INNOVATIONS IN LUNG CANCER TREATMENT

INNOVATIONS IN LUNG CANCER TREATMENTJAMES JETT, MD

EDWARD KIM, MD

DAVID SPIGEL, MD

KEVIN OEFFINGER, MD (FACILITATOR)

JANUARY 17, 2019

9:00 AM ET

TODAY’S AGENDA

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*Sessions will be recorded.*Please mute phones when not speaking. Mute cell phones and try to reduce extraneous noise. *Remember to e-mail Octavia Vogel by 1/21 if you are requesting CME/CEU credit.

Time Presentation Presenter (s)

9:00-9:10 Welcome, roll call, housekeeping Dr. Oeffinger

9:10-9:45 Didactic Presentation:

Part 1: 20 minutes <Title>

Part 2: 15 minutes <Title>

Dr. Kim

Dr. Jett

9:45-10:00 Q & A/Discussion Dr. Oeffinger

10:00-10:15 Program/Case Presentation: Dr. Spigel

10:15-10:25 Q & A/Discussion Dr. Oeffinger

10:25-10:30 Conclusion/Next session Dr. Oeffinger

Dawn Wiatrek, Ph.D.

Octavia Vogel, MPH

DISCLOSURE

UNM CME policy, in compliance with the ACCME Standards of

Commercial Support, requires that anyone who is in a position

to control the content of an activity disclose all relevant financial

relationships they have had within the last 12 months with a

commercial interest related to the content of this activity.

The following planners and faculty disclose that they have no

financial relationships with any commercial interest: (next slide)

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FACILITATOR & PRESENTERS

Lead Facilitator: Kevin OeffingerDirector, Duke Center for Onco-Primary Care Director, Duke Supportive Care and Survivorship Center Duke Cancer Institute

Presenters: James R. Jett, MD Professor of Medicine, Emeritus National Jewish Health Chief Medical Officer, Oncimmune Ltd Nottingham, United Kingdom.

Edward S. Kim, MD Chair of Solid Tumor Oncology and Investigational TherapeuticsDonald S. Kim Distinguished Chair for Cancer Research Levine Cancer InstituteCarolinas Health Care System, Charlotte, NC

Case Presenter: David Spigel, MDChief Scientific OfficerDirector, Lung Cancer Research ProgramSarah Cannon Health System

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LEARNING OBJECTIVES

This session will provide information on innovations in lung

cancer treatment including:1. Molecular assessment and targeted therapies

2. Immune checkpoint inhibitors

3. Long term survival rates

4. Implications for treatment decision making

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Molecular Assessment and Targeted Therapy of Lung Cancer Patients in 2019

Edward S. Kim, M.D., FACP

Chair, Solid Tumor Oncology and Investigational Therapeutics

Medical Director, Clinical Trials Office

Levine Cancer Institute, Atrium Health, Charlotte, NC

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

Disclosures

• Consulting

– AstraZeneca

– Boehringer-Ingelheim

– Pfizer

– Roche/Genentech

– Takeda

– Celltrion


The Era of Precision Medicine

• Genomic Testing– Tissue and blood

• Novel Therapeutics– Small molecules, Immunotherapy

• Less Chemotherapy

• More choices

• People living longer with cancer


Importance of Clinical Trials


Must Allow More Patients to Participate



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.


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

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BATTLE Trial

Erlotinib SorafenibVandetanib Erlotinib + Bexarotene

Randomization:Equal Adaptive

Primary end point: 8 week Disease Control (DC)

Umbrella Protocol

BATTLE Trial Schema

EGFR KRAS/BRAF VEGF RXR/CyclinD1

Core Biopsy

Biomarker Profile

ES Kim et al. Cancer Discovery 2011

The Changing Landscape of Lung Cancer: 200580 of 100 patients eligible for chemotherapy

Only 15-20% of tumors had a partial

response

Molecular subsets: EGFR MutationsThe Changing Landscape of Lung Cancer: 2019

Molecular subsets: ALK

The Changing Landscape of Lung Cancer: 2019

Molecular subsets: ROS1


Molecular subsets: PD-L1


Molecular subsets: BRAFv600E


Molecular subsets: 50% of patients candidates for targeted therapy



NSCLC Drug Approvals/Indications:

2015 - Present• Alectinib

• Necitumumab

• Nivolumab

• Osimertinib

• Gefitinib

• Ramucirumab

• Atezolizumab

• Ceritinib

• Brigatinib

• Dacomitinib

• Pembrolizumab

– PD-L1 + (1st, 2nd line)

– MSI-H or dMMR solid tumors

– NSCLC (Carboplatin + Pemetrexed)

• Crizotinib (ROS1)

• Lorlatinib

• Dabrafenib, Trametinib

• Durvalumab


Targeted Therapy in 2019

EGFR (10%)

ALK(4%)

ROS1(1%)

BRAF (2%)

2010: Erlotinib2013: Afatinib2015: Gefitinib2015: Osimertinib2018: Dacomitinib201?: Poziotinib

2011: Crizotinib2014: Ceritinib2015: Alectinib2017: Brigatinib2018: Lorlatinib

2015: Crizotinib2018: Lorlatinib201?: Entrectinib

2017:Dabrafenib and Trametinib



Osimertinib vs. Pemetrexed Platinum in T790M

Positive EGFR mutant NSCLC


Osimertinib vs. Pemetrexed Platinum in

T790M Positive EGFR mutant NSCLC


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 unacceptabl

e toxicity

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


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



FLAURA: Overall Survival Interim Analysis


PFS in Patients w/ & w/out CNS Metastases



Uncommon Mutations: Afatinib

• 3 patients in group 1 achieved complete response

– 1 each with G719X, K739_1744dup6, and L858R+Q709G/V

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

Max

imu

mch

ange

fro

m b

ase

line

(%)

Group 2 (n=14): de novo T790M mutationsT790M alone, T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X

Group 1 (n=33): point mutations or duplications in exons 18-21L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R,

S768I, L861P, P848L, R776H+L858R, L861Q+Del19, K739_1744dup6

Group 3 (n=20): exon 20 insertions


Alectinib vs crizotinib in treatment-naïve advanced ALK+ NSCLC: primary results of the global phase III ALEX study (LBA9008)

Presented By Alice Shaw at 2017 ASCO Annual Meeting


Primary endpoint: PFS, investigator-assessed

Presented By Alice Shaw at 2017 ASCO Annual Meeting


Leptomeningeal carcinomatosis responded to alectinib

Pre-alectinib 6 weeks on alectinib

Pre-alectinib

CSF cytology

Ou, S et al., WCLC 2013


ROS1+ NSCLC treated with Crizotinib


BRAF V600E: Dabrafenib and Trametinib


Larotrectinib (LOXO-101)


Biomarker Recommendations:

Practical Applications

• EGFR

• BRAF

• ALK

• ROS1

• PD-L1

• EGFR T790M (post EGFR-TKI therapy)

• TRK fusions

Biomarkers performed at baseline


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


Drugs Available in TAPUR

Pharmaceutical Company(Number of Drugs)

Drug(s) Provided for TAPUR Study

AstraZeneca (1) Olaparib

Bayer (1) Regorafenib

Bristol-Meyers Squibb (3) Dasatinib, Nivolumab + Ipilimumab

Eli Lilly (1) Cetuximab

Genentech (4) Trastuzumab + Pertuzumab, Vemurafenib + Cobimetinib

Merck (1) Pembrolizumab

Pfizer (6)Axitinib, Bosutinib, Crizotinib, Palbociclib, Sunitinib, Temsirolimus


HER2 and Breast Cancer Patients

• Would you ever treat a patient with breast cancer without knowing the HER2 status?


Conclusions: Delivering Precision Medicine

• Must practice Precision Medicine now

• Molecularly-base clinical medicine

– Genomic testing at appropriate points of care

– Reflex biomarker testing, Molecular tumor board

• Blood-based marker testing and collection system-wide

• Cutting-Edge Clinical trials

– ASCO TAPUR, Phase I sites


The Fight Against Lung Cancer:

Thank you for your attention

ECHO-ACSJanuary 17, 2019

James R. Jett, M.D.

Professor of Medicine, Emeritus

National Jewish Health

Immune Checkpoint Inhibitors

•Anti PD-1

•Nivolumab*

•Pembrolizumab*

•Anti PD-L1

•Atezolizumab*

•Durvalumab*

•Avelumab

•* FDA approved for NSCLC

Durvalumab after Chemoradiotherapy for Stage III NSCLC

•RCT of durvalumab (PD-L1) or placebo after chemoRT: Rx for 1 year duration

•713 patients randomized 2:1

•Median PFS from randomization

•16.8 months vs 5.6 months: HR 0.52

•Median time to death or distant mets

•23.2 months vs 14.6 months: p <.001

Antonia SJ et al NEJM 2017; 377:1919-1929

Antonia SJ et al NEJM 2017; 377:1919-1929

Antonia S et al NEJM 2018; 379:2342-2350

Pembrolizumab in Untreated NSCLC

•Phase III trial of 305 patients with untreated stage IV NSCLC (>50% PD-L1)

•Fixed dose 200mg IV q 3 weeks

•RCT of pembro vs platinum doublet CT

•No EGFR or ALK mutations

•PFS of 10.3 vs 6.0 months ( HR=0.50)

•6 month survival 80 vs 72% (HR 0.60)

Reck et al NEJM 2016; 375:1823-33

Reck et al NEJM 2016; 375:1823-33

Pembrolizumab in Untreated NSCLC

•Response rate: 44.8 vs 27.8%

•Median duration of response

•Not reached (1.9-14.1) vs 6.3 months

•Grade 3+ toxicity: 26.6% vs 53.3%

FDA approved pembrolizumab for frontline treatment in stage IV NSCLC with 50%+ staining of PD-L1 of tumor cells

Reck et al NEJM 2016; 375:1823-33

Reck et al NEJM 2016; 375:1823-33

Gandhi L et al NEJM 2018; 378:2078-2092

Pembro plus Chemotherapy in Nonsquamous NSCLC: KEYNOTE 189

•Phase III trial of pemetrexed and a platinum with or without pembrolizumab

•PFS 8.8 vs 4.9 mos

•Survival at 1-year 69% vs 49%

• Improvement in survival seen in all PD-L1 categories



Pembro plus Chemotherapy for Squamous Cell Lung: KEYNOTE 407

Paz-Ares L et al NEJM 2018; 379:2040-2051

Squamous Cell: KEYNOTE 407

Paz-Ares L et al NEJM 2018; 379:2040-2051

Horn L et al NEJM 2018; 379:2220-2229

Atezo in Frontline ED Small Cell

Horn L et al NEJM 2018; 379:2220-2229

Long Term Survival with Stage IV Non-Small Cell Lung Cancer

Five Year Survival in EGFR Mutant Lung Adenocarcinoma Treated with TKIs

•137 patients with metastatic adenoca

•PFS was 12.1 months

•Overall median survival of 30.9 months

•Five year survival of 14.6%

•95% CI of 9.7-21.9%

Lin JJ et al J Thorac Oncol 2016; 11:556-565

Solomon B et al J Clin Oncol pub online May 16, 2018

HR 0.76

HR 0.35

(85%

crossover

)

4 yr

survival

(57 vs 49%)

Solomon B et al J Clin Oncol pub online May 16, 2018

Pembrolizumab and Long Term Survival in Stage IV NSCLC

•KEYNOTE trials with pembrolizumab in second or greater line therapy

•Eval with long term survival models

•Estimated survival beyond 5 years at 21% and 25% in two trials

•With docetaxel long term survival 5%

Hellman MD et al ASCO-SITC Clin Immuno-

Oncology symposium abst #77, 2017

Five Year Survival in NSCLC Responders to Immunotherapy

•F/U of a Phase Ib dose ranging study of advanced NSCLC treated with nivolumab

•Dose excalating study of 129 pts

•Dose cohorts 1mg, 3mg, 10mg/kg

•At 5 years the overall survival was 16%

•5 year survival on docetaxel was 4%

Gettinger S et al J Clin Oncol 2018; 36:1675-1684

In Summary

CASE PRESENTATION

DAVID SPIGEL, MD

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CASE EXAMPLE

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CASE RELATED QUESTIONS FOR GROUP DISCUSSION

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JOIN US FOR LUNG CANCER PATIENT SUPPORT ECHO:

MULTIDISCIPLINARY TEAMS AND CARE COORDINATION IN LUNG

CANCER PATIENT CARE

JANUARY 31, 2019

9:00 AM ET

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Presenters:Thomas Asfeldt, RN, MAN, MBA

Director, Outpatient Cancer Services & Radiation Oncology, Sanford Health

ACCC Advisory Board Member for the

Optimal Care Coordination Model for Medicaid Patients with Lung Cancer

Peter Mazzone, M.D., MPH

Pulmonologist

Director, Lung Cancer Program

Respiratory Institute, Cleveland Clinic

Wendi Waugh Administrative Director of Cancer Services/Community Health and Wellness

Southern Ohio Medical Center

Pilot site director for the ACCC Optimal Care Coordination Model Pilot Study

INNOVATIONS IN LUNG CANCER TREATMENT

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