Next Generation EGFR Inhibitors

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1 Next Generation EGFR Inhibitors Tony Mok MD Li Shu Fan Medical Foundation Professor of Clinical Oncology Dept. of Clinical Oncology The Chinese University of Hong Kong

2 EGFR TKIs First Generation -Gefitinib -Erlotinib -Icotinib Second Generation -Afatinib -Dacomitinib Third Generation Fourth Generation?

3 EGFR TKI First Generation -Gefitinib -Erlotinib -Icotinib Second Generation -Afatinib -Dacomitinib Third Generation Fourth Generation?

4 EGFR Exon 20 T790M ATP Erlotinib Erlotinib +T790M

5 IC50 1 st generation gefitinib, erlotinib 2 nd generation Afatinib, dacomitinib T790M L858R/ X19 del WT Clinical tolerable dose

6 3rd-generation EGFR TKI Irreversible binding occurs due to covalent bond with C797. Mutation selective + irreversible binding + EGFR WT sparing more potent against T790M and 100 less potent against EGFR WT) Cross D, et al. Cancer Discov. 2014;4:

7 Pyrimidine-based TKI IC50 (nm) H1975 IC50 (nm) PC9 GR Gefitinib Gefitinib CL-387,785 CL-387,785 HKI-272 HKI-272 WZ3146 WZ3146 WZ4002 WZ4002 WZ8040 WZ8040 Zhou and Janne Nature 2009

8 L858R/T790M Del19/T790M p = p = w Vehicle 2w Relative Tumor Volume % Vehicle WZ-4002 Vehicle WZ w WZ4002 2w Del19/T790M L858R/T790M w Vehicle 2w Tumor Size (mm 3 ) Vehicle WZ4002 Erlotinib Day Zhou et al. Nature w WZ4002 2w A431 Cells EGFR WT & amplified

9 A New Generation of T790M inhibition Avitinib HM61713 CO1686 AZD9291

10 AZD9291 (Osimertinib)

11 Phas e I AURA: Phase I dose expansion study Patients with T790M positive advanced NSCLC whose disease has progressed following either one prior therapy with an EGFR-TKI or following treatment with both EGFR-TKI and other anticancer therapy Rolling six design Escalation Cohort 1 20 mg Cohort 2 40 mg Cohort 3 80 mg Cohort mg Cohort mg Expansion Positive Positive Positive Positive Positive Negative Negative First-line Biopsy Tablet Cytology Negative First-line Biopsy

12 AURA: RR of osimertinib in T790M positive patients RR: 64% Janne et al NEJM 372:1689, 2015

13 Impact of dose on RR

14 PFS in T790M +ive and ive populations Median PFS at 9.6 months

15 AURA2: Phase II, open-label, single-arm study on osimertinib Primary objective To investigate the efficacy of AZD9291 by assessment of ORR (RECIST 1.1 BICR) Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR-TKI Key inclusion criteria Aged 18 ( 20 in Japan) Confirmation of tumor EGFR mutation associated with EGFR-TKI At least one lesion suitable for accurate repeated measurements WHO performance status 0 or 1 Acceptable organ function Stable brain metastases allowed Central T790M mutation testing* of biopsy sample collected following confirmed disease progression T790M positive (n=210) T790M negative AZD mg once daily Not eligible for enrollment *Mitsudomi et al WCLC 2015

16 Tumor response by independent central review Best percentage change from baseline in target lesion all patients Complete response Partial response Stable disease Progressive disease Not evaluable Confirmed objective response Total ORR 71% (95% CI 64, 77) Complete response, n (%) Partial response, n (%) Stable disease 6 weeks, n (%) Progressive disease, n (%) DCR 2 (1) 139 (70) 41 (21) 15 (8) 92% (95% CI 87, 95) NOTE: Investigator-assessed ORR was also 71% (95% CI 64, 77) Data cut-off: May 1, Population: evaluable for response set (n=199). *Represents imputed values: if it is known that the patient has died, has new lesions or progression of non-target lesions, has withdrawn due to disease progression, and has no evaluable target lesion (before or at progression) assessments, best change will be imputed as 20%; ORR defined as the number (%) of patients with at least one visit response of complete response or partial response that was confirmed at least 4 weeks later; Response required confirmation after 4 weeks; Stable disease 6 weeks included the RECIST visit window (±7 days) CI, confidence interval; DCR, disease control rate (complete response + partial response + stable disease)

17 Probability of response Probability of progression-free survival Duration of response and progression-free survival Duration of response* (BICR) Progression-free survival* (BICR) Osimertinib approved by FDA on Nov , (2.5 years since the first patient enrollment) AZD mg Censored observations AZD mg Censored observations Number of patients at month: Month Number of patients at risk: Month KM-based estimated Total Median DoR, months (95% CI) Remaining in response, % (95% CI) 6 months 9 months 7.8 (7.1, NC) Maturity: 27% 75 (65, 82) NC (NC, NC) Range of DoR, months KM-based estimated Total Median PFS,** months (95% CI) 8.6 (8.3, 9.7) Maturity: 38% Remaining alive and progression free, % (95% CI) 6 months 9 months Median follow-up for PFS 70 (63, 76) 48 (36, 58) 6.7 months Data cut-off: May 1, *Green dotted lines represent 95% CI; Calculated using the Kaplan-Meier technique; Population: evaluable for response analysis set; Population: full analysis set (n=210); DoR is the time from the first documentation of complete/partial response (that is subsequently confirmed) until the date of progression or death in the absence of disease progression; **PFS is the time from date of first dosing until the date of objective disease progression or death; Median PFS (months) by investigator assessment was NC (95% CI 9.3, NC). Maturity: 37% DoR, duration of response; KM, Kaplan-Meier; NC, not calculable; PFS, progression-free survival

18 Phase I Pooled analysis of AURA 1+2 AURA Ph I/II Patients with T790M positive advanced NSCLC whose disease has progressed following either one prior therapy with an EGFR-TKI or following treatment with both EGFR-TKI and other anticancer therapy Rolling six design AURA2 Ph II Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR-TKI Escalation Cohort 1 20 mg Cohort 2 40 mg Cohort 3 80 mg Cohort mg Cohort mg Positive Positive Positive Positive Positive Negative Negative Negative T790M cohorts Central T790M mutation testing* of biopsy sample collected following confirmed disease progression First-line First-line Expansion Biopsy Tablet Cytology Biopsy T790M positive T790M negative AURA Phase II Extension (n=201) Osimertinib 80 mg QD Pooled Phase II AURA2 (n=210) Osimertinib 80 mg QD RR and PFS on 411 patients with T790M mutation Not eligible for enrollment AURA Ph I data cut-off 4 January, 2016; AURA pooled Ph II data cut-off 1 November, *The EGFR T790M mutation status of the patient s tumour was prospectively determined by the designated central laboratory using the cobas EGFR Mutation Test (Roche Molecular Systems) by biopsy taken after confirmation of disease progression on the most recent treatment regimen. Data from cohorts in grayed out boxes are not included in the analyses reported here. QD, once daily

19 Largest cohort (n=411) of T790M +ive population on osimertinib 80mg Median PFS: 11 months Yang et al ELCC 2016

20 AURA 3 Study Design Randomise ~470 patients 2:1 Central testing of ~ 1540 biopsy samples T790M+ (n=470) AZD9291 (80 mg p.o. qd) (n=407) Platinum-based doublet chemotherapy* every 3 weeks (n=203) Primary endpoint: PFS T790M- Not eligible for enrolment *Pemetrexed 500 mg/m 2 + carboplatin AUC5 or Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 P PI: T Mok YL Wu AUC5, area under the plasma concentration time curve 5 mg/ml 1 per minute; EGFRm+, EGFR mutation-positive; EGFR-TKI, EGFR tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer; p.o., orally; qd, once daily; T790M+, T790M mutation-positive; T790M-, T790M mutation-negative

21 Best timing for osimertinib? Dx of EGFR mutation positive lung cancer (+/- T790M) EGFR TKI Presence of T790M in plasma cfdna Clinical progression and T790M +ive To be supported by FLAURA?? Supported by AURA 1/2/3

22 Potential study concept: Osimertinib for molecular progression Time to osimertinib Failure (TTF) Monthly cfdna for T790M for patient on first line TKI Plasma positive for T790M without radiologic progression Continue the same TKI till radiologic progression Osimertinib osimertinib Primary endpoint: TTF or OS Time to osimertinib Failure (TTF)

23 Rociletinib (CO-1686)

24 Phase I/II dose escalation study T790M positive Confirmed RR by central review in 46 pts = 59% T790M negative Sequist et al NEJM 2015

25 Toxicity signal: hyperglycemia M502

26 TIGER-X: Phase 1/2 Trial of Rociletinib Key eligibility criteria Advanced or recurrent NSCLC with a documented activating EGFR mutation Prior treatment with EGFR-directed therapy Recent biopsy available or willing to undergo a new on-study biopsy; plasma samples collected Phase 2 only Disease progression while on treatment with EGFR-directed therapy T790M-positive biopsy at the time of entering study Treated stable CNS metastases are allowed Phase 1 (Dose Escalation) Phase 2 Expansion Cohorts CO-1686 Treatment 21-day cycles; escalate to MTD 2nd-line patients PD upon 1 immediate prior TKI >2nd-line patients PD upon 2 TKI or chemotherapy 500mg BID 625mg BID 750mg BID Key outcome measures Safety Tolerability PK profile ORR 26

27 SLD Change from Baseline (%) Best Response to Rociletinib (All Doses) in 256 Centrally Confirmed Tissue T790M+ Patients mg 625mg 750mg 1000 mg Total N ORR (%) DCR (%) Nov 2015: FDA denied the fast track application 500mg BID HBr 625mg BID HBr 750mg BID HBr 1000mg BID HBr + Ongoing May 2016: Cessation of future development of Rociletinib SLD, sum of longest diameters *3 patients currently have no evaluable baseline lesions per database and are omitted from this analysis 27

28 Olmutinib (HM61713)

29 HM61713 = BI

30 Phase I/II study in patients with EGFR TKI pre-treated NSCLC Dose escalation (N=66) 1 T790M-positive or negative Progression on 2 prior therapies, including EGFR TKI 75 mg 150 mg 100 mg 200 mg 250 mg 400 mg 300 mg 650 mg 500 mg 800 mg 1200 mg Expansion Part 2 (N=76; ongoing) T790M-positive (central test) Progression on 1 prior EGFR TKI Expansion Part 1 (N=83) 1 T790M positive or negative Progression on prior EGFR TKI 1. Park K, et al Santa Monica 2016.

31 Tumor volume change (%) ORR and tumor shrinkage in T790M+ patients (independent review) PR (n=43) Confirmed PR (n=32) SD (n=20) NE (n=3) PD (n=3) Evaluable patients (n=69) OR (confirmed and unconfirmed), n (%) 43 (62) Disease control, n (%) Confirmed OR, n (%) SD, n (%) 63 (91) 32 (46) 31 (45) PD, n (%) 3 (4) NE, n (%) 3 (4) DoR is immature; in patients with confirmed OR, response duration ranged between 6 and 31 weeks at data cut-off DoR, duration of response; OR, objective response; ORR, objective response rate; NE, not evaluable; PD, progressed disease; PR, partial response; SD, stable disease

32 Most frequent treatment-related adverse events at 800 mg QD BI (HM61713) 800 mg QD (n=76) AE, n (%) All grades Grade 3 Diarrhea 42 (55) 0 Rash 29 (38) 4 (5) Nausea 28 (37) 0 Pruritus 27 (36) 1 (1) Dry skin 22 (29) 1 (1) Palmar-plantar erythrodysesthesia syndrome 22 (29) 2 (3) Decreased appetite 20 (26) 0 Skin exfoliation 16 (21) 0 Vomiting 12 (16) 2 (3) Abdominal pain 11 (14) 0 ALT increased 11 (14) 2 (3) Abdominal pain upper 10 (13) 0 Constipation 10 (13) 0 Pyrexia 9 (12) 0 AST increased 9 (12) 2 (3) Platelet count decreased 9 (12) 0 Dyspepsia 8 (11) 0 Fatigue 8 (11) 0 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase

33 LUX Lung Program

34 ELUXA Lung Program ELUXA 1: Phase II trial in second-line patients with EGFR T790M+ NSCLC ELUXA 2: Phase III trial of second-line BI vs platinumdoublet chemotherapy in patients with EGFR T790M+ NSCLC ELUXA 3: Phase III trial of first-line BI vs afatinib in EGFR M+ NSCLC ELUXA 4: Phase I/II trial of BI in Japanese patients with EGFR T790M+ NSCLC

35 EGF816

36 Phase I/II study design Tan et al ASCO 2015

37 Tumor response (n=53) Tan et al ASCO 2015

38 Skin rash

39 Avitinib (AC0010)

40 Phase I dose Escalation/Expansion (BID) in T790M + NSCLC Patients (NCT )

41 Best Change in Target Lesion and Objective Response Rate (N=36) All doses level (N=36) ORR: 36%; DCR (PR+SD): 97% (35/36) Therapeutic doses level (200 mg to 300 mg, N=19) ORR: 58%; DCR (PR+SD): 95% (18/19) Wu YL Santa Monic

42 EGFR TKI First Generation -Gefitinib -Erlotinib -Icotinib Second Generation -Afatinib -Dacomitinib Third Generation Fourth Generation?

43 Evolution of resistance mechanisms in EGFR mutant lung cancer following successive EGFR TKI therapy Erlotinib T790M+ Osimertinib T790M+ plus C797S T790M- T790M+ plus unknown resistance EGFR activating mutation = EGFR T790M = EGFR C797S = resistance mechanism due to activation of bypass or downstream signaling pathway T790M plus unknown resistance Loss of T790M Oxnard et al. IASLC 2015, and Planchard et al. Ann Oncol 2015

44 C) EGFR - + C797S 1 um WZ - + pegfr 121 Pt Res # 1 EGFR perk EGFR C797 Covalent binding site of all mutant selective EGFR Inhibitors MGH121 pt MGH121 Res # ERK ps6 S6 Actin Gly 796 Cys 797 Leu 798 G G C T G C C T C Gly 796 Cys/Ser 797 Leu 798 G G C T G/C C C T C MGH121 pt MGH121 Res # 1 Zhou et al. Nature, 2009; Thress et al, Nature Medicine, 2015; 2 Oxnard et al. IASLC 2015; 3 Song et al. JTO 2016

45 Reported Resistance Mechanisms to Rociletinib and Osimertinib (n=34) SCLC/T790-wt 9% C797S/T790M 21% T790M Maintained (No additional resistance mechanism identified) 35% Her2 Amp/T790-wt 3% MET Amp/T790-wt 3% T790M "Lost" 29% Thress KS, Paweletz CP, Felip E, et al, Nat Med. 2015;21(6): Piotrowska Z, Niederst MJ, Karlovich CA, et al, Cancer Discov. 2015;5(7): Yu HA, Tian SK, Drilon AE, et al, JAMA Oncol. 2015;1(7): Planchard D, Loriot Y, André F, et al, Ann Oncol. 2015;26(10): Kim TM, Song A, Kim DW, et al, J Thorac Oncol Courtesy Zofia Piotrowska

46 EGFR L798I αd helix PNAS, 1991, 88, Jeabong Jang and Nathanael Gray

47 Chabon et al ASCO 201

48 The first report of a potential molecule targeting C797S

49 EGFR Allosteric Inhibitor: EAI-045

50 Limited activity as an single agent EAI045 binds the C- Helix, which can be displaced by dimerization of EGFR Prevention of dimerization may improve the potency of EAI045 in C797S mutation.

51 Summary AZD9291 (Osimertinib) Approved therapy for T790M+ disease RR at 64%, PFS 9.6month CO1686 (Rociletinib) RR is not confirmed at the FDA submission Hyperglycemia from active metabolite HM61713 (Olmutinib) Enter into phase III study after a partnership with BI EGF816 Phase I response rate at 75% Unusual maculopapular rash Fourth Generation? Targeting C797S Allosteric molecule EAI045

52 I am so confused!!

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