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Lung Cancer 101 and ASCO 2016 Highlights Dr. Jennifer Garst with ASCO slides by Dr. Jared Weiss Duke Cancer Institute at Duke Cancer Center Raleigh

8/20/2016

Build Hope. Take Action. End Lung Cancer.

…..To save lives and provide support to those affected by lung cancer through research,

awareness, education, and access programs across North Carolina.

Mission

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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.

USA Distribution

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Lung cancer is an uncontrolled growth of abnormal cells that starts in the lungs.

Cancer can develop with a mutation or error in the lung cell’s DNA.

DNA mutations can be caused by the normal aging process and through exposure to toxins

like smoke, viruses, radon, and other environmental factors.

What is lung cancer?

Cigarette Smoke

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• Current or past H/O smoking or second hand smoke exposure

• Radon exposure

• Previous cancer

• Lung disease, COPD, pulmonary fibrosis

• Toxic exposures: arsenic, chromium, asbestos, nickel,, cadmium, beryllium, silica, diesel fumes, viruses

• Genetic risks

Lung Cancer Risk Factors

It likely takes a series of mutations to create a lung cancer cell. Cells may be pre-cancerous

due to some mutations but continue to function like normal lung cells. As these cells divide, the mutations are passed down and can become

augmented from other toxic exposures until the cells do not behave like normal lung cells and take on the characteristics or “hallmarks” of

cancer.

What is lung cancer?

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Hanahan D, et al. Cell. 2000;100(1):57-70.

Self-sufficiency in growth signals

Evading

apoptosis

Sustained

angiogenesis

Limitless replicative potential

Insensitivity to

antigrowth signals

Tissue invasion

and metastasis

The Hallmarks of Cancer: New Targets

• 228,190 new cases of lung cancer

• 159,480 deaths due to lung cancer

Men

Lung and bronchus 28%

Prostate 10% Colon and rectum 9% Pancreas 6% Leukemia 5%

Women

Lung and bronchus 26%

Breast 14%

Colon and rectum 9%

Pancreas 7%

Ovary 5%

Leading Sites, United States, 2013 Estimates

Siegel R, et al. CA Cancer J Clin. 2013;63(1):11-30.

Cancer-Related Deaths

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Common causes of US cancer deaths, 2008

Rudin CM, et al. Clin Cancer Res. 2009;15(18):5622-5625.

Ever-Smokers

Never-Smokers

Types of Lung Cancer

• Non-Small Cell Lung Cancer – Adenocarcinoma

Squamous cell carcinoma

– Large cell

• Small Cell Lung Cancer

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NSCLC Stages at Presentation

Subramanian J, et al. J Thorac Oncol. 2010;5: 23–28.

Stage I:

•≤ 5cm; no lymph nodes involved

Stage II:

•≤ 7cm, if ipsilateral hilar lymph nodes involved

•>7cm, or local invasion, or multiple nodules in same lobe if no lymph nodes involved

Staging: NSCLC

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Stage III:

•Has not spread beyond lymph nodes in chest

•May have metastases within ipsilateral lung

•May have local invasion of major structures

Stage IV:

•Metastatic disease or disease with pleural effusion

Staging: NSCLC

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Less Invasive Lung Cancer Staging

EndoBronchial Ultrasound (EBUS) Mediastinoscopy

Use of an ultrasound-guided camera to biopsy lymph nodes around the airway with needle aspiration

Surgical removal of lymph nodes from around the main airway

ENDOBRONCHIAL ULTRASOUND

EBUS is done under general anesthesia

Angled, balloon-tipped ultrasound bronchoscope allows simultaneous endoscopic and ultrasound views

Endoscopic view

Ultrasound view EBUS probe in the main airway

http://www.ctsnet.org/graphics/experts/Thoracic/d_rice_endobronc_ultrasnd/Figure-2.jpg

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Current State of NSCLC • NSCLC: ~ 85% of lung cancers

• Histology-directed therapy

– Non-squamous: bevacizumab, pemetrexed

– Squamous: nab-paclitaxel, nivolumab

• Biomarker-directed therapy

– Erlotinib, afatinib, gefitinib, crizotinib, ceritinib

• Immunotherapy

• Overcoming resistance

– EGFR and ALK resistance

More Choices = More Decisions

patients, providers, payers

Strategies to Improve Outcome of Lung Cancer Patients

• Move away from approaching lung cancer as one disease

• Develop treatment strategies for different subsets of lung cancer

• Treatment improvements based on

– Histology

– Oncogenic alterations

– Proteomics

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First-line Second-line Third-line Maintenance Not approved

1970 1980 1990 2000

Median OS

(mos)

12+

~ 6 ~ 2–4

BSC Single-agent platinum Doublets Bevacizumab + PC

Carboplatina 1989

Erlotinib Pemetrexed

2004

Docetaxel 1999

Paclitaxel Gemcitabine

1998

Vinorelbine 1994

Docetaxel 2002

Bevacizumab 2006

Gefitinib 2003

Standard Therapies aLabel does not include NSCLC-specific indication. BSC = best supportive care; PC = paclitaxel/carboplatin; OS = overall survival. Adapted from Shrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins:2005.

Pemetrexed 2008/2009

Histology-directed therapy

Cisplatina 1978

History of Therapy in Advanced NSCLC: FDA Approval Dates 1970-2010

2010

Erlotinib 2010

~ 8–10

Maintenance Therapy

Targeted Therapy ALK Translocation EGFR Mutation

2011 2013

History of Therapy in Advanced NSCLC: FDA Approval Dates 2011-2013

Crizotinib 2011

Erlotinib 2013

Afatinib 2013

Median OS

(mos)

Targeted Therapy

20-30+ months

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Lung Cancer Mutation Consortium: Incidence of Driver Mutations

ROS-1 1%

Kris MG, et al. JAMA. 2014;311:1998-2006.

Lung Adenocarcinoma Mutations

Rudin CM, et al. Clin Cancer Res. 2009;15(18):5646-5661.

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MATCH trial

EGFR Signaling

Adapted from Ciardiello F, Tortora G. N Engl J Med. 2008;358:1160-1174.

gefitinib erlotinib

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EGFRMUT Disease Progression on an EGFR TKI

Molecular:

• Unknown (other pathways)

• EGFR T790M (exon 20)

• MET amplification

• PIK3CA

• SCLC

Clinical PD appearance:

• Rapid disease PD globally

• Slow growth globally

• Growth in several areas, but not all T790M

~ 40-55%

T790M +

EGFR amp

~ 10%

Other

EGFR mut

1-2%

SCLC w/

PI3K

~ 4%

SCLC

~ 6%

PIK3CA

~ 1-2%

MET amp

~ 5%

BRAF

~ 1%

HER2 Amp

~ 8-13%

EMT

~ 1-2%

Unknown

~ 15-20%

Camidge DR, et al. Nat Rev Clin Oncol. 2014;11(8):473-481.

Osimertinib activity in patients with leptomeningeal disease from non-small cell lung cancer: updated results from the BLOOM study

Presented By James Yang at 2016 ASCO Annual Meeting

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Changes in EGFRm DNA copy number in CSF with osimertinib treatment

Presented By James Yang at 2016 ASCO Annual Meeting

Phase I study (BLOOM) of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal

metastasis (LM)

Presented By Myung-Ju Ahn at 2016 ASCO Annual Meeting

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Third Generation EGFR TKIs

“3rd” Generation N RR* T790M-

RR T790M+

PFS Toxicity

Rociletinib (CO-1686)

256 37% 53% ~ 8.0 mo Hyperglycemia

AZD9291 253 21% 61% ~ 8.2 mo Diarrhea

HM61713 (800 mg)

62 12% (300 mg)

55% NR Dyspnea/rash

EGF816X* 53 60% NR Rash

ASP8273* 47 ~ 33% 61% NR Hyponatremia/ diarrhea

Sequist L, et al. J Clin Oncol. 2015;33(suppl). Abstract 8001; Jänne PA, et al. N Engl J Med. 2015;372(18):1689-

1699; Park K, et al. J Clin Oncol. 2015;33(suppl). Abstract 8084; Tan DS-W, et al. J Clin Oncol. 2015;33(suppl).

Abstract 8013; Goto Y, et al. J Clin Oncol. 2015;33(suppl). Abstract 8014.

Multiple other agents earlier in development *T790M subgroups are very small.

RR, response rate; PFS, progression-free survival.

ALK Fusion Oncogenes and Downstream Signaling

Shaw AT, Solomon B. Clin Cancer Res. 2011;17:2081-2086.

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Alectinib versus Crizotinib in ALK Inhibitor Naïve ALK-Positive Non-Small Cell Lung Cancer: Primary Results from the J-ALEX Study

Presented By Hiroshi Nokihara at 2016 ASCO Annual Meeting

J-ALEX Phase III Study Design

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Primary Endpoint: PFS by IRF (ITT Population)


Brigatinib in Patients With Crizotinib-Refractory ALK+ Non–Small Cell Lung Cancer: First Report of Efficacy and Safety From a Pivotal Randomized Phase 2 Trial (ALTA)

Presented By Dong-Wan Kim at 2016 ASCO Annual Meeting

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PFS by Arm


Survival by Arm


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ROS1 Rearrangement in Lung Cancer

Jänne PA, et al. J Clin Oncol. 2012;30(8):878-879.

Safety and Efficacy of Lorlatinib (PF-06463922) From the Dose Escalation Component of a Study in Patients With Advanced ALK+ or ROS1+ Non-Small-Cell Lung Cancer

Presented By Benjamin Solomon at 2016 ASCO Annual Meeting

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Phase I Design and Patient Population of an Ongoing Phase I/II Study


Clinical Activity: Progression-Free Survival in ALK+ Patients

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Majority of ROS1 Patients Had a Decrease in Target Lesion Size*


CNS Responses in ALK/ROS1+ Patients with Measurable Disease

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Other Drugs That Target ALK and/or ROS-1 • 1st-generation ALK

Crizotinib( plus ROS-1)

• 2nd-generation ALK Inhibitors

‒ Ceritinib (LDK378)( plus ROS-1)

‒ Alectinib (CH5424802)( no ROS-1 activity)

• ALK/EGFR/ROS-1 Inhibitors

‒ Brigatinib (AP26113)(nearing approval process)

Promising Others ALK/ROS-1: Lorlatinib, Ensartinib (X-396) in clinical trials

Resistance: Cabozantinib (FDA approved med thyroid/renal), TPX-0005 (ALK/SRC) in clinical trials

Response of An ROS1+ Patient

Baseline 12 Weeks Crizotinib

Bergethon K, et al. J Clin Oncol. 2012;30(8):863-870.

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Antitumor Activity and Safety of Crizotinib in Patients with Advanced MET Exon 14-Altered Non-Small Cell Lung Cancer

Presented By Alexander Drilon at 2016 ASCO Annual Meeting

Slide 11

Presented By Alexander Drilon at 2016 ASCO Annual Meeting

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An Open-Label Phase 2 Trial of Dabrafenib in Combination With Trametinib in Patients With Previously Treated BRAF V600E–Mutant Advanced Non-Small Cell Lung Cancer

(BRF113928)

Presented By David Planchard at 2016 ASCO Annual Meeting

Progression-Free Survival

Presented By David Planchard at 2016 ASCO Annual Meeting

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Slide 1

Presented By D. Camidge at 2016 ASCO Annual Meeting

Antibody Drug Conjugate: Sacituzumab Govitecan (IMMU-132)


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Progression-Free Survival and Overall Survival (8 or 10 mg/kg; median of 3 prior therapies)


Immunotherapy in NSCLC

• Immunotherapy

• Vaccines

• Check-point inhibitors:

• Preliminary evidence of activity with CTLA-4 and chemotherapy

• Preliminary evidence of activity with PD-1 or PD-L1

Lynch TJ, et al. J Clin Oncol. 2012. Genova C, et al. Expert Opin Biol Ther 2012. Brahmer JR et al NEJM

2012, Topalian S et al NEJM 2012

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PD-1, PD-L1 Antibodies

Target Agent

PD-1 Nivolumab (BMS-936558)

Pembrolizumab (MK-3475)

Pidilizumab (CT-011)

AMP-224

PD-L1 BMS-936559

Durvalumab (MEDI4736)

Atezolizumab (MPDL-3280A)

Davies M. Cancer Manag Res. 2014;6:63-75; Brahmer JR. J Clin Oncol. 2013;31(8):1021-1028;

Rizvi NA, et al. J Clin Oncol. 2014;32(suppl 15). Abstract 8007;

Brahmer JR, et al. J Clin Oncol. 2014;32(suppl 15). Abstract 8021.

PD-1, programmed death receptor-1; PD-L1, programmed death-ligand 1.

CheckMate 012: Safety and Efficacy of First‐line Nivolumab and Ipilimumab in Advanced NSCLC

Presented By Matthew Hellmann at 2016 ASCO Annual Meeting

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Nivolumab Plus Ipilimumab in First-line NSCLC: Summary of Efficacy


Nivolumab Plus Ipilimumab in First-line NSCLC: Efficacy Across All Tumor PD-L1 Expression Levels

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• Immune responses are dynamic and evolve.

• A single biomarker may not be the complete answer.

• “Mutational Load” is a very important factor and may be a better predictor of response to a single PD-1 blockade.

• Micro-environment influences responses to PD-1 blockade…....hypoxia, metabolism, genetics.

Immunotherapy Conclusions:

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Small cell lung cancer

Safety and efficacy of single agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell

lung cancer (SCLC)

Presented By Charles Rudin at 2016 ASCO Annual Meeting

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SCLC Kaplan-Meier Overall Survival


Favorable Comparison vs. Existing 2L and 3L CTX


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Local Consolidative Therapy (LCT) Improves Progression-Free Survival (PFS) in Patients with Oligometastatic Non-Small Cell Lung Cancer (NSCLC) who do not Progress after

Front Line Systemic Therapy (FLST): Results of a Multi-Institutional Phase II Randomized Study

Presented By Daniel Gomez at 2016 ASCO Annual Meeting

Trial Design


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Trial Design


Prognostic Factors for PFS


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Improved Overall Survival in Lung Cancer Patients using a Webapplication-mediated Follow-up compared to Standard Modalities: Results of a Phase III Randomized

Trial

Presented By Fabrice Denis at 2016 ASCO Annual Meeting

Phase 3 multi-centric randomized study

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Overall Survival Improvement


Other « intensive » clinical follow-up studies


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Challenges for the Next Decade

• Expanding biomarker-directed therapy

– Transitioning to multiplex testing

– BRAF, Exon 14 MET, HER2

• Defining role of immunotherapy

• Squamous histology-directed therapy

• Small cell lung cancer

• Maintenance ‒ what surrogate can we use?

Figure 6

Source: Cell , Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013)

Copyright © 2011 Elsevier Inc. Terms and Conditions

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Trends Continuing as Screening for Lung CA Evolves

• Earlier Detection

– NLST Results finding survival benefit with CT screening

• Earlier Diagnosis

– Navigational Bronchoscopy

• More Treatment Options

– Early stage Lung CA improved prognosis, more flexibility with treatment options tailored to patient

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Duke Raleigh Hospital Cancer Center Multidisciplinary Lung Cancer Care Team

Standing: Brenda Wilcox , RN; Dr. Jennifer Garst; Lisa Dowd, NP; Dr. Albert Chang Seated: Dr. Catherine Chang, Dr. David White, Katherine Gillis, PA-C

Radiation Fields

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Referral: Fast and Appropriate

• Medical oncologists – appropriate for every lung cancer patient

• Thoracic surgeons – role in treatment for all stage patients – Best results from centers that do higher

number of thoracic surgeries

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Clinical Trials: The Road to New Therapeutic Advances

• With the advances being made in lung cancer treatment, clinical trials are an attractive therapy option

• The family physician is often the most trusted – your advice carries a lot of weight!

• You don’t need to know that there is a trial available, just plant the seed!

Trends in Management of Lung CA

HOPE

Image Guidance

Less invasive

Better Outcomes

Targeted Therapy

Earlier Detection

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• We all need a team of support:

• Family and friends

• Advocacy groups like LCI

• Social media/blogs/ carebridges

• Local medical team

• Consulting medical team

• Spiritual support and more…...

Team HOPE

Our “A” team: Jonathan Choe, PA-C, Vereterrica Rushdan, RMA,

Jennifer Mizelle, RN, Elattmont Spiller, patient care coordinator

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Heather Hooper, Executive Director

Thank You to Our Staff!

Lynne Ritter, Director of Finance

Khaki Stelten, Communications & Development Manager

Jenni Danai Programs Manager

Parker Shields Administrative & Program Assistant

Cynamon Frierson, Communication & Marketing Manager

We are very much looking forward to partnering with you in the cause and making lung cancer awareness and

research a priority.

Together, there’s always something we can do!

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