top trends in oncology 2019 - piedmont

Top Trends in Oncology

2019

Andrew W. Pippas, M.D.

2/23/2019

John B. Amos Cancer Center

Piedmont Columbus Regional

2

DISCLOSURES

I have no significant financial relationships with the manufacturers of any of the

products discussed in this presentation: neither I nor my family receive any

commercial support from them.

Top Trends in Oncology 2019

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• Current Cancer World--at home and abroad

• Cathy’s Story

• Biology: Tumor morphology and Immunity, the “Third

Arm” of cancer Treatment

• Recent Approvals: All hands on deck

• “All we need is a blood test for cancer!”

• Using the tools we have will save lives—today

TRENDS


4

• 1.6 million Americans will be diagnosed with cancer this

year.

• 610,000 will die of cancer this year.

• WHO: “Cancer will become the leading of death in the

21st Century”

– Increases mortality will be more evident in China with

79% increase in cancer death by 2040.

– Sub-Sahara Africa by 106 %

CANCER MORTALITY: 2019 and Beyond


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9.6 million people died of cancer last

year world-wide

9.6 million people died of cancer last

year world-wide

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• “Non-communicable diseases (NCDs) are now

responsible for the majority of global deaths, and cancer

is expected to rank as the leading cause of death

and the single most important barrier to increasing life

expectancy in every country of the world in the 21st

century.”

International Agency for Research on Cancer(IARC)-12/9/2018.


7

Current Male Cancer Rates, American Cancer Society, 2018. Courtesy Dr. Otis Brawley, 2018 GASCO


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9

2030 Projected USA Incidence and Cancer Deaths - Both Sexes


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• September, 2015: Right flank/back pain after chopping wood.

• CT thorax: RUL 7.5 mm lung nodule, 2 other < 1 cm nodules, large

kidney mass. Lung biopsy “suspicious” for RCC

• Left nephrectomy, 10.2x10x9.5 cm RCC, clear cell type. 10/26/2015

• Started Herculonib, an oral TKI, December, 2015. Pulmonary

nodules remained stable until January 2018. RUL nodule 2.4 cm, 9

mm Right sub-pleural nodule, 4mm LUL nodule, unchanged.

• February 21, 2018. VATS: removal of both pulmonary nodules.

Rendered ‘NED’. Followed off of therapy.

• March CT. 7 mm LUL nodule. Slightly progressed, post op changes

on the right.

• May 9, 2018: Rapid onset of Dyspnea; CXR--near complete

opacification of the right lung.

• Thoracic surgery re-evaluation; not a candidate for re-exploration.

• Began Checkpoint Immune therapy for two months with worsening

orthopnea and platypnea.

Cathy’s Story: 52 year old diabetic… (Otherwise well until)…


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May 2018: Hospitalized, SOB and new-onset Atrial Fibrillation


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June 2018: No re-expansion of the lung, not Pleurex® candidate


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July 2018: 2 weeks on 3L, oral TKI “Olympianib”


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August, 2018


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January 10, 2019


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Second-line VEGFR TKI response after First line Immune Checkpoint blockade in Metastatic Renal

Cell Carcinoma. Kotecha R, et al. Seventeenth International Kidney Cancer Symposium: November 2-3, 2018, Miami, Florida.


ORR 41.2 %, PFS 13.2. months, OS not reached

17

Epithelial to

Mesenchymal

Transition (EMT)

and

Immuno-oncology


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Epithelial –to Mesenchymal Transformation: Shibue, T and Weinberg, R.A. 2017. Nat. Rev. Clin. Oncol. Oct: 14(10)


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720366/bin/nihms922113f2.jpg.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720366/bin/nihms922113f2.jpg

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Physiological and Morphological Changes seen In EMT

Shibue and Weinberg, 2017

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The Histology of Cancer: A “Rogue Organ”


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• The cellular make-up of the tumor

microenvironment (TME). The tumor niche

possesses a dynamic structural topography

with significant spatial variability in vascular

supply, growth factor and cytokine

accessibility, ECM-derived structural support

and interactions with immune cells. TME

hence contributes to tumor heterogeneity as a

“rogue organ,” formed by normal-malignant

cell associations

Frontiers In Immumo-Oncology

Front. Oncol., 23 August 2018 , Marshal and Djamgoz


https://doi.org/10.3389/fonc.2018.00315

https://doi.org/10.3389/fonc.2018.00315

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Immune suppressive mechanisms of the TME


TAM: Tumor-

associated M-

phages.

CTL: Cyto-toxic T-

cells

CAF: Cancer-

associated

Fibroblasts

23

Dossier of Receptors, their Ligands, Connecting Antigen Presenting

Cells, T- Cells, and Tumor Cells


Known and potential targets

for pharmacological manipulation

by immunomodulatory monoclonal

antibodies.

Frontiers in Immuno-Oncology

2018.

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• T-cell activation and cell-surface therapeutic targets. T-cell activation by APC/DCs and

impact upon the tumor cell is driven by many integrated signals.

– HVEM, herpes virus-entry mediator

– LIGHT, lymphocyte activation gene 3 protein

– GITR, glucocorticoid-induced TNFR family-related protein; ICOS, inducible T-cell

costimulatory

– LAG-3, lymphocyte activation gene 3 protein

– TIGIT, T-cell immunoreceptor with Ig and ITIM domains

– TIM-3, T-cell Ig mucin domain-containing 3

– BTLA, B-lymphocyte and T-lymphocyte attenuator

– VISTA, V-domain Ig suppressor of T-cell activation;

– TNF, tumor necrosis factor

Definitions of Cell-Surface Receptors and Ligands


Frontiers in Immuno-Oncology, 2018

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Targeting Mutations


Trend 1 Trend 2

Precision Medicine Immuno-oncology

Rx Target Altered gene function

Effect Direct

Specificity High

Complexity Low

Onset Fast

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Targeting Mutations


Trend 1 Trend 2

Precision Medicine Immuno-oncology

Rx Target Altered gene function Neoantigens

(Normal proteins)

Effect Direct Indirect

Specificity High Range

Complexity Low High

Onset Fast Slow

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Precision Medicine

V600E mutated BRAF inhibition in Metastatic Melanoma


www.researchgate.net. Accessed

Dec.12 2018

http://www.researchgate.net/

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• Nature: 2018. N=141 patient with Her2 and Her 3 mutant tumor

types across 21 unique cancers. Treated with Neratinib®- an

inhibitor of Her 1/2 and Her 4

• ErbB/HER 1-4 family receptors with protein Tyrosine kinase

activity

• Extracellular domains are targeted by monoclonal antibodies:

intracellular protein domains by kinase inhibitors

– No responses in those with Her 3 mutations

– Responses noted in breast, cervical, biliary, salivary and

NSCC lung cancers with specific mutations across tumor

types

8 FEBRUARY 2018 | VOL 554 | NATURE | 189

ARTICLE

doi:10.1038/nature25475

HER kinase inhibition in patients with

HER2- and HER3-mutant cancers: Hyman, D. et al.


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Complexities of Targeted Therapy


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Check Point Inhibitors


McDermott DF, Atkins MB. Cancer Medicine 2013: 2(5): 662-673

31

PD1 Antibodies for CSCC: Locally Advanced Disease in Patients

without Curative Surgical or Radio-therapeutic options


APPROVED Sept 28, 2018. Used with Permission. Regeneron Corp.

32

Immune Checkpoint Inhibitors Are Active In Most Tumors But in Limited

Patients: Creates Need for Checkpoint Enhancers


Slides 32-33-34 used with Permission, eFFECTOR

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eFT508 Compliments Checkpoint Inhibitors by Addressing Key Resistance Mechanisms


Increases

CD8+ T

cells

eFT508 Reprograms the Anti-tumor Immune Response

Proliferation

Cytotoxic Function

Exhaustion

Decreases

Immunosuppr

essive Treg

cells

Differentiation

Immunosuppressive

functions

Increases

Antigen

Presentation on

Immune and

Tumor Cells

Increases Memory T cells

Function

Memory Pools

MHC Class II

Key Mechanisms of CPI

ResistanceeFT508 Complementary Activity Potential Benefits

Poor antigen presentationActivates antigen presentation on immune and tumor

cellsIncrease Tumor Recognition

Immunosuppressive tumor micro

environment and cell types

• Blocks immunosuppressive cytokine expression

• Increases cytotoxic function of CD8+ T cells

• Decreases immunosuppressive Treg cells

Restore Immune Response

T cell exhaustionDecreases expression of checkpoint proteins including

PD-1, LAG3, PD-L1 and TIM3Improve Response Durability

Limited T cell memory Promotes memory T cells Preserve Immune Persistence

34

CAR-T Therapy


Chimeric antigen

receptor-modified T

cells In chronic

lymphoid leukemia.

NEJM 2011: 365:

725-33

Porter DL, et al.

35

• KYMRIAH™ (tisagenlecleucel)

– Adults with relapsed or refractory DLBCL

– Young adult patients up to age 25 with

relapsed or refractory ALL

• YESCARTA™ (axicabtagene ciloleucel),

relapsed or refractory following two or more

lines of therapy

– DLBCL

– Primary mediastinal B-cell NHL

– High grade B-cell lymphoma

– DLBCL that results from follicular

lymphoma

FDA Approved CAR T-cell Therapies


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Clinical Cancer Advances 2019: Annual Report on Progress Against

Cancer From the American Society of Clinical Oncology

Treatment Advances: ASCO/JCO. 1/31/2019. Nov. 2017 to Oct. 2018.

Pai, s et al. 10.1200/JCO.18.02037 Journal of Clinical Oncology

LAROTRECTINIB

OR: 75%Responses across

several tumor types

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ASCO 2019: Treatment Advances


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ASCO 2019: Treatment Advances – New Uses

Top Oncology Trends 2019

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• 11 new therapies or tests

• 38 new uses of previously approved

treatments

This is where we are….


ASCO, 2019 Advances

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This is where we are going…


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Biomarkers


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Biomarkers: ER + Breast Cancer


ER+

First Biomarker in

Oncology

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• 21 gene for pNO (Oncotype Dx®): predictive and prognostic

• RS < 26. No Benefit from chemo-consider in woman 50 years old or younger in whom chemotherapy associated with a lower rate of distant recurrence

• RS 26 to 30. Consider additional factors; the omission of chemo not prospectively studied.

• RA >= to 30. Chemotherapy recommended.

Preferred Breast Genomic Test


NCCN Breast Guidelines, 3.2018

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• 70 Gene MammaPrint® for node negative and 1-3 positive

nodes. Also level 1 NCCN evidence and consensus.

• Low versus High: At 5 year follow-up, patients at high clinical

risk(function of grade and tumor size) and low score had 94.7 %

survival without distant metastases without chemotherapy.

Patients with 1-3 positive nodes had 96.3% survival without

metastases and 95.6% without chemotherapy.

• PAM 50 Prosigna® for Node negative and 1-3 positive nodes,

• 12 gene EndoPredict ® for the same and the Breast Cancer

Index ® (T1-2, node negative breast cancer) also have

prognostic relevance: 2A consensus recommendations.

2017 ASCO Update/NCCN


NCCN Breast Guidelines 3.2018

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• International Thoracic Oncology Guidelines: “All patients

with NSCLC” to assess for presence of EGFR, ALK,

ROS1(all adenocarcinoma patients)

• Second generation testing: BRAF, MET, RET,Erb2(HER2)

• KRAS mutations largely exclude the likelihood of the

presence of driver mutations and can by used to mitigate

against other testing

• NTRK testing/treatment for patients progressing on first

line therapy

Lung Cancer and TKI: 2018


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Liquid Biopsy


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Liquid Biopsy: Exosomes, (tumor membranes), CTCs, cfDNA from necrotic tumor

cells.


RB Corcoran, BA Chabner. N Engl J Med

2018;379:1754-1765

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RB Corcoran, BA Chabner. N Engl J Med 2018;379:1754-1765

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The Use of cfDNA for the Detection of Residual Disease and

Management of Post-Operative Therapy

Top Trends of Oncology 2019

May be able to stratify risk better

as to who would truly benefit

from adjuvant chemotherapy to

treat subclinical disease.

RB Corcoran, BA Chabner. N Engl J Med 2018;379:1754-1765.

52

Circulating Tumor DNA-Defined Minimal Residual Disease in Solid

Tumors: Opportunities to Accelerate the Development of Adjuvant

Therapies • Analogous to MRD in myeloma or tumors marker in testicular cancer

• Clinical trial randomizing low risk patients with + ctDNA post-op to adjuvant vs SOC

• Escalate therapy for patients with rising ctDNA after adjuvant therapy.


Published in: Arvind Dasari; Axel Grothey; Scott Kopetz; Journal of Clinical Oncology 2018 363437-3440.

DOI: 10.1200/JCO.2018.78.9032

Copyright © 2018 American Society of Clinical Oncology

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De-escalation of Therapy


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• Early Stage Breast Cancer: 2013-2015, Chemotherapy prescriptions decreased 34.5%

to 21.3%, secondary to the use of Oncotype Dx® and MammaPrint®

• Duration of Adjuvant Chemotherapy for Stage III Colon mFOLFOX/CAPOX

• Fluoruracil-Oxaliplatin based chemotherapy improves 10 year OS from 59% to 67%,

above 5 FU chemotherapy, with grade1,2,3 remaining neuropathy at 15% at 4 years.

• Patients withT1, T2, or T3 and N1 colon cancer, 3 months of chemo therapy was non-

inferior to 6 months with a 3 year DFS of 83.1% vs 83.3%.

• Neurotoxicity, grade 2, 16% /14%(FOLFOX/CAPOX) in the 3 month group versus

47.7% and 44% in the 6 month group

• High risk patients should receive 6 months of therapy.

Forbe, Dec 31, 2018

NEJM March 29, 2018

Grothey, Et al

De-escalation: “Less is More”


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Screening Cancer Control

Prevention…and

Survivorship


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• 2018: Two studies confirmed high suicide rate.

• -Three university-affiliated practices. 15.7% patients

Suicidal ideation < 1 year from diagnosis

• 0.4% committed suicide within 3 months and 0.9% attempted it.

• ASCO 2018 Survivorship Symposium: SEER data queried for

suicide as cause of death: HNC compared with 19 other cancers.

2000 to 2014, 404 suicides in 151,167 HNC survivors.

63.4 suicides/100,000 person-years

23.6 suicides/100,000 person-year among other cancer

survivors

• Overall, nearly twice as high as other cancer survivors.

SURVIVORSHIP:

Suicide Risk in Head and Neck cancer patients


Up to Date: December 2018

Henry M, et al. Oto Head Neck Surg 2018: 159

Osazuma-Peters N, et al. Cancer 2018; 124: 4072

57

• “Human Proteome” generates more that 20,000 proteins:

this may be more reflective of cellular activity than

genomic based assays.

• Very dynamic range of protein concentrations, with “10 to

12 orders of magnitude in abundance.”

• Proteograph™ platform: Ongoing SEERPRO study at

PRC/JBACC for untreated Ovarian, NSCLC,CRC,HCC,

and Pancreatic cancer patients.

Web page accessed: Feb 2, 2109.https://seer.bio

Seer, Protein Based Diagnostic Assay: To Meet “ Unmet Need for

Molecular Testing that Provides Actionable Information Earlier in the

Diagnostic Odyssey”


58

US Continues to Lead the World in Obesity Rates


OECD Obesity Update 2012

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• Reduce Obesity’s Impact on Cancer Incidence and Outcomes

• The incidence of obesity has dramatically increased over the past

several decades.64 Despite being the second leading preventable

cause of cancer, a recent ASCO survey14 found that only 35% of

Americans recognize excess body weight as a cancer risk factor.

Obesity is associated with poorer cancer survival and can contribute

to increased risk of treatment-related adverse effects. If current

trends continue over the next 20 years, it is estimated that obesity

will lead to more than 500,000 additional cases of cancer each year

in the United States65 and will surpass smoking as the leading

preventable cause of cancer.

Pal, S et al; JCO. Online 1/31/2019

ASCO Position on Obesity: 2019


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• Feb. 7, 2008 -- The World Health Organization (WHO)

warned that 1 billion people worldwide could die of

tobacco-related causes this century unless "urgent action"

is taken.

• Of the more than 1 billion smokers alive today,

500 million will be killed by tobacco.

The 21st Century: The Cancer Century


Fortunately, smoking rates declined 5% over the

past 12 years in the USA. CDC, 2016

61

GEORGIA DATA: Smoking Rates by Districts


CDC 2017 DATA

Guam 26.4%

Alabama 20.96%

Utah 8.9%

Courtesy of Nancy Paris, GA Core 2018.

CDC Current Cigarette Use Among Adults 2017

62

Age-Standardized Death Rate (Per 100,000) by Educational Attainment,

All Races Combined, Ages 25 to 74Years, 2014


Courtesy of Dr. Brawley, Best of ASCO, 2018

63

• College educated Americans have a much lower risk

of cancer and cancer death compared to non-

college educated Americans.

• If all Americans had the risk of death of a college

educated American, 140,000 people would not die

this year.

Cancer Mortality and Educational Status


64

Since 1991, there have been almost 2.4 million fewer cancer deaths

as a result of two decades of consistent declines in cancer deaths

rates.


65

ACS Projected Decline in Cancer Death Rates


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• The continuous decline in cancer death rates since 1991 has resulted in

an overall drop of 27%, translating to approximately 2.6 million fewer

cancer deaths.

• The racial gap in cancer mortality is slowly narrowing, socioeconomic

inequalities are widening, with residents of the poorest counties

experiencing an increasingly disproportionate burden of the most

preventable cancers.

• These counties are low‐hanging fruit for locally focused cancer control

efforts, including increased access to basic health care and interventions

for smoking cessation, healthy living, and cancer screening programs.

• A broader application of existing cancer control knowledge with an

emphasis on disadvantaged groups would undoubtedly accelerate

progress against cancer.

CA Journal: 2019. Siegal, RL, et al.

CA, Vol 69 Issue 1, Jan/Feb. 2019


67

Cancer Mortality by Race/Ethnicity

1990 to 2015


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