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

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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 21

FGFR2 41

FGFR3 51

VEGFR1 1

VEGFR2 1.1

VEGFR3 7.1

PDGFRα 0.43

PDGFRβ 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.

Lucitanib

Lenvitanib

Cediranib

0 50

100

Lu

cit

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Le

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1000%

100%

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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.

0 10 20 30 40 500

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H22Liver Cancer

Days post initial dose

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MC38Colon Cancer

Days post initial dose

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(mean

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CT26Colon Cancer

Days post initial dose

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(mean

mm

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Vehicle

Lucitanib 10 mg/kg QD

Anti-PD-1 5-10 mg/kg BIW

Lucitanib + anti-PD-1

Dosing period

0 10 20 300

1000

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P-BR5FVB1-AktOvarian Cancer

Days post initial dose

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Ongoing Angiogenesis/PD-(L)1 Inhibition Clinical Development

- PROPOSED

• 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)

– Potential Activity of Combining an Anti-angiogenic with PARP Inhibitor

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

20 40 60 800

500

1000

1500

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2500

Days post-tumor implant

Tu

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Source: 1,2Clovis internal data; Subcutaneous syngeneic model performed at Crown Bioscience, n=10

BrKras BRCA1mut syngeneic model1

2 0 4 0 6 0 8 0

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1 0 0

D a y s p o s t tu m o r im p la n t

Pe

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urv

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R u c a p a r ib 2 5 m g /k g B ID

L u c ita n ib + R u c a p a r ib

V e h ic le

L u c ita n ib 5 m g /k g Q D

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

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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