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.

4

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

5

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

6

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

7

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

8

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.

Tu

mo

r vo

lum

e

(Mea

n m

m3

SE

M)

Tu

mo

r vo

lum

e

(mea

n m

m3

SE

M)

9

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

10

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

11

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

12

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

Tu

mo

r vo

lum

e

(Mea

n m

m3

SE

M)

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

13

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