Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort

Our plain-English summary of Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort, by S. Brosseau, C. Danel, A. Scherpereel, et al (Clinical Lung Cancer, 2019).

The study

• Authors: S. Brosseau, C. Danel, A. Scherpereel, J. Mazières, S. Lantuejoul, J. Margery, L. Greillier, C. Audigier-Valette, V. Gounant, M. Antoine, D. Moro-Sibilot, I. Rouquette, O. Molinier, R. Corre, I. Monnet, A. Langlais, F. Morin, E. Bergot, G. Zalcman, G. Levallet
• Journal: Clinical Lung Cancer
• Published: 2019;20(5):e564-e575
• Type of article: Randomized trial
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).

Patients And Methods: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.

Results: PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).

Conclusion: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.

Copyright © 2019 Elsevier Inc. All rights reserved.

In plain English

This study measured the protein PD-L1 in tumor samples from 214 of 448 patients in the French MAPS phase 3 trial. That trial treated malignant pleural mesothelioma that could not be removed surgically with pemetrexed and cisplatin, with or without bevacizumab. Most patients had documented occupational asbestos exposure. In 137 of 214 samples (64.1%), no tumor cells stained for PD-L1. In 27 samples, PD-L1 was present in 50% or more of tumor cells. Sarcomatoid and biphasic tumors were more often PD-L1 positive than epithelioid tumors. Patients with PD-L1 in 50% or more of tumor cells had a median overall survival of 10.5 months, versus 19.3 months for other patients. This difference was not statistically significant after adjusting for tumor subtype, performance status, smoking and treatment. Among the 179 patients with epithelioid tumors, the 13 with high PD-L1 had shorter median progression-free survival (time before the disease worsened): 6.7 versus 9.89 months. This remained significant after adjustment. The authors concluded that PD-L1 staining may not have a major prognostic role in pleural mesothelioma, though they could not exclude one in the epithelioid subset.

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: Preplanned but exploratory biomarker study (Bio-MAPS) using tumor samples from a randomized phase 3 treatment trial (IFCT-0701 MAPS), with survival analyzed by Cox models
• Who was studied: 214 of 448 patients with nonresectable malignant pleural mesothelioma enrolled in the French MAPS trial (randomized February 13, 2008 to January 5, 2014); 160 men and 54 women, median age 66.85 years; 179 epithelioid and 35 sarcomatoid or biphasic tumors
• Exposure: The factor studied was PD-L1 expression in tumor cells, measured by immunohistochemistry with the E1L3N antibody clone. All patients received pemetrexed plus cisplatin, with or without bevacizumab. Occupational asbestos exposure was documented by interview in most patients. No fiber types or doses were reported.
• Main results:
  • In 137 of 214 samples (64.1%), no PD-L1 staining was found in tumor cells; macrophages in these samples were checked as positive controls. 77 samples (35.9%) were PD-L1 positive.
  • Of the 77 positive samples, 27 (35.1%) had PD-L1 in 50% or more of tumor cells; the other 50 (64.9%) had it in fewer than 50%
  • Sarcomatoid or biphasic tumors were more often PD-L1 positive than epithelioid tumors: 24 of 77 positive samples (31.2%) versus 11 of 137 negative samples (8.0%), P less than .001
  • Whole group, 1% cutoff: median overall survival was 12.3 months for PD-L1-positive patients versus 22.2 months for others (HR 1.25; 95% CI 0.93-1.67; P = .14). After adjustment the HR was 1.10 (95% CI 0.81-1.49; P = .55), which was not statistically significant.
  • Whole group, 50% cutoff: median overall survival was 10.5 months for patients with high PD-L1 versus 19.3 months for patients with lower expression (HR 1.93; 95% CI 1.27-2.93)
  • After adjusting for histology subtype, performance status, smoking and treatment arm, the 50% cutoff overall survival difference was not statistically significant (adjusted HR 1.20; 95% CI 0.74-1.94; P = .47)
  • Whole group, 50% cutoff: median progression-free survival was 6.2 months with high PD-L1 versus 9.2 months with lower expression (HR 1.99; 95% CI 1.32-3.00; P = .001). The adjusted HR was 1.25 (95% CI 0.77-2.06; P = .37).
  • PD-L1 expression in 50% or more of tumor cells did not significantly predict survival differences between the bevacizumab and chemotherapy-only arms (P for interaction .12 for overall survival, .21 for progression-free survival)
  • 179 epithelioid patients: median overall survival was 23 months (95% CI 18.5-25.2) with PD-L1 below 50% (166 patients) versus 12.3 months (95% CI 4.3-21.6) with PD-L1 at 50% or more (13 patients), P = .071. The adjusted HR was 1.65 (95% CI 0.91-3.0; P = .098), not statistically significant.
  • 179 epithelioid patients: median progression-free survival was 9.89 months (95% CI 3.6-10.3) with PD-L1 below 50% versus 6.7 months (95% CI 3.6-10.35) with PD-L1 at 50% or more (P = .0047)
  • In the epithelioid group, high PD-L1 remained significantly associated with progression-free survival after adjustment (adjusted HR 2.16; 95% CI 1.2-3.84; P = .0087)
• The authors' conclusion: The authors concluded that PD-L1 staining may not have a major prognostic role in malignant pleural mesothelioma, although they could not exclude such an influence in the epithelioid subset. They stated that their data do not support routine use of PD-L1 staining in these patients until prospective data with immune checkpoint blocking agents become available.
• Limitations the authors state:
  • Only one PD-L1 antibody clone (E1L3N) was used, and staining differences between antibodies could affect positivity rates, especially at low expression levels
  • The study may lack enough statistical power to evaluate prognosis, although the authors considered this unlikely
  • The epithelioid subgroup analysis was unplanned and may have lacked power for overall survival
  • The test of whether PD-L1 predicted benefit from bevacizumab may have lacked statistical power

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, PD-L1, Sarcomatoid, Biphasic Mesothelioma, Histology, Immunohistochemistry, Epithelioid, Median Overall Survival.

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• High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma — H. Ollila, J. Paajanen, et al. (2021)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma — B.H. Nguyen, R. Montgomery, et al. (2018)
• Programmed cell death 1 ligand 1 (PD-L1) expression is associated with poor prognosis of malignant pleural mesothelioma patients with good performance status — E. Rrapaj, L. Giacometti, et al. (2021)

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