Everything You Need to Know About Molecular Testing and Targeted Therapies in NSCLC: Essential Guidance for Modern Patient-Centered Precision Lung Cancer Care
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Suresh S. Ramalingam, MD, FACP, FASCO, Alexander Drilon, MD, and John Heymach, MD, PhD, prepared useful Practice Aids pertaining to lung cancer for this CME/MOC activity titled "Everything You Need to Know About Molecular Testing and Targeted Therapies in NSCLC: Essential Guidance for Modern Patient-Centered Precision Lung Cancer Care." For the full presentation, complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/2IIiRzP. CME/MOC credit will be available until November 29, 2021.
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Everything You Need to Know About Molecular Testing and Targeted Therapies in NSCLC: Essential Guidance for Modern Patient-Centered Precision Lung Cancer Care
- 1. Shared decision-making (SDM)—a process of two-way communication during which clinicians and patients work together to make treatment and other care-related decisions—has been found to provide many important benefits to patients, clinicians, healthcare systems, and society as a whole Considering patient preferences, goals, and values is of increasing importance in the management of lung cancer because the complexity of the treatment landscape is growing, resulting in more options and the need for more individualized approaches to treatment selection and planning that, in addition to considering the evidence and best practice recommendations, should take into account the needs and preferences of patients with lung cancer and their caregivers High-quality information and resources are essential for supporting shared decision-making in lung cancer! • Transforming survivorship as the world’s leading organization dedicated to saving, extending, and improving the lives of those vulnerable to, at risk of, and diagnosed with lung cancer • Dedicated to providing those facing lung cancer with current and reader-friendly information go2foundation.org Patients communicate values, risk attitudes, and treatment goals Providers share key disease state and treatment-related information Lung Cancer Patient Education and Engagement in Care Decisions: Resource Compendium1-7 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40
- 2. Patient Education and Support Services Patient-focused, accessible, free programs are the foundation of GO2 resources that educate, support, empower, and provide hope to all those living with lung cancer Phone Buddies Peer-to-peer support Lung Cancer Support Group Network Online Support Communities LungMATCH Treatment and trial navigation Educational Materials Patient-/caregiver-friendly handbooks and brochures • Understanding Your Diagnosis • Understanding Non–Small Cell Lung Cancer • Targeted Therapy for Lung Cancer • LungMATCH • Biomarker Testing • Understanding Lung Cancer Clinical Trials • Playing a Critical Role: Lung Cancer Caregiver HelpLine Personalized navigation Lung Cancer Living Room™ “Bringing Hope Home” Lung Cancer Patient Education and Engagement in Care Decisions: Resource Compendium1-7 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40
- 3. Building Community and Making an Impact The annual National Advocacy Summit, awareness raising, and events bring people together to improve lung cancer at all levels Shine A Light Awareness events Ambassador Program Patient Advocacy Summit In Washington, D.C. Lung Cancer Registry National Event Series/Grassroots Events Walks and runs www.lungcancerregistry.org • Patient and caregiver reported data • ~2,000 participants • Diagnosis, treatment, and quality of life data • Quarterly, IRB-approved longitudinal surveys • Partnership with the American Lung Association and International Association for the Study of Lung Cancer (IASLC) National Ambassador Council Lung Cancer Patient Education and Engagement in Care Decisions: Resource Compendium1-7 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 1. National Quality Partners Playbook Playbook™: Shared Decision Making in Healthcare. 2018 National Quality Forum. 2. Preference Sensitive Care From the Patient Protection and Affordable Care Act (2010). 3. Center for the Evaluative Clinical Sciences. Preference-Sensitive Care. Lebanon, NH: Dartmouth Atlas Project; 2007. 4. Alston C et al. IOM 2014. https://nam.edu/wp-content/uploads/2015/06/SDMforBestCare2.pdf. 5. Sepucha KR et al. Med Decis Making. 2010;30(suppl 6):775-845. 6. Frosch DL et al. Health Aff (Millwood). 2012;3:1030-1038. 7. Cramm JM, Nieboer AP. BMJ Open. 2014;4:e005914.
- 4. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 a Approved by the FDA. b NCCN recommendation. c FDA-designated Breakthrough Therapy status. d FDA-designated Fast Track status. NTRK1 Fusions Larotrectiniba Entrectiniba Selitrectinib Repotrectinib ALK Rearrangements Crizotinib,a Ceritinib,a Alectinib,a Brigatinib,a Lorlatinib,a Ensartinib ROS1 Rearrangements Crizotiniba Entrectiniba Ceritinibb Lorlatinibb Repotrectinibd BRAF V600E Mutations Dabrafenib + Trametiniba Encorafenib + Binimetinib KRAS G12C Mutations AMG-510d MRTX849 LY3499446 RET Fusions Selpercatiniba Pralsetiniba Cabozantinibb Vandetanibb EGFR Exon 20 Mutations Osimertinib Mobocertinib (TAK-788)c Poziotinib Amivantamabc EGFR Mutations Osimertinib,a Afatinib,a Dacomitinib,a Erlotinib,a Gefitiniba Erlotinib + Ramucirumaba Erlotinib + Bevacizumabb Gefitinib + Chemotherapy Osimertinib + Chemotherapy MET Exon 14 Skipping Mutations Capmatiniba Crizotinibb Savolitinib Tepotinibc HER2 Mutations T-DM1b [Fam-] Trastuzumab Deruxtecanc Poziotinib MAP2K1 AKT1 PIK3CA FGFR3 FGFR2 FGFR1 DDR2 NRAS Clinically Important Genomic Alterations in NSCLC
- 5. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 ALK rearrangement Brigatinib Vysis ALK Break Apart FISH Probe Kit 90 mg PO QD for 7 d, then 180 mg PO QD (with/without food) 1L metastatic ALK+ NSCLC Ceritinib FoundationOne CDx; VENTANA ALK (D5F3) CDx Assay 450 mg PO QD (with food)1L metastatic ALK+ NSCLC Crizotinib FoundationOne CDx; VENTANA ALK (D5F3) CDx Assay; Vysis ALK Break Apart FISH Probe Kit 250 mg PO QD1L metastatic ALK+ NSCLC Alectinib FoundationOne CDx; VENTANA ALK (D5F3) CDx Assay 600 mg PO BID with food1L (NCCN preferred) metastatic ALK+ NSCLC Lorlatinib N/A 100 mg PO QD 2L metastatic ALK+ NSCLC after PD on alectinib or ceritinib as first ALK inhibitor; 3L metastatic ALK+ NSCLC after PD on crizotinib and ≥1 other ALK inhibitor Molecular Alteration Drug Approved Companion Diagnostic(s) Recommended DoseApproved Indication(s) FDA-Approved Targeted Therapies for NSCLC With Genomic Alterations BRAF V600E mutation Dabrafenib + trametinib FoundationOne CDx; Oncomine Dx Target Test Dabrafenib: 150 mg PO BID (without food); trametinib: 2 mg QD 1L metastatic BRAF V600E mutation–positive NSCLC
- 6. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 Molecular Alteration Drug Approved Companion Diagnostic(s) Recommended DoseApproved Indication(s) EGFR mutation Dacomitinib Therascreen EGFR RGQ PCR Kit 45 mg PO QD (with/without food) 1L metastatic EGFR exon 19 deletion or exon 21 L858R mutation–positive NSCLC Erlotinib cobas EGFR Mutation Test v2; FoundationOne CDx 150 mg PO QD (on empty stomach) Any line metastatic EGFR exon 19 deletion or exon 21 L858R mutation–positive NSCLC Erlotinib + ramucirumab cobas EGFR Mutation Test v2; FoundationOne CDx Erlotinib: 150 mg PO QD; ramucirumab: 10 mg/kg IV Q2W 1L metastatic EGFR exon 19 deletion or exon 21 L858R mutation–positive NSCLC Afatinib Therascreen EGFR RGQ PCR Kit; FoundationOne CDx 40 mg PO QD 1L metastatic NSCLC, EGFR exon 19 deletion, exon 21 L858R mutations, or other nonresistant EGFR mutations (S768I, L861Q, and/or G719X); 2L metastatic squamous NSCLC after PD on platinum-based chemo Gefitinib Therascreen EGFR RGQ PCR Kit; cobas EGFR Mutation Test v2; FoundationOne CDx 250 mg PO QD (with/without food) 1L metastatic EGFR exon 19 deletion or exon 21 L858R mutation–positive NSCLC Osimertinib FoundationOne CDx; cobas EGFR Mutation Test v2 80 mg PO QD (with/without food) 1L (NCCN preferred) unresectable or metastatic EGFR exon 19 deletion or exon 21 L585R mutation–positive NSCLC; 2L metastatic EGFR T790M mutation–positive NSCLC with PD on or after an EGFR TKI
- 7. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 Molecular Alteration Drug Approved Companion Diagnostic(s) Recommended DoseApproved Indication(s) NTRK1/2/3 fusion RET fusion MET exon 14 skipping mutation Capmatinib FoundationOne CDx 400 mg PO BID (with/without food) 1L metastatic MET exon 14 skipping mutation–positive NSCLC Selpercatinib N/A <50 kg: 120 mg PO BID; ≥50 kg: 160 mg PO BID 1L metastatic RET fusion–positive NSCLC Pralsetinib Oncomine Dx Target Test 400 mg PO QD1L metastatic RET fusion–positive NSCLC Entrectinib N/A 600 mg PO QD All lines metastatic NTRK fusion–positive tumors that have no satisfactory alternative treatments or show PD following treatment Larotrectinib N/A 600 mg PO QD All lines metastatic NTRK fusion–positive tumors that have no satisfactory alternative treatments or show PD following treatment ROS1 rearrangement Crizotinib Oncomine Dx Target Test 250 mg PO BID 1L metastatic ROS1-positive NSCLC Entrectinib N/A 600 mg PO QD1L metastatic ROS1-positive NSCLC
- 8. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 Alectinib Adjuvant (3) N/ANCT03456076 Lorlatinib 1L (3) N/ANCT03052608 Ensartinib 1L (3) N/AeXalt3/NCT02767804 Encorafenib + binimetinib 1L or 2L (2) N/APHAROS/NCT03915951 Osimertinib Adjuvant (3) FDA prioity reviewADAURA/NCT02511106 Gefitinib + chemo 1L (3) N/ANEJ009/UMIN000006340 Erlotinib + bevacizumab 1L (3) NCCN recommendationNEJ1026/UMIN000017069 Osimertinib + ramucirumab 1L (2) N/ATORG1833/CTI-184146 Osimertinib + chemo 1L (3)FLAURA2/NCT04035486 N/A ALK rearrangement BRAF V600E mutation EGFR mutation Investigational Targeted Therapies for NSCLC With Genomic Alterations Target Category Drug Treatment Stage (Phase) FDA or NCCN RecognitionStudy ID/Trial Identifier
- 9. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 Target Category Drug Treatment Stage (Phase) FDA or NCCN RecognitionStudy ID/Trial Identifier EGFR exon 20 mutation Amivantamab 2L (2) FDA breakthroughCHRYSALIS/NCT02609776 Poziotinib 2L (2) N/ANCT03066206 Mobocertinib 1L (3) FDA breakthroughTAK-788-3001/NCT04129502 Osimertinib 2L (2) N/AEA5162/NCT03191149 KRAS G12C mutation AMG 510 2L+ (3) FDA fast trackCodeBreak 200/NCT04303780 MRTX849 1L+ (2) N/AKRYSTAL-1/NCT03785249 HER2 mutation Ado-trastuzumab emtansine 2L+ (2) NCCN recommendationNCT02289833 [Fam-] trastuzumab deruxtecan 2L+ (2) FDA breakthrough DESTINY-Lung01/ NCT03505710 Poziotinib 1L+ (2)NCT03066206 N/A
- 10. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 Target Category Drug Treatment Stage (Phase) FDA or NCCN RecognitionStudy ID/Trial Identifier MET amplification Cabozantinib 1L+ (2) N/ANCT01639508 Crizotinib Any line (1) NCCN recommendationPROFILE 1001/NCT00585195 Tepotinib 1L+ (2) N/AVISION/NCT02864992 Capmatinib 1L or 2L (2) N/AGEOMETRY/NCT02414139 MET exon 14 skipping mutation Crizotinib Any line (1) NCCN recommendationPROFILE 1001/NCT00585195 Tepotinib 1L+ (2) FDA breakthroughVISION/NCT02864992 Savolitinib 2L+ (2) N/ANCT02897479 NTRK fusion Repotrectinib 1L or 2L (2) N/ANCT03093116 Selitrectinib 1L+ (2) N/ANCT03215511
- 11. Genomic Alterations in NSCLC and Approved or Emerging Matched Targeted Therapies1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Target Category Drug Treatment Stage (Phase) FDA or NCCN RecognitionStudy ID/Trial Identifier RET rearrangement Cabozantinib 1L+ (2) NCCN recommendationNCT01639508 Vandetanib 2L+ (2) NCCN recommendationNCT01823068 ROS1 rearrangement Ceritinib 1L+ (2) NCCN recommendationNCT01964157 Lorlatinib 2L+ (2) NCCN recommendationNCT01970865 Repotrectinib 1L+ (2)TRIDENT-1/NCT03093116 FDA fast track
- 12. Why Test Lung Cancer Patients for Genomic Alterations? Which Molecular Targets Are Relevant for Testing in NSCLC? • Genomic alterations are common in nonsquamous NSCLC (approximately 50%) • Targeted therapies produce better treatment outcomes (eg, higher response rates, improved quality of life) compared with chemotherapy as treatment of NSCLC with genomic alterations • Immunotherapy has low efficacy and a high risk of serious adverse events in patients with NSCLC with molecular driver alterations Genotypes with emerging targeted therapies EGFR exon 20 mutations HER2 mutations KRAS G12C mutations MET amplifications Many other promising targets with matched therapies are undergoing investigation in trials Genotypes with approved targeted therapies EGFR mutations ALK rearrangements ROS1 rearrangements BRAF V600E mutations NTRK fusions MET exon 14 skipping mutations RET fusions Molecular alterations to test for in patients with newly diagnosed stage IV NSCLC Molecular Testing Guidelines for NSCLC: Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40
- 13. Molecular Testing Guidelines for NSCLC: Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 Which Molecular Testing Techniques Should Be Used for Detection of Different Molecular Alterations in NSCLC?1 • NCCN guidelines recommend plasma-based testing for all patients with advanced-stage, treatment-naïve lung cancer for whom tissue sampling may be infeasible or insufficient • Recent studies found that simultaneously adding plasma ctDNA analysis to tissue testing enhanced the chances of detecting a relevant actionable mutation • Based on these findings, it is reasonable to consider plasma-based testing for every patient with advanced-stage, treatment-naïve lung cancer who has a tissue biopsy • A new tissue biopsy and/or ctDNA plasma test also needs to occur when patients with genotype-directed NSCLC develop resistance/disease progression while on targeted TKI therapy 75% more actionable mutations found with tissue + plasma vs tissue alone When Should Liquid Biopsies Be Considered for Use? ++: Highest sensitivity +: Lower sensitivity (higher chance of false negative) –: Not useful Tissue PCR sequencing Tissue allele–specific PCR sequencing Tissue FISH Tissue IHC Tissue NGS ctDNA PCR ctDNA NGS Tissue RNA EGFR (Sensitizing and T790M) + ++ – – ++ + + + HER2 Mutation + ++ – – ++ + + + MET Exon 14 Mutation – ++ – – ++ + + ++ BRAF Mutation + ++ – – ++ + + + KRAS Mutation + ++ – – ++ + + + ALK Rearrangement – – ++ ++ + + + ++ ROS1 Rearrangement – – ++ – + – + ++ MET Amplification – – ++ – + – + + RET Rearrangement – – ++ – + + + ++ PD-L1 Protein Expression – – – ++ – – – – NTRK Fusion – – ++ + + – + ++
- 14. Real-World, Patient-Reported Biomarker Data2,a Why should patients be educated about the importance of molecular testing and informed about their results? Shortcomings exist in current molecular testing rates as well as patient awareness about testing and their testing results Molecular Testing/Biomarker Testing 2018, % (n) 2019, % (n) 2020 (Q1-Q3), % (n) I don't know if the cancer was tested 27.21 (151) 21.22 (222) 21.75 (122) The cancer was not tested 12.25 (68) 10.13 (106) 10.16 (57) The cancer was tested and I know the results 48.11 (267) 56.12 (587) 58.65 (329) The cancer was tested and I don't know the results 12.43 (69) 12.52 (131) 9.45 (53) Total 100 (555) 100 (1,046) 100 (561) Molecular Testing Guidelines for NSCLC: Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/VVS40 a Patient self-reported data obtained from GO2 Foundation for Lung Cancer's 1-800 help line. Population comprised mostly of US-based patients (approx. 95%), and includes those being treated at community cancer centers and academic centers. 1. https://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer. 2. Provided courtesy of GO2 Foundation for Lung Cancer.