Determinants of activity and efficacy of anti-PD1/PD-L1 therapy in patients with advanced solid tumors recruited in a clinical trials unit: a longitudinal prospective biomarker-based study

Abstract

Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.

Impact of Perioperative Dexamethasone in the Context of Neurosurgical Brain Metastasis Resection

“…Therefore, patients that did not undergo surgery were excluded from this study. Our study has potential implications with respect to the efficacy of CPI in patients with brain metastases that may be candidates to receive CPIs after brain metastasis resection and RTx [20][21][22][23] . In this regard in patients with metastatic disease several retrospective studies indicated that timing of initiation of corticosteroids may influence therapy response to CPI; for example, Maslov and colleagues showed that patients treated with corticosteroids within 2 months of initiation with CPI showed significantly shorter OS than patients receiving corticosteroids after 2 months of initiation of treatment with CPIs 22 .…”

Next-Generation Sequencing-Based Evaluation of the Actionable Mutational Landscape in Solid Tumors: the “MOZART” Prospective Observational Study

“…Finally, PD-L1 is now used as a major predictive biomarker of response to ICI 9 . Here we aimed at evaluating its association with genomic alterations in solid tumors to speculate on a potential role beyond immunotherapy.…”

“…Tumor mutational burden (TMB) is usually de ned as the number of somatic mutations per megabase (Mb) of interrogated genomic sequence and is a potential biomarker of response to ICI 9 . The Oncofocus assay covers ~ 1.2 Mb over 505 genes, complying with the evidence-based suggestion that gene panels of at least 1 Mb are needed for TMB measurement [16][17][18] .…”

“…Here we report the analysis of test trending data from this large screening programme to investigate the prevalence of actionable mutations directed at either the prescription of speci c salvage targeted treatments (off-label or in indication) or alternatively to recruit patients to the most appropriate clinical trials. The NGS genomic data was also analyzed in combination with a PD-L1 companion diagnostic (CDx) immunohistochemistry (IHC) test, in order to assess potential correlations between clinically actionable tumor mutations and PD-L1 expression, a biomarker of response to anti-PD1/PD-L1 immune-checkpoint inhibitors (ICI) 9 .…”

Editorial: Diagnostic, prognostic and predictive factors of response in the era of precision oncology in breast cancer

“…The importance of the immune system in controlling cancer development, treatment responses and long-term survival of cancer patients by manipulating immune response with several therapeutic immunotherapeutic strategies has already been established or under intensive investigation (13)(14)(15); consequently, numerous researchers have directed their efforts toward investigating immune-related genes in the pursuit of developing reliable predictive models for immunotherapy outcomes and patients prognosis. On this Research Topic of Tian et al, Yang et al and Liu et al developed prognostic models based on different immunerelated genes, which seem to be promising in effectively assist clinicians with medical diagnoses, evaluating patient prognosis and formulating diverse treatment strategies.…”