Examination of irAE and treatment discontinuation irAE in patients with RCC with T effector phenotype.

Abstract

4549 Background: The standard of care for renal cell carcinoma (RCC) is physician-choice of dual immunotherapy with ipilimumab/nivolumab (IO/IO) or a combination a VEGF inhibitor with immunotherapy (VEGF/IO). The IMmotion 151 trial identified gene expression signatures that differentiate likelihood of response to IO/IO (cluster 4 and 5 – T effector) versus VEGF/IO (cluster 1 and 2 - Angiogenic). Given that the T effector RNA-seq signature consists of higher expression of genes associated with inflammation, we hypothesized that patients with the T effector phenotype would have higher rates of immune-related adverse events (irAE) on IO-based therapy. Methods: Patients with metastatic RCC treated with systemic IO-based therapy had RNA sequencing completed on the primary tumor or metastatic site. Charts of patients who had a T effector RNA-seq signature were manually curated to identify development of irAE by reading the most recent clinic note and searching ‘steroids’, ‘irAE’, ‘rash’, ‘thyroid’. Hits from searches were investigated by manual chart review. Results: 118 patients underwent RNA sequencing and 105 passed quality control. Nineteen patients (18%) were assigned the T effector phenotype. Of the 17 metastatic patients, twelve of these patients received at least one dose of IO/IO in the first or second line of therapy, five were treated with VEGF/IO Among patients treated with IO/IO, 8 developed any grade irAE (66%; 41% grade 3+), 5 (41%) required steroid treatment, 5 (41%) required hospitalization, and 4 (33%) discontinued treatment due to irAE. Grade 3 toxicities in this group included colitis, adrenal insufficiency, and hypophysitis. Of the 5 patients treated with VEGF/IO, 3 developed any grade irAE (60%; 20% grade 3+), none were treated with steroids, and none were hospitalized. The grade 3 toxicity in this group was adrenal insufficiency. Conclusions: Patients with a T effector RNA-seq signature had higher rates ofirAE than historic controls when treated with IO/IO leading to high rates of steroid use and treatment discontinuation. VEGF/IO-treated patients with the T effector RNA-seq signature had similar rates of irAE to historic controls. The ongoing OPTIC clinical will expand on these results by studying treatment assignment in a prospective manner.