Abstract 4348: Validation of an integrative pan-solid tumor predictor of pembrolizumab monotherapy benefit
Authors: Bulen Benjamin J. , Khazanov Nickolay A. , Lamb Laura E. , Hovelson Daniel H. , Kwiatkowski Kat , Johnson D. Bryan , Rhodes Daniel R. , Tomlins Scott A. 
Published: April 2023

Background: We previously reported the development and validation of an integrative Immunotherapy Response Score (IRS) algorithm, which integrates tumor mutation burden (TMB) and quantitative gene expression of PD-L1, PD-1, ADAM12 and TOP2A, to predict PD-1 or PD-L1 (together PD-[L]1) monotherapy (mono) benefit across solid tumors from routine formalin fixed paraffin embedded samples. Herein, we evaluated IRS performance for predicting pembrolizumab (pembro) mono benefit in a second, independent validation cohort.

Methods: We identified patients from an ongoing observational trial (NCT03061305) integrating molecular profiling with real world treatment data who were 1) treated with systemic pembro mono, 2) not included in the original IRS cohort, and 3) had valid molecular profiling data to generate IRS. IRS status (IRS-High [H] vs. -Low [L] by the previously validated threshold; -H with increased benefit) association with pembro real world progression free survival (rwPFS) by time-to-next therapy was determined by Cox proportional hazard modeling (adjusting for age, gender, line of systemic therapy, and PD-(L)1 mono indicated (microsatellite instable high [MSI-H], TMB-H, or approved tumor type) vs. not indicated. The predictive nature of the IRS biomarker was assessed in the subset of &gt;= 2nd line patients through a case cross-over analysis (pembro rwPFS vs. immediately preceding therapy line rwPFS) as assessed by likelihood ratio test (LRT).

Results: Of the 176 patients in this independent validation cohort (from 25 tumor types), 78 (44%) patients were IRS-H, while 40 (23%) were TMB-H. Pembro mono rwPFS was significantly longer in IRS-H vs. IRS-L patients (median rwPFS 18.7 vs. 6.4 months, adjusted hazard ratio [aHR] 0.46, p=0.007), while PD-(L)1 mono indicated status was not associated with pembro mono rwPFS (indicated vs. not indicated aHR 1.47, p=0.26). In the case cross-over analysis of 55 (31%) patients treated with systemic therapy prior to pembro mono, pembro rwPFS was significantly longer than preceding therapy in IRS-H patients (median 18.7 vs. 5.5 months) but not IRS-L patients (median 4.9 vs. 5.4 months); the LRT for interaction between IRS status and pembro/prior therapy was significant (p=0.046); results in the TMB-L/non-MSI-H subset (n=45) of patients was similar (LRT p=0.025).

Conclusion: These results confirm the pan-solid tumor PD-(L)1 monotherapy predictive nature of the IRS biomarker.

Citation Format: Benjamin J. Bulen, Nickolay A. Khazanov, Laura E. Lamb, Daniel H. Hovelson, Kat Kwiatkowski, D. Bryan Johnson, Daniel R. Rhodes, Scott A. Tomlins. Validation of an integrative pan-solid tumor predictor of pembrolizumab monotherapy benefit. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4348.