Rociletinib (CO-1686) April, 2015

Transcription

1 Rociletinib (CO-1686) April, 2015

2 Lung adenocarcinoma is increasingly treated according to driver mutation Lung cancer incidence Worldwide: 1.2M cases per year UK: 43K cases per year Activating mutations (e.g. del 19, L858R) in EGFR found in ~15% of all NSCLC Twice as common in East Asian populations Standard of care in mutant EGFR NSCLC is most often a reversible EGFR inhibitor as first-line therapy Globocan 2012; CRUK 2011; Blakely & Bivona, Cancer Discov

3 T790M is the most common reason for loss of initial benefit with EGFR inhibitors in newly diagnosed NSCLC patients Tumor genetics in 155 mutant EGFR lung cancer patients undergoing re-biopsy after development of acquired resistance to erlotinib/gefitinib Yu et al., Clinical Cancer Res

4 There are limited options for patients that progress on first generation EGFR TKIs There are no therapies currently available to specifically target T790M disease Current standard treatment is cytotoxic chemotherapy Platinum containing doublet chemotherapy (e.g. gemcitabine/cisplatin) Single agent chemotherapy (e.g. pemetrexed, docetaxel, gemcitabine) New treatment options with improved adverse event profiles and reduced requirements for hospital care are needed. Yu et al., Clinical Cancer Res

5 Rociletinib (CO-1686) nonclinical summary Rociletinib (CO-1686) Inhibits the T790M EGFR resistance mutation at clinically relevant exposures Oral dosing Irreversible (covalent) inhibitor Inhibits EGFR activating mutations Spares wild-type (WT) EGFR signaling Highly selective across the entire kinome Rociletinib demonstrates potent activity and EGFR pathway blockade in cell lines with activating and T790M EGFR mutations As a single agent rociletinib causes tumor regressions in front-line and T790M xenograft models Includes subcutaneous, PDX, and transgenic models CO-1686 Walter et al., Cancer Discov

6 Rociletinib (CO-1686) binds EGFR covalently Irreversible binding results in sustained EGFR pathway suppression Interaction between trifluoromethyl group and M790 increases potency Acrylamide forms covalent bond with C797 Walter et al., Cancer Discov

7 G I 5 0 [C O ] n M Rociletinib (CO-1686) inhibits mutant EGFR, including T790M, but spares wild-type EGFR Growth inhibition of tumor cell lines with rociletinib (CO-1686) G e n o ty p e D e l1 9 L R T M 1 0 N C I-H H C C P C 9 H C C E P R A N C I-H N C I-H Front line model Second line model (T790M) EGFR WT Walter et al., Cancer Discov

8 % v ia b ility (m e a n S E M ) Rociletinib (CO-1686) spares wild type EGFR Rociletinib (CO-1686) is uniquely WT EGFR sparing A (W T E G F R ) rociletinib (CO-1686) Symbol Compound EC 50 (nm) afatinib 15 gefitinib 107 AZD erlotinib 209 CO d o s e [n M ] Clovis Oncology, data on file 8

9 L858R M e a n tu m o r v o lu m e (m m 3 ) S E M Rociletinib (CO-1686) causes tumor regression in front-line L858R transgenic model No cell line based models with EGFR L858R mutation available Performed gold standard transgenic model Vehicle Erlotinib CO B a s e li n e d a y s p o s t - d o s in g * * * * * * Diffuse tumor cells in lung V e h i c l e E r lo t in ib 5 0 m g /k g Q D C O m g /k g B ID Conclusion: Xenograft and transgenic models show that rociletinib is an effective inhibitor of initial activating EGFR mutations (Del19 and L858R) and T790M Walter et al., Cancer Discov

10 C h a n g e fro m B a s e lin e (% ) Rociletinib WT EGFR sparing profile allows for dosing to efficacy - not MTD CO-1686 activity observed in L858R/T790M transgenic model Afatinib: Baseline Afatinib : 3W P D S D CO-1686 : Baseline CO-1686 : 3W P R C R A fa tin ib 2 0 m g /k g C O m g /k g B ID Walter et al., Cancer Discov

11 T u m o r v o lu m e (M e a n m m 3 S E M ) Long-term Rociletinib activity superior to erlotinib in PC-9 (EGFRdel19) front line model Inhibition of T790M may improve durability of response rociletinib (CO-1686) administration better tolerated Impressive anti-tumor response in ~500 mm3 tumors No body-weight loss compared to vehicle treated animals C o n tin u e d o s in g n = 3 m ic e w ith e rlo tin ib D o s e re m a in in g m ic e w ith C O V e h ic le C O (1 5 0 m g /k g B ID ) E rlo tin ib (5 0 m g /k g Q D ) D a y s o f d o s in g Clovis Oncology, data on file 11

12 TIGER-X Phase 1 identified 625 mg as Phase 2 dose TIGER-X, an international phase 1/2 study, examined 2 formulations and multiple doses/schedules of rociletinib Therapeutic doses defined as 900 mg BID (original formulation) or 500 mg BID HBr salt tablet (PK optimized formulation) Two clinical doses under exploration 500 mg BID and 625 mg BID 625 mg BID of optimized oral formulation (fed state) was identified as the optimal dose and schedule 500 mg BID remains under investigation as step-down dose Clinical dose group: patients treated with 625/500 mg BID (n=56) Early evidence of activity was observed with durable RECIST responses, particularly in T790M+ patients Wild-type EGFR sparing was confirmed by absence of cutaneous toxicity (rash, paronychia, stomatitis, etc) Breakthrough status was granted by FDA in May 2014 Soria et al., ENA, 2014 FDA = US Food and Drug Administration; HBr = hydrobromide; RECIST = Response Evaluation Criteria In Solid Tumors; RP2D = recommended phase 2 dose 12

13 TIGER-X expansion phase in T790M+ Key inclusion criteria: Advanced or metastatic EGFR mutation+ NSCLC At least 1 prior EGFR TKI therapy, with no upper limit or limit on chemotherapy Biopsy within 60 days of study entry molecular analysis T790M+ Key exclusion criteria: Symptomatic brain metastases Exon 20 insertion as activating EGFR mutation Patients with diabetes or cardiovascular disease were eligible Study sites in United States, Europe, and Australia Soria et al., ENA,

14 TIGER-X clinical dose group (T790M+): baseline characteristics 625 mg BID 500 mg BID Total N Median age, years Female, % Asian, % ECOG PS grade 0, % Median no. of prior Rx No. of prior TKIs, % Immediate prior TKI, % History of diabetes, % History of cardiovascular disease, % *7 patients started treatment with 900 mg BID free-base formulation and converted to 500 mg HBr salt tablet. The majority of their treatment was with HBr tablet and they are aggregated with the 500 mg BID HBr tablet group. ECOG PS = Eastern Cooperative Oncology Group Performance Status. Soria et al., ENA,

15 C O A U C (n g.h /m L ) Rociletinib demonstrated linear pharmacokinetics across efficacious dose range Rociletinib was absorbed rapidly with an elimination half-life of 2 4 hours, suitable for BID dosing regimen High fat breakfast slightly slowed the rate of absorption and increased the amount absorbed with no change in the peak plasma concentration of CO-1686 No accumulation of CO-1686 H B r D o s e v s A U C P h a s e 1 P h a s e 2 Wakelee et al., ELCC, B ID D o s e (m g ) 15

16 Change from Baseline (%) TIGER-X clinical dose group responses Best Response for Evaluable T790M+ Patients % ORR (per RECIST 1.1) 89% DCR Soria et al., ENA,

17 Survival Probability TIGER-X clinical dose group: PFS Kaplan-Meier Plot of PFS in T790M+ Patients PFS (months) + + Median PFS = 10.4 months* At Risk (events) 56(0) 52(1) 27(4) 21(5) 18(7) 16(8) 14(10) 11(13) 11(13) 7(13) 6(13) 5(14) 5(15) 2(17) 1(17) 1(17) 1(17) 0(17) + Soria et al., ENA, 2014 *Data as of 25 September 2014 reflecting 31% data maturity PFS = progression-free survival. 17

18 TIGER-X clinical dose group: adverse events 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 Soria et al., ENA,

19 TIGER-X adverse events of interest No grade 3/4 adverse events observed in >1 patient except for hyperglycemia Hyperglycemia readily managed with oral agent (typically metformin) and, on occasion, dose reduction No cutaneous toxicity of note Grade 1 rash observed in 2 patients (transient, not acneiform/folliculitis) No paronychia or stomatitis Grade 3 QTc prolongation observed in 1 patient (625 mg BID) Across entire clinical program (>200 patients, all doses, all genotypes): Pneumonitis observed in 4 patients all quickly reversible; last 2 cases resumed rociletinib therapy under steroid cover without recurrence of pneumonitis No heart failure observed Soria et al., ENA,

20 Observed hyperglycemia relates to metabolite of rociletinib Rociletinib metabolite M502 is an inhibitor of IGF1R and accumulates in humans causing hyperglycemia No hyperglycemia observed in toxicology studies of rociletinib Like rociletinib, M502 is wild-type EGFR sparing Assay Rociletinib M502 A431 (IC 50, nm) Cellular (wild-type EGFR) NCI-H1975 (IC 50, nm) Cellular (T790M EGFR) IGF1R (IC 50, nm) Kinase IGF1R (IC 50, nm) Cellular Soria et al., ENA, IC 50 = half maximal inhibitory concentration IGF1R = insulin-like growth factor 1 receptor 20

21 Percentage of Control IGF1R pathway activation may play a role in acquired resistance to EGFR TKI Multiple publications have demonstrated a role for IGF1R signaling in mediating resistance to EGFR inhibitors in NSCLC models Resistance to WZ4002 (a third-generation EGFR inhibitor structurally related to CO-1686) is mediated by IGF1R signaling and can be reversed by the addition of an IGF1R inhibitor (data from Janne lab) DMSO + BMS DMSO + BMS WZR3 WZR WZ4002 (μmol/l) WZ IGF1R inhibitor BMS restores activity in resistant cell lines with IGF1R pathway activation Cortot et al., Cancer Res. 2013; Sharma et al., Cell 2010; Vazquez-Martin et al., Sci Rep

22 IGF1R inhibitor can overcome resistance in mutant EGFR patient derived cell lines Cell line models derived from biopsy specimens collected after the development of acquired resistance to EGFR inhibitors IGF1R inhibitor combination restores activity in 3/11 patient cell lines IGF1R Crystal et al., Science 2014 Cell line Patient 22

23 Change from Baseline (%) Combined responses from TIGER-X Phase 1/ Best Response for All Patients (Any T790M Status) on Therapeutic Doses (n=179) ORR = 46% DCR = 84% Soria et al., ENA, 2014 DCR = disease control rate; ORR = overall response rate. 23

24 Striking Activity in T790M-negative Patients Best Response for Target Lesions Centrally Confirmed T790M Negative Pts at 500 or 625mg BID (Clinical Dose Group) RECIST ORR = 42% overall RECIST ORR = 50% in patients treated with 625mg BID immediately off prior TKI mpfs = 7.5mo 24 *Database as of January 2 nd 2015

25 Comprehensive Monotherapy Development Program TIGER-X (Ph 2) Single arm expansion cohorts 2nd-line mutant EGFR NSCLC, T790M+ TIGER-1 (Ph 2/3) Randomized rociletinib vs erlotinib 1st-line, treatment-naïve TIGER-2 (Ph 2) Single-arm 2nd-line mutant EGFR NSCLC, T790M+ Patients progressing on 1st-line EGFR TKI Now adding T790M cohort TIGER-3 (Ph 3) Randomized rociletinib vs chemotherapy >2nd-line mutant EGFR NSCLC, T790M+ and T790M (sequential analysis) Soria et al., ENA,

26 Qiagen s existing therascreen EGFR test is being developed as a tissue companion diagnostic (CDx) for rociletinib Qiagen therascreen EGFR test for FFPE specimens Detects 29 mutations in EGFR Uses allele-specific PCR FDA-approved (with Afatanib) Clinical validation required for approval with rociletinib FFPE = formalin-fixed paraffin-embedded 26

27 Combination studies to begin Rociletinib to be combined with several targeted therapeutics and checkpoint inhibitors Collaborations established with multiple partner companies/physicians Initial combination with: Target PDL1 PD1 MEK Aurora kinase Drug mab Pembrolizumab (Merck) Trametinib (GSK) small molecule inhibitor Soria et al., ENA,

28 Conclusions Rociletinib (CO-1686) is an oral, potent, irreversible inhibitor of activating EGFR mutations and T790M Compelling and durable activity was demonstrated with clinical doses in T790M+ patients 67% objective response rate Median (immature) PFS estimated at 10.4 months Wild-type sparing was confirmed, with no cutaneous toxicity The only grade 3/4 adverse event observed in >5% of patients was hyperglycemia, readily managed with oral Rx Encouraging activity was observed in T790M patients Comprehensive pivotal trial program is advancing rapidly NDA and MAA filings planned for mid

29 Differentiation and areas of interest Rociletinib (CO-1686) has a unique tolerability and efficacy profile No evidence of WT EGFR inhibition observed in patients Evidence of activity in T790M- patients Moderately short plasma half-life allows for flexibility in dosing regimens and management of potential combination AEs Clovis is interested in performing combination studies beyond those mentioned with rociletinib, for example: Combination Anti-angiogenesis Anti-EGFR antibody Met inhibitor PARP inhibitor Mathematical based alternative dosing strategies Radiotherapy Rationale PFS increase in mutant EGFR patients treated with EGFR TKI and bevacizumab Dual inhibition of EGFR; block dimerization; potential lack of overlapping toxicity Activating and T790M EGFR pathway blockade may drive bypass pathway activation Platinum sensitivity and HRD signature observed in NSCLC Use mathematical evolutionary modeling to delay the onset of acquired resistance Radio-sensitizing potential; lack of overlapping toxicity 29