%)Stable disease ≥6 weeks,§ n (%)Progressive disease, n (%)

2 (1)139 (70)41 (21)15 (8)

DCR 92% (95% CI 87, 95)

Best percentage change from baseline in target lesion – all patients

Complete responsePartial responseStable diseaseProgressive diseaseNot evaluable

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Mitsudomi et al, WCLC 2015Brustugun, Dresden Nov 2015

Presentation Number: Discussion 16.06-16.09 – Martin Reck

Confirmed efficacy in pretreated patientsAZD9291AURA21

AZD9291AURA 12

RociletenibTIGERX3

EGF8164

Patients 199 201 243 42

Dose 80 mg 80 mg 500-1000 mg (BID)

75-350 mg (QID)

Line oftreatment

1 TKI / > 1 TKI(1-9)

1 TKI / > 1 TKI(1-11)

1 TKI / > 1 TKI 1 TKI / > 1 TKI

RR 71% 61% 53% 60%

DCR 92% 91% 85% 93%

PFS 8.6 m (med)48% (9 m PFS rate)

72%(6 m PFS rate)

8m (med)

1 Mitsudomi 16.08., 2 Yang 16.06, 3 Sequist ASCO 2015, abstr. 8001, 4 Tam ASCO 2015, abstr. 8013


Presentation Number: Discussion 16.06-16.09 – Martin Reck

Tolerability?AZD9291AURA21

AZD9291AURA 12

RociletenibTIGERX3

Dose 80 mg 80 mg 500 mg BID

ILD 2% 4% (Gr.3 3%) 1.5%

Hyperglycemia 1% 1% 35% (Gr. 3 17%)

QT-Elongation 5% (Gr. 3 2%) 3% (Gr. 3 0%) 13% (Gr. 3 2.5%)

Rash 23% (Gr. 3 0%) 24% (Gr. 3 0%) Nr

Diarrhea 39% (Gr. 3 1%) 46% (Gr. 3 7%) 33% (Gr. 3 nr)

Discontinuation 4% 4% 2.5%

1 Mitsudomi 16.08., 2 Yang 16.06, 3 Sequist ASCO 2015, abstr. 8001


Future perspectives

CT

Today

CTEGFR-TKI (3. Gen.)

Option 1

EGFR-TKI (1. Gen.)

EGFR-TKI (1. Gen.)EGFR-TKI (1. Gen.) EGFR-TKI (3. Gen.) CT

Option 2 (more attractive?)

PFS


MTE12: Therapy for Driver Mutation Positive Advanced NSCLC – Federico Cappuzzo

Mechanisms responsible for acquired resistance to 3rd-generation EGFR-TKIs

Ercan D, et al. Clin Cancer Res 2015Thress KS, et al. Nature Med 2015

Piotrowska Z, et al. Cancer Discov 2015Eberlein CA, et al. Cancer Res 2015


Ongoing & planned combination studies with mutant selective EGFR inhibitors

EGFR Inhibitor AZD9291 Rociletinib EGF816

Combination MEDI4736 Trametinib INC280 (MET)

Volitinib (MET) Pembrolizumab Nivolumab

Selumetinib Atezolizumab

Necitumumab Aurora Kinase

Navitoclax

MLN0218

Which combination therapy should be used and when ?


ALK(anaplastic lymphoma kinase)


2nd generation ALKi inhibitors

Drug CompanyActivity against

L1196MOther kinases

inhibitedClinicalStage

Crizotinib Pfizer No MET, ROS1 Approved

Ceritinib Novartis Yes ROS1, IGFR1 Approved

Alectinib Chugai/ Roche Yes – Phase III

Brigatinib Ariad Yes ROS1, EGFR Phase II

ASP3026 Astellas Yes ROS1 Discontinued

Entrectinib Ignyta Unknown ROS1, TRK1/2/3 Phase II

X-396 Xcovery Yes ROS1 Phase I/II

TSR-011 Tesaro Yes TRK1/2/3 Phase I/II

Lorlatinib Pfizer Yes ROS1 Phase I/II


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2125: Brigatinib Efficacy and Safety in ALK+ NSCLC—Scott N Gettinger

Brigatinib Antitumor Activity in ALK+ NSCLC Patients (n=70)

Dotted line at –30% indicates threshold for partial responseAll patients had previously received crizotinib unless otherwise indicated; initial daily brigatinib doses ranged from 30 to 300 mg/da Received prior crizotinib and ceritinib (n=2)b Crizotinib-naive patients (n=8)

a

bb

b

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Partial response Complete responseProgressive disease Stable disease

a

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Lesi

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)


Clinical Activity of Lorlatinib (PF-06463922)

PD=progressive disease; R=ROS1+; ROS1=c-ros oncogene 1; TKI=tyrosine kinase inhibitor

295: Clinical Activity and Safety of the ALK/ROS1 TK Inhibitor Lorlatinib (PF-06463922) in Advanced NSCLC – T. M. Bauer 7

30

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% C

hang

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asel

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= Off treatment or PD

1 Prior TKI >1 Prior TKINo prior TKI

Patients

PD occurred in 14 patients: new lesions (n=8), non-target lesions (n=2), both new and non-target lesions (n=4).

MTE12: Therapy for Driver Mutation Positive Advanced NSCLC – Federico Cappuzzo

Alectinib in crizotinib-resistant ALK+ NSCLCs

Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting


•Data cut-off for both studies = 27 April 2015

Alectinib is active in CNS regardless of prior radiation

70605040302010

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–100

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max

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–20

Patients

Prior CNS Radiation

Yes (n=34)

No (n=16)

Waterfall plot of patients with measurable CNS disease

Gadgeel et al, WCLC 2015

Presentation Number: O33 Discussion Myung-Ju Ahn

CNS efficacy of Next generation ALK inhibitors in Crizotinib Pre-treated patients

Drug N Dose CNS activityORR PFS

G3/4 Side effect

Ceritinib Phase I (N=163/246)

50-750mg 18% ORR(n=75)

* 44% crizotinib naïve

6.9m Diarrhea 5.9%, Nausea 5.9%, Vomiting 5.9%

ASCEND-2(N=140)

750mg 39.4% ORR(n=33)

* 58.8% crizotinibnaïve

5.4m Diarrhea 6.4%, Nausea 6.4%, Vomiting 4.3%ALT elevation 17.1%

Alectinib Pooled analysis(n=136/225)

600mg bid 64% ORR(n=50)

DOR 10.8m

Rash 2%Neutropenia 4%

Brigatinib Phase I/II(N=65/137)

30-300mg 53% ORR(n=15)

DOR18.9 m

pulmonary symptoms 9%

Lorlatinib Phase I(n=30/50)

10-400mg 33% ORR(n=30)

DOR NA

Hypercholesterolemia 10%Hypertriglyceridemia 4%CNS effects 2%


Current landscape for ALK inhibitors in late development

Timing of therapy

Combination therapy

Other 2nd Generation ALKi

3rd Generation ALKi

Alectinib 600 mg BD

Crizotinib 250 mg BD

ALEX Phase III Study (NCT02075840)

No crossover R1st lineALK IHC

PD

Chemotherapy Crizotinib 2nd generation inhibitors

ASCEND 2 (ceritinib) PFS: 5.7

NP28761 (alectinib) PFS: 8.1

ALTA (brigatinib) PFS: ??

Biomarkers?

«Positive opinion» for 1st line Oct 22 2015


Other challenges


Costs

• All new FDA-approved drugs in 2014: >$120,000 per pt/year

• End of the Scandinavian «equalaccess to health services»-model…


Thanks for your attention


challenges/management of oncogene dependent...

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