Abstract 1184
Background
95% of metastatic colorectal cancers (mCRCs) have normal mismatch repair proficient (pMMR) expression and a stable microsatellite phenotype (MSS). As a consequence, checkpoint inhibiting immunotherapy currently plays no role in these tumours. We recently found that RAS/RAF wild type (WT) mCRCs (50% of all CRCs) that first responded to cetuximab and then acquired resistance had converted from an immune-excluded or immune-desert phenotype before treatment to an inflamed phenotype at progression. This progression was characterized by increased CD8+ T cell infiltrates and upregulation of PDL1 and LAG3 immune checkpoints. To assess if the cetuximab induced immune infiltrates can be exploited for therapeutic benefit, the iSCORE trial will treat 25 patients with combined anti-PD1 (nivolumab) and anti-LAG3 (relatlimab) immunotherapy starting ideally within 4 weeks after progression on immunogenic FOLFIRI chemotherapy and cetuximab.
Trial design
iSCORE is designed to evaluate the efficacy of nivolumab and relatlimab in patients with RAS/RAF WT mCRC who have had radiological response to first line FOLFIRI and cetuximab, but then progressed. Eligible patients will receive nivolumab 480mg and relatlimab 160mg every 4 weeks. The primary endpoint is disease control rate (DCR) at 6 months from treatment initiation. With an A’Hern single stage design for efficacy, 5% significance and a power of 80%, 25 patients would need to be treated and a minimum of 6 would need to be progression free at 6 months in order to support an increase of the DCR at 6 months from <10% to 30% or more. Secondary endpoints include DCR at 12 and 24 months, duration of disease control, best objective response rate at 6, 12 and 24 months, progression free survival and overall survival. Exploratory objectives include investigating dynamic changes in the gut microbiota/metabonome, immune infiltrates, immune checkpoints and molecular tumour characteristics induced by LAG3 and PDL1 blockade. This will be achieved through sequential collection of stool and tumour biopsies and baseline tumour characteristics will be correlated with tumour response and survival. iSCORE is a single-centre phase II trial. Recruitment opened in March 2019 and 25 patients will be recruited in 36 months.
Clinical trial identification
NCT03867799.
Editorial acknowledgement
Legal entity responsible for the study
The Royal Marsden NHS Foundation Trust.
Funding
The Royal Marsden NHS Foundation Trust, Bristol-Myers Squibb.
Disclosure
D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. I. Chau: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (self): Eli-Lilly. M. Gerlinger: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KG. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.
Resources from the same session
5205 - Immune status of patients with different stages of colorectal cancer with and without circulating tumor cells
Presenter: Anastasia Sitkovskaya
Session: Poster Display session 2
Resources:
Abstract
5658 - Detection of 5-hydroxymethylcytosine in Circulating-Free DNA for Early Diagnosis of Colorectal Cancer
Presenter: Tianyu Liu
Session: Poster Display session 2
Resources:
Abstract
5779 - Detection of 5-hydroxymethylcytosine in Circulating-Free DNA for Prediction of The Efficacy of Conversion Therapy for Colorectal Cancer Liver Metastases
Presenter: Wenju Chang
Session: Poster Display session 2
Resources:
Abstract
4672 - mCRC gene profiling using the Idylla platform
Presenter: Christopher Bricogne
Session: Poster Display session 2
Resources:
Abstract
3393 - PIK3CA mutation in metastatic colorectal cancer (mCRC): association with clinico-pathological features and outcome
Presenter: Valentina Fanotto
Session: Poster Display session 2
Resources:
Abstract
1317 - Patient-Derived Xenografts (PDX) Identifies JMJD6 Inhibitor as an Effective Therapeutic Medicine in Colorectal Cancer.
Presenter: Feng Ye
Session: Poster Display session 2
Resources:
Abstract
1228 - DACH1 induced stemness of intestinal organoids by directly suppressing BMP signaling and contributes to intestinal tumorigenesis
Presenter: Xiang Hu
Session: Poster Display session 2
Resources:
Abstract
1147 - miR-148a inhibits early relapsed colorectal cancers and the secretion of VEGF by indirectly targeting HIF-1α under non-hypoxia/hypoxia conditions
Presenter: Hsiang-lin Tsai
Session: Poster Display session 2
Resources:
Abstract
1158 - Long noncoding RNA CASC21 promotes cell proliferation and metastasis in colon cancer.
Presenter: Qun Zhang
Session: Poster Display session 2
Resources:
Abstract
1259 - Prognostic and Predictive Impact On FMS-like Tyrosine Kinase 3 (FLT3) Amplification In Patients With Metastatic Colorectal Cancer
Presenter: Hiroko Hasegawa
Session: Poster Display session 2
Resources:
Abstract