179 Immunotherapy trials lack a biomarker for inclusion: implications for drug development

Abstract

BackgroundNext-generation sequencing and other biomarkers have demonstrated the capability to identify potentially pathogenic molecular aberrancies. Immune checkpoint inhibitors (ICI) have benefited patients in almost every oncologic histology. Combining these innovations has transformed how oncologists treat previously untreatable diseases.MethodsThe 413 trials from clinicaltrials.gov website were reviewed using the terms ‘nivolumab’ or ‘pembrolizumab’ between January 1, 2019 and December 31, 2019. Additionally, all 33 interventional therapeutic trials for ‘glioblastoma multiforme’ and 79 for ‘pancreatic cancer’ that were either recruiting, not yet recruiting, or active not recruiting trials between January 1, 2019 and December 31, 2019 were analyzed.ResultsIn total of 413 trials, 57,853 were planned for enrollment with 37 (8.96%) trials requiring a biomarker for entry (n = 5,602 [9.7%]). Overall, there were 41 trials with single-agent immunotherapy planned to enroll 6222 patients and of those trials 7 (17.1%) required a biomarker for enrollment (n = 285 [4.6%]). There were 193 trials with >2 immunotherapies combined planned to enroll 21,360 patients and of those trials 17 (8.8%) required a biomarker for enrollment (n = 1254 [5.9%]). There were 69 trials with immunotherapy and chemotherapy combined planned to enroll 12,354 patients and of those trials 3 (4.3%) required a biomarker for enrollment (n = 83 [0.67%]). There were 58 trials with immunotherapy and targeted therapy combined planned to enroll 11,967 patients and of those trials 6 (10.3%) required a biomarker for enrollment (n = 3244 [27.1%]). There were 52 trials with other immunotherapy combinations (e.g. vaccine) planned to enroll 5950 patients and of those trials 4 (7.7%) required a biomarker for enrollment (736 [12.4%]). Within pancreatic cancer, 31 trials were planned to use immunotherapy (monotherapy, combination, with chemotherapy, with targeted therapy) including 4493 patients total; 5 (16%) of those trials required biomarkers enrolling 309 (7%) patients. Within glioblastoma multiforme, 13 trials were planned to use immunotherapy (monotherapy, combination, with chemotherapy, with targeted therapy) including 730 patients total; 1(8%) of those trials required biomarkers enrolling 10 (1%) patients.ConclusionsFor immunotherapy-based trials in 2019, <10% of patients expected to be enrolled would be selected by a biomarker for inclusion. Precision oncology continues to struggle in the era of ICI with an all-comers approach to patient selection and trial initiation. Selecting patients for trials based on biomarkers may help better identify responders to ICI.

Systemic immunity in cancer

“…Despite significant interest in the development of predictive biomarkers leveraging the systemic immune system, the vast majority of immunotherapy clinical trials are still performed without the use of a biomarker to guide inclusion 128 . Currently, there is no systemic immune biomarker that is sufficiently established to permit bedside decision-making, although some immunological features in the TME have been shown to be associated with prognosis in various contexts.…”

Combining Epigenetic and Immunotherapy in Cancer: Molecular Mechanisms

“…Furthermore, a number of studies have recently shown that dendritic cells play a crucial role in the effectiveness of PD-L1 inhibition. (76)(77)(78)(79) Although specific immunological traits in the TME have been found to be related to prognosis in diverse circumstances, we still need an adequate systemic immune biomarker to be able to predict outcomes (80), and to support patient treatment decisions.…”

Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations

“…Mechanisms of primary and acquired resistance during treatment with immunotherapies remain to be elucidated. Patient selection and stratification based on relevant biomarkers has been substantially limited and near non-existent; a study of planned clinical trials in 2019 showed that less than 10 % of the studies required biomarkers for enrollment [22]. A very limited number of biomarkers are linked to higher chance of response to anti-PD(L)1-based immunotherapies at the population level, e.g., PD-L1 and tumor mutational burden (TMB) [23].…”