Real-world evidence to inform clinical insights on tissue-agnostic approvals of therapies.

Abstract

6589 Background: Many tissue-agnostic (TA) approvals were based on clinical trials with limited patient numbers without covering all tissue types (TT), raising the question of whether these indications were truly tissue agnostic. Real world evidence (RWE) offers an opportunity to investigate TTs not included in clinical trials/studies to answer this question. Herein we investigate the seven TA approvals to date in a large real world database and report clinical outcomes. Methods: A total of 186,581 tumors from over 35 TTs tested with comprehensive molecular profiling including NextGen sequencing of DNA and RNA were investigated for TA alterations (TMB-High (≥10 mutations/MB), MSI-H/MMRd, BRAF V600E mutations and NTRK1/2/3/RET fusions) at Caris Life Sciences (Phoenix, AZ). Time-on-treatment (TOT) from RWE was obtained from insurance claims and calculated from treatment start to finish. Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Significance was determined as p values of <0.05. Results: Among all tumors, 21.2% carried at least one TA alteration, 17.2%, 3.4% and 0.6% had 1, 2 or 3 alterations, respectively. TMB-H in 18.7%, MSI-H/dMMR was seen in 3.9%, BRAF V600E in 2.8% of tumors, NTRK1/2/3 and RET fusion seen in 0.16% and 0.23%. TA alterations were most prevalent in BCC (86%) & SCC (82%) of skin, MEL (71%), THCA (51%) and NSCLC (44%) and least in liposarcoma (0), meningioma (0.7%) and GIST (1.4%). Among tumors treated based on TA indications, substantial variability of TOT among TTs was observed (see table). Looking at TTs included (INC) and not included (nINC) in KEYNOTE-158 and other studies for TMB-H and pembro, median TOT for nINC was similar to INC (N=242 vs 2322, 6.1 m vs 6.3 m, p = 0.55). Nevertheless, statistically significant differences in median TOTs were seen across nINC when comparing TMB-H vs. TMB-L (6.1m vs. 2.9m, HR: 0.58 [95% CI: 0.50-0.67], p<0.001) and in a subset of 838 MSS tumors (4.9m vs. 2.8m, p<0.001). Conclusions: RWE data adds substantially to our understanding of the demographics of TA indications and suggests that some TA treatment benefits may be tissue-specific. Recent TA indications will require further accumulation of cases to draw meaningful conclusions regarding whether TA indications are, in fact, tissue agnostic. [Table: see text]