EGFR TKI sequencing: does order matter?

EGFR TKI sequencing: does order matter? Nicolas Girard Thorax Institut Curie-Montsouris, Paris, France In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (Stage IIIb/IV) with activating mutations of EGFR (exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for whom immunotherapy is not suitable.

Disclosures Consultancy, symposia and research for Boehringer Ingelheim Consultancy, symposia, research and hospitality for Roche Consultancy, research and symposia for AstraZeneca 2

Afatinib Indications: In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (Stage IIIb/IV) with activating mutations of EGFR (exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for whom immunotherapy is not suitable. Posology: The recommended dose is 40 mg once daily, orally. Maximum daily dose in squamous cell carcinoma of the lung is 50 mg, orally. Not recommended in patients with an egfr <15 ml/min, in patients requiring dialysis and in severe hepatic failure. 3

Choosing the sequence in EGFR-mutant NSCLC Evidence #1 TKIs are standard up front EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. Girard. Future Oncol 2018. Epub ahead of print. 4

PFS (months) First- and second-generation EGFR TKIs are standard in the first-line treatment of NSCLC harbouring common EGFR mutations Better PFS versus platinum-based chemotherapy 16 13.1 * 13.6 14 12 11 10.8 11 9.7 9.2 9.5 * 10 * 8 6.3 6.3 * 6.9 5.2 5.5 5.4 6 4.6 4 2 0 5.6 Erlotinib Gefitinib* Afatinib Platinum-based chemotherapy *PFS not reported for common mutations only. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor;. Gefitinib. Summary of Product Characteristics, 2010; Maemondo M, et al. N Engl J Med 2010;362:2380 8; Mitsudomi T, et al. Lancet Oncol 2010;11:121 8; Mok TS, et al. N Engl J Med 2009;361:947 57; Rosell, et al. Lancet Oncol 2012;13:239 46; Sequist, et al. J Clin Oncol 2013;31:3327 34; Wu, et al. Lancet Oncol 2014;15:213 22; Wu, et al. Ann Oncol 2015;26:1883 9; Zhou, et al. Lancet Oncol 2011;12:735 42. 5

Choosing the sequence in EGFR-mutant NSCLC Evidence #1 TKIs are standard up front Evidence #2 Not all TKIs are equal Girard. Future Oncol 2018. Epub ahead of print. 6

First-, second- and third-generation EGFR TKIs are not equal: activity against EGFR mutations Wild-type EGFR Intrinsic mutant EGFR ErbB heterodimers, e.g. HER2: ErbB3 Acquired T790M EGFR K K K K K K K Erlotinib Gefitinib First-generation TKI EGFR inhibition Activity range Reversible binding to wild-type and mutant EGFR Inactive on T790M mutant Afatinib Dacomitinib Second-generation TKI ErbB family blockade Activity range Irreversible covalent binding to EGFR, ErbB2 and ErbB4 to inhibit all ErbB family signalling Broader activity to overcome EGFR TKI-resistant mutations Osimertinib Third-generation TKI EGFR mutant-specific inhibitor Activity Range Specificity for EGFR T790M mutant; EGFR wild-type sparing Irreversible covalent binding to mutant EGFR K Kinase domain 7 HER2, human epidermal growth factor 2. Girard. Future Oncol 2018. Epub ahead of print.

First-, second- and third-generation EGFR TKIs are not equal: activity against EGFR mutations T790M Wild-type 100 IC 50 10 Wild-type T790M 1 EGFRm Wild-type EGFRm EGFRm T790M Gefitinib Afatinib Osimertinib Wild-type EGFR T790M EGFR mutant: L858R, exon 19 del IC 50, half-maximal inhibitory concentration. Cross, et al. Cancer Discov 2014;4:1046 61; Hirano, et al. Oncotarget 2015;6:38789 803; Li, et al. Oncogene 2008;27:4702 11. 8

First-, second- and third-generation EGFR TKIs are not equal: metabolism Drug Enzymes involved in the metabolism of oral EGFR TKIs Metabolised by CYP enzymes 3A4 3A5 2D6 1A1 1A2 1B1 2C8 2C9 Gefitinib +++ ++ +++ ++ + Erlotinib +++ +++ + + ++ + + + May inhibit CYP2C19 (w) CYP2D6 (w) UGT1A9, BRCP CYP3A4 (m) CYP2C8 (m) CYP1A1 (s) UGT1A1 (s) May induce Afatinib Dacomitinib ++ ++ + CYP2D6 (s) CYP1A1 CYP1A2 Osimertinib +++ +++ BCRP CYP3A4 CYP1A2 CYP2C BCRP, breast cancer resistance protein; CYP, cytochrome P450 enzyme; UGT, UDP-glycosyltransferase. Cross, et al. Cancer Discov 2014;4:1046 61; Li, et al. Oncogene 2008;27:4702 11; Peters, et al. Cancer Treat Rev 2014;40:917 26; TAGRISSO. Prescribing Information, March 2017. 9

Choosing the sequence in EGFR-mutant NSCLC Evidence #1 TKIs are standard up front Evidence #2 Not all TKIs are equal Girard. Future Oncol 2018. Epub ahead of print. 10

Response rate (%) PFS (%) First- and second-generation EGFR TKIs are not equal: antitumour activity Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive NSCLC (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial 0.80 0.60 p=0.002 p=0.150 p=0.003 70% 75% 69% 66% 56% 100 80 Afatinib (n=160) Gefitinib (n=159) Median, months 11.0 10.9 HR (95% CI) p value 0.74 (0.57 0.95) 0.0178 42% 60 0.40 40 27% 0.20 0.00 ITT Del19 L858R Afatinib Gefitinib CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat. Corral, et al. Ann Onc 2017;28(Suppl. 2):ii28. 20 Afatinib Gefitinib 16% 16% 0 8% 0 3 6 9 12 15 18 21 24 27 30 33 26 39 42 45 48 51 Months 160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0 159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0 11

Probability of PFS First- and second-generation EGFR TKIs are not equal: antitumour activity ARCHER 1050: Dacomitinib vs Gefitinib (excluding CNS metastases) ARCHER 1050: study design Phase III, randomised, open-label study to evaluate dacomitinib as an alternative first-line treatment for patients with advanced NSCLC with an EGFR-activating mutation Advanced NSCLC with EGFRactivating mutation(s) No prior systematic treatment of advanced NSCLC No CNS metastasis No prior EGFR TKI or other TKI ECOG PS 0, 1 R 1:1 (N=452) Satisfaction factors Race (including Asian vs non-asian) EGFR mutation type (exon 19 vs 21) Dacomitinib 45 mg PO QD (N=227) Gefitinib 250 mg PO QD (N=225) Primary endpoint PFS by blinded independent review 256 PFS events PFS HR 0.667 (50% ) 90% power 1-sided ɑ=0.025 mpfs: 14.3 vs 9.5 months Secondary endpoints PFS (investigator assessed), ORR, DOR, TTF, OS, safety, PROs No. at risk Dacomitinib Gefitinib 1.0 0.8 0.6 0.4 0.2 227 225 PFS: blinded independent review (ITT population) Number of events, n (%) Median PFS (95% Cl) HR (95% Cl) Daco (n=227) Gef (n=225) 136 (59.9%) 179 (79.6%) 14.7 (11.1 16.6) 9.2 (9.1 11.0) 0.59 (0.47 0.74) p<0.0001 0 0 6 12 18 24 30 36 42 154 155 106 69 73 34 PFS rate 30.6% vs 9.6% Months CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; PO, orally; QD, once daily; mpfs = median progression-free survival; ORR, objective response rate; DOR, duration of response; TTF, time to treatment failure; OS, overall survival; PRO, patient-reported outcome. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/nct01774721 (Accessed March 2018); Mok, et al. J Clin Oncol 2017;35(Suppl.): Abstract LBA9007; Wu, et al. Lancet Oncol 2017;18:1454 66. 20 7 6 1 0 0 0 0 12

Probability of PFS First- and third-generation EGFR TKIs are not equal: antitumour activity PFS in FLAURA 1.0 Osimertinib (n=279) Erlotinib or gefitinib (n=277) 0.8 0.6 0.4 Median PFS (95% Cl) 17.7 (15.1 21.4) 9.7 (8.5 11.0) HR (95% Cl) 0.45 (0.36 0.57) p<0.001 Osimertinib 0.2 0 0 3 6 9 12 15 18 21 24 27 Months No. at risk Osimertinib 279 259 229 200 170 132 66 22 3 0 Erlotinib or Gefitinib 277 235 192 138 101 69 28 5 1 0 Date cut-off 12 Jun 2017. Tick marks indicate censored data. Soria, et al. N Engl J Med 2018;378:113 25. First-generation EGFR TKI 13

First-, second- and third-generation EGFR TKIs do not have equal safety Second- or third-generation TKIs versus first-generation TKIs LUX-Lung 7 1,2 ARCHER 1050 3 FLAURA 4 Treatment discontinuation rate Afatinib (n=160) Gefitinib (n=159) Dacomitinib (n=227) Gefitinib (n=225) Osimertinib (n=279) Erlotinib or gefitinib (n=277) 6.2% 6.3% 9.7% 6.7% 10% 14% Most common Grade 3 AEs Diarrhoea 12% Rash/acne 9% Liver enzyme elevation 9% Rash/acne 3% Acne 14% Diarrhoea 8% Paronychia 7% Liver enzyme elevation 12% Dyspnoea 3% Diarrhoea 2% Decreased appetite 2% Rash/acne 7% Liver enzyme elevation 12% AE, adverse event. 1. Park, et al. Lancet Oncol 2016;17:577 89; 2. Paz-Ares, et al. Ann Oncol 2017;28:270 7; 3. Wu, et al. Lancet Oncol 2017;18:1454 66; 4. Soria, et al. N Engl J Med 2018;378:113 25. 14

After reduction (<40 mg) Patients (%) Before reduction ( 40 mg) Patients (%) Estimated PFS probability Dose reduction of afatinib reduced drug-related AEs without compromising efficacy Treatment-related AEs in patients who had a dose reduction from 40 mg (n=63) 100 80 60 40 20 0 Any Diarrhoea Rash/acne Stomatitis Nail effect PFS in patients who received a dose reduction within the first 6 months of treatment 1.0 0.8 0.6 0.4 Median, months HR (95% CI) p value <40 mg in first 6 months (n=47) 40 mg for first 6 months (n=113) 12.8 11.0 1.34 (0.90 2.00) 0.1440 100 All grades Grade 3 80 60 40 20 0 Any Diarrhoea Rash/acne Stomatitis Nail effect Hirsh, et al. J Clin Oncol 2016;34(Suppl.): Abstract 9046. 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months No. at risk: <40 mg 47 45 34 28 22 15 11 10 9 7 3 1 0 0 40 mg 113 97 78 66 45 32 23 17 12 6 3 2 1 0 15

Choosing the sequence in EGFR-mutant NSCLC Evidence #1 TKIs are standard up front Evidence #2 Not all TKIs are equal Evidence #3 Biology drives sequence Girard. Future Oncol 2018. Epub ahead of print. 16

First-line: PFS efficacy of TKIs is different in EGFR del19/l858r mutations Impact of specific EGFR mutations and clinical characteristics on outcomes after treatment with EGFR TKIs versus chemotherapy in EGFRm+ lung cancer: a meta-analysis Trial HR 95% Cl HR 95% Cl Exon 19 deletions Exon 21 L858R substitution ENSURE 0.20 0.12 0.33 0.54 0.32 0.91 EURTAC 0.27 0.17 0.43 0.53 0.29 0.97 LUX-Lung 3 0.28 0.18 0.44 0.73 0.46 1.16 LUX-Lung 6 0.20 0.13 0.32 0.32 0.19 0.54 NEJ002 0.24 0.15 0.38 0.33 0.20 0.54 OPTIMAL 0.13 0.07 0.24 0.26 0.14 0.48 WJTOG 3405 0.42 0.26 0.66 0.69 0.44 1.07 AII 0.24 0.20 0.29 0.48 0.39 0.58 TKI Chemotherapy TKI Chemotherapy EGFRm+, epidermal growth factor receptor mutation positive. Lee, et al. J Clin Oncol 2015;33:1958 65. 17

First-line: OS Efficacy of TKIs Is Different in EGFR del19/l858r Mutations Agent Study HR (95% CI) Del19 HR (95% CI) L858R LUX-Lung 3 0.53 (0.36 0.79) 1.30 (0.80 2.11) Afatinib Erlotinib Gefitinib LUX-Lung 6 0.64 (0.44 0.94) 1.22 (0.81 1.83) Total 0.59 (0.45 0.77) 0.01 0.1 1 10 100 Favours afatinib Favours chemotherapy 1.25 (0.91 1.71) ENSURE 0.79 (0.48 1.30) 1.05 (0.60 1.84) EURTAC 0.94 (0.57 1.54) 1.00 (0.56 1.79) OPTIMAL 1.52 (0.91 2.52) 0.92 (0.55 1.54) Total 1.04 (0.71 1.51) 0.01 0.1 1 10 100 Favours erlotinib Favours chemotherapy 0.98 (0.72 1.35) IPASS 0.86 (0.61 1.22) 1.40 (0.91 2.15) NEJ002 0.83 (0.52 1.34) 0.82 (0.49 1.38) WJTOG3405 1.19 (0.65 2.18) 1.11 (0.60 2.05) 0.01 0.1 1 10 100 Favours afatinib Favours chemotherapy 0.01 0.1 1 10 100 Favours erlotinib Favours chemotherapy Total 0.90 (0.70 1.17) 0.01 0.1 1 10 100 1.11 (0.81 1.54) 0.01 0.1 1 10 100 Favours gefitinib Favours chemotherapy Favours gefitinib Favours chemotherapy Kato, et al. Value Health 2015;18:A436 (Abstract PCN40). 18

Maximum change from baseline (%) First-line: afatinib is effective for uncommon EGFR mutations Clinical activity of afatinib in patients with advanced NSCLC harbouring uncommon EGFR mutations: a combined post hoc analysis of LUX-Lung 2, 3, and 6 120 100 80 60 40 20 0 20 40 Group 1 (n=33): Exon 18-21: G719, L861Q Group 2 (n=14): T790M mutations Group 3 (n=20): Exon 20 insertions 40 35 30 25 20 15 10 5 0 PFS (months) Response rate (%) T790M (n=14) Exon 20 ins (n=23) Mut/ dup exon 18-21 (n=38) G719X (n=18) L861Q (n=16) S768I (n=8) 14.3 8.7 71.1 77.8 56.3 100.0 PFS (months) 2.9 2.7 10.7 13.8 8.2 14.7 OS (months) 14.9 9.2 19.4 26.9 17.1 NE Note: A patient may be presented in more than one category. 60 80 100 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 Patient index sorted by maximum percent decrease in descending order Yang, et al. Lancet Oncol 2015;16:830 8. 19

Molecular mechanisms of acquired resistance to first-/second-generation EGFR TKIs HER2 8% 155 EGFR-mutant NSCLC patients, acquired resistance after TKI Molecular analyses on re-biopsy specimen MET amplification 3% Small cell + MET 1% Small cell 1% Small cell + T790M 2% MET + T790M 3% Unknown 18% T790M 60% HER2 T790M 4% 21 MET, MET proto-oncogene. Yu, et al. Clin Cancer Res 2013;19:2240 7.

Molecular mechanisms of acquired resistance to first-/second-generation EGFR TKIs Initial diagnosis J170 Relapse 12.74% 29.04% 5.10% ETV6, WNK1-WAC, MYO18B 53.21% Chemotherapy Type cellulaire Normal AML Mutations Funding Activating Mutation Recurrence Resistance Passenger Pathogenic 22 HSC, haematopoietic stem cell. Ding, et al. Nature 2015;481:506 10.

Probability of PFS Osimertinib standard of care for T790M+ acquired resistance to first-/second-generation EGFR TKIs Patients in the population 1.0 No. at risk Osimertinib Platinum-pemetrexed 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 Month 279 140 Platinum-pemetrexed 240 93 162 44 Osimertinib 88 17 50 7 13 1 0 0 No. of patients Median PFS (months) (95% CI) Osimertinib 279 10.1 (8.3-12.3 Platinum-pemetrexed 140 4.4 (4.2-5.6) HR for PD or death, 0.30 (95% CI: 0.23 0.41) p<0.001 23 PD, progressive disease. Mok, et al. N Engl J Med 2017;376:629 40.

Choosing the sequence in EGFR-mutant NSCLC Evidence #1 TKIs are standard up front Evidence #2 Not all TKIs are equal Evidence #4 Biological monitoring is key Evidence #3 Biology drives sequence Girard. Future Oncol 2018. Epub ahead of print. 24

Identification of T790M at acquired resistance, is tissue re-biopsy feasible? Prospective, multicentre, real-world study: Re-biopsy methods Surgery Adrenalectomy 1 Lung surgery 3 Node surgery 1 Cytology Nodes 3 Pleura 2 (n=82) Biopsy Bronchial + E-BUS 43 Pulmonary under CT 19 Liver 2 Bone 6 Skin 2 Retrospective, single-centre study: EGFRm+ NSCLC: PD after EGFR TKI (n=139) Eligible for third-generation EGFR TKI (n=120; 86%) Re-biopsy (n=75) Pathologic diagnosis (n=71; 95%) EGFR mutation analysis (n=61) Ineligible for trial: poor PS: n=10; comorbidity: n=7; elderly: n=2 Ineligible for re-biopsy: inaccessible tumour sites: n=19 (18 brain metastases and one lung lesion <20 mm); physician decision: n=10 patient refusal: n=6 unknown: n=10 Re-biopsy could not be done in 18% of cases, mainly because of anticoagulation that the patient s physician considered to be a contraindication. One patient refused re-biopsy. Among the 82 patients who underwent re-biopsy, the sample could be analysed histologically in 94% of cases. Cytologic samples represented only. Chouaid, et al. Lung Cancer 2014;86:170 3; Kawamura T, et al. Cancer Sci 2016;107:1001 5. T790M (n=20; 33%) 25

Proposed algorithm for use of plasma genotyping for EGFR T790M A Acquired resistance to EGFR TKI All patients undergo biopsy, FDA-approved FFPE assay for T790M T790M+ T790M Third-generation EGFR TKI Chemotherapy B Acquired resistance to EGFR TKI FDA-approved plasma assay for T790M and sensitising mutations T790M+ T790M Skip biopsy, start third-generation EGFR TKI Biopsy, FDA-approved FFPE assay for T790M T790M+ T790M Third-generation EGFR TKI Chemotherapy FDA, US Food and Drug Administration; FFPE, formalin-fixed, paraffin-embedded. Oxnard, et al. J Clin Oncol 2016;34:3375 82. 26

Choosing the sequence in EGFR-mutant NSCLC Evidence #1 TKIs are standard up front Evidence #5 Sequence makes survival Evidence #2 Not all TKIs are equal Evidence #4 Biological monitoring is key Evidence #3 Biology drives sequence Girard. Future Oncol 2018. Epub ahead of print. 27

What is OS in EGFR-mutant NSCLC? Number of lines x Addition of the PFS of all treatment lines TKIs, chemotherapy, other At each patient level: NEED for the swimmer plot of individual patients NOT the sum of median PFS in trials 28

Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI First-/secondgeneration TKI Chemotherapy First-/secondgeneration TKI Girard. Future Oncol 2018. Epub ahead of print. 29

Estimated OS (probability) OS in EGFR-mutant NSCLC: LUX-LUNG 3 trial 1.0 0.8 Common mutations (Del19/L858R) (n=307) Afatinib Cisplatin/pemetrexed 0.6 0.4 0.2 Median, months Common mutations Afatinib (n=203) Cis/Pem (n=104) 31.6 28.2 No. at risk: Afatinib Cis/Pem Yang, et al. Ann Oncol 2015;16:141 51. 0 HR (95% CI) 0.78 (0.58 1.06) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 203 104 197 98 188 92 181 86 171 81 162 71 143 63 133 55 OS (months) 121 52 108 47 101 40 90 35 58 26 49 20 32 10 9 5 1 1 0 0 30

Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI T790M+ Osimertinib Chemotherapy? TKI? First-/secondgeneration TKI Except if molecular target Girard. Future Oncol 2018. Epub ahead of print. 31

AURA3: treatment beyond osimertinib Ongoing osimertinib treatment at time of data cut-off (n=166) Discontinue treatment (n=113) Objective PD (n=77) AE (n=18) Subject decision (n=9) Other (n=8) Severe protocol non-compliance (n=1) Anticancer treatment post-discontinuation of osimertinib (n=67) Platinum-containing chemotherapy regimen (n=48) Non-platinum-containing chemotherapy regimen (n=18) Radiotherapy (n=17) EGFR TKI (n=9) EGFR TKI + non-pd-1/pd-l1 (n=6) PD-1/PD-L1 (n=4) PD-1, programmed death-1; PD-L1, programmed death ligand-1. Mok, et al. N Engl J Med 2017;376:629 40. 32

Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI T790M+ Osimertinib Chemotherapy? TKI? First-/secondgeneration TKI Except if molecular target T790M Chemotherapy First-/secondgeneration TKI Other MET/HER2 inhibitor Girard. Future Oncol 2018. Epub ahead of print. 33

Estimated OS probability OS in patients treated with osimertinib subsequently in LUX-Lung 3, 6 and 7 1.0 0.8 0.6 0.4 0.2 Median follow-up = 4.7 years 0 0 6 12 18 24 30 36 42 48 54 60 66 72 No. at risk: Time to death (months) Afatinib 37 37 37 37 37 37 36 35 28 20 12 3 0 Sequist, et al. Ann Oncol 2017;28(Suppl. 5): v460-v496 10.1093/annonc/mdx380 36

Estimated PFS probability Estimated PFS probability Analysis of treatment sequence: first-/secondgeneration TKIs followed by third-generation TKIs 1.0 0.8 0.6 0.4 Median PFS in LUX-Lung 7 11.0 months with afatinib 10.9 months with gefitinib OS in patients treated with osimertinib subsequently in LUX-Lung 3, 6, and 7 0.2 Afatinib Gefitinib 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time of PFS (mo) Median PFS in AURA-3 (T790M+) 1.0 0.8 10.1 months with osimertinib 0.6 Osimertinib 0.4 0.2 Platinum-pemetrexed 0 0 3 6 9 12 15 18 Months Sequist, et al. Ann Oncol 2017;28(Suppl. 5): v460-v496 10.1093/annonc/mdx380; Mok TS, et al. N Engl J Med 2017;376:629 40; Park K, et al. Lancet Oncol. 2016;17:577. 37

Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI First-/secondgeneration TKI T790M+ T790M Osimertinib Chemotherapy Chemotherapy Except if molecular target First-/secondgeneration TKI Other MET/HER2 inhibitor Osimertinib Girard. Future Oncol 2018. Epub ahead of print. 38

FLAURA: treatment beyond osimertinib Regimen Osimertinib (n=279) Erlotinib or gefitinib (n=277) First post-treatment anticancer therapy (including crossover osimertinib), n (%) Discontinued randomised trial treatment 138 (49) 213 (77) First post-treatment anticancer therapy 82 (29) 129 (47) No post-treatment anticancer therapy 56 (20) 84 (30) Ongoing randomised trial treatment 141 (51) 64 (23) First post-treatment anticancer therapy, n (%) EGFR-TKI 29 (21) 97 (46) PD-1/PD-L1 3 (2) 2 (1) Non-platinum chemotherapy 50 (36) 27 (13) Platinum-based chemotherapy 48 (35) 26 (12) Other targeted therapy 2 (1) 3 (1) Anti-VEGF 7 (5) 4 (2) Second post-treatment anticancer therapy, n (%) Second post-treatment anticancer therapy 24 (9) 39 (14) Only one post-treatment anticancer therapy 58 (21) 90 (32) Second post-treatment anticancer therapy, n (%) EGFR TKI 10 (7) 14 (7) PD-1/PD-L1 2 (1) 1 (<1) Non-platinum chemotherapy 11 (8) 19 (9) Platinum-based chemotherapy 4 (3) 16 (8) Other targeted therapy 1 (1) 2 (1) Anti-VEGF 3 (2) 6 (3) VEGF, vascular endothelial growth factor. Soria, et al. N Engl J Med 2018;378:113 25. 39

How to optimise sequence? Clinical factors CNS disease and progression Loss of patients from one line to another Treatment beyond progression Optimisation of treatments Anti-angiogenics Anti-EGFR antibodies Understanding of biology Resistance mechanisms to sequencing versus osimertinib Impact of de novo T790M 43

Molecular characterization after osimertinib first-line failure (all T790M negative) Kras and EGFR ampl 11% Kras 11% C797S 23% Baselin mutatio Ex19de Ex19de L858R PIK3CA 11% JAK2 11% Mek 11% Met ampl 11% Her2 mut 11% Ex19de Ex19de L858R a T790M Ex19de G719S S768I L858R Ramalingam, et al. J Clin Oncol 2018;36:841 9. 44