Lucitanib Program Overview. August 2018

Transcription

1 Lucitanib Program Overview August 2018

2 Lucitanib Background and Partnership Update Oral, potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3), platelet-derived growth factor receptors alpha and beta (PDGFRα/β) and fibroblast growth factor receptors 1 through 3 (FGFR1-3) Partnered with Servier in 2013; Servier had rights to lucitanib worldwide, except for the U.S. and Japan, where Clovis holds rights Previously evaluated as monotherapy in breast and lung cancers in partnership Clovis has received notice from Servier that they will return their ex-u.s. rights (excluding China) for lucitanib later in 2018 Clovis to own global rights (excluding China) to lucitanib No payments from Clovis to Servier related to the return of these ex-us rights Composition of matter expires 2030 in the U.S. not including patent term extensions; EU patent protections will be similar 2

3 Recent Clinical Data Suggest a Compelling Alternate Hypothesis for Lucitanib Development Originally developed with the hypothesis of activity in FGFR driven tumors; monotherapy data in breast and lung cancer were insufficient to support continued development Recent data for a similar drug that inhibits FGF, VEGF and PDGF receptor TKwhen combined with a PD-1 inhibitor - provide rationale for development of lucitanib in combination with a PD-(L)1 inhibitor Clovis-sponsored combination studies now being planned Clovis also intends to initiate a study of lucitanib in combination with rucaparib, based on encouraging clinical data for vascular endothelial growth factor (VEGF) and PARP inhibitors in combination Each of these studies is expected to initiate before the end of Q

4 Lucitanib is a Potent Inhibitor of VEGFR1-3, PDGFR / and FGFR1-3 Lucitanib is a tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors 1-3 (VEGFR1-3), platelet derived growth factor receptors (PDGFR) α/β and fibroblast growth factor receptors 1-3 (FGFR1-3) Kinome profiling 1 Kinase binding profiling 2 Kinase Kd (nm) FGFR1 21 FGFR2 41 FGFR3 51 VEGFR1 1 VEGFR2 1.1 VEGFR3 7.1 PDGFRα 0.43 PDGFRβ Source: 1 Clovis internal data; KINOMEscan kinase profiling of 456 kinases with 100 nm lucitanib performed at DiscoveRx; 2 Clovis internal data; Kinase binding performed at DiscoveRx.

5 Lucitanib Has a Similar Biochemical Kinase Inhibition Profile to Lenvatinib Lucitanib 1 Lenvatinib 1 < 10% 10-20% 20-30% 30-40% 5 Source: 1 Clovis internal data; Functional enzymatic inhibition of 455 kinases with 500 nm of the indicated compounds and 10mM ATP performed at Reaction Biology

6 Cellular Inhibition Profiles of Lucitanib and Lenvatinib Both lucitanib and lenvatinib are potent inhibitors of VEGFR, PDGFR and to a lesser extent, FGFR phosphorylation and RTK dependent cell proliferation Inhibition of RTK downstream signaling (IC 50, nm) 1 Cell line HUVEC H1703 HLE H1581 SNU-16 RT-112 Receptor VEGFR2 PDGFR PDGFR FGFR1 FGFR2 FGFR3 Lucitanib Lenvatinib Inhibition of cell proliferation (IC 50, nm) 1 Cell line HUVEC H1703 H1581 SNU-16 OPM-3 Receptor VEGFR2 PDGFR FGFR1 FGFR2 FGFR3 Lucitanib Lenvatinib ND 6 RTK=Receptor tyrosine kinase Source: 1 Servier and Clovis internal data

7 T u m o r v o lu m e m e a n S E M (m m 3 ) T u m o r v o lu m e (M e a n m m 3 S E M ) T u m o r v o lu m e (M e a n m m 3 S E M ) Lucitanib Anti-tumor Efficacy in Murine Xenograft Models Lucitanib monotherapy shows significant tumor growth inhibition in multiple preclinical models RT112/84 bladder RXF393 renal cell carcinoma MDA-MB-231 breast cancer D ays post-im plantation D a y s p o s t-tu m o r im p la n t D a y s p o s t-tu m o r im p la n t V e h ic le S unitinib 40m g /kg Q D Lucitanib 20m g /kg Q D Lenvatinib 20m g /kg Q D V e h ic le B e v a c iz u m a b u g /m ic e q 4 d x 8 S u n itin ib 4 0 m g /k g Q D L u c ita n ib 2 0 m g /k g Q D V e h ic le L u c ita n ib 1 5 m g /k g Q D S o ra fe n ib 6 0 m g /k g Q D 5 -F U 7 5 m g /k g IV q 9 d x 3 7 Source: 1 Servier and Clovis internal data

8 Targeting Angiogenesis and Immune Checkpoints Pathways May Have a Synergistic Effect on Antitumor Activity VEGF and other angiogenic factors promote the formation of new blood vessels (angiogenesis), which is often exploited by tumors to stimulate tumor growth and metastasis 1 Angiogenesis also has the ability to be immunosuppressive within the tumor microenvironment, dampening anti-tumor immune responses 1 Immune effects of angiogenesis include modulation of T-cell infiltration into the tumor, inhibition of dendritic cell maturation, modulation of cell adhesion molecules and immune cell populations Inhibition of angiogenesis by small molecule RTK inhibitors or monoclonal antibodies may reverse immunosupression 1 These data suggest the clinical activity of PD-(L)1 inhibitors may be enhanced through the inhibition of angiogenesis by lucitanib 8 Source: 1 Fukumara 2018 Nature Reviews in Clinical Oncology

9 Mechanisms of Angiogenesis Suppression of the Antitumor Immune Response Key: TAM Tumor associated macrophages MDSC Myeloid derived suppressor cells DC Dendritic cells CTL Cytotoxic T-lymphocytes T reg cell Regulatory T-cell 9 Source: Fukumara 2018 Nature Reviews in Clinical Oncology

10 Preclinical Data Support Angiogenesis + PD-(L)1 Inhibition Combination MMTV-PyMT (breast) and RT2-PNET (pancreatic) transgenic models DC101 (anti-vegfr2) or anti PD-L1 alone vs. combination of both agents Increased anti-tumor efficacy observed in both models; not in a third transgenic model (GBM) MMTV-PyMT RT2-PNET IgG control DC101 PD-L1 DC101 + PD-L1 10 GBM=Glioblastoma multiforme Source: Allen 2017 Science Translational Medicine

11 T u m o r v o lu m e (M e a n m m 3 S E M ) Lucitanib Plus Anti-PD-1 Combination More Active Than Monotherapy in Syngeneic Models H 2 2 H e p a to c e llu la r c a r c in o m a V e h ic le L u c ita n ib 1 0 m g /k g Q D L e n v a tin ib 1 0 m g /k g Q D A n ti-m P D -1 5 m g /k g B IW L u c ita n ib + A n ti- m P D - 1 L e n v a tin ib + A n ti- m P D D a y s p o s t-tu m o r im p la n t Increased anti-tumor efficacy of lucitanib + anti-pd-1 combination vs. monotherapy observed in syngeneic (immune competent) murine tumor model Similar results observed in EMT-6 (TNBC) and MC38 (CRC) models 11 mpd-1 = murine PD-1 Source: 1 Clovis internal data; Subcutaneous syngeneic model performed at Shanghai Medicilon, Inc., n=10. Line denotes dosing period for lucitanib, and arrows denote dosing for anti-pd-1.

12 Ongoing Angiogenesis/PD-(L)1 Inhibition Clinical Studies Multiple phase I-III studies are examining the combination of angiogenesis and PD-(L)1 inhibitors in different indications 1 Lenvatinib and pembrolizumab combination in metastatic renal cell carcinoma (mrcc) granted breakthrough designation (BTD) by FDA in January ,3 BTD based on 63% ORR (n=30) Objective responses seen in both the PD-L1 positive and PD-L1 negative tumors Lenvatinib and pembrolizumab combination in advanced and/or metastatic non-microsatellite instability high (MSI-H)/proficient mismatch repair (pmmr) endometrial carcinoma granted breakthrough designation (BTD) by FDA in July Source: 1 Fukumura 2018 Nature Reviews in Clinical Oncology; 2 lenvatinib-breakthrough-designation-for-rcc,

13 Lenvatinib and Pembrolizumab is Active in Advanced Endometrial Cancer Data presented at ASCO 2018 showed pembrolizumab/lenvatinib combination encouraging antitumor activity in patients with advanced endometrial cancer 53 patients with advanced, recurrent endometrial cancer 31/53 (59%) receiving 3rd or later line treatment 8% MSI high; 85% MSI not high; 8% MSI unknown ORR 40% (investigator); 47% (independent read) Median DOR not estimable Activity comparable in MSI high and MSI-non high Duration of treatment up to 120 weeks suggests durable activity 13 MSI=Microsatellite instability; ORR=Overall response rate, DOR=Duration of response, IRR=Independent Radiology Review Source: Makker ASCO 2018 Abs 5596

14 Lucitanib + Rucaparib Combination: Preclinical and Clinical Data Support Potential Activity of Angiogenesis and PARP Inhibition There is a link between PARP inhibition and suppression of angiogenesis - chronic hypoxia induces down-regulation of BRCA1 and RAD51 and decreases homologous recombination in cancer cells 1 The definition contextual synthetic lethality has been suggested for the therapeutic approach of inducing HRD by hypoxia with an anti-angiogenic in combination with PARP inhibitor Olaparib has been investigated in combination with the oral VEGFR inhibitor cediranib in recurrent ovarian cancer 2 PFS was 17.7 months for cediranib + olaparib arm versus 9.0 months for the single-agent olaparib arm (HR = 0.42, 95% CI = ; p = 0.005) Increased activity of cediranib + olaparib versus olaparib alone in the subgroup of patients with wild-type or unknown BRCA status, with an improvement in median PFS from 5.7 to 16.5 months (HR = 0.32, p = 0.008) and ORR from 32% to 76% (p = 0.006) 14 HRD=homologous recombination deficiency; PFS=progression free survival; HR=Hazard ratio; CI= Confidence interval Source: 1 Bindra 2004 Molecular and Cellular Biology, Bindra 2005 Cancer Research, Chan 2008 Cancer Research, Chan 2010 Cancer Research; 2 Liu Lancet Oncology 2014

15 T u m o r v o lu m e (M e a n m m 3 S E M ) P e rc e n t s u rv iv a l Lucitanib + Rucaparib Combination More Active Than Monotherapy in Preclinical Ovarian Tumor Model Combination of lucitanib plus rucaparib showed durable suppression of tumor growth in BRCA1 mut BrKras syngeneic murine model, while single agent lucitanib or rucaparib showed continued tumor growth BrKras BRCA1 mut syngeneic model Tumor Volume Survival D a y s p o s t tu m o r im p la n t D a y s p o s t-tu m o r im p la n t V e h ic le L u c ita n ib 5 m g /k g Q D R u c a p a rib 2 5 m g /k g B ID L u c ita n ib + R u c a p a rib Source: 1 Clovis internal data; Subcutaneous syngeneic model performed at Crown Bioscience, n=10

16 Lucitanib Preclinical Summary An oral, potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3), platelet-derived growth factor receptors alpha and beta (PDGFRα/β) and fibroblast growth factor receptors 1 through 3 (FGFR1-3) Offers the potential benefit of targeting three relevant pro-angiogenic pathways, as well as simultaneously targeting proliferation and anti-vegfr therapy resistance driven by PDGF and FGF receptors Development opportunity for lucitanib in combination with a PARP inhibitor (rucaparib) or PD-(L)1 inhibitor in multiple tumor types 16

17 Lucitanib Clinical Development History Monotherapy development by Clovis and Servier focused on the hypothesis of activity in FGFR driven tumors (predominantly breast cancer) Completed Clovis sponsored studies: U.S. breast study: metastatic breast cancer in 178 patients 1 Lung cancer: metastatic lung cancer (SCLC/NSCLC) in VEGFR/PDGFR/FGFR genetic alterations in 17 patients 2 Completed Servier sponsored studies: FINESSE: metastatic breast cancer in 76 patients 3 INES: dose ranging study in solid tumors in combination with fulvestrant in 18 patients 4 FIM: Phase 1 study in solid tumors evaluating various dose schedules in ~134 patients 4 evaluated 5-30mg/day Recommended monotherapy dose 10 mg/day 4 Most patients (421/424 patients) in safety database treated at or above 10mg/day recommended dose Lucitanib monotherapy development in breast cancer discontinued in April 2017 Role of FGFR genomic amplifications as a driver in breast cancer questionable; clinical efficacy unlikely to be superior to standard-of-care 17 Source: 1 ClinicalTrials.gov NCT , 2 ClinicalTrials.gov NCT , 3 Study Report CL , 4 Lucitanib Investigator Brochure v7 Sept. 2016

18 Phase 1 Summary Phase 1 lucitanib monotherapy study enrolled 124/134 patients, evaluable for response across multiple tumor types Activity noted in thyroid patients (n=18) 2 Complete Responses 3 Partial Responses 12 Stable Disease 2 patients remain on drug > 6 years Initial recommended dose of 15 mg/day was reduced to 10 mg/day during the subsequent Phase 2 program 18 Source: Study report CL Final report

19 Adverse Event Profile of Lucitanib in Metastatic Breast Study Lucitanib TEAE 30% frequency, or grade 3 events 5% frequency Event Metastatic Breast Study (n=178) All grades Grade 3 Hypertension* 77% 48% Fatigue* 52% 6% Nausea 48% 3% Hypothyroidism* 45% <1% Headache 37% 3% Vomiting 33% 3% Decreased appetite 32% 1% Proteinuria 25% 6% Hyponatremia 10% 7% 19 TEAE=Treatment Emergent Adverse Events Source: CO CSR 14 April 2017 * combined terms

20 Lucitanib Clinical Development Plan: Combinations with PD-(L)1 and Rucaparib in Multiple Indications Initiate Phase 1b lucitanib combinations no later than Q Lucitanib and anti-pd-(l)1 Lucitanib and rucaparib (Clovis PARP inhibitor) Identify tumor types with the following criteria Scientific rationale for combination therapy Clear path to registration Clinical trials are feasible taking competition into account Several potential tumor types for lucitanib and anti-pd-(l)1 combination studies Strong clinical rationale to explore lucitanib and rucaparib in ovarian cancer 20

21 Lucitanib Summary Oral, potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3), plateletderived growth factor receptors alpha and beta (PDGFRα/β) and fibroblast growth factor receptors 1 through 3 (FGFR1-3) Has the potential benefit of targeting three relevant pro-angiogenic pathways, as well as simultaneously targeting proliferation and anti- VEGFR therapy resistance driven by PDGF and FGF receptors Development opportunity for lucitanib in combination with a PARP inhibitor (rucaparib) and PD-(L)1 in multiple tumor types Clovis to own global rights (excluding China) to lucitanib in 2018 Composition of matter expires 2030 in the U.S. not including patent term extensions; EU patent protections will be similar 21