Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population

Our plain-English summary of Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population, by T. Ahmadzada, W.A. Cooper, M. Holmes, et al (JTO Clinical and Research Reports, 2020).

The study

• Authors: T. Ahmadzada, W.A. Cooper, M. Holmes, A. Mahar, H. Westman, A.J. Gill, I. Nordman, P.Y. Yip, A. Pal, R. Zielinski, N. Pavlakis, A. Nagrial, D. Daneshvar, D. Brungs, D. Karikios, V. Aleksova, J. Burn, R. Asher, G.E. Grau, E. Hosseini-Beheshti, G. Reid, S. Clarke, S. Kao
• Journal: JTO Clinical and Research Reports
• Published: 2020;1(4):100075
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab.

Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples.

Results: A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate.

Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.

© 2020 The Authors.

In plain English

This retrospective study examined 98 people with mesothelioma (95 pleural, 3 peritoneal) in New South Wales, Australia. They received the immunotherapy pembrolizumab from 2015 to 2019 through iCare, a workers' compensation scheme for mesothelioma from occupational dust such as asbestos. Most had previous treatment. Eighteen percent responded (95% CI 12% to 28%); disease was controlled in 56% (47% to 66%). Median progression-free survival was 4.8 months (95% CI 3.6 to 6.2); median overall survival, 9.5 months (6.6 to 13.7). Immune-related side effects occurred in 27%; the main text counts eight (8%) at grade 3 or higher, the abstract nine. Patients with ECOG 0 (best fitness) or at least 5% CD3-positive immune cells in the tumor responded more often. PD-L1 in at least 1% of tumor cells was linked with longer progression-free survival. A baseline platelet count above 400 × 10^9 per liter was linked with shorter progression-free and overall survival; taking dexamethasone when pembrolizumab began, with shorter overall but not progression-free survival. The authors concluded pembrolizumab was well tolerated and effective in a small proportion; they named the retrospective design and size as main limitations.

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: Retrospective cohort study using data supplied by oncologists from several New South Wales cancer centers, with central re-examination of archived tumor samples
• Who was studied: 98 patients with mesothelioma treated with pembrolizumab between August 2015 and July 2019 under the NSW iCare compensation scheme. Median age 70 years (range 46 to 91); 92% men; 95 pleural and 3 peritoneal; 76% epithelioid. Pembrolizumab was first-line for 4, second-line for 63 and third-line or later for 31. Tumor samples were available for 76 patients.
• Exposure: The treatment studied was pembrolizumab (a PD-1 antibody): 200 mg every 3 weeks for 73% of patients and 2 mg/kg every 3 weeks for 27%. Asbestos exposure was not measured. Patients were eligible for the scheme because their mesothelioma resulted from occupational exposure to dust such as asbestos in an NSW workplace.
• Main results:
  • Whole cohort: overall response rate 18% (95% CI 12% to 28%), made up of 1 complete and 17 partial responses.
  • Whole cohort: disease control rate 56% (95% CI 47% to 66%), including 37 patients with stable disease.
  • Whole cohort: median progression-free survival 4.8 months (95% CI 3.6 to 6.2) and median overall survival 9.5 months (95% CI 6.6 to 13.7).
  • Whole cohort: overall survival was 41% at 12 months and 21% at 24 months.
  • Immune-related adverse events of any grade occurred in 26 patients (27%). The main text reports grade 3 or higher events in eight patients (8%).
  • Patients with baseline ECOG performance status 0 had higher odds of response. Odds ratio for ECOG 1 or higher versus 0: 0.25 (95% CI 0.08 to 0.77).
  • Response rate was 28% in patients with at least 5% CD3-positive tumor-infiltrating lymphocytes within the tumor, versus 5% in those with less (p less than 0.01). There was no association for these cells in the stroma (p = 0.26).
  • PD-L1 expression and BAP1 loss were not significantly associated with response. Response rates were numerically higher with PD-L1 at 1% or more (23% versus 11%) and with BAP1 loss (20% versus 13%).
  • In multivariable analysis of progression-free survival, ECOG performance status 1 or higher was linked with shorter progression-free survival (hazard ratio 3.85, 95% CI 1.54 to 9.64).
  • In multivariable analysis of progression-free survival, PD-L1 at 1% or more was linked with longer progression-free survival (hazard ratio 0.31). The printed confidence interval appears to be a typographical error.
  • In multivariable analysis of progression-free survival, a baseline platelet count above 400 × 10^9 per liter was linked with shorter progression-free survival (hazard ratio 1.93, 95% CI 1.01 to 3.67, p = 0.05).
  • In multivariable analysis of overall survival, a baseline platelet count above 400 × 10^9 per liter was independently linked with shorter overall survival (hazard ratio 2.37, 95% CI 1.21 to 4.63).
  • In multivariable analysis of overall survival, patients already taking dexamethasone when pembrolizumab treatment started had shorter overall survival (hazard ratio 4.37, 95% CI 1.45 to 13.13). In univariate analysis, median overall survival was 10 months without dexamethasone versus 3 months with it.
  • Dexamethasone use at the start of pembrolizumab was associated with shorter overall survival but not with progression-free survival.
  • Neither BAP1 loss nor CD3-positive lymphocytes in the stroma predicted progression-free or overall survival. Histologic subtype was not associated with response or survival.
• The authors' conclusion: The authors concluded that single-agent pembrolizumab was well tolerated and effective in a small proportion of patients. They concluded that standard performance status assessment remained the most robust predictor of outcome. They suggested that the absence of pretreatment dexamethasone, a non-elevated platelet count and PD-L1 expression may predict longer survival, and that tumor-infiltrating lymphocytes may help select patients likely to respond. They said these factors should be evaluated in larger studies.
• Limitations the authors state:
  • The authors named the retrospective design and the size of the study as its main limitations.
  • The authors stated that larger prospective trials are needed to confirm the benefits of immunotherapy compared with chemotherapy.
  • The authors said the lack of an association with BAP1 loss may reflect the small sample size.
  • The authors said the lack of an association with histologic subtype may reflect the small number of non-epithelioid patients (16).
  • The authors said it was unclear whether dexamethasone reduced pembrolizumab's effect or instead reflected poorer performance status.
  • The authors noted that including some patients with ECOG scores above 1 may have contributed to lower survival than in clinical trials.
  • The authors noted that it is difficult to infer a causal relationship between performance status and response.

Topics

Medical terms in this study, explained in our Lexicon: Pembrolizumab (Keytruda), Mesothelioma, Biomarker, PD-L1, BAP1, Tumor-Infiltrating Lymphocytes, Epithelioid, Performance Status.

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