Lung Cancer Updates 2018 · • NE, not estimable; NR, not reported. • 1. Gandhi L, ... 476 377...

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Lung Cancer Updates 2018

Edward S. Kim, M.D., FACP

Chair, Solid Tumor Oncology and Investigational Therapeutics

Donald S. Kim Distinguished Chair for Cancer Research

Medical Director, Clinical Trials Office

Levine Cancer Institute

Charlotte, NC

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L E V I N E C A N C E R I N S T I T U T E

Organizations

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NSCLC: A Major Public Health Problem

• Estimated 1.6 million deaths each year worldwide from lung cancer

• In 2015:

• Estimated 221,200 new cases of lung cancer expected to be diagnosed in US

• 158,000 Americans expected to die from lung cancer

• Leading cause of cancer-related deaths in US men and women

• More deaths from lung cancer than breast, prostate, colon, liver, melanoma, and kidney cancers combined

• Need for better thought out, patient-driven studies

Torre LA, et al. CA Cancer J Clin. 2015;65(2):87-108.Siegel RL, et al. CA Cancer J Clin. 2015;65(1):5-29.

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Importance of Clinical Trials

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Must Allow More Patients to Participate

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Lung Cancer Treatment 2000:

ECOG 1594 Comparison of 4 First-Line Doublet

Regimens in Advanced NSCLC

• Nonsquamous and

squamous

histologies

• No differences

• Efficacy not so

encouraging

• Easy for providers

to “take home a

message”

• “Treat with any

doublet you would

like”Schiller JH, et al. N Engl J Med. 2002;346:92-98.

Pro

bab

ilit

y o

f S

urv

ival

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E4599: Bevacizumab with Chemotherapy in NSCLCOverall Survival

0 6 12 18 24 30 36

0

20

40

60

80

100

Months

Carboplatin and paclitaxel

Carboplatin and paclitaxel + bevacizumab

Treatment group

Median survival: 12.5 vs 10.2 monthsHR = 0.77 (95% CI: .65, .93), P = 0.007

1-yr Survival: 52% vs 44%2-yr Survival: 22% vs 17%

Pati

ents

su

rviv

ing,

%

Sandler et al. NEJM 2006

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NSCLC Drug Approvals/Indications: 2015 - Present

• Alectinib

• Necitumumab

• Nivolumab

• Osimertinib

• Gefitinib

• Ramucirumab

• Atezolizumab

• Ceritinib

• Brigatinib

• Pembrolizumab

– PD-L1 + (1st, 2nd line)

– MSI-H or dMMR solid

tumors

– NSCLC (Carboplatin

+ Pemetrexed)

• Crizotinib (ROS1)

• Dabrafenib, Trametinib

• Durvalumab

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The Changing Landscape of Lung Cancer: 2005

80 of 100 patients eligible for chemotherapy

Only 15-20% of tumors had a partial

response

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Molecular subsets: EGFR Mutations


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Molecular subsets: ALK


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Molecular subsets: ROS1


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Molecular subsets: PD-L1


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Molecular subsets: BRAFv600E


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Molecular subsets: 50% of patients candidates for targeted therapy


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Screening for Lung Cancer

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Precision Medicine Works

Precision Medicine Works

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Biomarker Recommendations: Practical

Applications

• EGFR

• BRAF

• ALK

• ROS1

• PD-L1

• EGFR T790M

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Treatment Algorithm NSCLC 2018

PD-L1< 50%Carboplatin

nab-paclitaxel

Pembrolizumab

No targetable

mutations

PD-L1< 50%

Platinum-based

chemotherapy

Squamous

Pt w/treatment

naïve

metastatic

NSCLC

Non-squamous

• EGFR

• ALK

• BRAFV600E

Targeted therapy

• Osimertinib

• Alectinib

• Dabrafenib/Trametinib

• Crizotinib

• Other TKIs

• ROS-1

• C-MET exon 14

• RET

PD-L1 ≥ 50% Pembrolizumab

Carboplatin

Pemetrexed

Pembrolizumab

Nivolumab/IpilimumabTMB High

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KEYNOTE-042 Study Design: Pembrolizumab vs. chemotherapy

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L E V I N E C A N C E R I N S T I T U T ELopes, ASCO 2018

KEYNOTE-042

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KEYNOTE-042

Lopes, ASCO 2018

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KEYNOTE-042

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KEYNOTE-042

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Implications of KEYNOTE-042

• Single agent Pembrolizumab has activity in PD-L1 + lung

cancer

• PD-L1 ≥ 50% continue single agent

• Consider the response rates

• Fit patients should be considered for combination

chemotherapy (KEYNOTE-189)

• Medically less fit patients should be given single agent

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KEYNOTE-189 Study Design

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Pembrolizumab

(200 mg fixed dose

q3w) plus pemetrexed

(500 mg/m2), with

vitamin

supplementation,

plus cisplatin

(75 mg/m2) or

carboplatin AUC 5 on

Day 1 q3w for 4

cycles

Placebo plus

pemetrexed

(500 mg/m2), with

vitamin

supplementation, plus

cisplatin (75 mg/m2)

or carboplatin AUC 5

on Day 1 q3w for 4

cycles

Endpoints

Primary endpoints

• PFS per RECIST v1.1

• OS

Secondary endpoints

• ORR per RECIST

v1.1

• DoR

• Number of

participants who

experience an AE

• Number of

participants who

discontinue study

treatment due to an

AE

Key eligibility

criteria:

• ≥18 years old

• Histologically or

cytologically confirmed

diagnosis of stage IV

nonsquamous NSCLC

• No prior systemic therapy

for advanced or

metastatic disease

• Measurable disease

• Can provide tumor tissue

• ECOG PS 0 or 1

• Any PD-L1 status

• No EGFR and ALK

genomic tumor

mutations

N=614

R 2:1

Pembrolizumab

200 mg plus

pemetrexed

(500 mg/m2) q3w until

disease progression,

unacceptable toxicity,

physician decision, or

consent withdrawal

Placebo plus

pemetrexed

(500 mg/m2) q3w until

disease progression,

unacceptable toxicity,

physician decision, or

consent withdrawal

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KEYNOTE-189 Co-Primary Endpoint: PFS

• aITT, RECIST v1.1, BICR. Data cutoff date: Nov 8, 2017.

• BICR, blinded independent central review; Pembro, pembrolizumab; pem, pemetrexed; plat, platinum chemotherapy; TPS,

tumor proportion score.

• 1. Gandhi L, et al. N Engl J Med. 2018; 378(22):2078-2092. 2. Gandhi L, et al. Presented at: AACR 2018; April 14-18;

Chicago, IL. Abstract CT075.

PFS in all key subgroups

favored

Pembro/Pem/Plat

• Age (<65, ≥65)

• Sex (male, female)

• ECOG PS (0,1)

• Smoking status

(current/former, never)

• Baseline brain

metastases (yes, no)

• PD-L1 TPS (<1%, ≥1%,

1-49%, ≥50%)

• Platinum chemotherapy

(carboplatin, cisplatin)

• PD-L1 TPS (<1%, ≥1%,

1-49%, ≥50%)

Events HR (95% CI) P

Pembro/Pem/Plat 59.5% 0.52 (0.43-0.64) <0.001

Placebo/Pem/Plat 80.6%

34.1%

17.3%

Median (95% CI)

8.8 mo (7.6-9.2)

4.9 mo (4.7-5.5)

100

80

90

70

60

40

30

10

50

20

0

0 3 6 9 12 15 21

Months

410

No. at Risk

206

322

141

256

80

149

40

60

16

17

3

18

5

1

0

0

PF

S,

%

32

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KEYNOTE-189 Co-Primary Endpoint: OS

• Data cutoff date: Nov 8, 2017.

• NE, not estimable; NR, not reported.

• 1. Gandhi L, et al. N Engl J Med. 2018; 378(22):2078-2092. 2. Gandhi L, et al. Presented at: AACR 2018; April 14-

18; Chicago, IL. Abstract CT075.

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OS in all key subgroups

favored

Pembro/Pem/Plat

• Age (<65, ≥65)

• Sex (male, female)

• ECOG PS (0,1)

• Smoking status

(current/former, never)

• Baseline brain

metastases (yes, no)

• PD-L1 TPS (<1%, ≥1%,

1-49%, ≥50%)

• Platinum chemotherapy

(carboplatin, cisplatin)

• PD-L1 TPS (<1%, ≥1%,

1-49%, ≥50%)

Events HR (95% CI) P

Pembro/Pem/Plat 31.0% 0.49 (0.38-0.64) <0.001

Placebo/Pem/Plat 52.4%

69.2%

49.4%

Median (95% CI)

NR (NE-NE)

11.3 mo (8.7-15.1)OS

, %

100

80

90

70

60

40

30

10

50

20

0

0 3 6 9 12 15 21

Months

410

No. at Risk

206

377

183

347

149

278

104

163

59

71

25

18

18

8

0

0

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PFS

0%

OS

1-49%

>50%

0%

1-49%

>50%

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L E V I N E C A N C E R I N S T I T U T E Paz-Ares, ASCO 2018

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KEYNOTE-407

Paz-Ares, ASCO 2018

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Overall Survival at IA2, ITT

Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

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Implications of KEYNOTE-407

• New standard of care in the treatment of patients with

squamous cell lung cancer

• No steroids with nab-paclitaxel

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IMpower131: Study Design

R Jotte at 2018 ASCO

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IMpower 131 Carbo/Abraxane +/- Atezo

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TMB High Patients (Hellmann, NEJM 2018)

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TMB High Patients (Hellmann, NEJM 2018)

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TMB in Lung Cancer

• Tumor Mutational Burden is an interesting marker

• Will it be like MSI-H?

• Still trying to find best clinical fit

– Ipi-Nivo

– Dual markers?

– Logistics

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PACIFIC: Study DesignPhase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study

*Defined as the time from randomization (which occurred up to 6 weeks post-cCRT) to the first documented event of tumor progression or death in the absence of progression.

ClinicalTrials.gov number: NCT02125461 BICR, blinded independent central review; cCRT, concurrent chemoradiation therapy; DoR, duration of response;

NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes;

PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization

• Patients with stage III, locally

advanced, unresectable NSCLC

who have not progressed following

definitive platinum-based cCRT

(≥2 cycles)

• 18 years or older

• WHO PS score 0 or 1

• Estimated life expectancy of

≥12 weeks

• Archived tissue was collected

All-comers population

Durvalumab

10 mg/kg q2w for

up to 12 months

N=476

Placebo

10 mg/kg q2w for

up to 12 months

N=237

2:1 randomization,

stratified by age, sex,

and smoking history

N=713Key secondary endpoints

• ORR (per BICR)

• DoR (per BICR)

• Safety and tolerability

• PROs

Co-primary endpoints

• PFS by BICR using RECIST v1.1*

• OS

R

1–42 days

post-cCRT

Paz-Ares, ESMO 2017

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PACIFIC: PFS by BICR (Primary Endpoint; ITT)

PF

S p

robabili

ty

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27

Time from randomization (months)

Placebo

Durvalumab

476 377 301 264 159 86 44 21 4

237 163 106 87 52 28 15 4 3

1

0

No. at risk

Durvalumab

Placebo

Durvalumab(N=476)

Placebo(N=237)

Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)

12-month PFS rate (95% CI) 55.9% (51.0–60.4) 35.3% (29.0–41.7)

18-month PFS rate (95% CI) 44.2% (37.7–50.5) 27.0% (19.9–34.5)

BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-free survival

Stratified hazard ratio, 0.52 (95% CI, 0.42–0.65)Two-sided P<0.0001

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Effect of Steroids w/IO (Arbour, ASCO 2018)

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First-line Osimertinib vs SoC for EGFR

Mutant Advanced NSCLC (FLAURA)

• Primary endpoint: PFS

• Secondary endpoints including: ORR, DoR, OS, safety

Ramalingam S, et al. ESMO 2017. Abstract LBA2_PR.

Treatment-naive pts with

advanced NSCLC

adenocarcinoma with an

EGFR exon 19 or 21

mutation,

WHO PS 0/1,

stable CNS mets

permitted

(N = 556)

Osimertinib 80 mg PO daily

(n = 279)

Erlotinib 150 mg or Gefitinib 250 mg

PO daily

(n = 277)

Until disease progression

or unacceptable

toxicity

EGFR mutation (del19 vs L858R) and race (Asian vs non-Asian)

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FLAURA: PFS


PF

S (

%)

MosPts at Risk, n

Osimertinib

SoC

100806040200

0 6 9 2112 18 24 27

279277

262239

233197

210152

13978

7137

2610

00

153

178107

42

Osimertinib

(n = 279)

SoC

(n = 277)

Median PFS, mos 18.9 10.2

HR (95% CI) 0.46 (0.37-0.57); P < .0001

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FLAURA: Overall Survival Interim Analysis

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PFS in Patients w/ & w/out CNS Metastases


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Resistance to Third Generation EGFR TKIs

Thress KS, et al. Nat Med. 2015;21(6):560-562.

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• Other Targeted Therapy

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LIBRETTO-001

Drillon, ASCO 2018

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ARCHER 1050: Study Design

• Open-label, Phase III comparing dacomitinib with gefitinib in first-line metastatic EGFRm NSCLC

• Wu YL, et al. Lancet Oncol 2017;18:1454-1466.

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Patients

• EGFRm

• Advanced (IIIb/IV) NSCLC

• No prior systemic therapy

• ECOG PS 0 or 1

Endpoints:

Primary• PFS (by independent radiologic review)

Secondary• OS

• OS at 30 months

• PFS (by investigator review)

• Best overall response

• DoR

• Safety

• HRQoL

Patients with CNS metastases (including stable brain metastases) were excluded from the

study

aStratified by race and EGFRm status

Ra

nd

om

ize

da

1:1

Dacomitinib 45 mg

(n=227)

Gefitinib 250 mg

(n=225)

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ARCHER 1050: PFS (IRC)

64

HR 0.59 (95% CI 0.47, 0.74); p<0.0001

Dacomitinib (n=227)

Gefitinib (n=225)

Median PFS (months)

14.7 (95% CI 11.1, 16.6)

9.2 (95% CI 9.1, 11.0)

Pro

gre

ss

ion

-fre

e s

urv

ival

(%

)

100

80

60

40

20

0

0 6 12 18 24 30 42

Gefitinib

Dacomitinib

No. at risk(number censored)

Time (months)

36

227 (0) 154 (23) 106 (31) 73 (36) 20 (74) 6 (88) 0 (91)0 (91)

225 (0) 155 (15) 69 (23) 34 (27) 7 (40) 1 (45) 0 (46)0 (46)

Events

136

179

Patient

s

The ARCHER 1050 trial was independently assessed

Tick marks indicate censored data. CI, confidence interval; HR, hazard ratio; IRC, independent radiologic central review; PFS, progression-free survival.

Wu, et al. Lancet Oncol 2017;18:1454-1466.

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ARCHER 1050: Final OS (Primary Analysis)

65

227

225

206

213

188

186

167

144

138

113

77

63

14

12

3

3

0

0

No. at risk

Dacomitinib

Gefitinib

Dacomitinib

(n=227)

Gefitinib

(n=225)

OS probability at

30 months56.2% 46.3%

CNS metastases at

progression, n1 11

Pro

ba

bilit

y o

f O

S

Months

0 6 12 13 24 30 36 42 48

1.0

0.8

0.6

0.4

0.2

0.0

HR 0.760 (95% CI 0.582, 0.993); 2-side Pa=0.0438

Dacomitinib (n=227)

Gefitinib (n=225)

Median OS (months)

34.1 (95% CI 29.5, 37.7)

26.8 (95% CI 23.7, 32.1)

Numberof Deaths

103

117

Patient

s

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Poziotinib

• EGFR exon20 insertions (affecting 2% of NSCLCs) have

demonstrated resistance to current EGFR TKIs (PFS 2

months, RR <20% to other therapies)

• Poziotinib is an oral, quinazoline-based pan-HER

inhibitor

• Preliminary results of phase II trial

– 8 of 11 patients (73%) demonstrated partial response (ranging

from 30 to 50% tumor reduction)

– 6 of 11 patients required dose reduction (rash, diarrhea)

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ALK Targeted Therapy Updates

FIRST-LINE

• Crizotinib: mPFS 10.9 months

• Ceritinib: mPFS 16.6 months

• Alectinib: mPFS 25.7 months

NEXT-LINE

• Crizotinib: mPFS 7.7 months

• Ceritinib: mPFS 5.4 months

• Alectinib: mPFS 8.9 months

• Brigatinib: mPFS 12.9

months

• Lorlatinib

• Ensartinib

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ALEX: Results In CNS

• Alectinib reduced the risk for CNS progression by 84%

compared with crizotinib (HR, 0.16; 95% CI, 0.10-0.28;

p<0.0001).

• The 12-month cumulative rate of CNS progression was

9.4% vs 41.4%.

• CNS ORR = 81% vs 50% (CR rate 38% vs 5%)

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Lorlatinib

Any Prior Therapies

• ORR = 17/47 (36%)

• Intracranial ORR = 14/25 (56%)

• mDOR = 13.8 months

• DOR ≥ 6 months = 12/17 (71%)

• mPFS = 9.6 months

• 25 patients (53%) had brain

metastases at baseline.

Solomon, et al. IASLC 18th WCLC; 2017, Japan.

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BRAF V600E: Dabrafenib and Trametinib

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Larotrectinib (LOXO-101)

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Entrectinib (RXDX-101)

Target TrkA TrkB TrkC ROS1 ALK

IC50* (nM) 1.7 0.1 0.1 0.2 1.6

78* Biochemical kinase assay

Most potent, orally available pan-TRK inhibitor in clinical development

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46M with SQSTM1-NTRK1 NSCLC

Ongoing response at 15.1 months

Baseline Day 26: - 47% response Day 317: - 79% response

15-20 CNS mets CR CR

Images courtesy of A. Shaw, MD, PhD and A. Farago, MD, PhD (MGH)

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Levine Cancer Institute

Carolinas HealthCare System

• Started with 3 community practices

• 25 Locations

• EAPathways

• Multi-Site Phase I Unit

• Bone Marrow Transplant Unit

• Biostatistics Department

• Biospecimen Repository

• Patient Navigation

• Supportive Oncology Department

• Integrative Medicine

• Senior Oncology

• >100 Providers

• >400 Clinical Trials

• CAR-T cellular therapy performed

Derek Raghavan, MD

President, Levine Cancer

Institute

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Targeted Agent and Profiling Utilization

Registry (TAPUR) Study

• Pragmatic phase 2 study with FDA-approved, targeted

agents

• 60-70% match rates

• Incorporates general and drug-specific eligibility criteria

• Adopted ASCO-Friends Eligibility Criteria

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LCI Regional Network

LCI-Cleveland (2 MDs)

LCI-NorthEast (8 MDs)

LCI-Main (12 MDs)

LCI-Union (2 MDs)

LCI-Pineville (4 MDs)

LCI-University (2 MDs)

LCI-Ballantyne (3 MDs)

LCI-Rock Hill (3 MDs)

LCI-Mallard Creek (2 MDs)

LCI-South Tryon (3 MDs)

LCI-Southpark (3 MDs)

LCI-Matthews (2 MDs)

LCI-Carolina Lakes (2 MD)

LCI-Stanly (1 MD)

AnMed-LCI (2 MDs)

RSF-LCI (5 MDs)

LCI-Rutherford (2 MDs)

LCI-Blue Ridge (3 MDs)

LCI-Whiteville (1 MD)

LCI-Lincolnton (2 MDs)

*Med/Heme Oncology staff

Valdese, NCPop. ~4400

Lincolnton, NCPop. ~10,500

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Current State of Lung Cancer 2018

• Biomarker assessment as important as

histology

• Adequate tissue at diagnosis essential

• Less chemotherapy 1st line paradigm evolving

• Multiple TKI therapy

• Immunotherapy

• Sequencing

• Patient is the most precious resource

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The Fight Against Lung Cancer

Lung Cancer Updates 2018 · • NE, not estimable; NR, not reported. • 1. Gandhi L, ... 476 377...

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Transcript of Lung Cancer Updates 2018 · • NE, not estimable; NR, not reported. • 1. Gandhi L, ... 476 377...