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This document discusses recent updates in lung cancer. It begins by noting that lung cancer is the leading cause of cancer death in the US and is often diagnosed at an advanced stage. Screening with low-dose CT scans can detect lung cancer earlier and has been shown to decrease lung cancer mortality by 20% compared to chest x-rays. The National Lung Screening Trial established low-dose CT screening as an effective screening method for those at high risk. Biomarker testing is important to identify driver mutations and guide targeted therapy options, though barriers like tissue availability and turnaround time exist. Osimertinib has demonstrated superior progression-free survival compared to earlier EGFR TKIs for patients with EGFR-mut

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RECENT UPDATES IN LUING CANCER DR.R.RAJKUMAR D.M CONSULTANT MEDICAL ONCOLOGIST VELAMMAL MEDICAL COLLEGE HOSPITALS
LUNG CANCER FACTS • Lung Cancer is the #1 cancer killer in the US Cancer statistics, 2018, Volume: 68
LUNG CANCER FACTS • Most patients diagnosed with advanced disease Cancer statistics, 2018, Volume: 68 Stage at diagnosis
LUNG CANCER FACTS • Lung cancer is curable when diagnosed early Journal of Thoracic Oncology 2017 12: 1109-1121
LUNG CANCER SCREENING • What is screening? • A test done to detect a cancer before symptoms develop • Symptoms of lung cancer typically do not appear until the disease is advanced • Why hasn’t lung cancer screening been routine? • Until recently, there hasn’t been an effective test • Lung cancer screening with CXR showed no benefit • No change in lung cancer deaths
NATIONAL LUNG SCREENING TRIAL • Large clinical trial 2002-2007 • Over 50,000 patients at risk for lung cancer • 55-74 years old • Current or former smokers • Randomized to annual low-dose CT scan to CXR New England Journal of Medicine August 4th, 2011
NATIONAL LUNG SCREENING TRIAL • People who got low-dose CT scans had a 20% decreased risk of dying from lung cancer • 320 people need to be screened to prevent 1 lung cancer death • 1339 for breast cancer • More cancers detected at an early stage • First time that lung cancer screening has been shown to decrease lung cancer deaths! • Results announced in 2010 New England Journal of Medicine August 4th, 2011
WHO SHOULD GET SCREENED? • Age 55-80 • Current or former smoker • >30 pack year smoking history • Packs per day X years smoked • 1 pack per day for 30 years or 2 packs per day for 15 years • No symptoms of lung cancer • New or changing cough • Coughing up blood • New or increasing shortness of breath
NSCLC as one disease Squamous 34% Other 11% Adenoca 55% Non-Small-Cell Lung Cancer: Not One Disease, but Many! Then Histology-Based Subtyping Now Adenocarcinoma KRAS 25% ALK 7% EGFR Sensitizing 17% No Known Oncogenic Driver Detected 31% EGFR Other 4% MET 3% > 1 Mutation 3% HER2 2% ROS1 2% BRAF 2% RET 2% NTRK < 1% PIK3CA 1% MEK1 < 1%
EVOLUTION OF THERAPY IN LUNG CANCER • Heterogeneous disease Traditional View Present View NSCLC SCLC Histologic Breakdown (eg, SQ, NSQ, large cell, adenocarcinoma) Molecular Pathology (eg, EGFR, ALK, ROS1) PD-L1 Expression Level Lung Cancer ≥50% ≥1%-49% <1%
Fig. 1 Lung Cancer 2021 154161-175DOI: (10.1016/j.lungcan.2021.02.026)
Fig. 3 Lung Cancer 2021 154161-175DOI: (10.1016/j.lungcan.2021.02.026) Copyright © 2021 The Authors and
BIOPSY: ESTABLISH DIAGNOSIS, DETERMINE HISTOLOGIC SUBTYPE, BIOMARKER TESTING • Histologic subtyping: squamous or nonsquamous?[1] • For biomarker testing: • Primary tumors and metastatic lesions equally suitable[2] • Bone biopsy suboptimal due to decalcification and degradation of DNA[2] • Liquid biopsies (cell-free DNA in plasma) are another option[3] • Testing for PD-L1 expression indicated in all NSCLC[4] • Testing for EGFR, ALK, ROS1, BRAF V600E, NTRK, RET, and METex14 indicated in all nonsquamous NSCLC[4] • Broad NGS testing encouraged to detect a wider range of mutations using least amount of tissue[4,5] • For squamous NSCLC, consider testing in young, never or light smokers, or if biopsy specimen is small or of mixed histology[2] • Completion of testing within 10-14 working days of biopsy recommended[4,6] • TAT for PD-L1 much shorter than for NGS • Wait for results of NGS results before acting on PD-L1 testing results!
COMPARISON OF ALTERNATIVE MOLECULAR TESTING APPROACHES Single Gene Testing Multigene Testing (eg, by NGS) Advantages  Potentially routine in practice  Potential for local implementation, rapid turnaround  Higher sensitivity with PCR platforms  Minimizes use of tumor tissue  Facilitates testing of multiple biomarkers, including emerging biomarkers for clinical trial enrollment  Just need to know to test vs which biomarkers to test for  Generally less costly than sequential testing Limitations  Tumor tissue samples often inadequate for multiple necessary tests  May lead to repeat biopsy  Multiple platforms available using different methodology that affect types of alterations detected  Analysis of complex biomarker reports  Preauthorization requirements  May not be easily accessible in community practice .
LIQUID BIOPSY • What is liquid biopsy? • Blood sample containing cell-free DNA from multiple sources, including DNA shed from tumor • When do we use liquid biopsy? • Molecular testing is needed but amount of available biopsy tissue is inadequate or unknown, or tissue biopsy not possible • Resistance to TKIs • Advantages • Minimally invasive • May overcome tumor heterogenicity • Limitations • Sensitivity: 70%-80%; specificity: near 100% • Negative result is noninformative
APRIL 2020 TREATMENT PARADIGM FOR MOLECULAR BIOMARKER–POSITIVE ADVANCED NSCLC ALK positive Progression EGFR mutation positive Advanced NSCLC (molecular biomarker positive) ROS1 positive Crizotinib, ceritinib, or entrectinib Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker Osimertinib EGFR T790M mutation negative or previous osimertinib Alectinib, brigatinib, ceritinib, or lorlatinib dependent on previous therapy Alectinib (preferred), brigatinib, ceritinib, or crizotinib Osimertinib (preferred) erlotinib, afatinib, gefitinib, or dacomitinib* EGFR T790M mutation positive BRAF V600E positive Dabrafenib/ trametinib† First line Second line and beyond *Afatinib, dacomitinib, erlotinib, gefitinib, osimertinib approved for EGFR exon19del, exon 21 L858R; afatinib for EGFR G719X, S768I, L861Q. †Or as second line after CT. Entrectinib or larotrectinib NTRK positive
WHY DOES UPFRONT TESTING MATTER?  Only 48% of patients with advanced NSCLC and a driver mutation received NCCN- recommended targeted therapy1 ‒ Alterations included EGFR, ALK, ROS1, BRAF, MET, RET, ERBB2  Patients with driver mutations who received targeted therapy had an improved OS (18.6 vs 11.4 mo; P <.001)1  Always give the best treatment upfront ‒ ~30% of patients will NOT go on to receive second-line treatment2 . Patients with NSCLC1 (N = 1260) First-line Therapy Received by Driver Mutation2 % of First-line Therapies Other Therapy 52% NCCN- Recommended Targeted Therapy 48% 100 80 60 40 20 0 Other Anti–PD-1 EGFR or ALK TKI Nonplatinum regimen Platinum regimen Gene ALK (n = 98) EGFR (n = 535) ROS1 (n = 27) Other (n = 2092)
BARRIERS TO UNIVERSAL BIOMARKER TESTING  Not enough tissue in small biopsies—up to 25% lack sufficient tumor  TAT not fast enough— recommended <14 calendar/ 10 working days from biopsy  Poor communication—lack of reflex testing, differing sites for biopsy and treatment  Who pays? Oncology Team Members Biomarker Testing Tissue Acquisition Turnaround Time Payment/ Reimbursement Communication
EGFR MUTATIONAL EPIDEMIOLOGY  Found in ~ 20% to 30% of patients with NSCLC globally  More common in never- smokers, adenocarcinomas, females, Asians  Predominantly located in EGFR exons 18-21  The specific EGFR mutation identified is important: sensitive mutations, primary resistance mutations, and de novo and acquired resistance mutations EGFR Kinase Domain Mutations Ligand Binding Transmembrane Tyrosine Kinase Autophosphorylation N N K754R S768I* L861Q* A871G L833V/ H835L/ L838V E884K L858R ~ 41% Ins761 (EAFQ)/ Ins770 (ASV)/ Ins771 (G)/ Ins774 (NPH) ~ 3% G719S* ~ 5% E709A/ E709G C C Y891 Y920 Y992 Y1045 Y1068 Y1086 Y1148 Y1173 T790M ~ 3% EXON 18 19 20 21 22 23 24 del 747-752 and others ~ 48% *Noncanonical EGFR mutations.
EGFR MUTATIONS IN NSCLC  Exon 19 deletions and L858R mutation in exon 21 ‒ ~80% of all EGFR mutations ‒ Clinically relevant as patients respond to EGFR tyrosine kinase inhibitors  Uncommon or atypical EGFR mutations ‒ G719X, L861Q, S7681  EGFR exon 20 insertion mutations ‒ Inherently resistant to approved TKI ‒ Platinum-based chemotherapy remains the recommended first-line therapy Exon 18 ~4% Other exons ~3% Exon 21 ~41% Exon 19 ~45% Exon 20 ~6% Exon 19 mutations - Del 19 (44.8%) - Ins 19 (0.6%) Exon 21 mutations - L858R (39.8%) - L861Q (0.9%) Frequency of EGFR mutations
Parameter Erlotinib Gefitinib Afatinib Dacomitinib Osimertinib Generation First First Second Second Third EGFR mutations approved for in first-line setting Ex19del, Ex21 L858R Ex19del, Ex21 L858R Ex18 G719X,* Ex19del, Ex20 S768I,* Ex21 L858R, Ex21 L861Q* Ex19del, Ex21 L858R Ex19del, Ex21 L858R† EGFR binding Reversible Reversible Irreversible Irreversible Irreversible Half life, hr 36 48 37 59-85 48 Food effect (take on empty stomach) Increase F from ~60% to ~100% No change Decrease AUC by 39% No change No change CNS penetration, AUC ratio 0.03X CSF/plasma 0.01X CSF/serum 0.02X CSF/plasma CNS activity reported 2X brain/plasma EGFR TKIs: Properties *Uncommon nonresistant EGFR mutations. †Also approved for resistant mutation T790M in second-line setting and a preferred option for EGFR G719X, S768I, L861Q per NCCN guidelines.
FLAURA: PFS BY CNS METASTASES AT BASELINE  CNS progression occurred in 17 patients (6%) with osimertinib vs 42 (15%) with 1st-generation EGFR TKI Median PFS, Mo (95% CI) Osimertinib (n = 53) 15.2 (12.1-21.4) 1st-Generation EGFR TKI (n = 63) 9.6 (7.0-12.4) HR: 0.47 (95% CI: 0.30-0.74; P <.001) Soria. NEJM. 2018;378:113. Patients at Risk, n Osimertinib 1st-Generation EGFR TKI 53 63 51 57 40 40 37 33 22 13 9 6 4 2 0 0 32 24 1 1 Mo Patients at Risk, n Osimertinib 1st-Generation EGFR TKI 226 214 211 182 193 157 173 119 117 65 62 31 22 8 0 0 146 83 3 1 Mo Median PFS, Mo (95% CI) Osimertinib (n = 226) 19.1 (15.2-23.5) 1st-Generation EGFR TKI (n = 214) 10.9 (9.6-12.3) HR: 0.46 (95% CI: 0.36-0.59; P <.001) Probability of PFS Probability of PFS With CNS Metastases at BL (n = 116) Without CNS Metastases at BL (n = 440) 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 Slide credit: clinicaloptions.com
SUMMARY OF FIRST-LINE TREATMENT APPROACHES FOR PATIENTS WITH EGFR MUTATION–POSITIVE NSCLC First-line: Treatment Arms PFS, Mo (HR) AE Grade ≥3, % Erlotinib + bevacizumab vs erlotinib2 16.0 vs 9.7 (0.54) 91 vs 53 Erlotinib + ramucirumab vs erlotinib + placebo3 19.4 vs 12.3 (0.59) 72 vs 54 Erlotinib + bevacizumab vs erlotinib4 16.9 vs 13.3 (0.61) 88 vs 46 Gefitinib + carboplatin/ pemetrexed vs gefitinib5 20.9 vs 11.2 (0.49) NR vs NR Gefitinib + carboplatin/ pemetrexed vs gefitinib6 16.0 vs 8.0 (0.51) 75 vs 49.4 Afatinib vs gefitinib7 11.0 vs 10.9 (0.73) 57 vs 52 Dacomitinib vs gefitinib8 14.7 vs 9.2 (0.59) 63 vs 41 Osimertinib vs gefitinib or erlotinib9 18.9 vs 10.2 (0.46) 34 vs 45 First-line Treatment Approach Erlotinib + antiangiogenics Gefitinib + carboplatin/pemetrexed 2nd-gen EGFR inhibitors Osimertinib Time TOXICITY
ATYPICAL OR UNCOMMON EGFR MUTATIONS 3 most common point mutations: G719X, S768I, L861Q (approved drug: afatinib) Exon 20 insertions: ~9% of EGFR mutations 10%-15% of EGFR-mutant NSCLC, diverse alterations, and can occur in all exons Patients with EGFR-mutant NSCLC Ex20ins 9.1% Complex atypical 9.1% Atypical 12.6% Ex19del 32.7% L858R 23.0% Classical +T790M 11.1% N = 11619 Classical mutations (67%) Atypical mutations (31%) Classical + T790m + atypical (2%) Classical + T790M + atypical 2.2% T790M 0.3%
TREATMENT OPTIONS FOR PATIENTS WITH EGFR EXON 20 INSERTIONS
REAL-WORLD OUTCOMES IN PATIENTS WITH EGFR EXON 20 INSERTION+ ADVANCED NSCLC  Retrospective comparative analysis of real-world outcomes in patients with EGFR ex20ins+ advanced NSCLC (n = 181) vs those with common EGFR mutations (L858R or ex19del; n = 2833) ‒ Flatiron Health Database (January 2011 to May 2020)  75% increased risk of death with EGFR ex20ins vs common EGFR mutations (primary endpoint) ‒ 5-yr OS: 8% vs 19%  Secondary endpoints: ‒ 93% increased risk of progression or death ‒ 60% increased risk of shorter time to next therapy Prognostic Value of EGFR Ex20ins vs EGFR L858R or Ex19del: Real-World OS (N = 3014) Patients at Risk, n Common EGFR EGFR ex20ins 77% 53% 36% 25% 19% 57% 33% 23% 13% 8% 0 6 12 18 24 30 36 42 48 54 60 2833 181 2245 120 1728 77 1313 53 943 30 675 22 494 16 354 11 262 6 198 5 139 3 0 25 50 75 100 Mo Patients (%) Common EGFR Mut EGFR Ex20ins 25.5 16.2 Median rwOS, mo Adjusted HR: 1.75 (95% CI: 1.5-2.1; P <.0001)
RESISTANCE MORE CHALLENGING WITH NEWER EGFR TKIS *Overlap of reported resistance mechanism may occur. †n = 2 with de novo T790M mutations at BL; 1 acquired C797S at progression. Secondary EGFR mutations†: C797X: 7%; L718Q+C797S: 1%; L718Q + ex20ins: 1%; S768I: 1% HER2 amplification: 2% HER2 mutation: 1% MET amplification: 15% mTOR AKT p53 BIM BCL2 PIK3CA ERK BRAF mutations (V600E): 3% SPTBN1 ALK SPTBN1-ALK: 1% Survival Apoptosis Proliferation PIK3CA mutations: 7% Candidate Acquired Resistance Mechanisms With Osimertinib*3 MEK RAS RAF KRAS mutations (G12D/C, A146T): 3% Cell cycle gene alterations CCND amp: 3% CCNE1 amp: 2% CDK4/6 amp: 5% MET MET MET MET EGFR EGFR HER2 HER2 HER2 HER2 M G2 G1 S Small cell + MET 1% T790M is the dominant mechanism of resistance to 1st- and 2nd-gen EGFR TKIs‡ T790M 60% HER2 8% Unknown 18% HER2 + T790M 4% MET amplification 3% Small cell 1% Small cell + T790M 2% MET + T790M 3% No dominant and more heterogeneous mechanisms of resistance to 3rd-gen EGFR TKI osimertinib Acquired Resistance Mechanisms With Early-Gen EGFR TKIs1 ‡In
2022 Treatment Paradigm for Molecular Biomarker– Positive Advanced NSCLC Advanced NSCLC (molecular biomarker positive) *Osimertinib also approved as second-line therapy for EGFR T790M–positive disease after an earlier-generation EGFR TKI. †Afatinib, dacomitinib, erlotinib (alone or in combination with ramucirumab), gefitinib, and osimertinib approved for EGFR exon19del, exon 21 L858R; erlotinib, gefitinib, and dacomitinib also options for EGFR G719X, S768I, L861Q. ‡Or as second-line after CT. ^Crizotinib also an option for METex14 skipping mutation. ALK Progression EGFR ROS1 Crizotinib or entrectinib Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker (ie, chemotherapy ± immunotherapy) Alectinib, brigatinib, ceritinib, or lorlatinib dependent on previous therapy Alectinib, brigatinib, or lorlatinib (preferred); ceritinib, or crizotinib‡ Osimertinib (preferred)*, erlotinib, afatinib, gefitinib, or dacomitinib† BRAF V600E Dabrafenib/ trametinib† First line Second line and beyond Entrectinib or larotrectinib NTRK Selpercatinib or pralsetinib RET Capmatinib or Tepotinib^ METex14 skipping KRAS G12C Sotorasib Classical (del19 or L858R) Uncommon ex20ins Uncommon (S768I, L861Q, G719X) Amivantamab or mobocertinib Afatinib or osimertinib (preferred)†
IMMUNOTHERAPY FOR ADVANCED NSCLC
Molecular and PD-L1 Testing Should Be Done at Initial Diagnosis of Advanced NSCLC to Guide 1L Tx Decisions Initial Diagnosis of Advanced NSCLC Targetable Alteration PRESENT No Targetable Alteration Matched Targeted Therapy PD-L1 Low (1%-49%) or Negative (<1%) PD-L1 High (≥50%) Molecular Testing and PD-L1 IHC
Test Approach Malignancies Clinical Outcome Association PD-L1 Immunohistochemistry-based assessment of the proportion of PD-L1–positive tumor cells, immune cells, or both Multiple tumor types Positive PD-L1 tumor status Tumor-infiltrating lymphocyte Immunohistochemistry-based assessment of T-cells at invasive tumor margin or tumor parenchyma Melanoma; multiple tumor types Increased CD8+ tumor–infiltrating lymphocyte density T-cell receptor clonality Involves next-generation sequencing of T-cell receptor β chain Melanoma Restricted, clonal T-cell receptor β chain Mutational burden Whole or targeted exome sequencing to assess nonsynonymous somatic mutations Melanoma, NSCLC, bladder cancer High mutational count Neoantigen burden Predicted neoantigens derived from whole-exome sequencing data Melanoma, NSCLC High neoantigen count Immune gene signatures Assessment of gene expression from the tumor microenvironment using an automated platform Melanoma Interferon γ or T-cell inflamed profile Multiplex immunohistochemistry Direct assessment of multiple protein markers on tumor cells and immune cells, including spatial relationships Multiple tumor types Physical interaction with PD-1–positive and PD-L1–positive cells; others likely to be determined Gibney. Lancet Oncol. 2016:17:e542. Currently Available Biomarker Tests
What Is Tumor Mutation Burden and Is It Associated With Enhanced Clinical Benefit?
Mutational Burden in Various Tumor Types Pilocytic astrocytoma ALL Medulloblastoma AML Kidney chromophobe Thyroid CLL Neuroblastoma Glioblastoma Pancreas Breast Gliona low grade Lymphoma B-cell Myeloma Prostate Ovary Kidney papillary Kidney clear cell Liver Uterus Stomach Head and neck Cervix Colorectum Esophagus Melanoma Lung squamous Lung adenocarcinoma Bladder 1000 100 10 1.0 0.001 0.01 0.1 Somatic Mutation Prevalence (Number Mutations per Megabase) Lung small cell Alexandrov. Nature. 2013;500:415. Lung cancers are associated with particularly high tumor mutation burden* *Analyzed using an algorithm developed to extract mutational signatures from catalogues of somatic mutations in 7042 primary cancers.
High Tumor Mutation Burden May Influence Immune-Mediated Antitumor Response Tumor cells with high TMB…[1,2] …may have high neoantigen load…[1,2] …which can lead to increased immune and antitumor response[2-5] 1. Schumacher. Science. 2015;348:69. 2. Kim. Ann Oncol. 2016;27:1492. 3. Liontos. Ann Transl Med. 2016;4:264. 4. Sharma. Science. 2015;348:56. 5. Giannakis. Cell Rep. 2016;15:857. The hypothesis that high TMB increases the immunogenicity of tumors makes them a rational target for treatment with I-O therapies[1,2]
2022 Paradigm for Immunotherapy in Advanced NSCLC Without an Actionable Mutation  ICI monotherapy: pembrolizumab,* atezolizumab, cemiplimab  ICI + chemotherapy ‒ Pembrolizumab/carboplatin or cisplatin/pemetrexed (Nsq) ‒ Atezolizumab/carboplatin/paclitaxel/ bevacizumab (Nsq) ‒ Atezolizumab/carboplatin/nab-paclitaxel (Nsq) ‒ Pembrolizumab/carboplatin/taxane (Sq) ‒ Nivolumab/ipilimumab + 2 cycles of CT (Sq/Nsq)  ICI combination: nivolumab/ipilimumab NCCN. Clinical practice guidelines in oncology: NSCLC. v.3.2022. nccn.org. Advanced NSCLC w/o Actionable Mutation PD-1/PD-L1i PD-1/PD-L1i + Chemotherapy PD-1i + CTLA-4i + Chemotherapy PD-1i + CTLA-4i PD-1/PD-L1i + Chemotherapy PD-1i + CTLA-4i + Chemotherapy PD-1i + CTLA-4i PD-1/PD-L1i + Chemotherapy PD-1i + CTLA-4i + Chemotherapy PD-1i + CTLA-4i† PD-L1 1%-49%* PD-L1 ≥50% PD-L1 <1% *Single-agent pembrolizumab also approved for ≥1% PD-L1 but not broadly recommended by experts; guideline-recommended for PD-L1 1-49% if poor PS or contraindications to combining w/CT. †Not an FDA approved indication, but guideline recommended. Current first-line treatment paradigm based on PD-L1 expression in TC and/or IC Updated
CheckMate-026: Nivolumab vs Chemotherapy in First-line Therapy for Advanced NSCLC With PD-L1 ≥ 1%  Primary endpoint: PFS (≥ 5% PD-L1+) by BICR  Secondary endpoints: PFS (≥ 1% PD-L1+), ORR, OS, and safety Patients with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy for advanced disease, brain metastases permitted if adequately treated, no actionable EGFR/ALK mutations, and PD-L1 ≥ 1%* (N = 541) Nivolumab 3 mg/kg IV Q2W (n = 271) Chemotherapy IV Q3W (histology dependent) for up to 6 cycles (n = 270) Stratified by PD-L1 expression (< 5% vs ≥ 5%), histology (squamous vs nonsquamous) Carbone. NEJM. 2017;376:2415. Until PD or unacceptable toxicity Until PD (crossover to nivolumab allowed) *≥ 1% tumor cell staining using 28-8 antibody IHC assay by centralized laboratory.
CheckMate-026: Nivolumab vs Chemotherapy in First-line Therapy for Advanced NSCLC With PD-L1 ≥ 1%  Primary endpoint: PFS (≥ 5% PD-L1+) by BICR  Secondary endpoints: PFS (≥ 1% PD-L1+), ORR, OS, and safety Patients with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy for advanced disease, brain metastases permitted if adequately treated, no actionable EGFR/ALK mutations, and PD-L1 ≥ 1%* (N = 541) Nivolumab 3 mg/kg IV Q2W (n = 271) Chemotherapy IV Q3W (histology dependent) for up to 6 cycles (n = 270) Stratified by PD-L1 expression (< 5% vs ≥ 5%), histology (squamous vs nonsquamous) Carbone. NEJM. 2017;376:2415. Until PD or unacceptable toxicity Until PD (crossover to nivolumab allowed) *≥ 1% tumor cell staining using 28-8 antibody IHC assay by centralized laboratory.
Peters. AACR 2017. Abstr CT082. Carbone. NEJM. 2017:376:2415. High TMB Nivolumab Arm CheckMate 026: PFS With Nivolumab vs Chemo by TMB and PD-L1 Expression  DiscordantoutcomesinTMB high/PD-L1highvsTMB high/PD-L1 low 100 80 60 40 20 0 PFS (%) 0 3 6 9 12 15 18 21 Mos Nivolumab (n = 47) 9.7 (5.1-NR) Chemotherapy (n = 60) 5.8 (4.2-8.5) Median PFS, mos (95% CI) HR: 0.62 (95% CI: 0.38-1.00) Nivolumab Chemotherapy 100 80 60 40 20 0 PFS (%) 0 3 6 9 12 15 18 21 Mos 24 High TMB, PD-L1 1% to 49% High TMB, PD-L1 ≥ 50% Low/medium TMB, PD-L1 1% to 49% Low/medium TMB, PD-L1 ≥ 50%
 Responses enriched in patients whose tumors had both high TMB and high PD-L1 expression 1L, 2L mUC (IMvigor210, IMvigor211) n = 86 n = 26 n = 44 TMB-H IC2/3 2L NSCLC (OAK) n = 45 n = 16 n = 24 TMB-H IC2/3 or TC2/3 PD-L1 Status TMB* ORR, % (n/N) 2L NSCLC 1L,* 2L mUC IC0/1 or IC/TC0/1 TMB-L < 16 mut/Mb 9 (9/95) 12 (29/244) IC2/3 or IC/TC2/3 TMB-L < 16 mut/Mb 20 (9/45) 27 (23/86) IC0/1 or IC/TC0/1 TMB-H ≥ 16 mut/Mb 8 (2/24) 25 (11/44) IC2/3 or IC/TC2/3 TMB-H ≥ 16 mut/Mb 38 (6/16) 50 (13/26) Legrand. ASCO 2018. Abstr 12000. *Cisplatin ineligible. Tissue TMB ≥ 16 mut/Mb Identifies a Patient Population Distinct From PD-L1 IHC
POSITIVE FIRST-LINE ADVANCED NSCLC IMMUNOTHERAPY TRIALS: AN EVER-GROWING LIST 4 Trial Comparison Selection ORR, % PFS HR OS HR KEYNOTE-0241-3 Pembro vs plt-doublet CT PD-L1 ≥50% 46.1 vs 31.1 0.50 0.62 IMpower1104,5 Atezo vs plt-doublet CT PD-L1 ≥50% (TC) or 10% (IC) 38.3 vs 28.6 0.63 0.59 EMPOWER-Lung 16 Cemiplimab vs plt-doublet CT PD-L1 ≥50% 39.2 vs 20.4 0.54 0.57 KEYNOTE-0427,8 Pembro vs plt-doublet CT PD-L1 ≥1% 27.3 vs 26.7 1.05 0.80 KEYNOTE-1899,10 Pembro or placebo + carbo/pem PD-L1 unselected; nonsquamous 48.3 vs 19.9 0.49 0.56 IMpower13011 Atezo + carbo/nab-pac vs CT alone PD-L1 unselected; nonsquamous 49.2 vs 31.9 0.64 0.79 IMpower15012,13 Atezo + carbo/pac + bev vs CT + bev PD-L1 unselected; nonsquamous 63.5 vs 48.0 0.62 0.80 KEYNOTE-40714-16 Pembro or placebo + carbo/pac or nab-pac PD-L1 unselected; squamous 62.6 vs 38.8 0.59 0.71 EMPOWER-Lung 317 Cemiplimab or placebo + plt-doublet CT PD-L1 unselected 43.3 vs 22.7 0.56 0.71 CheckMate 22718-20 Nivo + ipi vs plt-doublet CT TMB high (≥10 mut/Mb) 45.3 vs 26.9 0.58 NR PD-L1 ≥1% 36.4 vs 30.0 0.81 0.76 PD-L1 <1% 27.3 vs 23.1 0.74 0.64 CheckMate 9LA21,22 Nivo + ipi + plt-doublet CT vs plt-doublet CT PD-L1 unselected 38.0 vs 25.4 0.67 0.72 1.
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lung cancer ppt.pptx

  • 1.
    RECENT UPDATES IN LUINGCANCER DR.R.RAJKUMAR D.M CONSULTANT MEDICAL ONCOLOGIST VELAMMAL MEDICAL COLLEGE HOSPITALS
  • 2.
    LUNG CANCER FACTS •Lung Cancer is the #1 cancer killer in the US Cancer statistics, 2018, Volume: 68
  • 3.
    LUNG CANCER FACTS •Most patients diagnosed with advanced disease Cancer statistics, 2018, Volume: 68 Stage at diagnosis
  • 4.
    LUNG CANCER FACTS •Lung cancer is curable when diagnosed early Journal of Thoracic Oncology 2017 12: 1109-1121
  • 5.
    LUNG CANCER SCREENING •What is screening? • A test done to detect a cancer before symptoms develop • Symptoms of lung cancer typically do not appear until the disease is advanced • Why hasn’t lung cancer screening been routine? • Until recently, there hasn’t been an effective test • Lung cancer screening with CXR showed no benefit • No change in lung cancer deaths
  • 6.
    NATIONAL LUNG SCREENINGTRIAL • Large clinical trial 2002-2007 • Over 50,000 patients at risk for lung cancer • 55-74 years old • Current or former smokers • Randomized to annual low-dose CT scan to CXR New England Journal of Medicine August 4th, 2011
  • 7.
    NATIONAL LUNG SCREENINGTRIAL • People who got low-dose CT scans had a 20% decreased risk of dying from lung cancer • 320 people need to be screened to prevent 1 lung cancer death • 1339 for breast cancer • More cancers detected at an early stage • First time that lung cancer screening has been shown to decrease lung cancer deaths! • Results announced in 2010 New England Journal of Medicine August 4th, 2011
  • 8.
    WHO SHOULD GETSCREENED? • Age 55-80 • Current or former smoker • >30 pack year smoking history • Packs per day X years smoked • 1 pack per day for 30 years or 2 packs per day for 15 years • No symptoms of lung cancer • New or changing cough • Coughing up blood • New or increasing shortness of breath
  • 9.
    NSCLC as one disease Squamous 34% Other 11% Adenoca 55% Non-Small-Cell LungCancer: Not One Disease, but Many! Then Histology-Based Subtyping Now Adenocarcinoma KRAS 25% ALK 7% EGFR Sensitizing 17% No Known Oncogenic Driver Detected 31% EGFR Other 4% MET 3% > 1 Mutation 3% HER2 2% ROS1 2% BRAF 2% RET 2% NTRK < 1% PIK3CA 1% MEK1 < 1%
  • 11.
    EVOLUTION OF THERAPYIN LUNG CANCER • Heterogeneous disease Traditional View Present View NSCLC SCLC Histologic Breakdown (eg, SQ, NSQ, large cell, adenocarcinoma) Molecular Pathology (eg, EGFR, ALK, ROS1) PD-L1 Expression Level Lung Cancer ≥50% ≥1%-49% <1%
  • 12.
    Fig. 1 Lung Cancer2021 154161-175DOI: (10.1016/j.lungcan.2021.02.026)
  • 13.
    Fig. 3 Lung Cancer2021 154161-175DOI: (10.1016/j.lungcan.2021.02.026) Copyright © 2021 The Authors and
  • 14.
    BIOPSY: ESTABLISH DIAGNOSIS,DETERMINE HISTOLOGIC SUBTYPE, BIOMARKER TESTING • Histologic subtyping: squamous or nonsquamous?[1] • For biomarker testing: • Primary tumors and metastatic lesions equally suitable[2] • Bone biopsy suboptimal due to decalcification and degradation of DNA[2] • Liquid biopsies (cell-free DNA in plasma) are another option[3] • Testing for PD-L1 expression indicated in all NSCLC[4] • Testing for EGFR, ALK, ROS1, BRAF V600E, NTRK, RET, and METex14 indicated in all nonsquamous NSCLC[4] • Broad NGS testing encouraged to detect a wider range of mutations using least amount of tissue[4,5] • For squamous NSCLC, consider testing in young, never or light smokers, or if biopsy specimen is small or of mixed histology[2] • Completion of testing within 10-14 working days of biopsy recommended[4,6] • TAT for PD-L1 much shorter than for NGS • Wait for results of NGS results before acting on PD-L1 testing results!
  • 15.
    COMPARISON OF ALTERNATIVEMOLECULAR TESTING APPROACHES Single Gene Testing Multigene Testing (eg, by NGS) Advantages  Potentially routine in practice  Potential for local implementation, rapid turnaround  Higher sensitivity with PCR platforms  Minimizes use of tumor tissue  Facilitates testing of multiple biomarkers, including emerging biomarkers for clinical trial enrollment  Just need to know to test vs which biomarkers to test for  Generally less costly than sequential testing Limitations  Tumor tissue samples often inadequate for multiple necessary tests  May lead to repeat biopsy  Multiple platforms available using different methodology that affect types of alterations detected  Analysis of complex biomarker reports  Preauthorization requirements  May not be easily accessible in community practice .
  • 16.
    LIQUID BIOPSY • Whatis liquid biopsy? • Blood sample containing cell-free DNA from multiple sources, including DNA shed from tumor • When do we use liquid biopsy? • Molecular testing is needed but amount of available biopsy tissue is inadequate or unknown, or tissue biopsy not possible • Resistance to TKIs • Advantages • Minimally invasive • May overcome tumor heterogenicity • Limitations • Sensitivity: 70%-80%; specificity: near 100% • Negative result is noninformative
  • 17.
    APRIL 2020 TREATMENTPARADIGM FOR MOLECULAR BIOMARKER–POSITIVE ADVANCED NSCLC ALK positive Progression EGFR mutation positive Advanced NSCLC (molecular biomarker positive) ROS1 positive Crizotinib, ceritinib, or entrectinib Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker Osimertinib EGFR T790M mutation negative or previous osimertinib Alectinib, brigatinib, ceritinib, or lorlatinib dependent on previous therapy Alectinib (preferred), brigatinib, ceritinib, or crizotinib Osimertinib (preferred) erlotinib, afatinib, gefitinib, or dacomitinib* EGFR T790M mutation positive BRAF V600E positive Dabrafenib/ trametinib† First line Second line and beyond *Afatinib, dacomitinib, erlotinib, gefitinib, osimertinib approved for EGFR exon19del, exon 21 L858R; afatinib for EGFR G719X, S768I, L861Q. †Or as second line after CT. Entrectinib or larotrectinib NTRK positive
  • 18.
    WHY DOES UPFRONTTESTING MATTER?  Only 48% of patients with advanced NSCLC and a driver mutation received NCCN- recommended targeted therapy1 ‒ Alterations included EGFR, ALK, ROS1, BRAF, MET, RET, ERBB2  Patients with driver mutations who received targeted therapy had an improved OS (18.6 vs 11.4 mo; P <.001)1  Always give the best treatment upfront ‒ ~30% of patients will NOT go on to receive second-line treatment2 . Patients with NSCLC1 (N = 1260) First-line Therapy Received by Driver Mutation2 % of First-line Therapies Other Therapy 52% NCCN- Recommended Targeted Therapy 48% 100 80 60 40 20 0 Other Anti–PD-1 EGFR or ALK TKI Nonplatinum regimen Platinum regimen Gene ALK (n = 98) EGFR (n = 535) ROS1 (n = 27) Other (n = 2092)
  • 19.
    BARRIERS TO UNIVERSALBIOMARKER TESTING  Not enough tissue in small biopsies—up to 25% lack sufficient tumor  TAT not fast enough— recommended <14 calendar/ 10 working days from biopsy  Poor communication—lack of reflex testing, differing sites for biopsy and treatment  Who pays? Oncology Team Members Biomarker Testing Tissue Acquisition Turnaround Time Payment/ Reimbursement Communication
  • 20.
    EGFR MUTATIONAL EPIDEMIOLOGY Found in ~ 20% to 30% of patients with NSCLC globally  More common in never- smokers, adenocarcinomas, females, Asians  Predominantly located in EGFR exons 18-21  The specific EGFR mutation identified is important: sensitive mutations, primary resistance mutations, and de novo and acquired resistance mutations EGFR Kinase Domain Mutations Ligand Binding Transmembrane Tyrosine Kinase Autophosphorylation N N K754R S768I* L861Q* A871G L833V/ H835L/ L838V E884K L858R ~ 41% Ins761 (EAFQ)/ Ins770 (ASV)/ Ins771 (G)/ Ins774 (NPH) ~ 3% G719S* ~ 5% E709A/ E709G C C Y891 Y920 Y992 Y1045 Y1068 Y1086 Y1148 Y1173 T790M ~ 3% EXON 18 19 20 21 22 23 24 del 747-752 and others ~ 48% *Noncanonical EGFR mutations.
  • 21.
    EGFR MUTATIONS INNSCLC  Exon 19 deletions and L858R mutation in exon 21 ‒ ~80% of all EGFR mutations ‒ Clinically relevant as patients respond to EGFR tyrosine kinase inhibitors  Uncommon or atypical EGFR mutations ‒ G719X, L861Q, S7681  EGFR exon 20 insertion mutations ‒ Inherently resistant to approved TKI ‒ Platinum-based chemotherapy remains the recommended first-line therapy Exon 18 ~4% Other exons ~3% Exon 21 ~41% Exon 19 ~45% Exon 20 ~6% Exon 19 mutations - Del 19 (44.8%) - Ins 19 (0.6%) Exon 21 mutations - L858R (39.8%) - L861Q (0.9%) Frequency of EGFR mutations
  • 22.
    Parameter Erlotinib GefitinibAfatinib Dacomitinib Osimertinib Generation First First Second Second Third EGFR mutations approved for in first-line setting Ex19del, Ex21 L858R Ex19del, Ex21 L858R Ex18 G719X,* Ex19del, Ex20 S768I,* Ex21 L858R, Ex21 L861Q* Ex19del, Ex21 L858R Ex19del, Ex21 L858R† EGFR binding Reversible Reversible Irreversible Irreversible Irreversible Half life, hr 36 48 37 59-85 48 Food effect (take on empty stomach) Increase F from ~60% to ~100% No change Decrease AUC by 39% No change No change CNS penetration, AUC ratio 0.03X CSF/plasma 0.01X CSF/serum 0.02X CSF/plasma CNS activity reported 2X brain/plasma EGFR TKIs: Properties *Uncommon nonresistant EGFR mutations. †Also approved for resistant mutation T790M in second-line setting and a preferred option for EGFR G719X, S768I, L861Q per NCCN guidelines.
  • 23.
    FLAURA: PFS BYCNS METASTASES AT BASELINE  CNS progression occurred in 17 patients (6%) with osimertinib vs 42 (15%) with 1st-generation EGFR TKI Median PFS, Mo (95% CI) Osimertinib (n = 53) 15.2 (12.1-21.4) 1st-Generation EGFR TKI (n = 63) 9.6 (7.0-12.4) HR: 0.47 (95% CI: 0.30-0.74; P <.001) Soria. NEJM. 2018;378:113. Patients at Risk, n Osimertinib 1st-Generation EGFR TKI 53 63 51 57 40 40 37 33 22 13 9 6 4 2 0 0 32 24 1 1 Mo Patients at Risk, n Osimertinib 1st-Generation EGFR TKI 226 214 211 182 193 157 173 119 117 65 62 31 22 8 0 0 146 83 3 1 Mo Median PFS, Mo (95% CI) Osimertinib (n = 226) 19.1 (15.2-23.5) 1st-Generation EGFR TKI (n = 214) 10.9 (9.6-12.3) HR: 0.46 (95% CI: 0.36-0.59; P <.001) Probability of PFS Probability of PFS With CNS Metastases at BL (n = 116) Without CNS Metastases at BL (n = 440) 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 Slide credit: clinicaloptions.com
  • 24.
    SUMMARY OF FIRST-LINETREATMENT APPROACHES FOR PATIENTS WITH EGFR MUTATION–POSITIVE NSCLC First-line: Treatment Arms PFS, Mo (HR) AE Grade ≥3, % Erlotinib + bevacizumab vs erlotinib2 16.0 vs 9.7 (0.54) 91 vs 53 Erlotinib + ramucirumab vs erlotinib + placebo3 19.4 vs 12.3 (0.59) 72 vs 54 Erlotinib + bevacizumab vs erlotinib4 16.9 vs 13.3 (0.61) 88 vs 46 Gefitinib + carboplatin/ pemetrexed vs gefitinib5 20.9 vs 11.2 (0.49) NR vs NR Gefitinib + carboplatin/ pemetrexed vs gefitinib6 16.0 vs 8.0 (0.51) 75 vs 49.4 Afatinib vs gefitinib7 11.0 vs 10.9 (0.73) 57 vs 52 Dacomitinib vs gefitinib8 14.7 vs 9.2 (0.59) 63 vs 41 Osimertinib vs gefitinib or erlotinib9 18.9 vs 10.2 (0.46) 34 vs 45 First-line Treatment Approach Erlotinib + antiangiogenics Gefitinib + carboplatin/pemetrexed 2nd-gen EGFR inhibitors Osimertinib Time TOXICITY
  • 25.
    ATYPICAL OR UNCOMMONEGFR MUTATIONS 3 most common point mutations: G719X, S768I, L861Q (approved drug: afatinib) Exon 20 insertions: ~9% of EGFR mutations 10%-15% of EGFR-mutant NSCLC, diverse alterations, and can occur in all exons Patients with EGFR-mutant NSCLC Ex20ins 9.1% Complex atypical 9.1% Atypical 12.6% Ex19del 32.7% L858R 23.0% Classical +T790M 11.1% N = 11619 Classical mutations (67%) Atypical mutations (31%) Classical + T790m + atypical (2%) Classical + T790M + atypical 2.2% T790M 0.3%
  • 26.
    TREATMENT OPTIONS FORPATIENTS WITH EGFR EXON 20 INSERTIONS
  • 27.
    REAL-WORLD OUTCOMES INPATIENTS WITH EGFR EXON 20 INSERTION+ ADVANCED NSCLC  Retrospective comparative analysis of real-world outcomes in patients with EGFR ex20ins+ advanced NSCLC (n = 181) vs those with common EGFR mutations (L858R or ex19del; n = 2833) ‒ Flatiron Health Database (January 2011 to May 2020)  75% increased risk of death with EGFR ex20ins vs common EGFR mutations (primary endpoint) ‒ 5-yr OS: 8% vs 19%  Secondary endpoints: ‒ 93% increased risk of progression or death ‒ 60% increased risk of shorter time to next therapy Prognostic Value of EGFR Ex20ins vs EGFR L858R or Ex19del: Real-World OS (N = 3014) Patients at Risk, n Common EGFR EGFR ex20ins 77% 53% 36% 25% 19% 57% 33% 23% 13% 8% 0 6 12 18 24 30 36 42 48 54 60 2833 181 2245 120 1728 77 1313 53 943 30 675 22 494 16 354 11 262 6 198 5 139 3 0 25 50 75 100 Mo Patients (%) Common EGFR Mut EGFR Ex20ins 25.5 16.2 Median rwOS, mo Adjusted HR: 1.75 (95% CI: 1.5-2.1; P <.0001)
  • 28.
    RESISTANCE MORE CHALLENGINGWITH NEWER EGFR TKIS *Overlap of reported resistance mechanism may occur. †n = 2 with de novo T790M mutations at BL; 1 acquired C797S at progression. Secondary EGFR mutations†: C797X: 7%; L718Q+C797S: 1%; L718Q + ex20ins: 1%; S768I: 1% HER2 amplification: 2% HER2 mutation: 1% MET amplification: 15% mTOR AKT p53 BIM BCL2 PIK3CA ERK BRAF mutations (V600E): 3% SPTBN1 ALK SPTBN1-ALK: 1% Survival Apoptosis Proliferation PIK3CA mutations: 7% Candidate Acquired Resistance Mechanisms With Osimertinib*3 MEK RAS RAF KRAS mutations (G12D/C, A146T): 3% Cell cycle gene alterations CCND amp: 3% CCNE1 amp: 2% CDK4/6 amp: 5% MET MET MET MET EGFR EGFR HER2 HER2 HER2 HER2 M G2 G1 S Small cell + MET 1% T790M is the dominant mechanism of resistance to 1st- and 2nd-gen EGFR TKIs‡ T790M 60% HER2 8% Unknown 18% HER2 + T790M 4% MET amplification 3% Small cell 1% Small cell + T790M 2% MET + T790M 3% No dominant and more heterogeneous mechanisms of resistance to 3rd-gen EGFR TKI osimertinib Acquired Resistance Mechanisms With Early-Gen EGFR TKIs1 ‡In
  • 29.
    2022 Treatment Paradigmfor Molecular Biomarker– Positive Advanced NSCLC Advanced NSCLC (molecular biomarker positive) *Osimertinib also approved as second-line therapy for EGFR T790M–positive disease after an earlier-generation EGFR TKI. †Afatinib, dacomitinib, erlotinib (alone or in combination with ramucirumab), gefitinib, and osimertinib approved for EGFR exon19del, exon 21 L858R; erlotinib, gefitinib, and dacomitinib also options for EGFR G719X, S768I, L861Q. ‡Or as second-line after CT. ^Crizotinib also an option for METex14 skipping mutation. ALK Progression EGFR ROS1 Crizotinib or entrectinib Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker (ie, chemotherapy ± immunotherapy) Alectinib, brigatinib, ceritinib, or lorlatinib dependent on previous therapy Alectinib, brigatinib, or lorlatinib (preferred); ceritinib, or crizotinib‡ Osimertinib (preferred)*, erlotinib, afatinib, gefitinib, or dacomitinib† BRAF V600E Dabrafenib/ trametinib† First line Second line and beyond Entrectinib or larotrectinib NTRK Selpercatinib or pralsetinib RET Capmatinib or Tepotinib^ METex14 skipping KRAS G12C Sotorasib Classical (del19 or L858R) Uncommon ex20ins Uncommon (S768I, L861Q, G719X) Amivantamab or mobocertinib Afatinib or osimertinib (preferred)†
  • 30.
  • 31.
    Molecular and PD-L1Testing Should Be Done at Initial Diagnosis of Advanced NSCLC to Guide 1L Tx Decisions Initial Diagnosis of Advanced NSCLC Targetable Alteration PRESENT No Targetable Alteration Matched Targeted Therapy PD-L1 Low (1%-49%) or Negative (<1%) PD-L1 High (≥50%) Molecular Testing and PD-L1 IHC
  • 32.
    Test Approach MalignanciesClinical Outcome Association PD-L1 Immunohistochemistry-based assessment of the proportion of PD-L1–positive tumor cells, immune cells, or both Multiple tumor types Positive PD-L1 tumor status Tumor-infiltrating lymphocyte Immunohistochemistry-based assessment of T-cells at invasive tumor margin or tumor parenchyma Melanoma; multiple tumor types Increased CD8+ tumor–infiltrating lymphocyte density T-cell receptor clonality Involves next-generation sequencing of T-cell receptor β chain Melanoma Restricted, clonal T-cell receptor β chain Mutational burden Whole or targeted exome sequencing to assess nonsynonymous somatic mutations Melanoma, NSCLC, bladder cancer High mutational count Neoantigen burden Predicted neoantigens derived from whole-exome sequencing data Melanoma, NSCLC High neoantigen count Immune gene signatures Assessment of gene expression from the tumor microenvironment using an automated platform Melanoma Interferon γ or T-cell inflamed profile Multiplex immunohistochemistry Direct assessment of multiple protein markers on tumor cells and immune cells, including spatial relationships Multiple tumor types Physical interaction with PD-1–positive and PD-L1–positive cells; others likely to be determined Gibney. Lancet Oncol. 2016:17:e542. Currently Available Biomarker Tests
  • 33.
    What Is TumorMutation Burden and Is It Associated With Enhanced Clinical Benefit?
  • 34.
    Mutational Burden inVarious Tumor Types Pilocytic astrocytoma ALL Medulloblastoma AML Kidney chromophobe Thyroid CLL Neuroblastoma Glioblastoma Pancreas Breast Gliona low grade Lymphoma B-cell Myeloma Prostate Ovary Kidney papillary Kidney clear cell Liver Uterus Stomach Head and neck Cervix Colorectum Esophagus Melanoma Lung squamous Lung adenocarcinoma Bladder 1000 100 10 1.0 0.001 0.01 0.1 Somatic Mutation Prevalence (Number Mutations per Megabase) Lung small cell Alexandrov. Nature. 2013;500:415. Lung cancers are associated with particularly high tumor mutation burden* *Analyzed using an algorithm developed to extract mutational signatures from catalogues of somatic mutations in 7042 primary cancers.
  • 35.
    High Tumor MutationBurden May Influence Immune-Mediated Antitumor Response Tumor cells with high TMB…[1,2] …may have high neoantigen load…[1,2] …which can lead to increased immune and antitumor response[2-5] 1. Schumacher. Science. 2015;348:69. 2. Kim. Ann Oncol. 2016;27:1492. 3. Liontos. Ann Transl Med. 2016;4:264. 4. Sharma. Science. 2015;348:56. 5. Giannakis. Cell Rep. 2016;15:857. The hypothesis that high TMB increases the immunogenicity of tumors makes them a rational target for treatment with I-O therapies[1,2]
  • 36.
    2022 Paradigm forImmunotherapy in Advanced NSCLC Without an Actionable Mutation  ICI monotherapy: pembrolizumab,* atezolizumab, cemiplimab  ICI + chemotherapy ‒ Pembrolizumab/carboplatin or cisplatin/pemetrexed (Nsq) ‒ Atezolizumab/carboplatin/paclitaxel/ bevacizumab (Nsq) ‒ Atezolizumab/carboplatin/nab-paclitaxel (Nsq) ‒ Pembrolizumab/carboplatin/taxane (Sq) ‒ Nivolumab/ipilimumab + 2 cycles of CT (Sq/Nsq)  ICI combination: nivolumab/ipilimumab NCCN. Clinical practice guidelines in oncology: NSCLC. v.3.2022. nccn.org. Advanced NSCLC w/o Actionable Mutation PD-1/PD-L1i PD-1/PD-L1i + Chemotherapy PD-1i + CTLA-4i + Chemotherapy PD-1i + CTLA-4i PD-1/PD-L1i + Chemotherapy PD-1i + CTLA-4i + Chemotherapy PD-1i + CTLA-4i PD-1/PD-L1i + Chemotherapy PD-1i + CTLA-4i + Chemotherapy PD-1i + CTLA-4i† PD-L1 1%-49%* PD-L1 ≥50% PD-L1 <1% *Single-agent pembrolizumab also approved for ≥1% PD-L1 but not broadly recommended by experts; guideline-recommended for PD-L1 1-49% if poor PS or contraindications to combining w/CT. †Not an FDA approved indication, but guideline recommended. Current first-line treatment paradigm based on PD-L1 expression in TC and/or IC Updated
  • 37.
    CheckMate-026: Nivolumab vsChemotherapy in First-line Therapy for Advanced NSCLC With PD-L1 ≥ 1%  Primary endpoint: PFS (≥ 5% PD-L1+) by BICR  Secondary endpoints: PFS (≥ 1% PD-L1+), ORR, OS, and safety Patients with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy for advanced disease, brain metastases permitted if adequately treated, no actionable EGFR/ALK mutations, and PD-L1 ≥ 1%* (N = 541) Nivolumab 3 mg/kg IV Q2W (n = 271) Chemotherapy IV Q3W (histology dependent) for up to 6 cycles (n = 270) Stratified by PD-L1 expression (< 5% vs ≥ 5%), histology (squamous vs nonsquamous) Carbone. NEJM. 2017;376:2415. Until PD or unacceptable toxicity Until PD (crossover to nivolumab allowed) *≥ 1% tumor cell staining using 28-8 antibody IHC assay by centralized laboratory.
  • 38.
    CheckMate-026: Nivolumab vsChemotherapy in First-line Therapy for Advanced NSCLC With PD-L1 ≥ 1%  Primary endpoint: PFS (≥ 5% PD-L1+) by BICR  Secondary endpoints: PFS (≥ 1% PD-L1+), ORR, OS, and safety Patients with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy for advanced disease, brain metastases permitted if adequately treated, no actionable EGFR/ALK mutations, and PD-L1 ≥ 1%* (N = 541) Nivolumab 3 mg/kg IV Q2W (n = 271) Chemotherapy IV Q3W (histology dependent) for up to 6 cycles (n = 270) Stratified by PD-L1 expression (< 5% vs ≥ 5%), histology (squamous vs nonsquamous) Carbone. NEJM. 2017;376:2415. Until PD or unacceptable toxicity Until PD (crossover to nivolumab allowed) *≥ 1% tumor cell staining using 28-8 antibody IHC assay by centralized laboratory.
  • 39.
    Peters. AACR 2017.Abstr CT082. Carbone. NEJM. 2017:376:2415. High TMB Nivolumab Arm CheckMate 026: PFS With Nivolumab vs Chemo by TMB and PD-L1 Expression  DiscordantoutcomesinTMB high/PD-L1highvsTMB high/PD-L1 low 100 80 60 40 20 0 PFS (%) 0 3 6 9 12 15 18 21 Mos Nivolumab (n = 47) 9.7 (5.1-NR) Chemotherapy (n = 60) 5.8 (4.2-8.5) Median PFS, mos (95% CI) HR: 0.62 (95% CI: 0.38-1.00) Nivolumab Chemotherapy 100 80 60 40 20 0 PFS (%) 0 3 6 9 12 15 18 21 Mos 24 High TMB, PD-L1 1% to 49% High TMB, PD-L1 ≥ 50% Low/medium TMB, PD-L1 1% to 49% Low/medium TMB, PD-L1 ≥ 50%
  • 40.
     Responses enrichedin patients whose tumors had both high TMB and high PD-L1 expression 1L, 2L mUC (IMvigor210, IMvigor211) n = 86 n = 26 n = 44 TMB-H IC2/3 2L NSCLC (OAK) n = 45 n = 16 n = 24 TMB-H IC2/3 or TC2/3 PD-L1 Status TMB* ORR, % (n/N) 2L NSCLC 1L,* 2L mUC IC0/1 or IC/TC0/1 TMB-L < 16 mut/Mb 9 (9/95) 12 (29/244) IC2/3 or IC/TC2/3 TMB-L < 16 mut/Mb 20 (9/45) 27 (23/86) IC0/1 or IC/TC0/1 TMB-H ≥ 16 mut/Mb 8 (2/24) 25 (11/44) IC2/3 or IC/TC2/3 TMB-H ≥ 16 mut/Mb 38 (6/16) 50 (13/26) Legrand. ASCO 2018. Abstr 12000. *Cisplatin ineligible. Tissue TMB ≥ 16 mut/Mb Identifies a Patient Population Distinct From PD-L1 IHC
  • 41.
    POSITIVE FIRST-LINE ADVANCEDNSCLC IMMUNOTHERAPY TRIALS: AN EVER-GROWING LIST 4 Trial Comparison Selection ORR, % PFS HR OS HR KEYNOTE-0241-3 Pembro vs plt-doublet CT PD-L1 ≥50% 46.1 vs 31.1 0.50 0.62 IMpower1104,5 Atezo vs plt-doublet CT PD-L1 ≥50% (TC) or 10% (IC) 38.3 vs 28.6 0.63 0.59 EMPOWER-Lung 16 Cemiplimab vs plt-doublet CT PD-L1 ≥50% 39.2 vs 20.4 0.54 0.57 KEYNOTE-0427,8 Pembro vs plt-doublet CT PD-L1 ≥1% 27.3 vs 26.7 1.05 0.80 KEYNOTE-1899,10 Pembro or placebo + carbo/pem PD-L1 unselected; nonsquamous 48.3 vs 19.9 0.49 0.56 IMpower13011 Atezo + carbo/nab-pac vs CT alone PD-L1 unselected; nonsquamous 49.2 vs 31.9 0.64 0.79 IMpower15012,13 Atezo + carbo/pac + bev vs CT + bev PD-L1 unselected; nonsquamous 63.5 vs 48.0 0.62 0.80 KEYNOTE-40714-16 Pembro or placebo + carbo/pac or nab-pac PD-L1 unselected; squamous 62.6 vs 38.8 0.59 0.71 EMPOWER-Lung 317 Cemiplimab or placebo + plt-doublet CT PD-L1 unselected 43.3 vs 22.7 0.56 0.71 CheckMate 22718-20 Nivo + ipi vs plt-doublet CT TMB high (≥10 mut/Mb) 45.3 vs 26.9 0.58 NR PD-L1 ≥1% 36.4 vs 30.0 0.81 0.76 PD-L1 <1% 27.3 vs 23.1 0.74 0.64 CheckMate 9LA21,22 Nivo + ipi + plt-doublet CT vs plt-doublet CT PD-L1 unselected 38.0 vs 25.4 0.67 0.72 1.

Editor's Notes

  • #10 Adenoca, adenocarcinoma; NSCLC, non-small-cell lung cancer.
  • #12 NSCLC, non-small-cell lung cancer; NSQ, nonsquamous; SCLC, small-cell-lung cancer; SQ, squamous.
  • #13 Guideline recommendations for (A) predictive biomarkers and (B) emerging biomarkers, to guide selection of precision therapies [6,24,28,47,48]. ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; BRAF, B-Raf proto-oncogene; CAP, College of American Pathologists; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; HER, human epidermal growth factor receptor; IASLC, International Association for the Study of Lung Cancer; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, hepatocyte growth factor receptor; NCCN, National Comprehensive Cancer Network; NTRK, neurotrophic tyrosine receptor kinase; PD-L1, programmed cell death ligand 1; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; TMB, tumour mutational burden.
  • #14 Best practice recommendations for the treatment of patients with (A) advanced treatment-naïve NSCLC and (B) progressive or recurrent NSCLC during treatment with a tyrosine kinase inhibitor. aConsider the use of ROSE to rapidly assess the suitability of material obtained by tissue biopsy. ROSE may help to improve diagnostic yield, reduce the need for additional procedures, obtain additional passes for molecular testing (if needed) and allow optimal use of laboratory resources [107]. ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; ctDNA, circulating tumour cell DNA; ddPCR, digital droplet PCR; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma viral oncogene homolog; MTB, molecular tumour board; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death ligand 1; ROS1, ROS proto-oncogene 1; ROSE, rapid on-site evaluation; SOC, standard of care; TAT, turnaround time; VAF, variant allele frequency.
  • #15 NSCLC, non-small-cell lung cancer; NGS, next-generation sequencing; TAT, turnaround time.
  • #16 NGS, next-generation sequencing.
  • #17 cfDNA, cell-free DNA; CTC, circulating tumor cell.
  • #18 CT, chemotherapy; NSCLC, non-small-cell lung cancer.
  • #19 NCCN, National Comprehensive Cancer Network; NSCLC, non-small-cell lung cancer; OS, overall survival; tx, treatment.
  • #20 TAT, turnaround time.
  • #21 del, deletion; ins, insertion; NSCLC, non-small-cell lung cancer.
  • #22 del, deletion; ins, insertion; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
  • #23 AUC, area under the curve; CNS, central nervous system; CSF, cerebrospinal fluid; EGFR, epidermal growth factor receptor; F, bioavailability; NCCN, National Comprehensive Cancer Network; TKI, tyrosine kinase inhibitor.
  • #24 BL, baseline; CNS, central nervous system; EGFR, epidermal growth factor receptor; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
  • #25 AE, adverse event; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival.
  • #26 NSCLC, non-small-cell lung cancer.
  • #28 Mut, mutation; NSCLC, non-small-cell lung cancer; OS, overall survival; rwOS, real-world overall survival.
  • #29 gen, generation; TKI, tyrosine kinase inhibitor.
  • #30 CT, chemotherapy; NSCLC, non-small-cell lung cancer.
  • #35 ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia.
  • #36 MHC=major histocompatibility complex; NK=natural killer; TCR=T-cell receptor; TMB=tumor mutation burden.
  • #37 CT, chemotherapy; IC, immune cell; ICI, immune checkpoint inhibitor; NSCLC, non-small-cell lung cancer; Nsq, nonsquamous; Sq, squamous; TC, tumor cell.
  • #38 Adv, advanced; BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status.
  • #39 Adv, advanced; BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status.
  • #41 IC, tumor-infiltrating immune cell; TC, tumor cell; IC0/1 or TC0/1, ≤1% PD-L1 expressing IC or TC; IC2/3 or TC2/3, ≥ 5% PD-L1 expressing IC or TC.
  • #42 atezo, atezolizumab; bev, bevacizumab; carbo, carboplatin; CT, chemotherapy; IC, immune cell; ipi, ipilimumab; nab-pac, nab-paclitaxel; nivo, nivolumab; NR, not reported; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; pac, paclitaxel; pem, pemetrexed; pembro, pembrolizumab; PFS, progression-free survival; plt, platinum; TC, tumor cell; TMB, tumor mutational burden; WT, wild-type.