Development and validation of the Immune Profile Score (IPS), a novel multi-omic algorithmic assay for stratifying outcomes in a real-world cohort of advanced solid cancer patients treated with immune checkpoint inhibitors

Background Immune checkpoint inhibitors (ICIs) have transformed the oncology treatment landscape. Despite substantial improvements for some patients, the majority do not benefit from ICIs, indicating a need for predictive biomarkers to better inform treatment decisions.

A de-identified pan-cancer cohort from the Tempus multimodal real-world database was used for the development and validation of the Immune Profile Score (IPS) algorithm leveraging Tempus xT (648 gene DNA panel) and xR (RNAseq). The cohort consisted of advanced stage cancer patients treated with any ICI-containing regimen as the first or second line of therapy. The IPS model was developed utilizing a machine learning framework that includes tumor mutational burden (TMB) and 11 RNA-based biomarkers as features.

IPS-High patients demonstrated significantly longer overall survival (OS) compared to IPS-Low patients (HR=0.45, 90% CI [0.40-0.52]). IPS was consistently prognostic in PD-L1 (positive/negative), TMB (High/Low), microsatellite status (MSS/MSI-H), and regimen (ICI only/ICI + other) subgroups. Additionally, IPS remained significant in multivariable models controlling for TMB, MSI, and PD-L1, with IPS HRs of 0.49 [0.42-0.56], 0.47 [0.41-0.53], and 0.45 [0.38-0.53] respectively. In an exploratory predictive utility analysis of the subset of patients (n=345) receiving first-line (1L) chemotherapy (CT) and second-line (2L) ICI, there was no significant effect of IPS for time to next treatment on CT in L1 (HR=1.06 [0.85-1.33]). However, there was a significant effect of IPS for OS on ICI in L2 (HR=0.63 [0.46-0.86]). A test of interaction was statistically significant (p<0.01).

Our results demonstrate that IPS is a generalizable multi-omic biomarker that can be widely utilized clinically as a prognosticator of ICI based regimens. Key Messages What is already known on this topic – Advancements of multi-omic profiling technology in research settings has demonstrated the potential value of novel immune biomarkers for forecasting response to ICI therapies. However, despite these advances there remains an unmet clinical need for implementation of more sensitive and generalizable biomarkers to better predict patient outcomes to ICI due to limited availability of clinical multi-omic testing and validation cohorts. What this study adds – Our results demonstrate that IPS is a generalizable multi-omic biomarker that can be widely utilized clinically as a prognosticator of ICI based regimens. Importantly, IPS-High may identify patients within subgroups (TMB-L, MSS, PD-L1 negative) who benefit from ICI beyond what is predicted by existing biomarkers. How this study might affect research, practice or policy – In the near term IPS results can support patient stratification across pan-solid tumor cohorts to help inform clinicians and researchers which patients are more likely to benefit from ICI based regimens. In the future IPS may support label expansion of ICIs into cancer types without current approvals, and also potentially improve patient selection to minimize over-treatment with ICI in patients unlikely to respond. Competing Interest Statement A.Z., R.E., Y.L., A.J., S.W.H, S.M., B.T., M.R, N.P., B.M., K.S., M.T-L., H.N., J.G, K.B, C.S., M.M.S., T.T., and E.C. are employees of and stockholders in Tempus AI, Inc. a for-profit company. T.A.C. is a co-founder of Gritstone Oncology and holds equity. T.A.C. holds equity in An2H. T.A.C. acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai. T.A.C. has served as an advisor for Bristol-Myers, MedImmune, Squibb, Illumina, Tempus, Eisai, AstraZeneca, and An2H. T.A.C. holds ownership of intellectual property on using tumor mutation burden to predict immunotherapy response, with pending patent, which has been licensed. S.P. receives scientific advisory income from: Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Eli Lilly, Jazz, Genentech, Illumina, Merck, Pfizer, Zai Labs. His university receives research funding from: Amgen, AstraZeneca, A2bio, Bristol-Myers Squibb, Eli Lilly, Fate Therapeutics, Gilead, Iovance, Merck, Pfizer, and Roche/Genentech. M.Z. reports Institutionally-directed research funding from BMS and Exelixis; Advisory income from Pfizer, Exelixis, Janssen, Merck; and Honoraria from Adicet Bio and Arcus Bio. D.R.A. reports consulting or scientific advisory board support from Adlai Nortye, Boehringer Ingelheim, Cue Biopharma, Exelixis, Genmab, Inhibrx, Immunitas, Sanofi, Kura Oncology, Merck, Merck KGaA, Merus, Natco Pharma, Purple Biotech, Regeneron, Seagen, and TargImmune Therapeutics; travel support from Natco Pharma; leadership role on the NCCN practice guidelines and the Barnes Jewish Hospital Pharmacy and Therapeutics committee; research support from Tempus, Pfizer, Eli Lilly, Merck, Celgene/BMS, Novartis, AstraZeneca, Blueprint Medicine, Kura Oncology, Cue Biopharma, Cofactor Genomics, Debiopharm International, Inhibrx, ISA Therapeutics, Gilead Sciences, BeiGene, Roche, Vaccinex, Hookipa Biotech, Adlai Nortye USA, Epizyme, BioAtla, Boehringer Ingelheim, Calliditas Therapeutics, Genmab, Natco Pharma, Tizona Therapeutics, Erasca, Alentix, Seagen, Coherus, Takeda, Xilio, GSK, Johnson & Johnson, and Immunotep. Funding Statement All work was funded by Tempus AI, Inc. a for-profit company. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with HIPAA regulations, where applicable, and IRB exempt determinations (Advarra Pro00076072, Pro00072742). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes * submitting author must have ORCID ID; encouraged for all other authors Authors have updated to consolidate the supplemental figures Data Availability Deidentified data used in the research were collected in a real-world health care setting and subject to controlled access for privacy and proprietary reasons. When possible, derived data supporting the findings of this study have been made available within the paper and its Supplementary Figures and Tables. List of abbreviations used - IPS - (immune profile score) - ICIs - (immune checkpoint inhibitors) - TMB - (tumor mutational burden) - MSS - (microsatellite stable) - MSI - (microsatellite instability) - OS - (overall survival) - 1L/2L - (first/second line) - IHC - (immunohistochemistry) - scIR - (single-cell immune resistance) - TTNT - (time to next treatment) - TCGA - (The Cancer Genome Atlas)