Therapies for EGFR-Mutated NSCLC 1 Current Approvals and Indications Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40 First-Generation Second-Generation Reversible EGFR TKIs Irreversible EGFR TKIs Getinib Erlotinib Afatinib Dacomitinib • 1L for EGFR exon 19 • 1L for EGFR exon 19 • 1L for EGFR exon 19 • 1L for EGFR exon 19 deletions or L858R, S768I, deletions or L858R deletions or L858R deletions or L858R L861Q, and/or G719X mutations mutations mutations mutations Metastatic Third-Generation EGFR TKI + VEGFR2 Irreversible EGFR TKI Antagonist Osimertinib Erlotinib + Ramucirumab • 1L for EGFR exon 19 deletions or L858R mutations • Treatment of T790M-positive NSCLC with progression • 1L for EGFR exon 19 deletions or L858R mutations on or after EGFR TKI therapy Early Stage Third-Generation Irreversible EGFR TKI • Adjuvant therapy after tumor resection in patients with stage IB-IIIA NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations Osimertinib 1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Molecular Testing Guidelines for NSCLC Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40 Why Test Lung Cancer Patients for Genomic Alterations? • 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 ecacy and a high risk of serious adverse events in patients with NSCLC with molecular driver alterations Which Molecular Targets Are Relevant for Testing in NSCLC? Molecular alterations to test for in patients with newly diagnosed stage IV NSCLC Genotypes with approved Genotypes with emerging targeted therapies targeted therapies q EGFR mutations q EGFR exon 20 mutations q ALK rearrangements q HER2 mutations q ROS1 rearrangements q KRAS G12C mutations q BRAF V600E mutations q MET amplifications q NTRK fusions q Many other promising targets with q MET exon 14 skipping mutations matched therapies are undergoing q RET fusions investigation in trials Molecular alterations to test for in patients with resectable stage IB-IIIA NSCLC • EGFR mutations (exon 19 deletions or exon 21 L858R mutations) Which Molecular Testing Techniques Should Be Used for Detection of Dierent Molecular Alterations in NSCLC?1 EGFR MET HER2 BRAF KRAS ALK ROS1 MET RET PD-L1 Protein NTRK (Sensitizing Exon 14 Mutation Mutation Mutation Rearrangement Rearrangement Amplication Rearrangement Expression Fusion and T790M) Mutation Tissue PCR + + – + + – – – – – – sequencing Tissue allele–specic ++ ++ ++ ++ ++ – – – – – – PCR sequencing Tissue FISH – – – – – ++ ++ ++ ++ – ++ Tissue IHC – – – – – ++ – – – ++ + Tissue NGS ++ ++ ++ ++ ++ + + + + – + ctDNA PCR + + + + + + – – + – – ctDNA NGS + + + + + + + + + – + Tissue RNA + + ++ + + ++ ++ + ++ – ++ ++: Highest sensitivity +: Lower sensitivity (higher chance of false negative) –: Not useful The specic genes covered vary by assay; therefore, it is important to know which genes/alterations are covered by each assay Molecular Testing Guidelines for NSCLC Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40 When Should Liquid Biopsies Be Considered for Use? • 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 75% • Recent studies found that simultaneously adding plasma ctDNA analysis to tissue testing more actionable enhanced the chances of detecting a relevant actionable mutation mutations found • Based on these findings, it is reasonable to consider plasma-based testing for every patient with with tissue + advanced-stage, treatment-naïve lung cancer who has a tissue biopsy plasma vs • A new tissue biopsy and/or ctDNA plasma test also needs to occur when patients with tissue alone genotype-directed NSCLC develop resistance/disease progression while on targeted TKI therapy cfDNA Use liquid biopsy when • Biopsy is insufficient • Biopsy is not feasible • cfDNA is a more suitable sample than biopsy Timing considerations Plasma Body Fluids Benefits ü Minimally invasive, highly accessible ü Multiple sampling easy: enables real-time monitoring ü Systemic approach: may effectively capture tumor heterogeneity Staging and Therapy Screening Diagnosis Monitoring prognosis selection Molecular Testing Guidelines for NSCLC Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40 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 Real-World, Patient-Reported Biomarker Data2,a 2018, % 2019, % 2020 (Q1-Q3), % Molecular Testing/Biomarker Testing (n) (n) (n) 27.21 21.22 21.75 I don't know if the cancer was tested (151) (222) (122) 12.25 10.13 10.16 The cancer was not tested (68) (106) (57) 48.11 56.12 58.65 The cancer was tested and I know the results (267) (587) (329) 12.43 12.52 9.45 The cancer was tested and I don't know the results (69) (131) (53) 100 21.22 100 Total (555) (1,046) (561) 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. Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC New Role for Adjuvant EGFR-Targeted Therapy1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40 Localized/early stage Regional/locally advanced Stage IB Stage II Stage IIIA • About 30% of patients with NSCLC present with resectable disease at diagnosis1-3 • Surgery with curative intent is the primary treatment for these patients4 • Adjuvant cisplatin-based chemotherapy is recommended for patients with resectable stage II-IIIA NSCLC and select patients with stage IB disease5 • Adjuvant impact depends on stage, and there is much room for improvement6 • Rates of disease recurrence following surgery remain high across disease stages, regardless of postoperative chemotherapy use7 On December 18, 2020, the FDA approved osimertinib NSCLC 5-Year Overall Survival New for adjuvant therapy after tumor resection in patients with NSCLC whose tumors have EGFR exon 19 deletions Stage I (IB) Stage II Stage III Approval or exon 21 L858R mutations, as detected by an CALGB 34 57 9 Death (%) with/without chemotherapy Survival without chemotherapy FDA-approved test JBR.10 30 7 63 32 45 23 Survival due to chemotherapy Death due to chemotherapy ALPI 36 60 4 53 32 15 76 19 5 IALT 33 65 2 53 43 4 55 30 15 ANITA 36 4 60 43 39 18 51 26 23 LACE 33 64 3 51 39 10 61 26 13 Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC New Role for Adjuvant EGFR-Targeted Therapy1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40 • EGFR TKIs are standard of care for patients with EGFRmut advanced NSCLC • Previous studies have suggested there may be a role for EGFR TKIs in the resected setting, but results have been inconclusive8,9 • ADAURA: Based on ecacy and safety data, and the new FDA approval, adjuvant osimertinib represents a big opportunity to improve outcomes in more patients with early-stage NSCLC10 ADAURA: Phase 3 Double-Blind Studya Patients with completely resected stageb IB, II, IIIA NSCLC, with or without adjuvant chemoc Patients Planned treatment duration: 3 y • ≥18 y (Japan/Taiwan, ≥20 y) Osimertinib Treatment continues until • WHO PS 0/1 Stratied by 80 mg, once daily • Disease recurrence • Conrmed primary nonsquamous NSCLC • Treatment completed d • Stage (IB vs II vs IIIA) • Ex19del/L858R • EGFRmut (ex19del • Discontinuation criteria met 1:1 randomization • Brain imaging, if not completed vs L858R) Follow-up preoperatively • Race (Asian • Until recurrence: wk 12 and 24, • Complete resection with negative marginse vs non-Asian) Placebo then every 24 wk to 5 y, then yearly • Maximum interval between surgery and once daily • After recurrence: every 24 wk for randomization: 10 wk without adjuvant 5 y, then yearly chemo; 26 wk with adjuvant chemo • Primary endpoints: DFS by investigator assessment in stage II/IIIA patients; designed for superiority under the assumed DFS HR of 0.70 • Secondary endpoints: DFS in the overall population;f DFS at 2, 3, 4, and 5 years; OS; safety; QoL DFS According to Investigator Assessment10 Stage I to IIA Disease Stage IB to IIIA Disease Osimertinib Osimertinib 90% DFS 89% DFS Placebo Placebo 44% DFS 52% DFS • In the overall population, 89% of patients treated with osimertinib (95% CI, 85-92) • At 24 mo, 90% of patients treated with osimertinib (95% CI, 84-93) and 44% and 52% of patients treated with placebo (95% CI, 46-58) were alive and disease free of patients treated with placebo (95% CI, 37-51) were alive and disease free at 24 mo • HR