Abstract 39P
Background
FOXC1, MKI67 and PDL1 expression that tracks plasticity, proliferation and immune evasion accurately predicts efficacy of Immune Checkpoint Blockade (ICB) with PD1/PDL1 inhibitor drugs. We sought to validate whether patient selection based on predicted Hyperprogressive Disease (HPD) risk using such an approach can improve Progression-free Survival (PFS) and/or Overall Survival (OS) in clinical trial and real world cohorts.
Methods
Pre-treatment tumor RNA-Seq data obtained from patients diagnosed with advanced/metastatic (a/m) melanoma (n=154,121), non-small cell lung cancer (NSCLC, n=82,140) and renal cell carcinoma (RCC, n=250,120) were analyzed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure (TTF) <=2 months post-treatment initiation. Optimized biomarker cutoff values based on model AUC were leave-one-out cross validated and cancer-type specific (CTS) prediction algorithms derived. The unmodified strategy was then validated in the independent, CTS validation datasets.
Results
Predicted Clinical Responders (CR) displayed marked improvement in PFS and OS compared to Predicted Non-Responders with standard Progressive Disease (PD) or Hyperprogressive Disease (HPD). [a/m Melanoma OS HR=0.35 (0.187-0.666)95%CI, p=0.0004; a/m NSCLC OS HR=0.24 (0.119-0.499)95%CI, p<0.0001; a/m RCC OS HR= 0.45 (0.255-0.810)95%CI, p=0.008]. Table: 39P
Patient stratification by HPD risk and median overall survival benefit
Cancer type | Sample size | ICB median OS | HPD median OS | PD median OS | CR median OS |
Melanoma Liu et al | 121 | 22.5 mos | 5 mos | 17 mos | 37.5 mos |
NSCLC SU2C-mark cohort Ravi et al | 140 | 17 mos | 13 mos | 19 mos | 35.5 mos |
RCC CM-025 cohort Motzer et al | 120 | 27.5 mos | 17.5 mos | 22.5 mos | 57 mos |
Conclusions
Compared to ICB administered in a non-patient stratified manner, restricting ICB treatment only to those patients who are predicted CRs results in nearly a two-fold or greater improvement in the median OS survival benefit in all cancer types examined. Patients predicted to have elevated HPD risk should be considered for treatment with non-ICB regimens or offered enrollment in clinical trials that combine ICB with other drugs.
Clinical trial identification
NCT01668784; Nov 5, 2015.
Legal entity responsible for the study
P.S. Ray.
Funding
Has not received any funding.
Disclosure
P.S. Ray: Non-Financial Interests, Institutional, Advisory Role: Onconostic Technologies: Practicing surgical oncologist and clinical investigator, identified as the presenting author on the submitted abstract. PSR is not an employee of the company (Onconostic Tehcnologies), but is founder and Chairman of the Scientific Advisory Board of the company which is an unpaid position. T. Ray, R. Hussa: Financial Interests, Personal, Full or part-time Employment: Onconostic Technologies, Inc.; Financial Interests, Personal, Stocks/Shares: Onconostic Technologies, Inc. C. Taylor: Financial Interests, Personal, Advisory Board: Onconostic Technologies, Inc.; Financial Interests, Personal, Stocks/Shares: Onconostic Technologies, Inc.
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