Download - Combination of the Angiogenesis Inhibitor Lucitanib with ...

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Rachel L. Dusek, Liliane Robillard, Thomas C. Harding, Andrew D. Simmons, Minh NguyenClovis Oncology, Inc., Boulder, CO

Combination of the Angiogenesis Inhibitor Lucitanib with Immune Checkpoint BlockadeAugments Antitumor Activity in Syngeneic Models

ACKNOWLEDGMENTSThese studies were funded by Clovis Oncology, Inc. Medical writing and editorial support were funded by Clovis Oncology and provided by Nathan Yardley and Frederique H. Evans of Ashfield Healthcare Communications.

SITC Annual Meeting | November 6-10, 2019 | National Harbor, MDCopies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission from the authors.Corresponding author: Rachel L. Dusek; email: [email protected].

CONCLUSIONS• Lucitanib enhances the antitumor activity resulting from immune checkpoint blockade of

either the CTLA-4 or PD-1 pathways in syngeneic nonclinical models• Lucitanib in combination with anti-PD-1 shows comparable or better antitumor activity than

other angiogenesis inhibitors combined with anti-PD-1 in nonclinical studies• Lucitanib combined with anti-PD-1 promotes intratumoral T-cell infiltration and immune-

associated gene expression changes important for antitumor immunity• Lucitanib’s antitumor mechanism of action involves both inhibiting angiogenesis and

modulating immune effector activity, potentially through CD8+ T cells • These data provide preclinical support for clinical studies evaluating lucitanib in combination

with immune checkpoint inhibitors• The combination of lucitanib and nivolumab is currently being evaluated as a treatment for

patients with solid tumors (NCT04042116)

Lucitanib Enhances the Antitumor Activity of Anti-PD-1 in Several Syngeneic Models

INTRODUCTION

Increase in Combination Efficacy No Increase in Combination Efficacy

Model H22 MC38 CT26P-BR5VFB1-

AktLLC1 EMT6 RENCA 4T1 B16F10

Cancer type Liver Colon Colon Ovarian Lung Breast Renal Breast MelanomaEfficacy (%)TGI anti-PD-1 53 64 43 19 6 5 0.6 0 –4TGI lucitanib 62 80 76 79 40 72 85 60 77TGI lucitanib + anti-PD-1 86 97 84 85 47 68 90 55 81P value combination vs best monotherapy < 0.01 < 0.0001 < 0.05 < 0.05 NS NS NS NS NSSurvival (days)MST vehicle 22 19.5 14 29 16 16 21 20 14MST anti-PD-1 46.5 29 19 43 16 17.5 19 19 14MST lucitanib 35 39 32 30.5 21 30 42 29.5 25MST lucitanib + anti-PD-1 NR (> 63) 45 40 55 21 31.5 43.5 31 26P value combination vs best monotherapy < 0.01 < 0.0001 < 0.01 < 0.001 NS NS NS NS NS

• Lucitanib (E-3810) is an oral multikinase inhibitor with targets that are associated with angiogenesis and other key cancer and immune pathways1

• Angiogenesis plays a critical role in cancer growth and metastasis through tumor vascularization and also promotes immunosuppression within the tumor microenvironment2,3

REFERENCES1. Bello et al. Cancer Res. 2011;71:1396-405.2. Fukumura et al. Nat Rev Clin Oncol. 2018;15:325-40.3. Khan et al. Nat Rev Clin Oncol. 2018;15:310-24.4. McDermott et al. Nat Med. 2018;24:749-57.5. Rini et al. N Engl J Med. 2019;380:1116-27.6. Allen et al. Sci Transl Med. 2017;9(385):eaak9679.

7. Kato et al. PLoS One. 2019;14(2):e0212513.8. Kimura et al. Cancer Sci. 2018;109(12):3993-4002.9. Makker et al. The Lancet. 2019;20(5):711-18.10. Lee et al. J Clin Oncol. 2018;36(15 suppl):abstr 4560.11. Hodi et al. Cancer Immunol Res. 2014; 2:632-42.

• Therapies simultaneously targeting angiogenesis and immune checkpoint pathways may enhance antitumor responses by modulating the tumor microenvironment2,3

– For example, inhibiting VEGF signaling is thought to induce vascular normalization, increase intratumoral T-cell infiltration, promote dendritic cell maturation, modulate the expression of cell adhesion molecules, and alter immune cell populations, whereas interfering with immune checkpoint pathways can enhance T-cell activation, expansion, and effector responses

Lucitanib Augments the Antitumor Activity of Anti-CTLA-4 in the MC38 Syngeneic Mouse Model

Antitumor Activity of Lucitanib Combined with Anti-PD-1 Is Similar to or Better Than That of Other Angiogenesis Inhibitor Anti-PD-1 Combinations

• Combination therapies targeting angiogenesis and immune checkpoint pathways have demonstrated favorable activity in preclinical and clinical studies.4-8 For example, – The combination of lenvatinib and pembrolizumab has shown encouraging activity in patients with

renal cell and endometrial carcinomas9,10

– The combination of bevacizumab and ipilimumab has shown promising activity in patients with melanoma11

• We hypothesize that the combination of lucitanib with an immune checkpoint inhibitor may also demonstrate beneficial preclinical and clinical activity

• Preclinical studies were performed to investigate the antitumor activity and the mechanism of action of lucitanib in combination with immune checkpoint blockade in syngeneic mouse tumor models

RESULTS

Lucitanib Treatment Alone and in Combination with Anti-PD-1 Results in Immune-Related Gene Expression Changes

MC38 Syngeneic Colon Cancer

Efficacy Day 17: TGI (%)Anti-CTLA-4 57Lucitanib 82Lucitanib + anti-CTLA-4 91P value lucitanib vs lucitanib + anti-CTLA-4 < 0.01

Survival: MST (days)Vehicle 18Anti-CTLA-4 25Lucitanib 45Lucitanib + anti-CTLA-4 NR (> 52)P value lucitanib vs lucitanib + anti-CTLA-4 < 0.0001

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Single-agent treatments of lucitanib and anti-CTLA-4 (clone 9D9), and the combination of the two agents were evaluated in the MC38 mouse syngeneic colon cancer model (n=10 mice/group). Treatment was initiated when tumors were ≈50 mm3 and continued for 35 days. A graph of mean tumor volume over time and the Kaplan-Meier survival curves are shown (left). Efficacy and survival data are shown in the table (right). The statistical analysis between groups was performed using a two-way ANOVA (efficacy) or log-rank (survival) test. ANOVA, analysis of variance; BIW, biweekly; IP, intraperitoneally; MST, median survival time; NR, not reached; PO, orally; QD, once daily; SEM, standard error of the mean; TGI, tumor growth inhibition

Tumor samples (n=5/group) from MC38 tumor-bearing mice were harvested following seven days of treatment with lucitanib(10 mg/kg, QD; PO), anti-PD-1 (10 mg/kg BIW; IP), anti-VEGFR2 (40 mg/kg, Q2D; IP), lucitanib + anti-PD-1, or anti-VEGFR2 + anti-PD-1, and gene expression was analyzed using the Nanostring Pan Cancer Immune panel. The heatmap (left) shows relative global significance scores for the top 20 molecular pathways affected by treatment. Specific pathway signature scores are shown plotted by treatment (right). Statistical significance was determined using one-way ANOVA. ***, p < 0.001; **, p < 0.01; *, p < 0.05.CD, cluster of differentiation; NK, natural killer; SD, standard deviation.

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Lucitanib Treatment Alone and in Combination with Anti-PD-1 Increases the Abundance of Intratumoral CD8+ T Cells

Tumor samples (n=5/group) from MC38 tumor bearing mice were harvested following seven days of treatment with lucitanib(10 mg/kg, QD; PO), anti-PD-1 (10 mg/kg, BIW; IP), anti-VEGFR2 (40 mg/kg, IP; Q2D), lucitanib + anti-PD-1, or anti-VEGFR2 + anti-PD-1. Intratumoral CD8-positive T-cell abundance was assessed by IHC. The IHC Profiler algorithm was used to determine the average CD8-positive area/tumor using five representative fields; the average CD8-positive tumor area per group was quantified (top left). Representative images are shown (right). To confirm these findings, RNA was isolated from the same tumorsand CD8 gene expression was assessed by Nanostring (bottom left). Statistical significance was determined using one-way ANOVA. **, p < 0.01; *, p < 0.05. IHC, immunohistochemistry

Proposed Mechanism of Action

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Single-agent treatments of lucitanib and anti-PD-1 (clone RMP1-14), and the combination of the two agents were evaluated in ninesyngeneic mouse cancer models (n=10 mice/group). Treatment was initiated when tumors were ≈50-115 mm3 and continued for up to 38 days. A graph of mean tumor volume over time and the Kaplan-Meier survival curves are shown for the CT26 colon cancer model as an example (top). Efficacy and survival data across models are shown in the table (bottom). The statistical analysis between groups was performed using a two-way ANOVA (efficacy) or log-rank (survival) test. NS, Not significant

Single-agent treatments of lucitanib, anti-PD-1, anti-VEGFR2 (clone DC101), and lenvatinib, and combinations of lucitanib + anti-PD-1, anti-VEGFR2 + anti-PD-1, or lenvatinib + anti-PD-1 were evaluated in MC38 or H22 syngeneic tumor bearing mice. Treatment was initiated when tumors reached ≈50 mm3 and continued for 28 days. Mean tumor volume over time graphs are shown (left). Treatment efficacy comparisons (TGI [%]) and statistics determined using a two-way ANOVA are shown in the table (right).Q2D, every two days

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Lucitanib Compared to Lenvatinib

CD8+ T Cells Contribute to the Antitumor Activity of Lucitanib Monotherapy

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MC38 Syngeneic Colon Cancer

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MST (days)Vehicle + isotype control – 19Vehicle + anti-mCD8a –50 17

Lucitanib + isotype control 78 56Lucitanib + anti-mCD8a 60 37.5

Anti-PD-1 + isotype control 56 31Anti-PD-1 + anti-mCD8a –68 17

P value lucitanib + isotype control vs lucitanib + anti-mCD8 < 0.01 < 0.0001

MC38 tumor bearing mice were treated with lucitanib or anti-PD-1, in combination with either an isotype control (rat IgG2b cloneLTF-2) or an anti-mCD8a antibody (clone 2.43). Mean tumor volumes over time are graphed (top). The Kaplan-Meier survival analysis is shown (bottom left). Efficacy and survival statistics are shown in the table (bottom right). P-values were determined using the two-way ANOVA (efficacy) or log-rank (survival) test. Q3D, every three days

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MC38 Syngeneic Colon Cancer Efficacy (Day 19)

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Anti-PD-1 56 < 0.001Lucitanib 88 < 0.01Anti-VEGFR2 47 < 0.0001Lucitanib + anti-PD-1 98 –Anti-VEGFR2 + anti-PD-1 63 < 0.001

H22 Syngeneic Liver CancerEfficacy (Day 16)

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Anti-PD-1 53 NSLucitanib 62 NSLenvatinib 50 < 0.001Lucitanib + anti-PD-1 86 –Lenvatinib + anti-PD-1 86 NS

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