Inhibidores de EGFR Noemi Reguart, MD, PhD Hospital Clínic Barcelona IDIPAPS

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1 Inhibidores de EGFR Noemi Reguart, MD, PhD Hospital Clínic Barcelona IDIPAPS

Driver Mutations to Classify Lung Cancer Unknown 36% KRAS 25% EGFR 15% ALK 4% HER2 2% Double Mut 2% BRAF 2% PIK3CA <1% MET <1% MEK <1% NRAS <1% Unknown 56% FGFR1 amp 20% PIK3CA

2 Driver Mutations to Classify Lung Cancer Unknown 36% KRAS 25% EGFR 15% ALK 4% HER2 2% Double Mut 2% BRAF 2% PIK3CA <1% MET <1% MEK <1% NRAS <1% Unknown 56% FGFR1 amp 20% PIK3CA 10% PTEN 10% DDR2 4% Carcinoid Large Cell Large Cell Neuroendocrine 5% Unknown 90% PIK3CA amp 10% Lung Cancer Consortium ASCO 2011; Perez-Moreno Mountain, et al. CCR Chest

Selecting Targeted Drugs in Lung Adenocarcinoma 0.69 [95%CI, 0.53-0.9], P =.

3 Selecting Targeted Drugs in Lung Adenocarcinoma 0.69 [95%CI, ], P =.006 Over 64% of lung ADK have an actionable driver oncogene Mark G. Kris,et al, JAMA 2014

4 EGFR mutations in lung cancer ACTIVATING MUTATIONS 10-14% white 30-40% asian * Most frequent Sharma SV, et al. Nat Rev Cancer 2007;7; Sharma SV, et al. Nat Rev Cancer 2007;7:169 81

Nat Rev Cancer 2007;7;169 81 Greulich H,

5 EGFR mutations are oncogenic in vitro & in vivo Sharma SV, et al. Nat Rev Cancer 2007;7; Greulich H, et al. PLoS 2005 ; Hongbin Ji, et al. Cancer Cell 2006

6 EGFR mutations are sensitive to TKIs Paez Science 2004; Lynch NEJM 2004; Pao PNAS 2004

Efficacy of 1 st & 2 nd Generation TKIs in First Line STUDY EGFR TKI N RR (%) PFS (mo) OS (mo) Ref IPASS Gefitinib 261 71 vs 47 9.5 vs 6.3* 21.6 vs 21.

3* 36 vs 39 Yoshioka, 2014 Phase III TKI vs TKI : ARCHER 1050 (NCT01774721): phase III NEJ002 Gefitinib 228 73 vs 30 10.8 vs 5.4* 27.7 vs 26.

7 Efficacy of 1 st & 2 nd Generation TKIs in First Line STUDY EGFR TKI N RR (%) PFS (mo) OS (mo) Ref IPASS Gefitinib vs vs 6.3* 21.6 vs 21.9 Fukuoka, 2011 Erlotinib, Gefitinib, Afatinib, approved First-Signal Gefitinib vs vs vs 25.6 Han, 2012 WJTOG3405 Gefitinib vs vs 6.3* 36 vs 39 Yoshioka, 2014 Phase III TKI vs TKI : ARCHER 1050 (NCT ): phase III NEJ002 Gefitinib vs vs 5.4* 27.7 vs 26.6 Inoue, 2013 dacomitinib vs gefitinib, final accrual Febr 2015 OPTIMAL Erlotinib vs vs 4.6* 22.6 vs 28.8 Zhou, 2011 LUX-Lung 7 (NCT ): phase IIb EURTACC Erlotinib vs vs 5.2* 19.3 vs 19.5 Rosell, 2012 afatinib vs gefitinib, final accrual Sept 2013 ENSURE Erlotinib vs vs 5.5* NR Wu, 2013 LUX-LUNG 3 Afatinib vs vs 6.9* 31.6 vs 28.2 Sequist, 2013 LUX-LUNG 6 Afatinib vs vs 5.6* 23.6 vs 23.5 Wu, 2014

8 Del 19 Common mutations L858R Yang et al. Lancet Oncol 2015

9 Current treatment beyond TKI progression EGFR MUT FIRST LINE TKI 12 mo SECOND LINE QTP 6 mo THIRD LINE QTP 3-5 mo BSC 2 mo OS mo

10 Resistance Mechanisms for TKIs Pooled data from the 2 largest re-biopsy series after TKI-progression. Arcila, CCR 2011; Sequist et al. Sci Transl Med 2011

11 Strategies to overcome AR to TKIs Chong et al, Nature Medicine 2013

3 rd Generation T790M inhibitors TKIs spare EGFR WT Generation TKI EGFR wt H2073 EGFR m ELREA (Exon 19) T790M- PC-9 T790M+ PC-9 VanR EGFR m L858R (Exon 21) T790M- H3255 T790M+ H1975 FIRST Gefitinib

12 3 rd Generation T790M inhibitors TKIs spare EGFR WT Generation TKI EGFR wt H2073 EGFR m ELREA (Exon 19) T790M- PC-9 T790M+ PC-9 VanR EGFR m L858R (Exon 21) T790M- H3255 T790M+ H1975 FIRST Gefitinib Erlotinib SECOND Afatinib Dacomitinib THIRD AZD CO HM Data form Cross et al, Cancer Discov 2014; Walter et al, Cancer Discov 2013

13 Log tumour volume Log tumour volume Activity of AZD9291 in vitro & in vivo In vitro resistance to AZD9291 took significantly longer to emerge Sustained tumour shrinkage in tumour xenografts PC9 (EGFR exon 19 deletion) (cm 3) 0.01 Vehicle only BID Gefitinib 6.25 mg/kg QD AZD mg/kg QD AZD mg/kg QD Da ys H3255 (EGFR L858R) (cm 3) Vehicle only BID Gefitinib 6.25 mg/kg QD AZD mg/kg QD Afatinib 7.5 mg/kg QD Day s Eberlein et al. Proceedings of the 105th AACR 2014; abstract 1722.

Phase I dose escalation/expansion study design (AURA) Escalation Not preselected by T790M

Cohort 5 240 mg Expansion Enrolment by local testing followed by central laboratory

alone T790M+ T790M+ T790M- T790M+ T790M- 1st-line EGFRm+ * Biopsy # T790M+ T790M- 1st-line

14 Phase I dose escalation/expansion study design (AURA) Escalation Not preselected by T790M status Cohort 1 20 mg Cohort 2 40 mg Rolling six design Cohort 3 80 mg Cohort mg Cohort mg Expansion Enrolment by local testing followed by central laboratory confirmation (cobas EGFR Mutation Test) of T790M status or by central laboratory testing alone T790M+ T790M+ T790M- T790M+ T790M- 1st-line EGFRm+ * Biopsy # T790M+ T790M- 1st-line EGFRm+ * Biopsy # T790M+ Tablet ## Total 253 patients included Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009

ORR in T790M+ patients (central test) 40 61% ORR (per RECIST) 20 0-20 -40-60 -80 20 mg 40

70) DCR (CR+PR+SD) was 95% (121/127; 95% CI 90, 98) 20 mg 40 mg 80 mg 160 mg 240 mg N

15 ORR in T790M+ patients (central test) 40 61% ORR (per RECIST) mg 40 mg 80 mg 160 mg 240 mg -100 Confirmed ORR in patients with T790M+ 61% (78/127; 95% CI 52, 70) DCR (CR+PR+SD) was 95% (121/127; 95% CI 90, 98) 20 mg 40 mg 80 mg 160 mg 240 mg N (127) ORR 50% 59% 70% 61% 50% Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009

ORR in T790M- patients (central test) 40 21% ORR (per RECIST) 20 0-20 -40-60 -80-100 20 mg 40 mg 80 mg 160 mg Confirmed ORR in patients with T790M- 21% (13/61; 95% CI 12,

16 ORR in T790M- patients (central test) 40 21% ORR (per RECIST) mg 40 mg 80 mg 160 mg Confirmed ORR in patients with T790M- 21% (13/61; 95% CI 12, 34) DCR (CR+PR+SD) was 61% (37/61; 95% CI 47, 73) 20 mg 40 mg 80 mg 160 mg 240 mg N (127) ORR 67% 6% 17% 33% - Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009

Probability of progression-free survival Progression-free survival in T790M+ (central test) 1.0 0.9 0.8 0.7 0.6 0.5 T790M+ (95% CI) 0.4 0.3 0.2 0.1 0 Preliminary median PFS = 9.

17 Probability of progression-free survival Progression-free survival in T790M+ (central test) T790M+ (95% CI) Preliminary median PFS = 9.6 months (95% CI 8.3, not reached) (30% maturity, 41/138 events) Patients at risk: T790M Study month Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009

Probability of progression-free survival Progression-free survival in T790M- (central test) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Preliminary median PFS = 2.

18 Probability of progression-free survival Progression-free survival in T790M- (central test) Preliminary median PFS = 2.8 months (95% CI 2.1, 4.3) (71% maturity, 44/62 events) T790M- (95% CI) Patients at risk: T790M Study month Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009

All-causality AEs, all grades Patients with an AE, n (%) 20 mg N=21 40 mg N=58 80 mg N=90 160 mg N=63 240 mg N=21 Total N=253 AE by preferred term occurring in at least 10% of patients overall

19 All-causality AEs, all grades Patients with an AE, n (%) 20 mg N=21 40 mg N=58 80 mg N= mg N= mg N=21 Total N=253 AE by preferred term occurring in at least 10% of patients overall Diarrhoea 5 (24) 24 (41) 30 (33) 43 (68) 16 (76) 118 (47) Rash 5 (24) 13 (22) 29 (32) 40 (63) 15 (71) 102 (40) Fatigue 4 (19) 15 (26) 9 (10) 11 (17) 5 (24) 44 (17) Paronychia 2 (10) 5 (9) 11 (12) 18 (29) 6 (29) 42 (17) Hyperglycaemia 0 1 (2) 3 (3) 2 (3) 0 6 (2) QT prolongation 0 2 (3) 4 (4) 4 (6) 1 (5) 11 (4) Pneumonitis-like ev (2) 4 (6) 0 6 (2) - No dose-limiting toxicities at any dose - MTD not defined Pasi A. J. et al, NEJM 2015; ASCO 2014, abst 8009

Phase 1/2 of CO-1686 (Rociletinib) Key eligibility criteria Advanced or recurrent NSCLC with a documented activating EGFR mutation Prior treatment with EGFR-directed therapy Recent biopsy available

20 Phase 1/2 of CO-1686 (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 Phase 2 only Disease progression while on treatment with EGFR-directed therapy T790M-positive biopsy at the time of entering study Phase 1 (Dose-escalation period) CO-1686 Treatment 21-day cycles; escalate to MTD Phase 2 (RP2D evaluation) TIGER X Expansion Cohorts 2 nd -line patients PD upon 1 immediate prior TKI >2 nd -line patients PD upon 2 TKI or chemotherapy 500 mg BID 625 mg BID 750 mg BID DoR, duration of response; ORR, objective response rate; FIH, first in human; MTD, maximum tolerated dose PK, pharmacokinetic; 20 RP2D, recommended Phase 2 dose L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014

21 Best Response for Evaluable T790M+ Patients (N= 46) 59% ORR 93% DCR Median PFS 13.1 months* L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014

22 Best Response for Evaluable T790M- Patients (N=17) 29% ORR (per RECIST) Median PFS 5.6 months L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014

23 Signs of brain activity with CO-1686 (Rociletinib) 3 previous treatment lines Erlotinib immediately before CO mg BID 82% target lesion reduction at C2 CNS lesion response Baseline C2 L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014

24 TIGER-X clinical dose group: AEs Treatment-related adverse events (all grades) seen in >10% of patients Adverse event Frequency, % Hyperglycemia 32 Diarrhea 25 Nausea 25 Reduced appetite 20 Fatigue 14 Muscle spasm 13 Vomiting 11 Grade 3/4 treatment-related adverse events seen in >5% of patients* Adverse event Frequency, % Hyperglycemia 14 *21% of patients had a grade 3/4 treatment-related adverse event and only hyperglycemia was observed in 5% of patients Rociletinib metabolite M502 is an inhibitor of IGF1R and accumulates in humans causing hyperglycemia Grade 3 QTc prolongation observed in 1 patient (625 mg BID) Pneumonitis observed in 4 patients (>200 patients, all doses, all genotypes) all quickly reversible 24 L.V. Sequist, et al, NEJM 2015; Soria J.C, EORTC-AACR 2014

25 Ongoing Trials with 3 rd Generation TKI AZD9291 -AURA- CO1686 -TIGER- The U.S. FDA has granted Breakthrough Therapy designation for Rociletinib and AZD9291 as treatment for mutant NSCLC in patients with the T790M mutation after progression on EGFRdirected therapy

LINE QTP 3-5 mo BSC 2 mo OS 35 mo EGFR MUT/T790M- FIRST LINE

26 Current treatment beyond TKI progression EGFR MUT/T790M+ FIRST LINE TKI 12 mo T790M INH mo SECOND LINE QTP 6 mo THIRD LINE QTP 3-5 mo BSC 2 mo OS 35 mo EGFR MUT/T790M- FIRST LINE TKI 12 mo????? SECOND LINE QTP 6 mo THIRD LINE QTP 3-5 mo BSC 2 mo

27 Final remarks Search for alternative options for EGFR MUT/T790M- : Selective c-met inhibitors (INC280, AZD6094) for c- Met AMP Best sequence 1 st /2 nd then 3 rd generation vs 3 rd generation TKI upfront Rebiopsies, when, where, how? cfdnat790m a good biomarker? Combos to delay resistance? TKIs plus c-met inhibitors or MEK inhibitors (selumetinib) or immune-checkpoint inhibitors?

29 EGFR mutations among ethnicity (Asian vs Caucasian) Barlesi, et al ASCO 2013; Johnson, et al. ASCO 2013; Sun et al. JCO 2010

- Percentage of tumour cells ( >50-80%)?

30 Re-biopsies to asses for resistance mechanisms When? Local PD? Gradual PD? Dramatic PD? Where? How? High-FDG uptake: T790M+? - Percentage of tumour cells ( >50-80%)? - LCM or macrodisection? - More sensitive technics? Low-FDG uptake:t790m-?

31 Oncogenic Drivers in Lung Adenocarcinoma * ROS1 rearrangements in ~1% Over 64% of lung ADK have an actionable driver oncogene Mark Kris, P03.07, WLCC Sidney 2013

32 Third Generation T790M inhibitors AZD9291 CO1686 (Rociletinib) HM61713

33 IMPRESS Trial: Phase III continuation of Gefitinib beyond progression Advanced EGFR + NSCLC CR/PR> 4 mo or SD> 6 mo with fiirst line Gefitinib No prior chemotherapy RECIST progression to Gefitinib ECOG 0/1 1:1 Random N=265 EU & Asia Primary endpoint: PFS Secondary endpoints: OS, RR, DCR Symptoms & QoL Pemetrexed, IV, 500mg/m2 Cisplatin, IV, 75mg/m2 q 21 days x 6 cycles plus Gefitinib 250 mg QD Pemetrexed, IV, 500mg/m2 Cisplatin, IV, 75mg/m2 q 21 days x 6 cycles plus placebo Mok et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA2_PR

34 Probability of PFS Probability of OS IMPRESS: Phase III continuation of Gefitinib beyond progression PFS OS (33% of events) Gefitinib (n=133) Placebo (n=132) PFS, mo HR a (95% CI) 0.86 (0.65, 1.13); p= Gefitinib (n=133) Placebo (n=132) Median OS, months HR a (95% CI) 1.62 (1.05, 2.52) p= Time of randomisation (months) Time of randomisation (months) Mok et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA2_PR

35 Phase Ib of combined afatinib and cetuximab in EGFR MUT 29% ORR (per RECIST) Median PFS 4.7 months 126 pts ORR: T % and T790M - 25% MTD: afatinib 40 mg daily and cetuximab 500 mg/m 2 every 2 weeks Janjigian, ESMO 2011; Cancer Discovery 2014

Treatment of EGFR mutant advanced NSCLC

Treatment of EGFR mutant advanced NSCLC Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester, Manchester, UK Outline Data on first-line Overcoming T790M