Lung cancer Zeena Nackerdien

• Basics• Epidemiology/risk factors• Three main disease types• NSCLC

• Disease stages

• Selected mutations

• Some drug-resistance mechanisms• Management

• ACCP guidelines• Individualized treatment algorithm• Genotype-directed therapy in practice

OutlineLung cancer

(2001-2007): Average 5-year survival rate for

localized tumor was 52.2% compared to 15.6 % overall

and 3.6 % for a distant tumor (1)

Most common cancer cause of death; Rises and declines in disease parallel smoking

trends (1)

ACCP, American College of Chest Physicians; NSCLC, non-small cell lung cancer 1. American Lung Association Trends in Lung Cancer Morbidity and Mortality. 2012 Available from: http://www.lung.org/finding-cures/our-research/trend-reports/lc-trend-report.pdf.

• Investigational agents (parts 1 and 2)• Anti-angiogenic agents/immunocheckpoint regulators• Therapeutic vaccines (NSCLC)

• Summary

OutlineLung cancer

FISH=fluorescence in situ hybridization; NSCLC=non-small cell lung cancer

Examples of molecular assays (FISH and sequencing)

Smoking causes about 70% of global deaths

Genetics in early-onset lung

cancer

Radon gas (20,000 US deaths/y)

Other environmental

agents and prior lung disease

Risk factors

Basics: epidemiology/risk factorsMost commonly diagnosed cancer in the world (2)

2. Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. Journal of cancer research updates. 2013;2(4):265-82.

(A) SCLC• Respiratory tract

neoplasm• Aggressive

(B) NSCLC• Squamous-, adeno-,

and large-cell carcinomas

• Small (≤20 mm),pre-defined lung cancers: no metastasis outside tumor-bearing segment

• Slow and widespread metastases

(C) Mesothelioma• Asbestos-related

epithelial neoplasm

• Aggressive

Three main disease types(1)(A) SCLC (~14%); (B) NSCLC (85%); (C) Mesothelioma (≤ 1%)

SCLC, small-cell lung cancer1. American Lung Association,. Trends in Lung Cancer Morbidity and Mortality. 2012 [cited March 2014]. Available from: http://

www.lung.org/findicures/our-research/trend-reports/lc-trend-report.pdf

• Occult: cancer cells in sputum• Stage 0: innermost lining of lung• Stages IA/IB: Isolated intrapulmonary tumor or cancer has spread to

the lung’s main airways/inner lining• Stages IIA/IIB: Tumor spread to nearby lymph nodes, chest wall,

diaphragm, membrane around the heart, lining between the lungs or the main airway

• Stages IIIA/IIIB: Further spread to sites listed in stages IIA/IIB. It may have spread to the aorta, heart, trachea, sternum, and esophagus. Lung may be inflamed or may have collapsed

• Stage IV: Malignant growths in more than one lobe of one lung, in both lungs or cancer has spread to other organs

3. National Cancer Institute, American Cancer Society: lung cancer.org, Principal Health News Centers for Disease Control &

Prevention. Lung cancer infographic. 2014.

NSCLC* stages (3)*Most common type of lung cancer (85% of diagnosed cases)

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Selected mutations in NSCLC(Adenocarcinoma; Patients were smokers or non-smokers)

Molecular pathology(4)• KRAS (ALK/BRAF/PI3K)• EGFR (ALK inhibitors)• EML4-ALK • BRAF (EGFR TKI)• MET (Kinase domain mut.)• ERBB2/HER2 (EGFR TKI)• MAP2K1(MEK inhibitor-sens.)• NRAS (MEK inhibitor-sens.)

BRAF, proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B1; EGFR, epidermal growth factor receptor; EML4-ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; ERBB2/HER2, Receptor tyrosine-protein kinase erbB-2; MAP2K1, dual specificity mitogen-activated protein kinase kinase 1; MET, proto-oncogene (hepatocyte growth factor receptor); mut., mutation; NRAS, Neuroblastoma RAS viral oncogene homolog; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PIKC3A, Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; sens., sensitive; TRKI, tyrosine kinase inhibitor4. Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, et al. Molecular pathology of lung cancer: key to personalized medicine. Modern pathology 2012;25(3):347-69.

.

Some drug resistance mechanisms(2)

AKT, protein Kinase B; HSP90, heat shock protein 90; IGFR, insulin-like growth factor 1 receptor2. Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. Journal of cancer arch updates. 2013;2(4):265-82.

Secondary mutations

Acquired resistanceEML4-ALK

ProliferationEGFR (PI3K/AKT↑;IGFR

crosstalk)KRAS

Gene amplification/copy

number gain (C)/fusion

METALK-C/ALK-fusion-negative tumors

Cellular/ChaperoneHSP90

Epithelial-to-mesenchymal

transitionMulti-drug resistance

proteins

.

Management: ACCP guidelines(5)

CT Screening• Only to smokers

age 55-74, with > 30 pack-years of smoking

• Annual low-dose CT scanning in NLST-compliant setting

• Not to pts. with severe comorbidities

Stages I & II

• VATS with systematic lymph node sampling preferred

• Better outcomes with specialty-trained surgeons & at high-volume centers

Stage III

• Chemo + radiation therapy for most N2,3 pts

• Trimodal approach for toxicity mgmt.

• Tailor treatment depending on mediastinal involvement

Stage IV• EGFR+-pts:

targeted therapy is 1st line of treatment

• Appropriate maintenance chemotherapy

• VEGF inhibitors safe & useful

• Doublet chemotherapy in selected cases

ACCP, American College of Chest Physicians; chemo, chemotherapy; mgmt., management; NLST, National Lung Cancer Screening Trial; pts., patients; VATS, video-assisted thoracic surgery; VEGF, Vascular endothelial growth factor5. Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):7s-37s.

Advances in treatment for different stages

Diagnostic biopsy

Biomarker testing

Mutations/Copy

numbers/sequencing

Restaging

Molecular imaging

Adjust treatment according to disease

status

Ideally, sufficient tissue, blood, and other samples can be collected for diagnostic purposes. Validated biomarkers will be monitored in < 2 weeks and guide disease management. Restaging and subsequent treatment would depend on disease status, individual quality of life, and the possible need for re-biopsy and re-evaluation of biomarkers.

Individualized treatment algorithm(6)

6. Carrizosa DR, Mileham KF, Haggstrom DE, Brouse GM, Induru R, Kim ES. New Targets and New Mechanisms in Lung Cancer. Journal of Oncology [Internet]. 2013. Available from: http://www.cancernetwork.com/lung-cancer/new-targets-and-new-mechanisms-in-lung-cancer.

• OPTIMAL (erlotinib vs.

chemotherapy; 83 vs. 82

randomized pts.): one of

the Phase III trials showing

value of TKI plus

chemotherapy

Initial trials showing utility of genotype-directed treatments (7)

EORTC 08114-GEM intergroup translational research-observational study will focus on the genetics of EGFR+ - NSCLC; EGFR, epidermal growth factor receptor; PFS, progression-free survival; pts., patients; TKI, tyrosine kinase inhibitors7.Verma S, Tsao M, Sivjee K. Webinar Archive: Integration of Targeted Therapies in the Management of NSCLC: oncologyeducation.com; 2014. Available from: http://www.oncologyeducation.com/information/lung/lung-cancer-videos/webinar-archive-nsclc/

EGFR* as 1st line TKI(Trial acronyms: IPASS, WJTOG3405, OPTIMAL)

• LUX-lung 3 (afatinib vs. cisplatin/pemetrexed; 345/1,269 pts randomized to intervention): PFS prolongation & acceptable safety profile

• LUX-lung7 (1st vs. 2nd generation TKIs; 264 pts. to be recruited); awaiting data

EGFR as 2nd- line TKIand 1st vs. 2nd generation TKIs (selected patients)

• Slightly better outcomes

with chemotherapy in

mutation-negative

patients

EGFR vs. chemo in 2nd-line therapy (Trial

acronyms: INTEREST, V-15-32, ISTANA, TITAN,

HORG, TAILOR, unselected patients)

• EGFR & ALK testing actionable in NSCLC

• Images of EGFR signaling pathway & ALK + crizotinib• Testing mainly performed on non-squamous tumors

• Multi-disciplinary approach needed for molecular testing

• Multiplex-testing by next-generation sequencing can resolve complexity associated with molecular testing

Genotype-directed therapy in practiceSuggestions by Verma et al(7)

7. Verma S, Tsao M, Sivjee K. Webinar Archive: Integration of Targeted Therapies in the Management of NSCLC: oncologyeducation.com; 2014. Available from: http://www.oncologyeducation.com/information/lung/lung-cancer-videos/webinar-archive-nsclc/.

Ramucirumab (NCT00735696)

Ipilimumab (NCT00527735)

Ipilimumab (NCT01331525)

Tremelimumab (NCT02000947)

Nivolumab (NCT01673867)

Nivolumab (NCT01642004)

MK-3475 (NCT01840579)

MPDL3280A (NCT02008227)

2000 2005 2010 2015 2020

Estimated completion date

Acti

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tion

The CTLA-4 antibody, ipilimumab (Yervoy™)(8,9), was the first treatment proven to extend survival in metastatic melanoma. It is now being tested for NSCLC and SCLC. Based on promising early results, PD-1 (eg, nivolumab and MK-3475) and PD-L1 (eg, MPDL3280 and MEDI4736) immunocheckpoint regulators are also being tested in lung cancer patients. In addition, combination immune checkpoint and therapeutic vaccine approaches are being evaluated in separate trials.

Investigational agents (part 1)Anti-angiogenics/Immunocheckpoint regulators

CTLA-4, Cytotoxic T-Lymphocyte Antigen 4 ; PD-1 or PD-L1, programmed death or programmed death-ligand 18. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(17):2046-54.9. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Annals of Oncology 2013;24(1):75-83.

Dabrafenib (NCT01336634)

BVD523 (NCT01781429)

Crizotinib (NCT01154140)

Sirolimus (NCT00923273)

MK2206 (NCT01294306)

Ganetespib (NCT01348126)

2000 2005 2010 2015 2020

Estimated completion date

Acti

ve I

nte

rven

tion

Trial results showed that EGFR tyrosine kinase inhibitors and crizotinib were effective targeted therapies in metastatic NSCLC. The following agents have been approved for the treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4-ALK) translocation and bevacizumab. Ceritinib (LDK378), a new ALK inhibitor that has shown greater pre-clinical antitumor potency than crizotinib, was highly active in patients with advanced, ALK-rearranged NSCLC, in a Phase I trial.

Investigational agents (part 2)Chaperones and other targeted therapies(10-11)

10. Reungwetwattana T, Dy GK. Targeted therapies in development for non-small cell lung cancer. Journal of carcinogenesis. 2013;12:22.11. Shaw AT, Kim D-W, Mehra R, Tan DSW, Felip E, Chow LQM, et al. Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2014;370(13):1189-97.

NSCLC and therapeutic vaccines(12)Full protein vaccine (MAGE-A3 vs. placebo); Ph. II (N=182, stage

II*)

Peptide (L-BLP25 vaccine vs placebo; Ph III; N=1514, stage III)

Ganglioside vaccine (Racotumomab + BSC vs BSC; Ph III,; N=1082; stage IIIB/IV*)

Whole tumor cell vaccine (Belagen-pumatucel+BSC vs BSC; Ph III; N=532)

Full protein vaccine (chemo. + TG4010 vaccine vs. chemo); Ph II (N=148; stage IIIB/IV)

Trials did not meet primary endpoints, but significant benefits seen in sub-groups.

12. Cuppens K, Vansteenkiste J. Vaccination therapy for non-small-cell lung cancer. Current opinion in oncology. 2014;26(2):165-70.

Immune regulators & suppressive mechanisms(13)Potential biomarkers/drug targets

IDO, indoleamine 2,3 dioxygenase; GITR, Glucocorticoid-induced tumor necrosis factor receptor; KIR, killer immunoglobulin receptor ; OX40 (CD134), Tumor necrosis factor receptor superfamily, member 4, P-serine, phosphatidylserine; TAA, tumor-associated antigen 13. Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer control 2014;21(1):80-9.

P-serine externalizatio

n

KIR 2DL1 promotion

B7-3 overexpression

N-glycolil-GM3 expression

MHC-1 loss

TAA deletion/

nitrosylation

TIM-3LAG-3

IDO-upregulation

GITRPD1-

overexpression

OX40

LUNG CANCER MANAGEMENT• Lung cancer 5-year survival

rates continue to be low (16.3%)(14)

• Smoking remains the number one cause of the disease

• ACCP guidelines recommend targeted therapies as part of lung cancer treatment

• Gene-directed therapies and Inducing/potentiating immune responses via immunotherapies are viable options for improving outcomes

• Tailored mono-/combination-/adjunctive therapies

• Targeted therapies include promising immunotherapies & other drugs

• PDL-1, PD-L1, CTLA-4 immunocheckpoint regulators combined with TRKIs may be one path to improving outcomes

INDIVIDUALIZED TREATMENT

Summary

1. American Lung Association, Research and Program Services Division, Trends in Lung Cancer Morbidity and Mortality. 2012 Available from: http://www.lung.org/finding-cures/our-research/trend-reports/lc-trend-report.pdf.