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Lucitanib Program Overview
November 2019
2
Lucitanib Overview
• Strong rationale to study lucitanib in combinations with checkpoint inhibitors
– Recent data for lenvatinib which inhibits the same three pathways as lucitanib – when combined with the PD-1 inhibitor, pembrolizumab – showed encouraging results and rationale for development of lucitanib in combination with a PD-1 inhibitor
– Global strategic clinical collaboration between Eisai and Merck resulting in jointly initiated new clinical studies evaluating the combination of lenvatinib and pembrolizumab to support 13 potential indications including a basket trial
– Preclinical data for lucitanib in combination with PD-1 inhibitor demonstrated enhanced anti-tumor activity compared to that of single agents
• Lucitanib added to Clovis’ clinical collaboration with Bristol-Myers Squibb; combination study with Opdivo in advanced gynecologic cancers and other solid tumors now enrolling
• Based on encouraging preclinical and clinical data of VEGF and PARP inhibitors in combination, a study of lucitanib in combination with Rubraca in advanced ovarian cancer now enrolling
• Clovis owns global rights (excluding China) to lucitanib
• Composition of matter expires 2030 in the U.S. and 2028 in Europe; with up to five years patent term extension available
3
Lucitanib is an Oral Tyrosine Kinase Inhibitor
• Lucitanib is an investigational, oral, potent inhibitor of the tyrosine kinase activity of 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)
Kinase Kd (nM)FGFR1 21FGFR2 41FGFR3 51VEGFR1 1VEGFR2 1.1VEGFR3 7.1PDGFRα 0.43PDGFRβ 0.26
Kinome profiling1
Kinase binding profiling2
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.
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Lucitanib is a Potent and Selective Kinase Inhibitor
• Heatmap shows percent kinase inhibition by the indicated compounds profiled against 256 kinases
– Lucitanib, lenvatinib, and cediranib inhibit the activity of multiple tyrosine kinases
– Lenvatinib and cediranib have activity against additional kinases not targeted by lucitanib
– Data highlight the highly selective inhibition profile of lucitanib
Source: 1 Clovis internal data: kinase activity profiling by HotSpot assay was performed at Reaction Biology using 0.5 µM of each compound, with 10 µM ATP, 2018.
0%
100%
50%
Percent kinase inhibition
Kinases
Lucitanib
Lenvatinib
Cediranib
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Lucitanib Clinical Development History
• Monotherapy development by Clovis and Servier focused on activity assessment in FGFR driven tumors (predominantly breast and lung cancers)
– Monotherapy data in breast and lung cancers were insufficient to support continued development
• Recommended monotherapy dose was 10 mg/day1
– Most patients (421/424) in safety database treated at or above recommended dose
– Safety profile consistent with potent VEGF pathway inhibition
Source: 1Lucitanib Investigator Brochure v7 Sept. 2016
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Lucitanib Development Rationale Today
• Strong rationale to study lucitanib in combinations with checkpoint and PARP inhibitors
– The combination of inhibiting angiogenic pathways and blocking an immune checkpoint has shown encouraging results in preclinical and clinical studies, providing a rationale for development of lucitanib in combination with a PD-1 inhibitor
– Preclinical and clinical data demonstrate a link between PARP inhibition and suppression of angiogenesis; these results provide a rationale for development of lucitanib in combination with a PARP inhibitor
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Targeting Angiogenesis and Immune Checkpoint 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 metastasis1
• Angiogenesis has been shown to be immunosuppressive within the tumor microenvironment, dampening anti-tumor immune responses1
– Immune effects of angiogenesis include modulation of T-cell infiltration into the tumor, inhibition of dendritic cell maturation, and the modulation of cell adhesion molecules and immune cell populations
• Inhibition of angiogenesis by small molecule RTK inhibitors or monoclonal antibodies may reverse immunosupression1
• These data suggest the clinical activity of PD-(L)1 inhibitors may be enhanced through the inhibition of angiogenesis by lucitanib
Source: 1Fukumara 2018 Nature Reviews in Clinical Oncology
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Lucitanib+Anti-PD-1 Combination Delivers Superior Activity
Syngeneic Tumor Models1
Model H22 MC38 CT26P-BR5VFB1-
Akt
Cancer type Liver Colon Colon Ovarian
Efficacy
TGI anti-PD-1 (%) 50 62 42 18
TGI lucitanib (%) 59 78 74 75
TGI combo (%) 81 93 82 81
P value <0.01 <0.001 <0.001 <0.001
Survival
MST vehicle (days) 22 20 14 29
MST anti-PD-1 (days)
46.5 29 19 29
MST lucitanib (days) 35 39 32 43
MST combo (days) >63 45 40 53
P value <0.001 <0.001 <0.001 <0.001
Source: 1 Clovis internal data; Subcutaneous syngeneic models performed at Shanghai Medicilon, Inc., and Crown Biosciences, n=10. P values are between combination and vehicle treated groups. Line denotes dosing period for lucitanib and anti-PD-1.
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Ongoing Angiogenesis/PD-(L)1 Inhibition Clinical Development
• Multiple Phase 1-3 studies are examining the combination of angiogenesis and PD-(L)1 inhibitors in different indications1
• Lenvatinib and pembrolizumab granted 3 breakthrough designations (BTD) by FDA.2,3,4
– renal
– hepatocellular
– endometrial
• Activity of lenvatinib/pembrolizumab seen in both PD-L1 positive and PD-L1 negative tumors, and MSI-High & Microsatellite stable5
Source: 1 Fukumura 2018 Nature Reviews in Clinical Oncology; 2http://www.ascopost.com/News/58430, 3
https://investors.merck.com/news/press-release-details/2019/Merck-and-Eisai-Receive-Third-Breakthrough-Therapy-Designation-from-FDA-for-KEYTRUDA-pembrolizumab-plus-LENVIMA-lenvatinib-Combination-Treatment/default.aspx, 4 https://www.mrknewsroom.com/news-release/oncology/eisai-and-merck-announce-fda-grants-breakthrough-therapy-designation-lenvima-l, 5 Makker et al., Lancet Oncology, 2019
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Lenvatinib and Pembrolizumab Granted Accelerated Approval in Advanced Endometrial Cancer
Source: 1USPI accessed 10.2019, 2Makker et al., Lancet Oncology, 2019
MSI-H=Microsatellite instability high; dMMR=mismatch repair deficient; ORR=Overall response rate;DOR=Duration of response
• Accelerated approval granted by FDA for combination in September 2019 for advanced endometrial cancer in selected populations1
– 38.3% ORR in 94 patients whose tumors were not MSI-H or dMMR
• 10.6% complete responses; 27.7% partial responses by RECIST 1.1
– Median DOR not reached; 69% of responders had responses ≥ 6 mos.
• Data published in 2019 in Lancet Oncology showed anti-tumor activity for combination2
– 53 patients with advanced, recurrent endometrial cancer
• 30/53 (57%) receiving 3rd or later line treatment
– 8% MSI high; 85% MSI not high; 8% MSI unknown
Makker et al., Lancet Oncology, 2019
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Lucitanib and Rucaparib Combination: Preclinical and Clinical Data Support Potential Activity of Combining an Anti-angiogenic with PARP Inhibitor
• 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 cells1
• The oral VEGFR inhibitor cediranib has been investigated in combination with olaparib in recurrent ovarian cancer2
– PFS was 17.7 months for cediranib + olaparib arm versus 9.0 months for the single-agent olaparib arm (HR = 0.42, 95% CI = 0.23–0.76; 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)
Source: 1Bindra 2004 Molecular and Cellular Biology, Bindra 2005 Cancer Research, Chan 2008 Cancer Research, Chan 2010 Cancer Research; 2 Liu Lancet Oncology 2014
PFS=progression free survival; HR=Hazard ratio; CI= Confidence interval
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Lucitanib and Rucaparib Combination More Active Than Monotherapy in Preclinical Ovarian Tumor Model
• Combination of lucitanib plus rucaparib showed more durable suppression of tumor growth in BRCA1mut BrKras syngeneic murine model, than either lucitanib or rucaparib as a single agent
• Lucitanib and rucaparib demonstrated similar anti-tumor activity to cediranib and rucaparib2
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Source: 1,2Clovis internal data; Subcutaneous syngeneic model performed at Crown Bioscience, n=10
BrKras BRCA1mut syngeneic model1
20 40 60 800
20
40
60
80
100
Days post tumor implant
Rucaparib 25 mg/kg BIDLucitanib + Rucaparib
Vehicle
Lucitanib 5 mg/kg QD
Tumor Volume Survival
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Lucitanib Clinical Development Plan: Combinations with Opdivo and Rucaparib in Multiple Solid Tumors
• Two Clovis-sponsored Phase 1b/2 lucitanib combinations now enrolling
– Lucitanib and anti-PD-1 nivolumab (Bristol-Myers Squibb) combination in advanced gynecologic cancers and other solid tumors
– Lucitanib and rucaparib combination in advanced ovarian cancer as an arm of the SEASTAR study
• Initial data anticipated at medical meetings beginning mid-2020
• Criteria to identify additional tumor types for clinical development
– Scientific rationale for combination therapy
– Clear path to registration
– Clinical trials are feasible taking competition into account
14
Lucitanib Summary
• 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)
• 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 underway for lucitanib in combination with a PD-1 (nivolumab) and PARP inhibitor (rucaparib) in multiple solid tumors; studies currently enrolling
• Clovis holds global rights (excluding China) to lucitanib
• Composition of matter expires 2030 in the U.S. and 2028 in Europe; with up to five years patent term extension available