MUTATION-POSITIVE ADVANCED EGFR NSCLC

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1 Creative Educational Concepts, Inc Alysheba Way, Suite 100 Lexington, KY Toll-Free Fax November CEC. All rights reserved. ADVANCED EGFR MUTATION-POSITIVE NSCLC Strategies for Tailoring Therapy and Improving Patient Outcomes Disclaimer: The information in this pocket guide is intended as reference material and should not replace clinical judgment or updated recommendations that may supersede those provided here.

2 LUNG CANCER OVERVIEW Incidence and Mortality 1 Annually, 1.8 million people are diagnosed with lung cancer and 1.6 million people die from lung cancer. 2 Five-year survival varies from 4-17% (17.8% in the US). 2,3 1 Gridelli C, et al. Nat Rev Dis Primers. 2015; 2 Hirsch FR, et al. Lancet. 2016; 3 Bender E. Nature LUNG CANCER Precision Oncology Future Evolutionary trajectory Natural clinical history of cancer Paired tumor-circulating tumor cells-plasma Multisector profiling Longitudinal sampling Other traits DNA damage repair Metabolic state Stemness of tumor Past history Etiology eg, smoking status Prior response to therapy Mutational signatures Multidimensional profiling Targeted sequencing for drivers Whole exome/whole genome sequencing RNA sequencing Proteomic profiling Chromatin state Immunophenotyping Immune checkpoint biomarkers Mutational burden Neoantigen prediction HLA typing T-cell repertoire sequencing Inflammatory state Patient-derived models High throughput screening for therapeutic vulnerabilities Ex vivo immune killing assays Adapted from Tan WL, et al. Lancet Oncol

3 Paronychia Management Wear comfortable shoes Trim nails without aggressive manicuring in order to avoid micro-abrasions that may lead to infection Wear gloves while cleaning Inflammation - Use topical corticosteroids or tetracycline Excessive tissue granulation - Use electrocautery, silver nitrate and nail avulsion If infection occurs, tissue must be cultured in order to guide antibiotic therapy Lacouture ME, et al. Support Care Cancer Lung Cancer Classification 1 Lung Cancer Small-Cell Lung Cancer 15% Non-Small Cell Lung Cancer 85% Squamous 30% Non-squamous 70% Large-Cell Carcinoma (10%) Large-cell Neuroendocrine Carcinoma Adenocarcinoma (90%) Mixed subtypes Lepidic (non-mucinous or mucinous) Acinar Papillary Micropapillary Solid Adenocarcinoma Mutation Frequencies 2 KRAS, 25% EGFR-sensitizing, 17% ALK, 7% EGFR other, 4% MET, 3% Unknown oncogenic driver detected, 31% EGFR other, 4% >1 mutation, 3% HER2, 2% ROS1, 2% BRAF, 2% RET, 2% NTRK1, 1% PIK3CA, 1% Adapted from 1 Gridelli C, et al. Nat Rev Dis Primers. 2015; 2 Hirsch FR, et al. Lancet

4 3 EGFR MUTATION-POSITIVE NSCLC Mutation Frequencies L858R 31% Exon 20 insertion 13% G719X 6% L881Q 3% S768I 3% EGFR rearrangement 0.3% Exon 19 deletion 44% Exon 19 insertion 0.2% Exon duplication (KDD) 0.2% Adapted from Costa DB. Transl Lung Cancer Res Diarrhea Management Grade 1 Grade 2 Grade 3 & 4 Stop laxatives. Drink 8 10 glasses of clear fluids daily. Immediately start loperamide: 4 mg (2 tablets) followed by 2 mg (1 tablet) after each loose stool (up to 20 mg daily) until bowel movements cease for 12 hours. Maintain dose level of EGFR TKI. Continue loperamide. Assess for dehydration and electrolyte imbalance. Consider intravenous fluids and electrolyte replacement. If diarrhea does not improve after 48 hours, temporarily discontinue EGFR TKI. Upon improvement to grade 1, restart at a reduced dose (except gefitinib, which should be restarted at the original dose). Plus: Use stool cultures to rule out an infectious process. Apply aggressive intravenous fluid replacement for 24 hours or more. Use hospitalization to monitor the patient s progress. Consider prophylactic antibiotics if the patient is also neutropenic. Temporarily discontinue EGFR TKI. Upon improvement to grade 1, restart at a reduced dose (except gefitinib, which should be restarted at the original dose). Permanently discontinue EGFR TKI if diarrhea does not return to grade 1 within 14 days despite treatment discontinuation and best supportive care. Hirsh V, et al. Curr Oncol

5 MANAGEMENT OF EGFR TKI TOXICITIES Rash Management Topical Recommended Hydrocortisone 1% cream with moisturizer and sunscreen BID Potential New Paradigm Not Recommended Preventive IASLC Definitions Pimecrolimus 1% cream Tazarotene 0.05% cream Sunscreen as single agent Recommendation Grades C Comments Systemic Topical Minocycline 100 mg daily Doxycyline 100 mg BID Alclometasone 0.05% cream Fluocinonide 0.05% cream BID Clindamycin 1% Tetracycline 550 mg BID Treatment Vitamin K1 Cream C A Doxycycline is preferred in patients with renal impairment. Minocycline is less photosensitizing. Fluocinonide 0.05% cream BID should not be used on the face for more than 2 weeks at a time. Systemic Doxycycline 100 mg BID Minocycline 100 mg daily Isotretinoin at low doses (20-30 mg/d) Isotretinoin is photosensitizing and can Acitretin C cause xerosis. Monitor lipids and liver Hirsh V, et al. Curr enzymes Oncol with retinoids. 15 Adapted from Lacouture ME, et al. Support Care Cancer Worldwide Incidence of EGFR Mutations Americas Europe Africa Asia Country Incidence Country Incidence Country Incidence Country Incidence US White 13.0% (62/476) Holland 10.6% (66/620) Morocco 21.0% (29/137) China 40.6% (368/906) US African American Argentina Mexico Colombia Peru Panama Costa Rica 19.0% (23/121) 14.4% (247/1713) 37.8% (486/1287) 26.5% (479/1807) 51.1% (201/393) 29.0% (47/162) 33.0% (32/97) France Germany Italy Poland Russia Spain UK 19.6% (118/601) 9.9% (93/944) 10% (39/375) 14% (26/186) 20% (38/192) 12.0% (10/83) 13.5% (29/215) Korea India Bangladesh Japan Malaysia Singapore Hong Kong Taiwan 53.1% (190/358) 25.9% (43/166) 23.0% (14/61) 49.4% (196/397) 36.3% (151/416) 60.8% (464/762) 47.2% (76/161) 55.3% (471/851) Thailand 53.8% (63/117) Vietnam 64.2% (77/120) Tan DS, et al. J Clin Oncol

6 EGFR MUTATION TESTING Summary of Guidelines Why test? To select patients who are likely to benefit from EGFR TKIs Which tumors to test? When to test? What to test? How fast should test results be available? Any tumor with adenocarcinoma component or NSCLC NOS At diagnosis: TNM stage IV disease (consider TNM stage I-III disease) At recurrence/progression: TNM stage I-III disease, not previously tested; and prior to changing therapy, to determine mechanism of acquired resistance Primary tumors or metastatic lesions - T790M testing: if tissue biopsy is not feasible, plasma biopsy should be considered* Formalin-fixed, paraffin-embedded; or fresh, frozen or alcohol-fixed specimens (decalcifying solutions should be avoided) Cytologic specimens are acceptable Test results should be made available within 10 business days of receiving the specimen in the laboratory How to test? Must be able to detect mutations in specimens with >50% cancer cell content Testing assay should be able to detect all individual mutations that have been reported with a frequency of >1% of EGFR-mutated adenocarcinomas IHC, FISH, and CISH are not recommended Sheikine Y, et al. Clin Lung Cancer. 2016; *NCCN Guidelines Version Use of Plasma EGFR Genotyping Potential New Paradigm Acquired resistance to EGFR TKI FDA-approved plasma assay for T790M and sensitizing mutations T790M+ T790M- T790M- Skip biopsy, start 3rd gen EGFR TKI Biopsy, FDA approved FFPE assay for T790M T790M+ 3rd gen EGFR TKI Chemo Adapted from Oxnard GR, et al. J Clin Oncol

7 Detection of T790M Tumor Biopsy vs Liquid Biopsy Comparison Agreement (%) 95% CI Kappa CTC vs all biopsy ctdna vs all biopsy CTC/ctDNA vs all biopsy No single diagnostic test for acquired resistance, including tumor biopsy, can be considered a gold standard. Adapted from Oxnard GR, et al. J Clin Oncol Implementing Guidelines Staying current with rapidly evolving practice standards - Consider promoting a local physician champion to educate colleagues in their region or community - Establish formal venues for the communication of biomarker education Managing resources and communication between stakeholders - Every patient suspected of having advancedstage disease should, ideally, be evaluated by a multidisciplinary team - Each institution should establish a molecular testing policy that covers reflex testing - Nurse navigators may help streamline patient care and facilitate consistent communication among multidisciplinary teams - Electronic health records should be maintained and shared among the multidisciplinary teams Optimizing tissue acquisition and processing - Tissue acquirers and pathologists should communicate effectively to ensure that tissue obtained for molecular testing is of sufficient quantity and quality - Decision on the optimal diagnostic procedure for molecular testing should be individualized and include risk-benefit analysis - Ensure timely identification of actionable biomarkers - Efficient use of pleural fluid may facilitate molecular testing Levy BP, et al. Oncologist

8 Methods and Applications Technique Direct sequencing Sensitivity (% Mutant DNA) 10-25% Mutations Identified Known and new Detection of Co-mutations Potential Applications No Tissue Pyrosequencing 5-10% Known only No Tissue Multiplex PCR (SnaPshot) 5% Known only Yes (hotspots) Tissue cobas 3-5% Known only No Tissue, Plasma WAVE-surveyor 2% Known only No Tissue, Plasma Mass spectrometry based 1-10% Known only Yes (hotspots) Tissue, Plasma 1-10% High-depth NGS (at least 200x depth) (depending on error rates and sequencing depth) Known and new Yes Tissue, Plasma Therascreen 1-5% Known only No Tissue, Plasma Scorpions ARMS Locked nucleic acid clamp TAm-Seq 2% 1% Known only No Tissue, Plasma 1% Known only No Tissue, Plasma Known and new Yes Tissue, Plasma BEAMing <0.1% Known only No Tissue, Plasma Digital droplet PCR CAPP-Seq ~0.02% <0.1% Known only No Tissue, Plasma Known and new Yes Plasma Adapted from Tan DS, et al. J Thorac Oncol LIQUID BIOPSY Genotyping Circulating Tumor DNA Tumor cells release small fragments of cell-free plasma DNA (cfdna) into circulation by multiple mechanisms: - Secretion - Apoptosis - Necrosis cfdna includes normal and circulating tumor DNA (ctdna) - ctdna size: Average of base pairs - Half-life: ~2 hours Applications Early disease detection Assessment of molecular heterogeneity of overall disease Monitoring of tumor dynamics Identification of genetic determinants for targeted therapy Evaluation of early treatment response Monitoring of minimal residual disease Assessment of evolution of resistance in real time Diaz LA Jr., Bardelli A. J Clin Oncol

9 Potential Clinical Algorithm Continued TKI beyond PD No No Consider cfdna EGFR testing* Surveillance Is disease progression clinically significant? Is rebiopsy feasible? No Yes Yes Is disease progression localized? Histological review EGFR testing Yes Continued TKI beyond PD Local ablative therapy CNS vs extracranial SRS, RT, Cryo, RFA, Surgery Tissue acquired No tissue acquired Plasma T790M+ T790M Positive T790M Negative Switch to 3 rd generation EGFR TKI Screen for other resistance mechanisms, e.g., MET, HER2, PIK3CA, BRAF Plasma T790M- PD Are there clinical trials available? Start chemotherapy +/- EGFR TKI PD: progressive disease Cryo: cryotherapy CNS: central nervous system SRS: stereotactic radiosurgery RT: radiation therapy RFA: radiofrequency ablation Adapted from Tan DS, et al. J Thorac Oncol *NCCN Guidelines Version EGFRm+ NSCLC Treatment Algorithm First-line Afatinib, erlotinib, gefitinib Second-line Osimertinib for T790M+ Third-line Chemotherapy Levy BP, et al. Oncologist

10 EGFR TKI RESISTANCE IASLC Definitions Primary Stable disease as best response after EGFR TKI monotherapy Secondary Partial response or stable disease for more than 6 months with an enlarging extracranial target lesion(s) Documented resistance mechanism (eg, T790M mutation, MET amplification, or other emerging mechanism relevant to the TKI) Adapted from Tan DS, et al. J Thorac Oncol Common Mechanisms Mechanism Gene Alterations Prevalence Detection Method EGFRdominant Bypass signaling tracts Phenotypic alterations EGFR SNV: T790M 41-63% SNV: D761Y, T854A, L747S LNA-PCR/ sequencing assay <5% PCR-RFLP Amplification 8% FISH PIK3CA SNV 5% SNaPshot BRAF SNV 1% SNaPshot MET Amplification 5% FISH HER2 Amplification 12-13% FISH AXL HGF Increased expression Increased expression 20% IHC 61% IHC PTEN Loss 10% IHC RB1 loss - Transformation to small cell lung cancer Transition to EMT 14% 16-20% Histological examination and confirmed by expression of neuroendocrine markers ICH stain of vimentin and e-cadherin SNV: single nucleotide variation, EMT: epithelial-mesenchymal transition, LNA: Locked Nucleic Acid, PCR: polymerase chain reaction, RFLP: restriction fragment length polymorphism, FISH: fluorescence in situ hybridization, IHC: ImmunoHistoChemistry Tan DS, et al. J Thorac Oncol