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Progress in EGFR-Mutant NSCLC

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Progress in EGFR-Mutant NSCLC touchEXPERT OPINIONS Progress in EGFR-mutant NSCLC: Where are we going? Disclaimer ∙ Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. ∙ The presenting faculty have been advised by touchIME to ensure that they disclose any such references made to unlabelled or unapproved use. ∙ No endorsement by touchIME of any unapproved products or unapproved uses is either made or implied by mention of these products or uses in touchIME activities. ∙ touchIME accepts no responsibility for errors or omissions. Are combination strategies the way forward for EGFR-mutant NSCLC? Dr Raffaele Califano The Christie Hospital Manchester University Hospital University of Manchester Manchester, UK EGFR mutations in patients with NSCLC EGF or other Mutations in the catalytic tyrosine EGFR ligand kinase domain (exons 18–21) Constitutive EGFR activation EGFR dimer EGFR mutations in lung cancer: • 10–15% Caucasian patients Tyrosine • Up to 50% in East-Asian patients kinase More frequent in: • Cell proliferation • Patients with adenocarcinoma • Cell survival • Migration • Female patients • Never/former smokers EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer. 1. Passaro A, et al. ESMO Open. 2020;5:e000919; 2. O’Leary C, et al. Pharmaceuticals. 2020;13:273. EGFR-TKI as first-line therapy for NSCLC LUX-LUNG 71 ARCHER 10502,3 FLAURA4,5 Median PFS Median PFS Median OS Median PFS Median OS 14 18 40 25 45 HR=0.73 HR=0.59 HR=0.76 HR=0.46 HR=0.80 40 12 p=0.017 16 p<0.0001 35 p=0.044 p<0.001 p=0.046 20 14 30 35 10 12 30 25 15 8 10 25 20 8 20 Months Months Months Months 6 Months 15 10 6 15 4 10 4 5 10 2 2 5 5 0 0 0 0 0 Afatinib Dacomitinib Osimertinib Gefitini Gefitinib Gefitinib or b erlotinib EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survical; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. 1. Park K, et al. Lancet Oncol. 2016;17:577–89; 2. Mok TS, et al. J Clin Oncol. 2018;36:2244–50; 3. Wu YL, et al. Lancet Oncol. 2017;18:1454–66; 4. Soria J-C, et al. N Engl J Med. 2018;378:113–25; 5. Ramalingam SS, et al. N Engl J Med. 2020;382:41–50. FLAURA trial: Subsequent therapies First subsequent Second subsequent anticancer therapy anticancer therapy Osimertinib 48% 54 26% of all randomized patients (N=279) % received a second subsequent therapy Received first Received second subsequent therapy subsequent therapy Gefitinib 51 or 65% % 33% of all randomized patients erlotinib received a second subsequent therapy (N=277) 47 % Received osimertinib as first subsequent therapy 1. Ramalingam SS, et al. N Engl J Med. 2020;382:41–50. EGFR-TKI combined with anti-VEGF therapy NEJ026 and RELAY: Study design NEJ0261 Erlotinib • Stage IIIB–IV NSCLC plus • Activating EGFR genomic aberrations bevacizuma 1: • Performance status 2 ≤ 1 Erlotinibb N=228 • No prior chemotherapy for advanced monotherap disease y RELAY2 Erlotinib • Metastatic NSCLC plus • Activating EGFR genomic aberrations ramuciruma 1: • No CNS metastases 1 b N=449 • Performance status ≤1 Erlotinib • No prior treatment plus placebo CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor. 1. Saito H, et al. Lancet Oncol. 2019;20:625–35; 2. Nakagawa K, et al. Lancet Oncol. 2019;20:1655–69. EGFR-TKI combined with anti-VEGF therapy Median PFS Median OS Grade 3/4 AE NEJ0261,2 25 60 100 HR=0.61 HR=1.00 Erlotinib plus bevacizumab 20 80 p=0.016 Erlotinib monotherapy 40 15 60 Approved by EMA for first-line treatment 10 40 Months Months 20 of unresectable advanced, metastatic or 5 Event rate (%) 20 recurrent EGFR-mutant 0 0 0 NSCLC4 RELAY3 25 80 HR=0.59 Erlotinib plus ramucirumab 20 p<0.0001 Median OS not 60 Erlotinib plus placebo 15 reached for 40 Approved by EMA 10 erlotinib plus Months and FDA ramucirumab for first-line 20 treatment of metastatic 5 Event rate (%) EGFR-mutant NSCLC5,6 0 0 AE, adverse events; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PI, product information; PFS, progression-free survival; SPC, summary of product characteristics; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor. 1. Saito H, et al. Lancet Oncol. 2019;20:625–35; 2. Maemondon M, et al. J Clin Oncol. 2020;38(15_Suppl):9506; 3. Nakagawa K, et al. Lancet Oncol. 2019;20:1655–69; 4. EMA. Avastin (bevacizumab) infusion, SPC. 2020. Available at: www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf; 5. EMA. Cyramza (ramucirumab) infusion, SPC. 2020. Available at: www.ema.europa.eu/en/documents/product-information/cyramza-epar-product-information_en.pdf; 6. FDA. Cyramza (ramucirumab) injection, PI 2020. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2020/125477s034lbl.pdf. (PI and SPC accessed 4 Nov 2020). EGFR-TKI combined with chemotherapy NEJ009 and Tata Memorial Centre: Study design Maintenance NEJ0091 Gefitinib plus Gefitinib and • Stage IIIB–IV NSCLC chemothera pemetrexed • Activating EGFR genomic 1: py aberrations 1 Gefitinib N=345 • Performance status ≤1 monotherap The primary y endpoint for both trials was PFS Maintenance Tata2 Gefitinib plus Pemetrexed • Advanced NSCLC chemothera • Activating EGFR genomic 1: py aberrations 1 Gefitinib N=350 • Performance status ≤2 monotherap y Chemotherapy consisted of pemetrexed and carboplatin in both trials EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. 1. Hosomi Y, et al. J Clin Oncol. 2020;38:115–23; 2. Noronha V, et al. J Clin Oncol. 2020;38:124–36. EGFR-TKI combined with chemotherapy Median PFS Median OS Grade 3/4 AE 1 30 70 70 NEJ009 HR=0.49 HR=0.72 60 60 25 p<0.001 p=0.021 20 50 50 40 40 15 30 30 Months Months 10 20 20 Event Event rate (%) 5 10 10 0 0 0 Gefitinib plus chemotherapy 2 20 60 Gefitinib monotherapy Tata HR=0.51 50 15 p<0.001 40 Median OS not 10 30 reached for gefitinib Months 20 5 plus chemotherapy Event Event rate (%) 10 0 0 AE, adverse events; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. 1. Hosomi Y, et al. J Clin Oncol. 2020;38:115–23; 2. Noronha V, et al. J Clin Oncol. 2020;38:124–36. Immunotherapy for EGFR-mutant NSCLC NCT028799941 Enrolment was ceased due to lack Phase II trial of pembrolizumab in TKI-naive patients with EGFR- of efficacy even on tumours with mutation positive, advanced NSCLC and PD-L1 positive (≥1%) PD-L1 expression >50% tumours Italian expanded access programme2,3 Worse clinical outcomes with PD-1 Analysis of nivolumab therapy in patients who had relapsed after inhibition in patients with EGFR- one or more prior systemic treatments for stage IIIB/IV NSCLC, mutant tumours than EGFR-WT with a focus on never-smokers and patients with EGFR-mutant tumours tumours EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor; WT, wild type. 1. Lisberg A, et al. J Clin Oncol. 2018;13:1138–45; 2. Garassino MC, et al. J Thorac Oncol. 2018;13:1146–55; 3. Lisberg A, et al. J Thorac Oncol. 2018;13:1058–9. ICI, chemotherapy and anti-VEGF combination IMpower150: Study design1 and OS analysis2 • Stage IV or recurrent metastatic NSCLC • No prior chemotherapy ACPB CPB N=400 ACPB Population better better Atezolizumab Overall (n=800) + carboplatin + paclitaxel Wild type (n=696) + bevacizumab EGFR/ALK mutant (n=104) N=400 CPB 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Carboplatin Hazard ratio for OS + paclitaxel + bevacizumab ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; OS, overall survival; VEGF, vascular endothelial growth factor. 1. Socinski MA, et al. N Engl J Med. 2018;378:2288–301; 2. Socinski MA, et al. J Clin Oncol. 2018;36(15_Suppl):9002. How will acquired resistance drive treatment choices in EGFR-mutant NSCLC? Prof. Lecia Sequist Harvard Medical School Massachusetts General Hospital Boston, MA, USA Mechanisms of resistance to EGFR-TKIs Resistance to EGFR-TKIs is complex and setting-dependent First-line first and second Second or further-line 3rd generation EGFR-TKIs1 generation EGFR-TKI2–4 First-line third generation5,6 MET amp MET amp EGFR T790M (~10–22%) EGFR C797S (~15%) Cell cycle MET amp (~55–70%) (~19–22%) (~11%) (~1–13%) EGFR C797S (~7%) Squamous Unknown Unknown (~7%) (~18%) Unknown Cell cycle (~30%) (~15%) (~30%) Pleomorphic (~7%) SCLC (~0–6%) SCLC SCLC (~2–15%) (~7%) HER2 amp Others Others (~3–32%) Amp, amplification; EGFR, epithelial growth factor receptor; HER2, human epidermal growth factor receptor 2; MET, mesenchymal-epithelial transition factor; SCLC, small cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Yu HA, et al. Clin Cancer Res. 2013;19:2240–7; 2. Piotrowska Z, et al. Cancer Discov. 2018;8:1529–39; 3. Oxnard GR, et al. JAMA Oncol. 2018;4:1527–34; 4. Papadimitrakopoulou VA, et al.
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