Contents. CAP Companion Meeting at USCAP Contents. The revised guidelines are in progress. These are not final Recommendations!

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Contents CAP Companion Meeting at USCAP 2016 Introduction New Key Questions Old Key Questions Revision of the CAP/IASLC/AMP Molecular Testing Guideline for Lung Cancer Biomarkers Dr. Philip T.

1 Contents CAP Companion Meeting at USCAP 2016 Introduction New Key Questions Old Key Questions Revision of the CAP/IASLC/AMP Molecular Testing Guideline for Lung Cancer Biomarkers Dr. Philip T. Cagle has nothing to disclose Philip T. Cagle, MD Houston Methodist Hospital Weill Cornell Medical College Sunday, March 13, College of American Pathologists. All rights reserved. 2 The revised guidelines are in progress. These are not final Recommendations! Advisory Panel review! Revisions! Posting for public comment soon! Revisions! Contents Introduction New Key Questions Old Key Questions Society approvals! Independent Review! Journal Review! Revisions! 2016 College of American Pathologists. All rights reserved. 4 1

Expert Panel Members Initiated in 2014 Writing began in 2015 CO-CHAIRS Philip T. Cagle, MD (CAP) Yasushi Yatabe, MD, PhD (IASLC) Neal Lindeman, MD (AMP) This work is still in progress!

Arcila, MD Eric Bernicker, MD Mary Beth Beasley, MD Sanja Dacic, MD, PhD Keith Kerr, MB ChB David Kwiatkowski, MD, PhD Marc Ladanyi, MD Lynette Sholl, MD Benjamin Solomon, MBBS, PhD Erik Thunnissen,

2 Expert Panel Members Initiated in 2014 Writing began in 2015 CO-CHAIRS Philip T. Cagle, MD (CAP) Yasushi Yatabe, MD, PhD (IASLC) Neal Lindeman, MD (AMP) This work is still in progress! Current revisions underway! Advisory Panel review! Posting for public comment soon! These are not final Recommendations! EXPERT PANELISTS Dara L. Aisner, MD, PhD Maria E. Arcila, MD Eric Bernicker, MD Mary Beth Beasley, MD Sanja Dacic, MD, PhD Keith Kerr, MB ChB David Kwiatkowski, MD, PhD Marc Ladanyi, MD Lynette Sholl, MD Benjamin Solomon, MBBS, PhD Erik Thunnissen, MD, PhD Ming S. Tsao, MD 2016 College of American Pathologists. All rights reserved. 6 Steering Committee and Staff Steering Committee Jan Nowak, MD, PhD (CAP) Fred Hirsch MD, PhD (IASLC) Neal Lindeman, MD (AMP) Staff Christina Ventura, MLS(ASCP) (CAP) Murry Wynes, PhD (IASLC) Robyn Temple-Smolkin, PhD (AMP) Lesley Souter, PhD (CAP) Carol Calasacco, MLIS, SCT (ASCP) (CAP) Pia Hirsch (IASLC) Mrudula Pullambhatla, MS (AMP) Patient Advocates Bonnie Addario The Bonnie J. Addario Lung Cancer Foundation Kim Norris Lung Cancer Foundation of America 2

Bethesda, February, 2016 Co-Chairs Advisory Panel Members Contents Natasha

Cappuzzo, MD Antonio Marchetti, MD, PhD Juan Sebastian Saldivar, MD Marileila

Chitale, MD John Iafrate, MD, PhD Suresh Ramalingam, MD Lukas Bubendorf, MD

Bridge, MD Tetsuya Mitsudomi, MD, PhD Paul Bunn, MD Mark G Kris, MD

3 Bethesda, February, 2016 Co-Chairs Advisory Panel Members Contents Natasha Rekhtman, MD, PhD Timothy Craig Allen, MD, JD Marina Nikiforova, MD Federico Cappuzzo, MD Antonio Marchetti, MD, PhD Juan Sebastian Saldivar, MD Marileila Varella Garcia, PhD Edmund S. Cibas, MD Dhananjay A. Chitale, MD John Iafrate, MD, PhD Suresh Ramalingam, MD Lukas Bubendorf, MD Yi Long Wu, MD Charles Powell, MD Tony Mok, MD Pasi A. Janne, MD, PhD Julia A. Bridge, MD Tetsuya Mitsudomi, MD, PhD Paul Bunn, MD Mark G Kris, MD Introduction New Key Questions Old Key Questions 2016 College of American Pathologists. All rights reserved. 12 3

4 KQ I. What other genes, previously not addressed, should be tested in lung adenocarcinoma? ROS1: 1-2% rearrangement RET: 1-2% rearrangement BRAF: 4% half are non-v600e MET: 3% exon 14 deletion and amplification ERBB2/ HER2: 2% (KRAS: 30% mutation MEK inhibitors) ROS1 Rearrangements in NSCLC Most auspicious; clinical trials Chromosomal rearrangements Approximately 1% to 2% of lung cancers with adenocarcinoma histology About 2,000 to 4,000 new cases of ROS1 positive lung cancer each year in the United States College of American Pathologists. All rights reserved College of American Pathologists. All rights reserved. 14 Late Breaking News ROS1 and Crizotinib This past Friday afternoon March 11 US FDA approved Crizotinib for ROS1 positive advanced NSCLC Lung cancers with ROS1 translocations respond to crizotinib (already approved for ALK positive lung cancers) Oncologists have been requesting ROS1 testing and treating ROS1 positive lung cancers with crizotinib Crizotinib has received FDA Breakthrough Therapy Designation Approval in ROS1 positive lung cancers College of American Pathologists. All rights reserved. 16 4

5 Tests for ROS1 Rearrangements in NSCLC NO GOLD STANDARD METHOD FISH Immunohistochemistry (IHC) Anchored multiplex PCR Reverse-transcriptase PCR Next generation sequencing ROS 1 Considerations? To select patients for ROS1 targeted therapy, ROS1 testing on all lung adenocarcinoma patients? Maybe other cell types in never smokers, etc? Molecular or cytogenetic test no specific method based on clinical trials? IHC for screening, but needs molecular or cytogenetic confirmation? 2016 College of American Pathologists. All rights reserved. 17 Related thought RET, BRAF,HER2/ERBB2, KRAS In addition to histological diagnosis, important to prioritize lung adenocarcinoma biopsy tissue for EGFR, ALK, and ROS1 testing As with EGFR, ALK and ROS1, these are generally mutually exclusive with occasional exceptions Mostly or exclusively adenocarcinomas Clinical trials and/or potential drugs for each (KRAS may predict for downstream targets such as MEK) Literature evidence not to recommendation level?? 5

6 RET Rearrangements in NSCLC Chromosomal rearrangements in about 1% to 2% of lung cancers with Adenocarcinoma histology Tests for RET Rearrangements in NSCLC FISH Anchored multiplex PCR Next generation sequencing IHC-variable results; not widely accepted yet 2016 College of American Pathologists. All rights reserved College of American Pathologists. All rights reserved. 22 BRAF Mutations in NSCLC BRAF mutations occur in about 5% of NSCLC In contrast to melanomas, only half of BRAF mutations in NSCLC are V600E mutations. Responses reported to V600E targeted drugs Tests for BRAF Mutations in NSCLC Sanger sequencing and other molecular Next generation sequencing IHC not established for NSCLC Only half of BRAF mutations in NSCLC are V600E College of American Pathologists. All rights reserved. 24 6

7 ERBB2/HER2 in NSCLC KRAS Mutations in NSCLC Amplification or overexpression of HER2 well known predictive biomarker for breast cancer HER2 activation in lung cancer is associated with mutations, mostly insertions in exon 20, which are independent of HER2 gene amplification These mutations are not seen in breast cancer. HER 2 mutations are found in 2% of lung adenocarcinomas 30% Adenocarcinomas No approved direct KRAS inhibitors hence, testing for KRAS has not been useful as a predictive biomarker for a KRAS inhibitor But recent reports of response to MEK inhibitors downstream of KRAS 2016 College of American Pathologists. All rights reserved College of American Pathologists. All rights reserved. 26 RET, BRAF,HER2/ERBB2, KRAS Considerations Adenocarcinomas, maybe other cell types in never smokers, etc? Not indicated as a routine stand-alone assay outside the context of a clinical trial? Can be part of larger testing panels performed either Initially? or when routine EGFR, ALK, and ROS1 testing are negative? MET in NSCLC De novo MET amplification has been associated with profound responses to therapy with crizotinib. Recently, splicing variants and insertion-deletion mutations leading to MET exon 14 deletion have been found in about 3% of lung Adenocarcinomas Lead to MET activation and response to crizotinb and cabozantinib College of American Pathologists. All rights reserved. 28 7

8 MET in NSCLC MET amplification can be seen in tumors with MET exon 14 deletion MET protein overexpression appears to correlate with MET amplification, although MET IHC is controversial as a biomarker for MET-targeted therapies Squamous cell as well as adenocarcinoma Tests for MET Activation in NSCLC Mutational analysis exon 14 Sequencing NGS Copy number FISH, CISH NGS IHC? 2016 College of American Pathologists. All rights reserved College of American Pathologists. All rights reserved. 30 MET Considerations KQ II. Is immunohistochemistry reliable for screening for ALK translocations? Not indicated as a routine stand-alone assay outside the context of a clinical trial? Can be part of larger testing panels performed either Initially? or when routine EGFR, ALK, and ROS1 testing are negative? 2016 College of American Pathologists. All rights reserved. 32 8

9 FDA Approval VENTANA ALK (D5F3) CDx Assay is intended for the qualitative detection of the ALK protein in FFPE NSCLC tissue stained with a BenchMark XT automated staining instrument. It is indicated as an aid in identifying patients eligible for treatment with XALKORI (crizotinib). ALK IHC Considerations When testing for ALK rearrangements, IHC as an equivalent alternative to FISH for adenocarcinoma May identify some cases not readily recognized by FISH 2016 College of American Pathologists. All rights reserved. 33 KQ III. In patients who are undergoing treatment with targeted tyrosine kinase inhibitors, what are the types and rates of secondary resistance? Secondary resistance considerations Molecular tests with appropriate performance characteristics for detection of secondary mutations EGFR T790M mutation testing to select patients for EGFR T790M mutation targeted therapy ALK mutational testing to select patients for ALK secondary resistance mutation targeted therapy 2016 College of American Pathologists. All rights reserved. 35 9

10 KQ IV. Are there biomarkers that are predictive of clinical outcome in squamous and small cell carcinomas? Squamous cell carcinoma Considerations Testing if squamous cell not excluded; especially if never smoker, young age, etc Insufficient evidence for new specific markers? 2016 College of American Pathologists. All rights reserved. 37 EGFR Inhibiting Monoclonal Antibodies for Squamous Cell Carcinoma EGFR copy number (FISH) as potential biomarker Cetuximab (Erbitux) Portrazza (Necitumumab) Eli Lilly FDA approved with chemo in advanced squamous cell carcinoma V. What are the clinical performance characteristics of circulating DNA/CTC in plasma when used for diagnosis of primary lung adenocarcinoma or relapse? 2016 College of American Pathologists. All rights reserved

11 cfdna and CTC Considerations In general, insufficient evidence for recommendation? Maybe cfdna when insufficient biopsy tissue for EGFR testing? May consider cfdna for T790M mutation testing when progression on EGFR TKIs (follow up biopsy if the result is negative)? Contents Introduction New Key Questions Old Key Questions 2016 College of American Pathologists. All rights reserved. 42 Old Key Questions (from 2013 guideline) NGS Considerations Has new data emerged to warrant changing the original recommendations? Strengthen previous statement Benefits vs availability Multiplexed genetic sequencing preferred over multiple single-gene tests for selecting lung adenocarcinomas for targeted therapy beyond EGFR, ALK, and ROS1 specific circumstances 2016 College of American Pathologists. All rights reserved

12 Cytology Specimen Revision Considerations Previously, cell blocks preferred over cytology smears Cytology smears or cell blocks, both suitable for lung cancer biomarker molecular testing. The End 2016 College of American Pathologists. All rights reserved. 46 Introduction References Politi K, Ayeni D, Lynch T. The Next Wave of EGFR Tyrosine Kinase Inhibitors Enter the Clinic. Cancer Cell Jun 8;27(6): Roth JA, Sullivan SD, Goulart BH, Ravelo A, Sanderson JC, Ramsey SD. Projected Clinical, Resource Use, and Fiscal Impacts of Implementing Low- Dose Computed Tomography Lung Cancer Screening in Medicare. J Oncol Pract Jul;11(4): Cagle PT. The new American Cancer Society Lung Cancer Screening guidelines and the role of the pathologist. Arch Pathol Lab Med Apr;137(4):451. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med Jun;137(6): Cagle PT, Sholl LM, Lindeman NI, et al. Template for reporting results of biomarker testing of specimens from patients with non-small cell carcinoma of the lung. Arch Pathol Lab Med Feb;138(2): ROS1 References Mazières J, Zalcman G, Crinò L, Biondani P, Barlesi F, Filleron T, Dingemans AM, Léna H, Monnet I, Rothschild SI, Cappuzzo F, Besse B, Thiberville L, Rouvière D, Dziadziuszko R, Smit EF, Wolf J, Spirig C, Pecuchet N, Leenders F, Heuckmann JM, Diebold J, Milia JD, Thomas RK, Gautschi O. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol Mar 20;33(9):992-9 Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med Nov 20;371(21): Sholl LM, Sun H, Butaney M, Zhang C, Lee C, Jänne PA, Rodig SJ. ROS1 immunohistochemistry for detection of ROS1-rearranged lung adenocarcinomas. Am J Surg Pathol Sep;37(9): Yoshida A, Kohno T, Tsuta K, et al. ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases. Am J Surg Pathol. 2013;37(4): Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):

13 RET References BRAF References Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3): Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012; 30(35): Sasaki H, Shimizu S, Tani Y, et al. RET expression and detection of KIF5B/ RET gene rearrangements in japanese lung cancer. Cancer Med. 2012;1(1): Tsuta K, Kohno T, Yoshida A, et al. RET-rearranged non-smallcell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 2014; 110(6): Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013; 3(6): Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res 2013 Aug 15;19(16): Planchard D, Groen H, Kim T, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2015;33(Supp) Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26): Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol. 2013;31(20):e341 e344. Lin L, Asthana S, Chan E, et al. Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci U S A. 2014;111(7):E748 E757. MET References ERBB2/HER2 References Frampton GM, Ali SM, Rosenzweig M, Chmielecki J, Lu X, Bauer TM, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 2015 May 13. Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015 May 13. Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, et al. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib+/-onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res 2014 Sep 1;20(17): Stephens P, Hunter C, Bignell G, et al. Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431(7008): Li C, Sun Y, Fang R, et al. Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains. J Thorac Oncol. 2012;7(1): Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65(5): Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31(16): De Greve J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012;76(1): Greulich H, Kaplan B, Mertins P, et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A. 2012;109(36):

14 KRAS references Sholl LM. Biomarkers in lung adenocarcinoma: a decade of progress. Arch Pathol Lab Med Apr;139(4): Cagle PT, Sholl LM, Lindeman NI, et al. Template for reporting results of biomarker testing of specimens from patients with non-small cell carcinoma of the lung. Arch Pathol Lab Med Feb;138(2): Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med Jun;137(6): Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19(15): Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18(22): Kranenburg O. The KRAS oncogene: past, present, and future. Biochim Biophys Acta. 2005;1756(2): KRAS references Jänne PA, Smith I, McWalter G, et al. Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J Cancer Jul 14;113(2): Blumenschein GR Jr, Smit EF, Planchard D, et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK ) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer. Ann Oncol May;26(5): KRAS references Stinchcombe TE, Johnson GL. MEK inhibition in nonsmall cell lung cancer. Lung Cancer Nov;86(2): Jänne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebocontrolled, phase 2 study. Lancet Oncol Jan;14(1): Squamous Cell Carcinoma References Goss GD, Spaans JN. Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung. Oncologist Jan 14. pii: theoncologist [Epub ahead of print] Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol Jul;16(7): Pirker R. Epidermal growth factor receptor-directed monoclonal antibodies in nonsmall cell lung cancer: an update. Curr Opin Oncol Mar;27(2):

15 Squamous Cell Carcinoma References ALK IHC References Kim HS, Mitsudomi T, Soo RA, Cho BC. Personalized therapy on the horizon for squamous cell carcinoma of the lung. Lung Cancer Jun;80(3): Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamouscell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. The Lancet Oncology Volume 13, No. 10, e418 e426, October 2012 Chan BA, Hughes BGM. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015;4(1): doi: /j.issn Sholl LM. Protein correlates of molecular alterations in lung adenocarcinoma: Immunohistochemistry as a surrogate for molecular analysis. Semin Diagn Pathol Feb 4. pii: S (15) doi: /j.semdp [Epub ahead of print] Pekar-Zlotin M, Hirsch FR, Soussan-Gutman L, Ilouze M, Dvir A, Boyle T, Wynes M, Miller VA, Lipson D, Palmer GA, Ali SM, Dekel S, Brenner R, Bunn PA Jr, Peled N. Fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. Oncologist Mar;20(3): Wynes MW, Sholl LM, Dietel M, Schuuring E, Tsao MS, Yatabe Y, Tubbs RR, Hirsch FR. An international interpretation study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators. J Thorac Oncol May;9(5):

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors Guideline from the College of American Pathologists, the International