Circulating Levels of PD-L1 in Mesothelioma Patients from the NIBIT-MESO-1 Study: Correlation with Survival

Our plain-English summary of Circulating Levels of PD-L1 in Mesothelioma Patients from the NIBIT-MESO-1 Study: Correlation with Survival, by C. Chiarucci, S. Cannito, M.G. Daffinà, et al (Cancers, 2020).

The study

• Authors: C. Chiarucci, S. Cannito, M.G. Daffinà, G. Amato, G. Giacobini, O. Cutaia, M.F. Lofiego, C. Fazio, D. Giannarelli, R. Danielli, A.M. Di Giacomo, S. Coral, L. Calabrò, M. Maio, A. Covre
• Journal: Cancers
• Published: 2020;12(2)
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Targeting of the programmed cell death protein (PD)-1/programmed death-ligand 1 (PD-L1) axis has shown a significant clinical impact in several tumor types. Accordingly, our phase II NIBIT-MESO-1 study demonstrated an improved clinical efficacy in mesothelioma patients treated with the anti-PD-L1 durvalumab combined with the anti-cytotoxic T-lymphocyte antigen (CTLA)-4 tremelimumab, as compared to tremelimumab alone. Due to the promising therapeutic activity of immune check-point inhibitors (ICIs) in mesothelioma patients, the identification of biomarkers predictive of response to treatment is of crucial relevance. The prognostic role of soluble PD-L1 (sPD-L1) proposed in cancer patients prompted us to investigate this protein in sera from mesothelioma patients (n = 40) enrolled in the NIBIT-MESO-1 study. A significant (p < 0.001) increase in sPD-L1 levels was detected in patients after the first cycle and during therapy vs. baseline. A longer overall survival (OS) was observed in patients with sPD-L1 concentrations below (at baseline, d1C2, d1C5 (p < 0.01)) or FC values above (p < 0.05 at d1C2, d1C3, d1C5) their statistically calculated optimal cut-offs. On the basis of these initial results, the specific role of CTLA-4-, PD-L1-, or PD-1-targeting on sPD-L1 release was then investigated in sera from 81 additional ICI-treated solid cancer patients. Results showed a significant (p < 0.001) increase of sPD-L1 levels during therapy compared to baseline only in anti-PD-L1-treated patients, supporting the specific involvement of PD-L1 targeting in the release of its soluble form. Our findings suggest that sPD-L1 represents a predictive biomarker of clinical response to anti-PD-L1 cancer immunotherapy.

In plain English

Researchers in Siena, Italy, measured the blood protein soluble PD-L1 in 40 mesothelioma patients given tremelimumab and durvalumab in the NIBIT-MESO-1 trial. Pre-treatment levels were compared with 22 healthy donors. The article does not discuss asbestos exposure. Before treatment, patients had higher levels than donors (0.07 versus 0.05 ng/mL, p less than 0.001). Levels rose significantly by cycle 2 and stayed raised, with medians of 22.71 to 27.28 times baseline across visits. Levels below cut-offs set separately for each time point went with longer overall survival at baseline (16.49 versus 11.07 months) and at cycles 2 and 5, but not cycle 3. Larger rises also went with longer survival, for example at cycle 3 (32.75 versus 13.14 months, p = 0.006). No statistically significant link was found between levels and tumor response. In 81 other solid cancer patients, levels rose significantly only with drugs targeting PD-L1. The authors concluded the results warrant further study of soluble PD-L1 as a predictor of anti-PD-L1 treatment response. They said the data need validation, as this was the first such report in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory biomarker study of stored serum samples from patients in a phase II immunotherapy trial (NIBIT-MESO-1), extended to additional immunotherapy-treated cancer patients
• Who was studied: 121 cancer patients and 22 healthy volunteers, studied by researchers at the University Hospital of Siena, Italy. The patients were 40 mesothelioma patients from the NIBIT-MESO-1 trial, 32 other solid cancer patients given anti-PD-L1 drugs (alone or with tremelimumab), 20 given anti-CTLA-4 drugs and 29 given anti-PD-1 drugs. The data cut-off was 30 March 2019.
• Exposure: Not an asbestos exposure study. The exposure was immunotherapy: the anti-CTLA-4 antibody tremelimumab combined with the anti-PD-L1 antibody durvalumab. Other patients received other anti-PD-L1, anti-CTLA-4 or anti-PD-1 antibodies. Soluble PD-L1 was measured in serum by ELISA at baseline and during treatment.
• Main results:
  • Before treatment, soluble PD-L1 was higher in mesothelioma patients (0.07 ng/mL, range 0.01 to 0.15) than in healthy donors (0.05 ng/mL, range 0.03 to 0.06), p less than 0.001.
  • In the NIBIT-MESO-1 mesothelioma patients, levels rose significantly by day 1 of cycle 2 compared with baseline (p less than 0.001), and the rise was maintained during treatment. Median levels at the treatment visits ranged from 1.52 ng/mL (d1C2) to 1.76 ng/mL (d1C5). Median fold changes ranged from 22.71 (d1C2) to 27.28 (d1C3).
  • Optimal cut-offs were calculated separately for each time point. Mesothelioma patients with levels below the cut-off had longer overall survival at baseline (16.49 vs. 11.07 months), at d1C2 (17.56 vs. 11.04 months) and at d1C5 (20.80 vs. 11.00 months, p = 0.004). There was no association at d1C3.
  • Mesothelioma patients whose fold change was above the cut-off had longer overall survival: 17.94 vs. 13.14 months (p = 0.018) at d1C2, 32.75 vs. 13.14 months (p = 0.006) at d1C3, and 27.35 vs. 12.86 months (p = 0.016) at d1C5.
  • In mesothelioma patients at baseline, soluble PD-L1 correlated positively with absolute neutrophil count (r = 0.48), neutrophil-to-lymphocyte ratio (r = 0.33) and C-reactive protein (r = 0.42).
  • In mesothelioma patients, soluble PD-L1 levels were not significantly correlated with response rate, disease-control rate, age, gender or clinical stage.
  • In other cancer patients given anti-PD-L1 antibody, levels rose significantly during treatment (p less than 0.01).
  • Patients given anti-CTLA-4 antibodies alone showed no significant change in levels.
  • Patients given anti-PD-1 antibodies showed no significant change in levels.
  • In all 72 anti-PD-L1-treated patients combined, levels rose from a median of 0.06 ng/mL at baseline to 1.50 ng/mL after the first cycle (p less than 0.001). However, lower levels were linked to longer survival only at d1C2 and d1C5.
• The authors' conclusion: The authors concluded that low baseline soluble PD-L1 and a large rise during therapy correlated with longer overall survival in NIBIT-MESO-1 mesothelioma patients. They also concluded that increased soluble PD-L1 is specifically associated with anti-PD-L1 therapy. They said the results warrant further investigation of soluble PD-L1 as a predictive biomarker.
• Limitations the authors state:
  • The authors said further studies are needed to validate the data, because this is the first study reporting soluble PD-L1 levels in mesothelioma patients.
  • In the combined anti-PD-L1 group, the survival association appeared only at selected time points. The authors said this was possibly due to differences in cancer type and in the timing and doses of treatment, and they called for a larger cohort.
  • The authors noted that differences from other studies may reflect sample type, assay sensitivity or sampling time. They said measurement procedures need standardization.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Mesothelioma, Durvalumab (Imfinzi), Tremelimumab, Biomarker, Overall Survival, CTLA-4, Immunotherapy.

Related studies

• Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study — L. Calabrò, G. Rossi, et al. (2021)
• Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study — L. Calabrò, A. Morra, et al. (2018)
• Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy — M.F. Lofiego, S. Cannito, et al. (2021)
• A vision of immuno-oncology: the Siena think tank of the Italian network for tumor biotherapy (NIBIT) foundation — M. Maio, M. Lahn, et al. (2021)
• Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study — L. Calabrò, A. Morra, et al. (2015)
• Circulating and local nuclear expression of survivin and fibulin-3 genes in discriminating benign from malignant respiratory diseases: correlation analysis — M.H. Hassan, S. Abuhamdah, et al. (2021)

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