7/6/2015. Cancer Related Deaths: United States. Management of NSCLC TODAY. Emerging mutations as predictive biomarkers in lung cancer: Overview

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1 Emerging mutations as predictive biomarkers in lung cancer: Overview Kirtee Raparia, MD Assistant Professor of Pathology Cancer Related Deaths: United States 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% 228,190 new cases of lung cancer 159,480 deaths due to lung cancer Overall 5 year survival 15% Siegel R, et al. CA Cancer J Clin. 2013;63(1): Evolution of Identification of Genomic Alterations in Lung Adenocarcinoma Management of NSCLC TODAY Non-small cell carcinoma (NSCLC) No known genotype No known genotype Squamous cell carcinoma Non Squamous Cell Carcinoma Adenocarcinoma Non- Adenocarcinoma Surgery Chemotherapy ECEPT Bevacizumab Pemetrexed Radiation Therapy (depending on stage) Targeted Therapy EGFR inhibitors ALK inhibitors and/or Conventional Therapy Any combination of Surgery Chemotherapy Radiation therapy (depending on stage) 1

2 Paradigm Shift in Pathology Tissue Objectives EGFR Mutation (Update) Her-2 neu Mutation Sample evaluation Careful cutting of block Spare sections for reflex testing Focussed Morphologic Analysis IHC Tumor Genotyping Tumor Biomarkers BRAF Mutation PIK3CA Mutation EGFR Mutation EGFR Mutations in NSCLC ~ 10% caucasians and ~ 40% asians Epidermal growth factor receptor (EGFR, ERBB1): cell surface protein kinase Most Common mutations: belonging to the Erb B transmembrane deletions in exon 19 and growth factor receptor family L858R point mutation in exon 21 (85-90%) Ligand binding by EGF and others triggers homodimerization or Sensitizing Mutations heterodimerization of EGFR molecule Autophosphorylation and Resistant Mutations transphosphorylation of the receptors Primary through their tyrosine kinase domains Secondary leads to activation of downstream PI3K/AKT/mTOR and RAS/RAF/MAPK Compound mutations pathways (14% of EGFR mutated Leads to tumor cell proliferation, cell tumors) survival, angiogenesis and epithelialmesenchymal transitions. Gately et al J Clin Pathol 2012;65:1-7 2

3 Pretreatment T790M mutation had a negative impact on the PFS of NSCLC patients Clustering of Mutations in the EGFR Gene at Critical Sites within the ATP-Binding Pocket Dng et al ioncotargets and Therapy 2014: Lynch, T. J. et al. N Engl J Med 2004;350: EGFR Mutation (IPASS Study) EGFR Mutation (OPTIMAL Study) EGFR gene mutations are considered the strong predictor of a better outcome with gefitinib This trial confirmed that gefitinib is superior to carboplatin paclitaxel as an initial treatment for pulmonary adenocarcinoma in the presence of a mutation of the EGFR gene Mok et al N Engl J Med Erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC Zhou et al Lancet Oncol

4 EGFR Mutation (LU-Lung 3 study) Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations Sequist et al J Clin Oncol EGFR Mutation Testing Mechanism of Resistance to EGFR Inhibitors Method Screening Technology (all EGFR mutations, known and novel) Targeted Mutation Detection (analyzed for known EGFR mutations) PCR/Sequencing Pyrosequencing PCR/HRMA/dHPLC Melt Analysis) ARMS Allele-specific real time PCR SNaPshot PNA Clamp PCR/Fluorescent RFLP 4

5 Clinical Trials to Overcome Resistant to EGFR TKIs New Targetable Oncogenes Agent Phase Clinical Setting Clinical Trials Second-Generation TKIs II EGFR mutation +, PD during TKI treatment NCT Afatinib Afatinib intermittent high I T790M mutation +, PD during TKI treatment NCT dose Oncogenic Target Prevalence (%) Reported Clinical Associations HER2 mutations 2.8 Never Smokers Asian Race Female Sex Potential Kinase Inhibitors Afatinib (BIBW-2992) Neratinib (HKI-272) Dacomitinib (PF ) Third-Generation TKIs CO-1686 AZD-9291 II II EGFR mutation +, PD during TKI treatment T790M mutation +, PD during TKI treatment NCT NCT AZD9291 has robust efficacy and is well tolerated in EGFR m+ NSCLC patients with acquired resistance to EGFR-TKIs. Patients with EGFR T790M+ tumors have higher ORR with AZD9291 compared with those with EGFR T790M- tumors (64% vs 23%) BRAF mutations 2 to 4.9 Ever Smokers White race V600 E: never smokers, and females PIK3CA mutations 1.5 to 2.6 No association seen Vemurafenib GSK GDC-0941 L147 BKM120 Her2 Mutation Incidence of HER2 Alterations 6-35 % % 2-4 % The HER2 oncogene, known as c-erbb-2, HER2/neu or p185neu, located in the chromosomal region 17q11.2- q12 (first reported in 1984) Family of tyrosine kinase receptors with no specific ligand When activated, is able to form dimers with other EGFR family receptors, activating the downstream signaling pathway Mar et al Lung Cancer Mar Adapted from Mazières et al J Clin Oncol

6 HER2 overexpression is a poor prognostic factor in lung cancer Prognostic value of HER2 Mutation HER2 overexpression determined by IHC is significantly associated with a poor prognosis in lung adenocarcinoma HER2 predicted worse prognosis in early-stage NSCLC Japanese Population Western Population Association was significant by IHC, not by FISH Liu et al J Thorac Oncol N =27 Stage 1 =21 patients No difference in overall survival N =25 (Total 1478 cases) Stages 1-2 = 15 Stage 3-4 = 10 Tomizawa et al Lung Cancer Oct Arcila et al Clin Cancer Res Sep Laboratory Methods for HER2 Testing Targeted drug therapies, mechanisms of action and available clinical trials in HER2 positive NSCLC. Three principal mechanisms of HER2 alteration Drug Class Antibodies targeting HER2 Representative Drug Trastuzumab Mechanism Available Data in NSCLC Targets extracellular domain IV Mixed results of HER2 receptor, prevents dimerization Immunohistochemistry (IHC) for protein overexpression Fluorescent in situ hybridization (FISH) for gene amplification Next generation sequencing (NGS) for gene mutations HER-family tyrosine kinase inhibitors Pertuzumab Trastuzumabemtansine (TDM1) Lapatinib Targets extracellular domain II of HER2 receptor, prevents dimerization A cytotoxic microtubule inhibitor, DM-1, is conjugated to trastuzumab, which delivers it to HER2 labeled tumor cells Inhibits EGFR/HER1 and HER2 None Ongoing (NCT ) None Afatinib Inhibits EGFR/HER1, HER2, and HER4 Objective response was observed in all 3 patients Mutually exclusive with other activating mutations Neratinib Dacomitinib Inhibits EGFR/HER1 and HER2 Inhibits EGFR/HER1, HER2, and HER4 Phase 1 study: n=14; 2 patients showed response Phase 2 trial: Responders included 1 of 3 patients with HER2 amplification NCCN has included trastuzumab and afatinib as potential therapy options for NSCLC patients with HER2 mutations 6

7 BRAF Mutation Inducible expression of BRAF leads to MAPK activation and lung adenocarcinoma development BRAF is a serine threonine kinase downstream from KRAS in the mitogen-activated protein kinase (MAPK) signaling cascade Seen in 2-5% of NSCLC Non-V600E mutations relatively more common in NSCLC than in colorectal cancer or melanoma and were found to occur exclusively in patients with a smoking history V600E mutations more common in never smokers In vivo expression of V600E in mouse models leads to development of invasive adenocarcinoma, a phenotype that is reversed when V600E expression is stopped Ji et al Cancer Res May BRAF Mutation A Patient With BRAF V600E Lung Adenocarcinoma Responding to Vemurafenib BRAF mutations are mutually exclusive to EGFR and KRAS mutations and have been associated with decreased sensitivity to the EGFR TKI, gefitinib Multiple BRAF inhibitors PL4032 (molecular inhibitor selective for BRAF) Sorafenib (a multikinase inhibitor of RAF-1, BRAF, VEGF, and PDGF) CI-1040 (a first-generation-specific inhibitor of MAP kinase) are currently under development After 2 weeks of treatment, follow-up fluorodeoxyglucose positron emission tomography/ct showed good metabolic response Gautschi et al J Thorac Oncol Oct 7

8 PIK3CA Mutation Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that play an important role in regulating cell growth, proliferation, and survival PIK3CA mutations are reported in 1 to 3% of lung adenocarcinoma, with prevalence being higher in squamous cell carcinoma PIK3CA mutations in lung adenocarcinoma often coexist with another oncogenic mutation, such as an EGFR or KRAS mutation: a secondary process and not a true driver mutation Ongoing Trials In Tumors with PIK3CA Mutation Single-agent PI3K inhibitors (NCT ) Combinations with chemotherapy (NCT , NCT ) Combinations with other targeted agents (NCT ) In human NSCLC lines, the novel PI3K inhibitor imidazopyridine demonstrated anti-proliferative effects Conclusion Several new molecular mutations in NSCLC have been identified, including HER2, BRAF, and PIK3CA mutations Identification and characterization of these molecular targets are having a growing impact on the management of patients with lung cancer Thank You 8