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8/19/2018 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

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

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

Importance of Clinical Trials

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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

Must Allow More Patients to Participate

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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

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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

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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

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.

Probability of Survival

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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

E4599: Bevacizumab with Chemotherapy in NSCLC Overall Survival

6 12 18 24 30 36 20 40 60 80 100

Months

Carboplatin and paclitaxel Carboplatin and paclitaxel + bevacizumab Treatment group

Median survival: 12.5 vs 10.2 months HR = 0.77 (95% CI: .65, .93), P = 0.007 1-yr Survival: 52% vs 44% 2-yr Survival: 22% vs 17% Patients surviving, %

Sandler et al. NEJM 2006

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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

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

The Changing Landscape of Lung Cancer: 2018

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Molecular subsets: ALK

The Changing Landscape of Lung Cancer: 2018

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Molecular subsets: ROS1

The Changing Landscape of Lung Cancer: 2018

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Molecular subsets: PD-L1

The Changing Landscape of Lung Cancer: 2018

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Molecular subsets: BRAFv600E

The Changing Landscape of Lung Cancer: 2018

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Molecular subsets: 50% of patients candidates for targeted therapy

The Changing Landscape of Lung Cancer: 2018

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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

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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

Screening for Lung Cancer

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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

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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

Precision Medicine Works

Precision Medicine Works

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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

Biomarker Recommendations: Practical Applications

  • EGFR
  • BRAF
  • ALK
  • ROS1
  • PD-L1
  • EGFR T790M
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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

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/Ipilimumab TMB High

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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

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 E

Lopes, ASCO 2018

KEYNOTE-042

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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

KEYNOTE-042

Lopes, ASCO 2018

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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

KEYNOTE-042

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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

KEYNOTE-042

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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

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

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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

KEYNOTE-189 Study Design

31 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)

  • r carboplatin AUC 5
  • n 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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L E V I N E C A N C E R I N S T I T U T E

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 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

PFS, %

32

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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

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.

33 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 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

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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 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

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

KEYNOTE-407

Paz-Ares, ASCO 2018

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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

Overall Survival at IA2, ITT

Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

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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

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

IMpower131: Study Design

R Jotte at 2018 ASCO

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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

IMpower 131 Carbo/Abraxane +/- Atezo

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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

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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

TMB High Patients (Hellmann, NEJM 2018)

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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

TMB High Patients (Hellmann, NEJM 2018)

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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

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

PACIFIC: Study Design

Phase 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=713

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

PACIFIC: PFS by BICR (Primary Endpoint; ITT)

PFS probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 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

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

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

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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

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

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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

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

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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

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

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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

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

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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

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

  • r

unacceptable toxicity

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

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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

FLAURA: PFS

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

PFS (%) Mos Pts at Risk, n Osimertinib SoC

10 8 6 4 2 0 0 6 9 21 12 18 24 27

279 277 262 239 233 197 210 152 139 78 71 37 26 10

15 3

178 107 4 2 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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L E V I N E C A N C E R I N S T I T U T E

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

FLAURA: Overall Survival Interim Analysis

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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

PFS in Patients w/ & w/out CNS Metastases

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

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

  • Other Targeted Therapy
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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

LIBRETTO-001

Drillon, ASCO 2018

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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

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.

63

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

Randomizeda 1:1

Dacomitinib 45 mg (n=227) Gefitinib 250 mg (n=225)

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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

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) Progression-free survival (%) 100 80 60 40 20 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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L E V I N E C A N C E R I N S T I T U T E

ARCHER 1050: Final OS (Primary Analysis)

65

227 225 206 213 188 186 167 144 138 113 77 63 14 12 3 3

  • No. at risk

Dacomitinib Gefitinib Dacomitinib (n=227) Gefitinib (n=225) OS probability at 30 months 56.2% 46.3% CNS metastases at progression, n 1 11

Probability of OS Months 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) Number

  • f Deaths

103 117 Patient s

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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

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

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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

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

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

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

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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

BRAF V600E: Dabrafenib and Trametinib

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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

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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

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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

Larotrectinib (LOXO-101)

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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

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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

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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, NC

  • Pop. ~4400

Lincolnton, NC

  • Pop. ~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