Clinical Use of Molecular in the Treatment of Lung Cancer

Transcription

1 Clinical Use of Molecular in the Treatment of Lung Cancer Tianhong Tina Li, MD, PhD Associate Professor of Clinical Medicine, School of Medicine

2 Disclosures Grants/Research Support: Astellas; Genentech; Eli Lilly Speakers Bureau: Pfizer Consultant: Clovis, Foundation Medicine, Inc. No conflicts of interest in this presentation

3 A for genomics- driven cancer medicine Garraway L A et al. JCO 2013;31:

4 Actionable Targets in Molecularly-Defined NSCLC Subsets Histologic Subtypes Other 11% Adenocarcinomas ALK Unknown EGFR AKT BRAF VEGFR HER2 EPHA/B PDGFR FGFR INSR PI3K Squamous 34% Adenoca 55% KRAS MAPK Squamous Cell Carcinomas FGFR1 Amp Green, FDA approved drugs Blue, FDA approved for other Dash green, in clinical trials Li et al. J Clin Oncol. 31(8): , 2013 Unknown EGFRvIII PI3KCA EGFR TK DDR2

5 NCCN Guideline: mnsclc Histologic assessment Non- squamous Squamous cell EGFR or ALK FISH+ EGFR WT/ALK WT or unknown EGFR TKI ALK TKI doublet * Bevacizumab Pla@num doublet* 1 st Line EGFR TKI (Erlo@nib) Con@nua@on of bevacizumab Start erlo@nib or pemetrexed Maintenance Con@nua@on of gemcitabine, or switch to erlo@nib or docetaxel or observa@on 3 rd Genera@on EGFR TKI (?) 2 nd or 3 rd Genera@on ALK TKI Pla@num doublet* Bevacizumab Erlo@nib or pemetrexed or Docetaxel, or nivolumab /pembrolizumab Erlo@nib or docetaxel ± ramucirumab or nivolumab /pembrolizumab 2 nd Line No standard of care: gemcitabine, vinorelbine, abraxane, based on prior therapy 3 rd Line and Beyond *For PS 0 1 only; If eligible for bevacizumab; Bevacizumab is not licensed for second- line use in NSCLC.

6 A of Cancer Molecular Diagnosis and Treatment Figure 3. Personalized Medicine: A Scientific Revolution of Cancer Molecular Diagnosis and Treatment 1. Histomorphological Diagnosis: 2. Molecular Diagnosis: Archival FFPE tumor specimens Cancerous Archival cancer specimens Macro- or Micro- dissection of Tumors Empirically Personalized Medicine (Compound- Based Therapy): Use clinicopathological factors to select available drugs for an individual patient Extract tumor nucleic acids: Current Personalized Medicine (Targeted- Based Therapy V1.0): Use single gene- based molecular tests to select specific drugs for an individual patient Evolving Personalized Medicine (Targeted- Based Therapy V2.0): Use multiplexed molecular tests with increased sensitivity and outputs for the cost- effective selection of available drugs for an individual patient Future Personalized Medicine (Patient- Based Therapy): Use an integrated genomic profile from high throughput next generation sequences to design and apply targeted treatment for an individual patient Li et al. J Clin Oncol. 31(8): , 2013 DNA and RNA Representative technologies: Single Biomarker Tests: Sanger DNA Sequencing or pyrosequencing RT- PCR FISH IHC Multiplex, Hot Spot Mutation Tests: PCR- based SNapShot PCR- based Mass Array SNP Sequenom Initial High- Throughput Technologies: SNP/CNV DNA microarray RNA microarray Epigenetic modifications Next Generation Sequencing: Whole Genome or Exome capture Sequencing (DNA) Whole or Targeted Transcriptome Sequencing (RNA) Epigenetic profiling

7 Non Small Cell Lung Cancer, Version hh The NCCN NSCLC Guidelines Panel strongly endorses broader molecular profiling with the goal of rare driver for which drugs may already be available, or to appropriately counsel regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of pa@ents with NSCLC. See Emerging Targeted Agents for Pa@ents With Gene@c Altera@ons (NSCL- H).

8 Non Small Cell Lung Cancer, Version

9 Case 1: Newly Diagnosed Metastatic NSCLC 73-year-old Hispanic woman Presents with persistent cough with back pain. She also had shortness of breath and weight loss of 20 Ibs/3 mos mild hemoptysis Never smoker ECOG PS=3 PET/CT scan revealed large volume right pleural effusion with extensive lung and pleural lesions, liver metastases. Diagnosis #1 #2 Brain MRI revealed 2 foci of 2-3 mm enhancements, highly suspicious for metastases (Patient is asymptomatic)

10 Q1. How would you consult the patient and family? 1. Poor prognosis, hospice care 2. Prognosis and treatment options depend on tissue diagnosis (histological assessment) 3. Prognosis and treatment options depend on tumor molecular profiling 4. Prognosis and treatment options depend on host immune system 5. Others?

11 Case 1 Continued: Patient underwent several thoracentesis procedures and at least 3 liters of bloody, malignant pleural effusion were collected. Cytology revealed poorly differentiated adenocarcinoma, favoring lung primary.

12 Q2. How would you order the diagnostic tests? Last week 1. Order core needle biopsy for sufficient tumor specimen for molecular testing 2. Order molecular testing for sensitive EGFR mutations and ALK FISH test only 3. Order a multiplexed molecular test for actionable oncogene targets (including somatic mutations in EGFR and KRAS and FISH test for ALK and ROS1 rearrangements) 4. Order a broader, targeted NGS panel of at least 50 gene panel

13 Q3. How would you order the diagnostic tests? Next Week 1. Order core needle biopsy for sufficient tumor specimen for molecular testing 2. Order molecular testing for sensitive EGFR mutations and ALK FISH test only 3. Order a multiplexed molecular test for actionable oncogene targets (including somatic mutations in EGFR and KRAS and FISH test for ALK and ROS1 rearrangements) 4. Order a broader, targeted NGS panel of at least 50 gene panel

14 Q4. How would you order the diagnostic tests? In the future, if there is no financial limitation! 1. Order core needle biopsy for sufficient tumor specimen for molecular testing 2. Order molecular testing for sensitive EGFR mutations and ALK FISH test only 3. Order a multiplexed molecular test for actionable oncogene targets (including somatic mutations in EGFR and KRAS and FISH test for ALK and ROS1 rearrangements) 4. Order a broader, targeted NGS panel of at least 50 gene panel

15 Case 1 Continued: Tumor genomic profiling by a targeted NSG panel Genomic Assay Targeted NSG Panel Date of Collection 3/4/2015 Tissue Cytology Block EGFR L858R + EGFR amplification + CDKN2A/B loss 0 CCNE1 amplification + MYC amplification + NKX2-1 amplification + TP53 splice site 993+2T>C +

16 Case 1 Continued: PET/CT Scans for monitoring tumor response Erlotinib (4/22/2015) 4/3/2015 6/1/2015 9/2/ Weeks 4 Months

17 Resistance Mechanisms and Strategies to Overcome Resistance to Molecularly Targeted Therapy --An Evolving Story

18 Mechanisms of Resistance to EGFR TKI Adenocarcinoma H&E Synaptophysin SCLC H&E Synaptophysin Sequist L V et al. Sci Transl Med 2011;3:75ra26-75ra26

19 Enabling components for genomics-driven cancer medicine Garraway L A JCO 2013;31:

20 Case 2: tumor progression after 4 years of erlotinib A 50-year-old Caucasian female, never smoker, initially diagnosed with stage IIIA (T2N2) NSCLC with the right lower lobe (RLL) primary in May She received concurrent chemoradiation. 3 months after the treatment, she was found to have metastatic in contralateral lung, mediastinal lymph nodes and pleural effusion. She was enrolled in a clinical trial and started on erlotinib 150 mg/day the treatment in Nov Erlotinib was reduced to 100 mg/day since cycle 1 due to the severe rashes. She achieved radiographic complete remission after one year of treatment. Four years later, surveillance CT scan revealed 2 new liver masses. Fine-needle aspiration (FNA) of one liver lesion confirmed metastatic disease of lung primary but the residual tumor specimen was insufficient for any molecular profiling test.

21 Q5. How would you order the diagnostic tests? 1. Order a molecular test on old tumor specimen obtained in Order liver rebiopsy for sufficient tumor specimen for molecular testing 3. Order biopsy for new bony lesion for molecular testing 4. Proceed with chemotherapy 5. Proceed with local therapy with radiation or chemoembolization 6. Others

22 Case 2 Continued: Patient received carboplatin and pemetrexed for 2 cycles, continue tumor progression in the liver and a new bony metastasis in the right pelvis. Patient was enrolled in clinical trial containing ramucirumab and chemotherapy for 2 cycles, disease progression in the liver although there was response in the bone metastasis. 3/23//2015 5/18/2015 8/5/2015

23 Q6. How would you order a biomarker test now? 1. Order liver rebiopsy for sufficient tumor specimen for a tumor molecular profiling test 2. Order blood liquid biopsy for a tumor molecular profiling test 3. Order PD-1 IHC using old tumor specimen 4. Order PD-1 IHC only on new tumor specimen 5. I would NOT order any biomarker test

24 Tumor molecular profiling by a NGS panel using liver rebiopsy specimen Tumor Specimen Lung in 2009 Liver in Aug 2015 Oncogene Genetic Alterations MAF Percentage /copy number MAF Percentage /copy number ASXL1 E453fs* % 45.0% EGFR E746_A750del 11.0% 78.0% EGFR amplification TP53 S166fs*3 63.0% RICTOR CNV amplification 7 MCL1 CNV amplification 13 NKX2 1 CNV amplification 8 95 CCND1 CNV amplification 27 FGF10 CNV amplification 7 EGFR CNV amplification 21 FGF19 CNV amplification 27 CDKN2A CNV loss 0 CDKN2B CNV loss 0 FGF4 CNV 27

25 Tumor genomic profiling by a NGS panel using cell-free, ciruculating tumor DNA Genomic Assay % cfdna Date of Collection 8/7/2015 Tissue Blood EGFR Exon % EGFR T790M 1.33% KIT K602T 0.14% GATA3 L348I 0.1% Total Tumor Burden (%) 60.58%

26 Q7. What would you recommend to this patient? 1. Order a NSG test from another vendor 2. Order a repeat tissue biopsy from another tumor site for a repeat tumor molecular profiling test 3. Offer patient a third generation EGFR TKI (assuming you have access to the drug) 4. Recommend afatinib and cetuximab off-label 5. Recommend a PD-1 inhibitor 6. Others

27 Courtesy A Bardelli

28 A for biomarker- driven cancer medicine Lung Cancer Patient Lung nodule/metastases Tumor Biopsy (and blood) Comprehensive Tumor Molecular Portrait Diagnostic Prognosis Chemotherapy Targeted therapy Immunotherapy sensitivity sensitivity sensitivity Cancer? Yes/ No Need for treatment? ERCC1 RRM1 Which treatment and when? PD-1/PD-L1 OX40 Other Pathways

29 Take Home Messages We have made tremendous progress in personalizing lung cancer care Progress requires change Culture Change Requirement for more or (Molecular Profiling/Biomarker Assessment) Ungroup NSCLC for individual (Personalized Therapy) Paradigm Change : Change in how we develop new cancer drugs Account for complexity of underlying systems biology Account for inter- and intra- pa@ent heterogeneity Reality: The transi@on from Empiric to Molecularly based & Personalized Therapy is challenging In every challenge there are opportuni@es Hope for CURE $$$

30 QuesAons?