P223: Correlation of Objective Response Rate (ORR) and Overall Survival Hazard Ratio (OS HR) with Immunotherapy in Cancer Patients
Poster Presenter
Ramon Mohanlal
CEO
RND Pharmaceuticals Inc United States
Objectives
We evaluated whether ORR with PD1/PD-L1 inhibitors (ICI) as monotherapy in a patient (pt) population x in early-stage trials was predictive of OS HR in late-stage controlled trials in a different pt population y receiving monotherapy ICI, in a range of cancer (Ca) types with published outcomes data.
Method
A meta-analysis was conducted with ORR and OS HR data retrieved in an unbiased manner from published ICI monotherapy trials in Pubmed. To mimic actual trial settings, ORR and OSHR were obtained from a different pt population. Next, ORR and OS HR were correlated, using cancer type as the anchor.
Results
We retrieved n=114 clinical trials (in a total of n=17309 patients) with ICI monotherapy for ORR evaluation, and a separate set of n=38 trials (with a total of n=9804 patients) with ICI monotherapy from controlled trials for OS HR evaluation, in patients with NSCLC, HNSCC, Cervical Ca, RCC, HCC, Mesothelioma, Endometrial Ca, Melanoma, Urothelial Ca, Ovarian Ca, Gastric Ca, mBC, TNBC, Esophageal Ca, GBM, SCLC, Prostate Ca, CRC and Biliary Ca. ORR was highly correlated with OS HR, with a correlation coefficient (r-value) of -0.931 (n=9804; p<0.0001) after linear regression. An ORR of 18% was associated with an OS HR of 0.8.
Conclusion
Previous reports on correlation studies between ORR and OS HR from Oncology trials were inconclusive. Whereas a large meta-analytic study from Oxnard (JAMA Oncology 2016) in n=578 eligible Oncology trials demonstrated that high ORR (>30%) is highly predictive of FDA approval, other publications, including from FDA researchers suggested otherwise (Mushti, Clin Can Res 2018; Sheth, Ca Treat and Res Comm, 2021). Mushti and Sheth analyzed a limited number of trials (n=13 each), and treatment regimens were highly variable. At the time of these publications, ICI outcomes were available for a small number of cancer types, and hence the ‘dynamic’ ORR range is limited. With widening of the dynamic range, and with selecting only ICI monotherapy trials, we observed an excellent correlation (r=-0.931) between ORR and OS HR, even with ORR and OS HR data obtained from different patient pools. Immunotherapy with PD1/PD-L1-inhibition as a therapeutic class has demonstrated effectiveness in cancer patients. Considering the excellent correlation (-0.931) between ORR from single-arm studies and OS HR from controlled trials with ICI monotherapy and considering the proven mechanism of PD1/PD-L1-inhibition, it could be argued that regulatory approval could be obtained, based on ‘positive’ ORR data alone with ICI monotherapy. An ORR >18% was associated with an OS HR < 0.8, which typically is the OS HR threshold for regulatory approval. Oxnard suggested that an ORR exceeding 30% has a high likelihood for predicting future regulatory approval. To achieve these high ORR values, it will be necessary to enrich for potential responders, which will require a test highly predictive for response to ICI. RND is developing a novel test with superior prediction of resistance to ICI compared to PD-L1, based on a novel peripheral resistance concept (Mohanlal, JITC 2025). This test could potentially enable high ORR results with ICI monotherapy in cancer types where ORR in ‘all-comers’ is inadequate.
