ASCO 2021: Inducible T-Cell Co-Stimulatory (ICOS) Receptor Agonist, Feladilimab (Fela), Alone and in Combination (Combo) with Pembrolizumab (P): Results from INDUCE-1 Urothelial Carcinoma (UC) Expansion Cohorts (ECs).

(UroToday.com) Given multiple lines of evidence supporting the efficacy of immunotherapy in urothelial cancers, there is interest in identifying therapeutic strategies that can augment patient outcomes. The Inducible T-cell co-stimulator (ICOS) protein is a member of the CD28 immunoglobulin receptor superfamily, which is the same receptor superfamily that CTLA-4 and PD-1 belong to. ICOS is expressed in urothelial cancers at high levels across all stages of disease and is induced on T-cells following activation of the T-cell receptor. Interestingly, higher expression of ICOS on CD4+ T cells is observed after anti-CTLA4 immunotherapy in urothelial cancers. In melanoma and mesothelioma, tumors expressing higher levels of ICOS tended to have more response and longer survival when treated with anti-CTLA4 monotherapy. Feladilimab is a humanized IgG4 monoclonal antibody that agonizes T-cell activity through the ICOS receptor and does not deplete T-cells. In refractory melanoma and head and neck squamous cell cancers, Feladilimab showed single-agent antitumor activity when administered after PD-1 axis immunotherapy.

To further investigate the potential for ICOS agonism in combination with PD-1 therapy, the INDUCE-1 study was designed as shown below. This is an open-label first in human phase 1 study in advanced solid tumors, including urothelial cancers. In this presentation, Dr. Balar showed the preliminary safety and efficacy data including exploratory biomarker analysis from the urothelial cancer expansion cohort.

Patient characteristics are shown below.

From a safety profile, there were no grade 5 treatment-related adverse events, and the majority of events were grade 1 or 2. Four subjects in the monotherapy Feladilimab cohort received corticosteroids for adverse events, and 9 subjects in the combination arm received corticosteroids. Grade 3 events, only seen in the combination arm, included rash, asthenia, and decreased appetite.

Efficacy data are shown below.

Seven out of 32 patients in the combination arm had an overall response (partial response), and one patient in the monotherapy cohort had a confirmed partial response with a duration of response of 6.1 months. Almost half of the patients in the combination arm had a disease control rate of greater than 18 weeks. In PD-L1 positive subcohorts, the disease control rate was 77% in the combination cohort and 25% in the monotherapy cohort, compared to 50% and 22% in the PD-L1 negative subcohorts, respectively. When stratified by ICOS expression, disease control rate for ICOS-positive patients was 40% in the monotherapy arm and 80% in the combination arm, compared to 13% and 46% in ICOS-negative tumors. Preliminary overall survival data with very small sample sizes are shown below.

Dr. Balar concluded his presentation by stating that feladilimab mono- or combination therapy with pembrolizumab had a manageable safety profile, and ICOS agonism had evidence of clinical activity with some durable responses, especially in patients whose tumors expressed PD-L1 or ICOS. Ongoing clinical development will be planned based on this data in urothelial cancers and other contexts.

Presented by: Arjun V. Balar, MD, NYU Langone’s Perlmutter Cancer Center, NYU Langone Health, New York, NY

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

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