A clinicians view on NGS of (lung) cancer

A clinicians view on NGS of (lung) cancer oliver.gautschi@onkologie.ch 14.1.2015

Predictive Role of Biomarkers for Lung Cancer Therapy Chemotherapy: not confirmed Anti-Angiogenic-Therapy: not confirmed Immunotherapy: research ongoing Targeted therapy: standard-of-care for Point mutations: EGFR L858R Deletions: EGFR del19 Translocations: EML4-ALK Gautschi 2015 2

«True» Targeted Therapy Tumor-specific High response rate Low toxicity Commonly refered to the «targeting of oncogenic drivers». Distinction from chemotherapy, and from «untargeted» use of targeted therapies Mok, Clin Lung Cancer 2010 3

www.mycancergenome.org 4

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NGS revealed targets in tumors diagnosed as «negative» Drilon, Clin Cancer Res 2015

3-tiered test algorithm in Luzern Stage 1 Sequencing: EGFR + KRAS FISH/IHC: ALK (ROS1) «Triple-negative NSCLC» Stage 2 ARAF BRAF DDR2 HER2 MEK1 NRAS ROS1 RET KIF5B HER2 MET FGFR «Pan-negative NSCLC» Stage 3 NGS (iontorrent lung/colon) Gautschi, Diebold 2014

Clinical requirements for NGS Turn around time is currently 3-4 weeks, but therapy starts within 1-2 weeks Distinction of «relevant» versus «irrelevant» Translocations are mandatory and fusion partners are promiscuous Gene expressions are potentially important for immunotherapy and other antibody-based therapies

Systemic Lung Cancer Therapy Advanced NSCLC (Histology/Cytology) Sqamous Non-squamous: EGFR, ALK and KRAS testing (no molecular diagnostics) EGFR or ALK «positive» KRAS+ or «triple-negative» 4-6 cycles of platinum-based chemotherapy Option: erlotinib (or afatinib*) maintenance therapy Frontline targeted therapy: EGFR: afatinib, erlotinib, or gefitinib ALK: crizotinib* 4 cycles of platinum-based chemotherapy (+bev), followed by maintenance with pemetrexed (or erlotinib) Progression: Docetaxel or erlotinib Immunotherapy* (trial) *Not registered in Switzerland for this indication Adapted from: ESMO Guidelines 2014 (www.esmo.org) Progression: continuation + local ther. switch to chemotherapy new inhibitor* (trial) immunotherapy* (trial) Progression: Docetaxel or erlotinib Tripel-neg: further testing and therapy* (trial) Immunotherapy* (trial)

EGFR mutation: targeted therapy is standard of care IPASS trial, Mok NEJM 2009 11

Different EGFR mutations Cheng, Modern Pathology 2012 12

ALK fusion: targeted therapy is standard of care PROFILE1014, Solomon NEJM 2014 13

Mechanisms of resistance: ALK KIT, MET, EGFR Choi NEJM 2010; Sasaki CR 2011; Doebele CR 2012; Yu CR 2013 14

ALK inhibitor profiles Gettinger ASCO 2014 15

Other targets and therapies «Molecular» off-label use of therapies approved for other indications. Examples: crizotinib for CD74-ROS1 (lung) crizotinib for MET+ (lung) trastuzumab for HER2ins20 (breast) vemurafenib for BRAFV600E (melanoma) vandetanib for KIF5B-RET (thyroid) Gautschi 2015 16

Crizotinib for ROS1-NSCLC: EUROS1 Cohort Study Mazieres JCO 2015 (in press) 17

Crizotinib for MET ampl Camidge, ASCO 2014 18

Trastuzumab for HER2ins20 Mazières JCO 2013 (and update in progress) 19

Vemurafenib for BRAF V600E Gautschi, JTO 2012; Peters JCO 2013

BRAF G469L is vem-resistant Gautschi, Lung Cancer 2013 21

Vandetanib for KIF5B-RET Gautschi, JTO 2013 and Leenders/Thomas, Univ Cologne/Blackfield 22

A never ending story? Roman coin: Fortuna with Cornucopia 23

Words of caution We are coming to the end of the first period of the game. We are just beginning to understand our opponent's offensive and defensive strategies. The outcome will depend on combining therapies, mixing in immune approaches, and adding new players. We need to remember that these drugs also have toxic effects, they are expensive, and they haven't cured anyone yet. D. Longo, NEJM 2014 24

Planned or ongoing trials (CH) Indication/Marker Title/Sponsor Drug EGFR mut. untreated AURA (AstraZeneca) AZ9291 EGFR mut. pretreated TIGER (Clovis) Rociletinib ALK pos. untreated ALEX (Roche) Alectinib ALK pos. pretreated ASCEND (Novartis) Ceritinib KRAS mutated SAKK 19/13 MEK162 ROS1 pos. pretreated EUCROSS Crizotinib HER2 mut. pretreated ETOP NICHE Afatinib HER2 pos. pretreated Roche T-DM1 BRAF V600E In discussion In discussion SAKK trial radar 25

Summary Lung cancer is a model for precision medicine Acquired resistance and patient allocation to clinical trials remains a challenge Multidisciplinary international collaborations are important Thank you for your attention. Gautschi 2015 26