(UroToday.com) The 2023 ESMO annual meeting included a session on novel targets, therapies, and toxicities in genitourinary cancers, featuring a presentation by Dr. Sasha Gusev discussing the prediction of toxicity in current systemic treatment of genitourinary cancers. Dr. Gusev notes that immunotherapy toxicities are still common in genitourinary cancers, with 20-80% of patients developing grade 3+ immune-related adverse events, leading to 10-40% of patients discontinuing treatment:
Importantly, immune-related adverse events have many causes:
Two mechanisms by which germline variants influence immune-related adverse events include polygenic risk for a related trait and individual variants. With regards to polygenic risks, polygenic risk scores for psoriasis predict skin immune-related adverse events, which was assessed in the atezolizumab IMvigor211 trial:
Polygenic effects are also seen in other immune-related adverse events, including thyroid autoimmunity. Looking at individual variant predictors of immune-related adverse events, Dr. Gusev discussed work from his group looking at germline variants associated with toxicity to immune checkpoint blockade.1 For this study, 2,678 patients on immune checkpoint inhibitors from 12 cancer types were manually curated for grade 2+ immune-related adverse events, with the discovery cohort coming from Dana-Farber Cancer Institute patients. These patients underwent genome-wide association (GWAS) evaluation and were stratified by those that experienced versus those that did not experience immune-related adverse events, identifying three specific loci:
The novel germline variant near IL7 had a large effect on immune-related adverse events, with the largest effect on kidney and bladder cancer patients (HR 4.9 for RCC; HR 4.3 for bladder cancer). IL7 was then replicated in independent cohorts, including a pan-cancer cohort at MGH a pan-cancer cohort a Roche/Genentech:
But what is the mechanism between germline associations and immune-related adverse events? Of note, germline mutation carriers exhibit increased lymphocyte stability:
Dr. Gusev emphasized that an important subsequent collaboration developed with Fairfax, which had IL7 genetic variation data on 214 melanoma patients They were able to replicate IL7 having a large effect on immune-related adverse events among these patients:
Also, these carriers exhibit novel activation of IL7 expression, as well as exhibit cell-type and treatment specific effects:
A final validation occurred in the CheckMate 025 trial (n=189), with a hazard ratio of 3 and >50% of SNP carriers developing immune-related adverse events within ~6 months. There was a significant association with multiple recurrent immune-related adverse events:2 
Although Dr. Gusev and colleagues have assessed outcomes (survival/benefit) in each cohort, there is no association at this point in time for clinical benefit, only toxicity.
Dr. Gusev concluded his presentation discussing prediction of toxicity in current systemic treatment of genitourinary cancers with the following take-home points:
- Polygenic predisposition for known complex disease translates into corresponding immune-related adverse events
- Novel individual germline variants can also influence immune-related adverse events
- Molecular data reveals novel biological pathways and immune responses
- There is no compensatory effect on survival or response
- IL7 variant and B-cell IL7 expression is a novel biomarker of toxicity
- Further study in the adjuvant setting will prioritize non-carriers
Presented by: Sasha Gusev, PhD, Dana Farber Cancer Institute, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
References:
- Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat Med. 2022 Dec;28(12):2584-2591.
- Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1803-1813.