SUMMARY INTRODUCTION

TRIAL OVERVIEW

• Clinical studies have shown that the combination of tyrosine kinase inhibitors (TKIs) that inhibit angiogenesis and immune checkpoint inhibitors can resultin improved e� cacy compared with either monotherapy

• The phase 2 part of the international, open-label LIO-1 study aims to assess the e� cacy and safety of the combination of the TKI lucitanib and the programmed cell death receptor 1 (PD-1) inhibitor nivolumab in patients with an advanced gynaecological solid tumour

• A safety-based dose-titration approach is being used for lucitanib dosing to manage tolerability and maintain dose intensity

• Up to 161 patients will be enrolled across6 countries

• Lucitanib is an oral, potent tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptors 1–3 (VEGFR1–3), platelet-derived growth factor receptors alpha and beta (PDGFR α/β) and fibroblast growth factor receptors 1–3 (FGFR1–3)1

• Nivolumab is a human monoclonal antibody that binds to programmed cell death receptor 1 (PD-1) and blocks its interaction with programmed cell death ligand 1 (PD-L1) and 2 (PD-L2), releasing PD-1–mediated inhibition of the antitumour immune response2

• Proangiogenic growth factors secreted by tumours promote the generation of new blood vessels and mediate immunosuppression,3,4 which may dampen the effect of immune checkpoint inhibitors. Inhibiting angiogenesis with a TKI may, therefore, relieve immunosuppression and enhance the efficacy of PD-(L)1 inhibitors (Figure 1)

• In multiple syngeneic mouse models, the combination of lucitanib and anti-PD-1 inhibited tumour growth and improved survival to a greater extent than the single agents5

• LIO-1 (NCT04042116; ENGOT-GYN3/AGO/LIO) is a 2-part open-label study:‒ The phase 1b part of the study established the recommended starting dose of lucitanib as

6 mg orally once daily in combination with nivolumab (480 mg intravenously every 28 days) in patients with an advanced solid tumour6

‒ The phase 2 part of the study described here is evaluating the e� cacy and safety of the combination of lucitanib and nivolumab in patients with an advanced gynaecological solid tumour (Figure 2)

‒ The primary objective is to evaluate the preliminary e� cacy of the combination by investigator-assessed confi rmed best overall response rate (Table 1)

Patients• Key eligibility criteria are provided in Table 2

Dose Titration• Due to high inter-patient pharmacokinetic (PK) variability, the phase 2 part of LIO-1 will use

a safety-based dose titration. This will allow individual optimisation of lucitanib dosing to maintain dose intensity and enhance drug exposure with the anticipated benefi t of tolerability and improved clinical benefi t of the combination

• All patients in the phase 2 part of LIO-1 will start on oral lucitanib 6 mg once daily (QD) in combination with the fi xed dose of nivolumab (480 mg intravenously every 28 days)

• Patients who meet the dose-titration criteria will dose escalate to lucitanib 8 mg and then10 mg QD (Figure 3)‒ Patients who meet the criteria at cycle 2 day 1 and cycle 3 day 1 but whose dose is not

escalated may be permitted to dose escalate at a subsequent cycle provided ≤2 cycles have elapsed between dose escalations

‒ Lucitanib dose can be interrupted and/or reduced in 2-mg decrements to a minimum of2 mg at the investigator’s discretion in the event of toxicity

‒ Nivolumab dose reductions are not permitted

Biomarker and PK Assessments• Blood and tissue samples will be collected throughout the study and may be tested for DNA,

RNA and protein biomarkers to identify associations with response or resistance to treatment (Table 3)

• Trough-level plasma PK samples will be collected and used for developing lucitanib population PK and exposure-response analysis in combination with nivolumab. Blood samples will be collected for the assessment of nivolumab PK and anti-nivolumab antibodies in patient serum

Trial Enrolment• Six countries will participate in LIO-1, across a total of 28 sites (Figure 4)

Figure 1. Proposed Mechanism of Action of Lucitanib and Nivolumab

Adapted from original presentation (AACR Annual Meeting, 29 March–3 April 2019, Atlanta, USA) with permission from the corresponding author.

Figure 2. LIO-1 Phase 2 Expansion Study Design Overview

*Excluding clear-cell histology.IV, intravenous; PO, oral.

Figure 3. Clinical Criteria for Lucitanib Dose Escalation

AE, adverse event; BP, blood pressure; C, cycle; D, day; IV, intravenous; QD, once daily.

Figure 4. Countries Participating in LIO-1

AGO, Arbeitsgemeinschaft Gynäkologische Onkologie; BGOG, Belgium and Luxembourg Gynaecological Oncology Group; GEICO, Grupo Español de Investigación en Cáncer de Ovario;MITO, Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies.

ESMO Congress | 19–21 September 2020 | Virtual Meeting

ACKNOWLEDGEMENTS

PRESENTING AUTHOR DISCLOSURE

1. Bello et al. Cancer Res. 2011;71:1396-405.2. Mahoney et al. Clin Ther. 2015;37:764-82.3. Fukumura et al. Nat Rev Clin Oncol. 2018;15:325-40.

4. Khan et al. Nat Rev Clin Oncol. 2018;15:310-24.5. Dusek et al. Cancer Res. 2019;79(suppl 13):abst 1214.6. Hamilton et al. ESMO 2020 Poster 556P.

This research was sponsored by Clovis Oncology, Inc. Medical writing support was provided by Andrew Croskery, MPharm, PhD (Clovis Oncology, Ltd., London, UK) and editorial support funded by Clovis Oncology was provided by Frederique H. Evans, MBS, of Ashfi eld Healthcare Communications.

Nicole Concin has been an advisor for AstraZeneca, Mersana, and Seattle Genetics; has received travel/accommodation expenses from Amgen, Genmab, and Roche; and has received personal fees and travel expenses from Medscape.

REFERENCES

Table 3. Biomarker Assessments and Translational Research

Pretreatment On-treatmentEnd of treatment Follow-up Potential biomarker assessments

Tumour tissue Yes Yesa Yesb –

• TMB• MSI• PD-L1• CD8/immune phenotype• RNA expression• Cancer-related gene alterations

Blood Yes Yes Yes Yes• Soluble analytes (growth factors,

cytokines, etc.)• Germline/somatic gene alterations

aMandatory for EC cohort, optional for others; bOptional for all patients.MSI, microsatellite instability; PD-L1, programmed cell death ligand 1; TMB, tumour mutation burden.

Table 1. Endpoints

Primary endpoint• Investigator-assessed confi rmed best ORR by RECIST

Secondary endpoints• Acute and long-term safety and tolerability• DOR, DCR, PFS, OS• PK profi le of lucitanib when administered in combination with nivolumab

Exploratory endpoints• Potential relationship between biomarkers and e� cacy and safety• PK profi le of nivolumab when administered in combination with lucitanib• Development of anti-nivolumab antibodies• Lucitanib PPK and exposure-response in combination with nivolumab

DCR, disease control rate; DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; PPK, population pharmacokinetics; RECIST, Response Evaluation Criteria In Solid Tumors, version 1.1.

Table 2. Key Eligibility CriteriaGeneral• Measurable disease • ECOG PS 0 or 1• Fresh biopsy or su� cient archival tumour tissue (≤6 months before the start of treatment with no intervening

anticancer therapies)• No prior VEGFR TKI or PD-(L)1 inhibitora allowed

Endometrial cancer (excluding clear-cell carcinoma) cohort• Recurrent endometrial carcinoma• ≥1 prior platinum-based chemotherapy regimen• Up to 10 patients who have progressed on treatment with 1 prior PD-(L)1 inhibitor administered

as monotherapy

Cervical cancer cohort• Persistent or recurrent cervical cancer• ≥1 prior regimen of platinum-based chemotherapy, with or without bevacizumab, for metastatic disease

Ovarian cancer (excluding clear-cell carcinoma) cohort• Recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer• ≥2 prior chemotherapy regimens (including ≥1 platinum doublet) OR disease progression ≤6 months after

completing fi rst-line platinum-based chemotherapy (up to 10 patients)

Clear-cell ovarian/endometrial carcinoma cohort• Recurrent, metastatic clear-cell carcinoma of ovarian, fallopian tube, primary peritoneal or endometrial origin• ≥1 prior platinum- and taxane-based chemotherapy regimen

aUnless otherwise specified. ECOG PS, Eastern Cooperative Oncology Group performance status; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death ligand 1; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.

Also available at: https://clovisoncology.com/fi les/ESMO2020_Concin_Poster.pdfCopies of this e-poster obtained through Quick Response (QR) codes and/or web links are for personal use only and may not be reproduced without written permission of the authors. Corresponding author: Nicole Concin; nicole.concin@i-med.ac.at.

Poster Download

Also available at: https://clovisoncology.com/fi les/ESMO2020_Hamilton_Poster.pdfHamilton et al. Initial clinical experience of lucitanib + nivolumab in advanced metastatic solid tumours: data from the phase 1b/2 LIO-1 study (CO-3810-101; NCT04042116). ESMO 2020 Poster 556P.

LIO-1 Phase 1b Results Poster

Antigen releasefrom dying tumour cells

LucitanibNH2N

O O

NH

O

O

Lucitanib promotes dendritic cell maturation

Nivolumab

Nivolumab promotes T-cell activation

Activated T-cells tra�c to tumours

Lucitanib increases T-cell infiltration by normalising the tumour vasculature

Lucitanib decreases the activityof immunosuppressive cells

Combination promotes cytotoxic T-cell–mediated cancer cell death

Advanced, recurrent, or metastaticgynaecological tumours; Simon 2-stage design

Endometrial Cancer*N up to 22–41

Cervical CancerN up to 22–40

Ovarian Cancer* N up to 22–40

Clear-Cell Ovarian/Endometrial CancerN up to 22–40

LucitanibDose Titration

Starting dose:6 mg PO daily

Dose escalationIF certain clinical criteria are met

(Figure 3)

Nivolumab480 mg IVon day 1

every 28 days

• Enrolling up to 161 patients• Study duration ≈3 years

• Treatment with lucitanib until disease progression, unacceptable toxicity or other reason for discontinuation• Treatment with nivolumab for up to 24 months or disease progression, unacceptable toxicity or other reason for discontinuation

• BP ≤150/90 mmHg

• No treatment-related AEs >grade 2

• No proteinuria >1+ (or urinary protein >1.0 g/24 h)

• No treatment-related diarrhoea >grade 1

• Not requiring any antihypertensive agents (or change to existing antihypertensive regimen if pre-existing stable, well-controlled BP at baseline) C1D1 C2D1 C3D1

+ nivolumab 480 mg IV every 28 days

10 mgQD

8 mgQD

6 mgQD

Italy

Belgium

Spain

USA

Austria(single centreco-opted by AGO)

Germany

LIO-1: A Phase 2 Study of Lucitanib + Nivolumab in Patients (pts) With Gynaecological Tumours (CO-3810-101; NCT04042116; ENGOT-GYN3/AGO/LIO)

Nicole Concin,1,2 Antonio Gonzalez Martin,3 Ignace Vergote,4 Sandro Pignata,5 Philipp Harter,1 Manish R. Patel,6 Camille Catherine Gunderson,7 Kenton Wride,8 Denise Lepley,8 Rachel Dusek,8 Jowell Go,8 Sabrina Hurley,8 Terri Cameron,9 Erika Hamilton10

1Ev. Kliniken Essen Mitte, Essen, Germany; 2Medizinische Universität Innsbruck, Austria; 3Clínica Universidad de Navarra, Madrid, Spain; 4Universitair Ziekenhuis, Leuven, Belgium; 5Istituto Nazionale Tumori - Fondazione G. Pascale, Naples, Italy; 6Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, USA; 7Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, USA; 8Clovis Oncology, Inc., Boulder, USA; 9Clovis Oncology UK Ltd., Cambridge, UK; 10Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA

Poster number: 885TiP