PD-L1 pfeRNAs as blood-based predictors of treatment response of unresectable malignant pleural mesothelioma patients administered Durvalumab with cisplatin and pemetrexed as first-line therapy

Our plain-English summary of PD-L1 pfeRNAs as blood-based predictors of treatment response of unresectable malignant pleural mesothelioma patients administered Durvalumab with cisplatin and pemetrexed as first-line therapy, by A. Gurau, S. Yamauchi, K. Ecoff, et al (Non-coding RNA Research, 2025).

The study

• Authors: A. Gurau, S. Yamauchi, K. Ecoff, K.P. Rodgers, J.R. Eshleman, C.C. Talbot, P. Huang, J. Choi, P.M. Forde, V. Anagnostou, M. Brock, Y. Mei
• Journal: Non-coding RNA Research
• Published: 2025;12:34-41
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: A new therapeutic avenue combining Durvalumab with cisplatin-pemetrexed (Durva-CP) has delivered a promising outcome for previously untreated patients with unresectable malignant pleural mesothelioma (MPM) in clinical trials. However, the limited patient response to Durva-CP needs predictors to select optimal candidates and monitor the developed resistance. Protein functional effector sncRNA (pfeRNA) reveals a fundamental mechanism underlying the regulation of protein activity. The common mechanisms underlying durvalumab, cisplatin, and pemetrexed indicate that PD-L1 pfeRNAs (PDLpfeRNAs) are key molecules that control the treatment response.

Methods: We specified PDLpfeRNAs by sncRNA deep sequencing, confirmed their binding to PD-L1 by immunoprecipitation and reverse pull-down assays, and demonstrated their roles in controlling the interaction behaviors of PD1/L1 through quality-controlled drug development assays. Following the standards required for the CLIA-compliant LDT, we measured their expression levels in 60 plasma biospecimens from 30 unresectable MPM patients enrolled in the PrE0505 Phase II multicenter study. Using the Cox proportional hazards model and Kaplan-Meier analyses, we described their significance in predicting the treatment response of unresectable MPM patients administered Durva-CP as first-line therapy.

Results: Two PDLpfeRNAs, PDLpfeRNAa and PDLpfeRNAb, were characterized, confirmed to bind to PD-L1, and identified to control the interaction behaviors of PD-1/L1. Their plasma relative expression levels (REL) demonstrated significant prognostic value for both overall survival (p = 0.0019) and progression-free survival (p = 0.019), and the association remained significant after adjusting for histological subtype (HR 2.59, 95 % CI: 1.00-6.70, p = 0.050) and age (HR 1.03, 95 % CI: 0.98-1.07, p = 0.269).

Conclusions: Plasma PDLpfeRNAs are predictors of treatment response of unresectable MPM patients treated with Durva-CP as first-line therapy to select optimal candidates and monitor the developed resistance.

© 2025 The Authors.

In plain English

This study combined laboratory experiments with analysis of stored blood samples. It sought small RNAs that might predict response to first-line durvalumab plus cisplatin and pemetrexed (Durva-CP) in unresectable malignant pleural mesothelioma. In patient tissue, the authors identified two small RNAs, PDLpfeRNAa and PDLpfeRNAb, binding PD-L1, the protein durvalumab targets. Both were far more abundant in cancerous than normal adjacent tissue. In cell-based tests, the first appeared to strengthen the PD-1 and PD-L1 interaction and the second to weaken it. The authors then measured the ratio of the two (REL) in 60 plasma samples from 30 PrE0505 phase II trial patients. The methods state patients were split into high and low groups at the median change between their two samples. The high group had worse overall survival (hazard ratio 4.31, 95% confidence interval 1.49 to 12.42) after adjusting for age and histological subtype. Survival curves differed between the groups for overall survival (p = 0.0019) and progression-free survival (p = 0.019). The authors concluded these plasma RNAs are predictors of treatment response. They noted the study was retrospective and needs prospective multicenter validation.

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 study (RNA sequencing, binding and cell-based assays) plus a retrospective analysis of plasma samples from patients in a phase II clinical trial
• Who was studied: 30 patients with unresectable malignant pleural mesothelioma in the PrE0505 trial at 15 U.S. sites, June 2017 to June 2018. They were 4 female and 26 male, with an average age of 68 plus or minus 11.8 years (range 35 to 82). Each gave two plasma samples, 60 in total. 21 had epithelioid, 6 sarcomatoid and 3 biphasic tumors. Responses were 15 partial response, 12 stable disease and 3 progressive disease. The laboratory work used patient-matched cancerous and normal adjacent tissues and the H1975 cell line.
• Exposure: First-line treatment with durvalumab plus cisplatin and pemetrexed (Durva-CP). The measured factor was the plasma relative expression level (REL) of PDLpfeRNAa to PDLpfeRNAb. No asbestos exposure was studied.
• Main results:
  • In samples precipitated with PD-L1 antibody, copy numbers of PDLpfeRNAa and PDLpfeRNAb were 407 and 419 in normal adjacent tissues. In cancerous tissues they were 1,315,332 and 12,417. Both were at 0 copies with the control antibody.
  • In H1975 cells, the two RNAs were detected with PD-L1 antibody but not with control antibody. PD-L1 was pulled down by the RNAs but not by scrambled RNA.
  • In a cell-based luminescence assay, PDLpfeRNAa reduced the signal, which the authors interpreted as enhancing the PD-1/PD-L1 interaction. PDLpfeRNAb increased the signal, which they interpreted as inhibiting the interaction.
  • According to the methods, patients were classified into high and low groups at the median of the change in levels between their second and first measurements.
  • Among the 30 patients, high REL was associated with worse overall survival (HR 4.31, 95% CI 1.49 to 12.42, p = 0.007) after adjusting for age and histology.
  • Kaplan-Meier survival curves separated between the high and low REL groups (15 patients each) for overall survival (p = 0.0019) and progression-free survival (p = 0.019). In both, high REL was linked to shorter survival.
  • In the same model, sarcomatoid or biphasic subtype versus epithelioid had HR 2.59 (95% CI 1.00 to 6.70, p = 0.050). Age had HR 1.03 (95% CI 0.98 to 1.07, p = 0.269), which was not statistically significant.
• The authors' conclusion: The authors concluded that plasma PDLpfeRNAs are predictors of treatment response in unresectable malignant pleural mesothelioma patients given Durva-CP as first-line therapy. They said these markers could be used to select candidates and monitor developing resistance.
• Limitations the authors state:
  • The study was retrospective and needs validation in a multicenter prospective trial.
  • Patient numbers were limited because mesothelioma is rare, and only participants who had two treatment cycles could be included.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Unresectable, Pleural Mesothelioma, Durvalumab (Imfinzi), Cisplatin, Pemetrexed (Alimta), First-line Therapy, Clinical Trial.

Related studies

• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma — Y. Miyamoto, T. Kozuki, et al. (2021)
• A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol — N. Fujimoto, K. Aoe, et al. (2018)
• Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial — P.S. Kok, P.M. Forde, et al. (2022)
• Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial — P.M. Forde, V. Anagnostou, et al. (2021)
• Cost-effectiveness of nivolumab plus ipilimumab as first-line treatment for American patients with unresectable malignant pleural mesothelioma — Z.M. Ye, Z.Q. Tang, et al. (2022)

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