EGFR-M+ NSCLC: Mechanistic and Clinical Considerations for Choosing the Best TKI

Transcription

1 EGFR-M+ NSCLC: Mechanistic and Clinical Considerations for Choosing the Best TKI 217 Conversations in Oncology in Shanghai, China Dr. Daniel SW Tan Division of Medical Oncology, National Cancer Centre Singapore Senior Clinician Scientist, Genome Institute of Singapore Associate Professor (Adjunct), Duke-NUS Medical School BI Symposium

2 Disclosures Advisory Role and Consultant: Novartis, Bayer, Boehringer Ingelheim Travel and Honorarium: Merck, Pfizer, Novartis, Boehringer Ingelheim, AstraZeneca, Roche Research Funding: Novartis, GSK, Bayer, AstraZeneca 2

3 Driver Mutations and Resistance Mechanisms to EGFR TKIs Molecular driver mutations in NSCLC 1 Resistance mechanisms to EGFR TKIs 3 EGFR 2 : ~ 15% (Western population) ~ 3% (Asian population) KRAS BRAF PIK3CA MEK AKT1 ROS1 translocation EGFR ALK translocation HER2 NRAS RET translocation Other With EGFR amp MET amp PIK3CA T79M SCLC transformation Unknown mechanism 1. Baumgart M. Am J Hematol Oncol. 215;11(6):1-13; 2. Van Assche K, et al. Front Oncol ;4:35. doi: /fonc ; 3. Sequist LV, et al. Sci Transl Med. 211;3(75):75ra26. 3

4 EGFR Mutations in NSCLC EGF binding EGF binding TM Tyrosine kinase Autophosphorylation Exon T79M Exon 18 (nucleotide binding loop) Exon 19 Exon 2 Ex19Del Exon 21 (activation loop) L858R G719X Ex2 Ins L861Q Mitsudomi T and Yatabe Y. Cancer Sci. 27;98(12):

5 Clinical Course of a Patient with EGFR Mutation-positive NSCLC RESISTANCE First-line therapy Second-line therapy NSCLC (Stage IV) EGFR activating mutation First generation (erlotinib, gefitinib) or second generation (afatinib) TKI T79M ~5%, most common 1,2,3 MET amplification ~5 11% 1,2 Unknown 3% 2 Osimertinib (FDA, EMA approved) C-MET inhibitor (clinical trials) Chemotherapy ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; NSCLC, non-small lung cancer; SCLC, small cell lung cancer; TKI, tyrosine kinase inhibitor Arcila ME, et al. Clin Cancer Res. 211;17(5):1169 8; 2. Sequist LV, et al. Sci Transl Med. 211;3(75):75ra26; 3. Wang S, et al. J Hematol Oncol. 216;9:34.

6 Scope How I choose 1 st line therapy from currently available EGFR TKI? Management algorithm after progression on 1 st line EGFR TKI How to determine actionability from genomic analysis? Emerging biomarker parameters of clinical relevance Understanding the genomic landscape of EGFR mutant NSCLC Some future perspectives 6

7 Currently Approved EGFR-TKIs Gefitinib Afatinib Osimertinib First Generation Second Generation Third Generation Examples Gefitinib, Erlotinib Afatinib WZ42 1, Osimertinib, Nazartinib, etc. MoA Reversible ATP competitive Irreversible, covalent (Cys797) Irreversible, covalent (Cys797) Structure Quinazoline-based Quinazoline-based Pyrimadine-based Other features - Pan-HER inhibition WT sparing 7 1. Zhou W, et al. Nature 29;462: doi:1.138/nature8622.

8 Key Considerations Outcomes of TKIs (response, duration, survival) Mutation type: Exon 19 del, L858R Clinical parameters (performance status, age, AE profile) Brain disease (presence/absence) 8

9 First line EGFR TKI Trials in EGFR mutant NSCLC Trial TKI Comparing Tx ORR % PFS (months) HR OS (months) IPASS 1 Gefitinib Cb/Pac 71 v v ( ) 21.6 v 21.9 First-Signal 2 Gefitinib Cis/Gem 55 v v ( ) 27.2 v 25.6 WJTOG 3 Gefitinib Cis/Doc 62 v v ( ) 3.9 v NR NEJ2 4 Gefitinib Cb/Pac 74 v v ( ) 3.5 v 23.6 OPTIMAL 5 Erlotinib Cis/Gem 83 v v (.1-.26) Not mature EURTAC 6 Erlotinib Cis/Doc or Gem 58 v v ( ) 19.3 v 19.5 LUX-Lung 3 7,12,13 Afatinib Cis/Pem 62 v v ( ) 31.6 v 28.2 LUX-Lung 6 8,12,13 Afatinib Cis/Gem 68 v v (.2-.39) 23.6 v 23.5 LUX-Lung 7 9,14 Afatinib Gefitinib 73 v v ( ) 27.9 v 24.5 ARCHER 15 1 Dacomitinib Gefitinib 75 v v ( ) Not mature FLAURA 11 Osimertinib Gefitinib/ Erlotinib 8 v v ( ) Not mature Note: Unlike the other studies that reflect data from the overall population, LUX-Lung 3, -6 and -7 show values for patients with common mutations obtained by independent review. FLAURA results reflect data obtained investigator review. 1. Mok TS, et al. N Engl J Med. 29;361: ; 2. Han JY, et al. J Clin Oncol. 212;3(1):1122-8; 3. Mitsudomi T, et al. Lancet Oncol. 21;11(2):121-8; 4. Maemondo M, et al. N Engl J Med. 21;362(25):238-8; 5. Zhou C, et al, Lancet Oncol. 21;12(8):735-42; 6. Rosell R, et al. Lancet Oncol. 212;13(3):239-46; 7. Sequist LV, et al. J Clin Oncol. 213;31(27): ; 8. Wu YL,et al. Lancet Oncol. 214;15(2):213-22; 9. Park K, et al. Lancet Oncol. 216;17(5):577-89; 1. Wu YL, et al. Lancet Oncol. 217 Sep 25. pii: S (17)368-3; 11. Soria J-C, et al. N Engl J Med. Nov 18, 217 [Epub]. DOI: 1.156/NEJMoa ; 12. Yang JCH, et al. Lancet Oncol. 215;16(2):141-51; 13. Data on file. Boehringer Ingelheim; 14. Paz-Ares L, et al. Ann Oncol. 217; 28:

10 Pooled OS Analysis of LUX-3 and LUX-6 Exon 19 deletions L858R Yang JC, et al. Lancet Oncol. 215; 16(2):

11 LUX-Lung 3 and 6: Preplanned OS Analysis by Mutation Subgroups Estimated OS probability Estimated OS probability LUX-Lung 3: Del 19 LUX-Lung 6: Del Afatinib (n=112) Cis/pem (n=57) 1. Afatinib (n=124) Cis/gem (n=62).8 Median, months HR (95% CI) p value (.36.79) p=.15.8 Median, months HR (95% CI) p value (.44.94) p= No. at risk: Afatini b Cis/pe m L858R Time (months) No. at risk: Time (months) LUX-Lung 3 LUX-Lung 6 Afatinib (n=91) Cis/pem (n=47) Afatinib (n=92) Cis/gem (n=46) Median, months HR (95% CI), p value 1.3 ( ), p= ( ), p=.34 Afatini b Cis/ge m Yang JC, et al. Lancet Oncol. 215;16:

12 Exploratory Combined OS Analysis: Subsequent Therapy According to Mutational Subgroup Afatinib (n=236) Del19 Chemo (n=119) Afatinib (n=183) L858R Chemo (n=93) Discontinued study treatment (%) 21 (1) 119 (1) 168 (1) 93 (1) Received subsequent systemic therapy (%) 155 (73.8) 88 (73.9) 112 (66.7) 7 (75.3) Chemotherapy (%) 141 (67.1) 45 (37.8) 14 (61.9) 33 (35.5) EGFR TKI (%) 7 (33.3) 71 (59.7) 48 (28.6) 6 (64.5) Erlotinib Gefitinib Afatinib 47 (22.4) 29 (13.8) 1 (.5) 38 (31.9) 45 (37.8) 6 (5.) 35 (2.8) 18 (1.7) 1 (.6) 3 (32.3) 38 (4.9) 1 (1.1) EGFR TKI combination (%) 6 (2.9) 7 (5.9) 4 (2.4) 4 (4.3) Other (%) 13 (6.2) 7 (5.9) 8 (4.8) 4 (4.3) Yang JC, et al. Lancet Oncol. 215; 16(2): % 68.8% 12

13 LUX-Lung 7: Randomised Trial Evaluating Two EGFR-Directed Therapies in EGFRm NSCLC Patients (N=319) Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumour tissue* No prior treatment for advanced/metastatic disease ECOG PS /1 n=16 1:1 n=159 Afatinib 4 mg QD Stratified by: Mutation type (Del19/L858R) Brain metastases (present/absent) Gefitinib 25 mg QD Co-primary endpoints: PFS (independent review) TTF OS Secondary endpoints: ORR Time to response Duration of response Tumour shrinkage HRQoL Treatment beyond progression allowed if deemed beneficial by investigator RECIST assessment performed at Weeks 4 and 8, and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter Primary PFS analysis conducted after ~25 events; primary OS analysis conducted after ~213 events and 32-month follow-up All statistical testing at two-sided 5% alpha level with no adjustment for multiplicity *Central or local test; Dose modification to 5, 3 or 2 mg was permitted in line with prescribing information. ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QD, once daily; RECIST, Response Evaluation Criteria In Solid Tumors; TTF, time to treatment failure. Park K, et al. Lancet Oncol. 216;17:

14 Relative Clinical Efficacy of Afatinib vs Gefitinib Exon 19 del L858R 14 Park K, et al. Lancet Oncol. 216;17:

15 Estimated OS probability LUX-Lung 7: OS in the Overall Population 1. Afatinib Gefitinib.8 Median, months HR (95% CI) p value.86 ( ).258* Median follow-up: 42.6 months (as of 8 April 216) Median treatment duration (afatinib vs gefitinib): 13.7 vs 11.5 months No. at risk: Time (months) Afatinib Gefitinib *Unadjusted. CI, confidence interval; HR, hazard ratio; OS, overall survival. 15 Paz-Ares L, et al. Ann Oncol. 217; 28:

16 Estimated OS probability Estimated OS probability LUX-Lung 7: OS and Response by EGFR Mutation Subtype 1..8 Afatinib Gefitinib Median,months HR (95% CI) p-value.83 ( ) Del Time (months) No. at risk: Afatinib Gefitinib Afatinib Gefitinib Median,months HR (95% CI) p-value.91 ( ).6585 L858R Time (months) No. at risk: Afatinib Gefitinib CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; OS, overall survival. 1. Paz-Ares L, et al. Ann Oncol. 217; 28:27 277; 2. Park K, et al. Lancet Oncol. 216;17:

17 ARCHER 15: Dacomitinib vs Gefitinib (Excluding CNS Metastases) Probability of PFS ARCHER 15: 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 EGFR-activating mutation(s) No prior systematic treatment of advanced NSCLC No CNS metastasis No prior EGFR TKI or other TKI ECOG PS, 1 R 1:1 (N=452) Dacomitinib 45 mg PO QD (N=227) Gefitinib 25 mg PO QD (N=225) Primary endpoint PFS by blinded independent review 256 PFS events PFS HR.667 (5% ) 9% power 1-sided ɑ=.25 mpfs: 14.3 vs 9.5 months PFS: Blinded Independent Review (ITT population) Number of events, n (%) Median PFS (95% Cl) HR (95% Cl) PFS rate 3.6% vs 9.6% Daco (N=227) Gef (N=225) 136 (59.9%) 179 (79.6%) 14.7 (11.1, 16.6).59 (.47.74) p< (9.1, 11.) Censored Satisfaction factors Race (incl. Asian vs non-asian) EGFR mutation type (exon 19 vs 21) Secondary endpoints PFS (investigator assessed), ORR, DOR, TTF, OS, safety, PROs No. at risk Months Dacomitinib Gefitinib Mok T, et al. ASCO 217 Abstract LBA97. 17

18 Key Considerations Outcomes of TKIs (response, duration, survival) Mutation type: Exon 19 del, L858R Clinical parameters (performance status, age, AE profile) Brain disease (presence/absence) 18

19 Differences in Adverse Event Profile of EGFR TKIs Gefitinib Erlotinib Afatinib Osimertinib 1 st generation 1 st generation 2 nd generation 3 rd generation Mechanism ATP competitive ATP competitive Covalent (797) Covalent (797) Dose 25 mg 15 mg 4 mg 8 mg Dose intensity < 1/3 of MTD MTD MTD < 1/3 MTD Side effects, Any grade (G3/4) Rash Diarrhoea Mucositis Anorexia ISEL 1 37% (2) 27% (3) NR 17% (2) BR % (9) 55% (6) NR 69% (9) LUX % (9) 78% (13) 6% (4) 16% (1) AURA 4 32% () 33% (1) 1% () 11% (1) Discontinuation Rate 5% 5% 6% 6% 1. Thatcher N, et al. Lancet. 25;366(9496): ; 2. Shepherd FA, et al. N Engl J Med. 25;353(2):123-32; 3. Park K, et al. Lancet Oncol. 216;17(5):577-89; 4. Jänne PA, et al. N Engl J Med. 215;372(18):

20 Identifying Groups at Risk for Afatinib AEs 3 Factors associated with severe GI toxicity and DLT induced by afatinib in patients with advanced NSCLC 1 Severe GI toxicity DLT HR 95% CI p value Female Age, years ECOG PS Weight, kg Malnourished Body surface, m Malnourished Post-hoc analysis LUX-Lung 3: dose reductions more common in females, older patients, East Asian ethnicity, low body weight (<5 kg) and low body surface m 2 (BSA) 2 2 AE, adverse event; BSA, body surface area; CI, confidence interval; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; GI, gastrointestinal; HR, hazard ratio; NSCLC, non-small cell lung cancer. 1. Arrieta O, et al. Oncologist. 215;2:967 74; 2. Yang J, et al. J Clin Oncol. 215;33(Suppl.): abstract 873 (poster).

21 Key Considerations Outcomes of TKIs (response, duration, survival) Mutation type: Exon 19 del, L858R Clinical parameters (performance status, age, AE profile) Brain disease (presence/absence) 21

22 CNS Penetration of Different EGFR TKIs At baseline, 15-16% (LUX-7) and up to 26% in retrospective series 1 ; have brain metastases Dose intensity may have some degree of impact reported therapeutic success with pulsed dosing 2 CNS concentration and penetration gefitinib vs erlotinib 3 CNS concentration of afatinib 4 Overall CNS response rate 35% (n=11/31) in patients pre-treated with 1 st gen TKI 4 Mean Plasma Conc (nm) Mean CSF Conc (nm) Penetration rate (%) Gefitinib (n=8) ± ± ±.36 Erlotinib (n=9) ± ± ±.45 Afatinib (n=11) ± ± ± Jain A, et al. PLoS One. 215;1(5):e123587; 2. Grommes C, et al. Neuro Oncol. 211;13(12):1364-9; 3. Togashi Y, et al. Cancer Chemother Pharmacol. 212;7(3):399-45; 4. Hoffknecht P, et al. J Thorac Oncol. 215;1(1):156-63; 5. Tamiya A, et al. Anticancer Res. 217;37(8):

23 Estimated PFS probability Estimated PFS probability LUX-Lung 7: PFS in Patients With and Without Brain Metastases by Independent Review With brain metastases Without brain metastases 1. Afatinib (n=26) Gefitinib (n=25) Median, mo Afatinib (n=134) Gefitinib (n=134) Median, mo HR (95% CI), P-value.76 ( ).41.8 HR (95% CI), P-value.74 ( ) Afatinib Gefitinib.6 Afatinib Gefitinib Time of progression-free survival (months) No. at risk: Afatinib Gefitinib Time of progression-free survival (months) No. at risk: Afatinib Gefitinib Park K, et al. Ann Oncol. 215;26: (suppl 9; abstract LBA2). 46% of patients on afatinib arm had dose reductions 23

24 Estimated PFS probability Estimated PFS probability Estimated PFS Probability Median PFS was Similar in Patients who had Dose Reductions in the First 6 Months and Those who Remained on Afatinib 4 mg Once Daily LUX-Lung 3 LUX-Lung <4 mg in first 6 months 4 mg in first 6 months Time (months) Time (months) LUX-Lung 7 LUX-Lung 3 Median PFS (mo) <4 mg in first 6 months 11.3 (n=15) 4 mg for first 6 months 11. (n=124) HR (95% CI) P-value 1.25 ( ) Time of progression-free survival (months) LUX-Lung 6 LUX-Lung (n=55) 11. (n=184) PFS in overall population 12.8 (n=47) 11. (n=113) 1. ( ) 1.34 (.9-2.) 1. Yang J, et al. J Clin Oncol. 215;33(suppl):abstr 873; 2. Schuler M, et al. ELCC 216: #138PD; 3. Hirsh V. J Clin Oncol. 216;34(suppl):abstr

25 LUX-Lung 3, 6 and 7: PFS and Long-term Responders 1 PFS in LUX-Lung 3/6 2 and TTF in LUX-Lung 7 3 Percentage progression free 4 12 months 18 months 24 months LUX-Lung 3 51% 26% 14% LUX-Lung 6 47% 27% 17% LUX-Lung 7 47% 27% 18% 1 12% In the LUX-Lung 3, 6 and 7 studies, 1 12% of afatinib-treated patients were long-term responders (treated 3 years) 25 LL, LUX-Lung; PFS, progression -free survival; TTF, time to treatment failure. 1. Schuler M, et al. ECCO 217 Oral Presentation; 2. Wu Y-L, et al. ESMO 214 Poster 1251P; 3. Paz-Ares L, et al. ESMO 216 Abstract 2988; 4. Boehringer Ingelheim data on file.

26 Long-term Response Independent of Dose Adjustment: Post-hoc Analysis of LUX-Lung 7 Long-term treatment (>3 years) was independent of tolerability-guided dose adjustment, or the presence of brain metastases at time of enrolment *Patients were ordered and numbered by treatment duration, with Patient 1 being on treatment longest; At the time of enrolment. LTR, long-term responders; OS, overall survival. Schuler M, et al. ECCO 217 Oral Presentation. 26

27 Clinical Course of a Patient with EGFR Mutation-positive NSCLC RESISTANCE First-line therapy Second-line therapy NSCLC (Stage IV) EGFR activating mutation First generation (erlotinib, gefitinib) or second generation (afatinib) TKI T79M ~5%, most common 1,2,3 MET amplification ~5 11% 1,2 Unknown 3% 2 Osimertinib (FDA, EMA approved) C-MET inhibitor (clinical trials) Chemotherapy ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; NSCLC, non-small lung cancer; SCLC, small cell lung cancer; TKI, tyrosine kinase inhibitor Arcila ME, et al. Clin Cancer Res. 211;17(5):1169 8; 2. Sequist LV, et al. Sci Transl Med. 211;3(75):75ra26; 3. Wang S, et al. J Hematol Oncol. 216;9:34.

28 Define the Type of Progression Progressive Disease Oligo-progressive Multi-site progression CNS Extra-cranial PD Symptomatic Asymptomatic 4 or less lesions > 4 LMD Indolent growth Rapid growth SRS TKI TKI WBRT TKI TKI Watch TKI RT Chemo Chemo TKI Chemo 28

29 Current Clinical Algorithm Continue TKI beyond PD No tissue acquired Local ablative therapy CNS vs extracranial SRS, RT, RFA, cryo, surgery Tissue acquired No T79M negative surveillance Yes Is disease progression clinically significant? Yes Is disease progression localized? No Is re-biopsy feasible? Yes Histological review EGFR sequencing The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 216. No T79M positive Consider cfdna EGFR testing* Plasma T79M+ Screen for alternative resistance mechanisms Are there clinical trials available? Switch to 3 rd gen EGFR TKI PD, consider re-biopsy Plasma T79M- *if validated and qualified assay available Tan DS, et al. J Thorac Oncol. 216;11(7): Start chemotherapy +/- EGFR TKI 29

30 T79M is a Common Resistance Mechanism after 1 st /2 nd Gen TKI Singapore (n=116) 1 MGH (n=37) 2 MSKCC (n=155) 3 [CATEGO RY NAME], n=[value ], [PERCENT AGE] [CATEGO RY NAME], n=[value ], [PERCENT AGE] [CATEGO [CATEGO RY NAME], RY NAME], n=[value], n=[value] [PERCENT, AGE] [PERCENT AGE] [CATEGO RY NAME], n=[value ], [PERCENT AGE] Japan 5 [CATEGORY NAME], n=[value], [PERCENTA GE] 3 1. Teng R, et al. Ann Oncol. 217;28(suppl2):ii28-ii51. ELCC 217 Poster; 3. Sequist LV, et al. Sci Transl Med. 211;3(75):75ra26; 4. Yu HA, et al. Clin Cancer Res. 213;19(8): ; 5. Hata A, et al. Cancer. 213;119(24):

31 EGFR T79M ATP Erlotinib Erlotinib + T79M Threonine replaced by Methionine at position 79 on exon 2 results in: 1. Increases relative affinity of mutant EGFR for ATP 1 2. May also cause steric hindrance to 1 st generation TKI 2 1. Yun C-H, et al. Proc Natl Acad Sci U S A. 28;15(6):27-275; 2. Kobayashi S, et al. N Engl J Med. 25;352:

32 Probability of Progression-free Survival Probability of Progression-free Survival PFS Benefit in AURA3 Patients with CNS Metastases at Baseline 1. With CNS metastases Median progression-free survival, months (95% Cl) Osimertinib (n=93) 8.5 ( ) Platinum-pemetrexed (n=51) 4.2 ( ) 1. Without CNS metastases Median progression-free survival, months (95% Cl) Osimertinib (n=186) Platinum-pemetrexed (n=89) 1.8 ( ) 5.6 ( ).8 Hazard ratio for disease progression or death,.32 (95% Cl,.21.49).8 Hazard ratio for disease progression or death,.4 (95% Cl,.29.55) No. at risk Osimertinib Platinumpemetrexed Months Months Population: intent-to-treat. Progression-free survival defined as time from randomisation until date of objective disease progression or death. Progression included deaths in the absence of RECIST progression. CNS metastases determined programmatically from baseline data of CNS lesion site, medical history, surgery and/or radiotherapy. 1. Mok TS, et al. N Engl J Med. 217;376:629-4; 2. Tan DS, et al. J Thorac Oncol. 216;11(7):

33 Oxnard et al. JCO 216 cfdna by BEAMing in AURA study Exon 19 del L858R T79M Sensitivity 82.3% 86.3% 7.3% Specificity 97.5% 96.5% 69% Assay performance Biology Plasma T79M negative Plasma T79M positive 33

34 Evolving Definition of T79M+ Disease 1 st line 2 nd line 1 st or 2 nd generation TKI TBP 3 rd generation TKI T79M+ using high sensitivity assays T79M+ cfdna? T79M+ RECIST PD? De novo T79M Molecular PD RECIST PD Clinical PD 34 TBP: Treatment beyond progression

35 Landscape of Secondary Resistance Mechanisms 1 st vs 3 rd Generation EGFR TKI 1 st generation (erlotinib or gefitinib) 3 rd generation (Osimertinib) EGFR C797S 1 EGFR C797S EGFR C797S EGFR C797S 1 EGFR C797S EGFR C797S EGFR C797S MET amplification PIK3CA N345K SCLC transformation KRAS Q61K FGFR3-TACC fusion PIK3CA R88Q EGFR C797S EGFR C797S BRAF V6E SCLC transformation MET amplification CCDC6-RET rearrangement SCLC transformation SCLC transformation MET amplification T79M+ at resistance T79M- at resistance T79M- in tumor/ T79M+ in plasma at resistance 1 EGFR C797S detected in plasma but not tumor SCLC transformation + PIK3CA E545K 1. Yu HA, et al. Clin Cancer Res. 213;19(8): ; 2. Oxnard GR, et al. ORAL17.7. WCLC 217 Oral Presentation TTF (months) 35

36 EGFR C797S in Acquired Resistance to 3rd Gen EGFR TKIs EGFR del19 EGFR T79M EGFR C797S 36 Thress KS, et al. Nat Med. 215;21(6):

37 Niederst MJ, et al. Clin Cancer Res. 215;21(17):

38 Niederst MJ, et al. Clin Cancer Res. 215;21(17):

39 Secondary Resistance Mechanisms 1 st vs 3 rd generation EGFR TKI 1 st generation (erlotinib or gefitinib) 3 rd generation (Osimertinib) EGFR C797S 1 EGFR C797S EGFR C797S EGFR C797S 1 EGFR C797S EGFR C797S EGFR C797S MET amplification PIK3CA N345K SCLC transformation KRAS Q61K FGFR3-TACC fusion PIK3CA R88Q EGFR C797S EGFR C797S BRAF V6E SCLC transformation MET amplification CCDC6-RET rearrangement SCLC transformation SCLC transformation MET amplification T79M+ at resistance T79M- at resistance T79M- in tumor/ T79M+ in plasma at resistance 1 EGFR C797S detected in plasma but not tumor SCLC transformation + PIK3CA E545K 1. Yu HA, et al. Clin Cancer Res. 213;19(8): ; 2. Oxnard GR, et al. ORAL17.7. WCLC 217 Oral Presentation TTF (months) 39

40 Resistance Mechanisms to Nazartinib (EGF816) Best % change from baseline PFS (months) Patient ID no. Baseline EGFR mutations 9 EX19DEL, T79M EX19DEL 11 EX19DEL EX19DEL 3 EX19DEL, T79M EX19DEL Progression 6 EX19DEL, T79M EX19DEL, T79M, C797S Other cancer-related genetic alterations at progression 8 EX19DEL, T79M EX19DEL PIK3CA Y121C, RB1 loss, IRS2 amp 1 EX19DEL, T79M EX19DEL, T79M TP53 S183*, RB1 D68fs*9, EGFR amp 2 EX19DEL, T79M EX19DEL TP53 R273C, CDKN2A M53I, BRAF rearrangement (CLDN15 partner), HGF amp, MYST3 amp AKT2 amp, ARFRP1 amp, AXL amp, CCNE1 amp, CDKN2A Y44fs*1 (13_131insA), TP53 L13R TP53 P278S, CDKN2A/2B loss, EGFR amp, BRIP1 truncation, ETV6 truncation 1 L858R, T79M L858R TP53 S241Y, PIK3CA P447_L455del, CCNE1 amp CTNNB1 D32G, PIK3CA Q546K, CDKN2A/2B loss, MTOR A1828_1831del, PTPRD splice site G>T 4 EX19DEL, T79M EX19DEL CTNNB1 S33F 5 L858R, T79M L858R, T79M PTCH1 T416S, EGFR amp, MDM2 amp, FRS2 amp, NKX2-1 amp, JUN amp, ZNF217 amp, AURKA amp 7 EX19DEL, T79M EX19DEL, G724S TP53 L45fs*71 MET amp, BRAF rearrangement (PRKAR1B partner), EMSY amp, MDM2 amp, FRS2 amp, EGFR amp Amp, amplification; DEL, deletion; EX, exon; ID no, identification number. Central testing (Qiagen Therascreen); Equivocal amplification; Patient 4 and 7 are qualified reports: presence of identified alterations can be confirmed, but absence of other alterations cannot, due to specimen quality; Patient 11 was T79M-negative at baseline. This plot only includes patients with PD tumor biopsies. At baseline, testing was by local clinical test except where noted. At progression, testing was by Foundation Medicine T7 panel. 4 Tan DS, et al. J Clin Oncol. 217;35(suppl15):1156. ASCO 217 Abstract #1156.

41 Genomic Architecture of 16 EGFR Mutant NSCLC 41 Nahar R, et al. Nat Commun. In press.

42 Co-drivers can Portend Poor Outcomes EGFR TP53 PTEN CLIP1 RBM1 42 Nahar R, et al. Nat Commun. In press.

43 EGFR M+ NSCLC have a Highly Variegated Copy Number Landscape Higher variance in high amplitude copy number changes across sectors 43 Nahar R, et al. Nat Commun. In press.

44 Genomic Landscape can Dictate Clinical Trajectories GGO Primary TKI resistance 44 Nahar R, et al. Nat Commun. In press.

45 Copy no alterations Allelic frequency Somatic mutations Value of Sequential Rebiopsies Genomic Alterations and Allele Frequencies Pre/Post EGF816 Baseline At Progression EX19DEL, T79M 19 th Dec th March th June 216 EX19DEL, T79M, C797S CTNNB1 D32G, PIK3CA Q546K CDKN2A/2B loss CCND3 Amp VEGFA Amp NKX2-1 Amp ERBB2 Amp TOP2A Amp Screening Visit *Equivocal amplification. Gene alterations detected at: baseline only (red), progression only (orange) or both baseline and progression biopsies (green). Tan DS, et al. J Clin Oncol. 217;35(suppl15):1156. ASCO 217 Abstract #1156. PD Gene Name CTNNB1_D32G EGFR_C797S EGFR_L747_P753>S EGFR_T79M MTOR_A1828_A1831del PIK3CA_Q546K PTPRD_splice site G>T CTNNB1 D32G, PIK3CA Q546K MTOR A1828_1831del, PTPRD splice site G>T, CDKN2A/2B loss 45

46 Conclusions Small cell transformation C797S Need to improve stratification of EGFR mutant NSCLC TP53 wild type vs TP53 mutant cmet Exon 19 deletion, L858R and other SNPs Changing landscape of EGFR TKI resistance:? optimal sequence of therapy Genomic alterations at time of resistance need to be carefully evaluated for rational application of combination approaches Trunk vs branch cmet amp (MET inhibitors), C797S in trans (1 st gen EGFR TKI), BRAF alterations (?) Ex19 del T79M 46

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