Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis

Our plain-English summary of Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis, by Y.C. Tsai, H.L. Chen, T.H. Lee, et al (Cancers, 2021).

The study

• Authors: Y.C. Tsai, H.L. Chen, T.H. Lee, H.M. Chang, K.L. Wu, C.H. Chuang, Y.C. Chang, Y.K. Tu, J.Y. Hung, C.J. Yang, I.W. Chong
• Journal: Cancers
• Published: 2021;14(1)
• Type of article: Review
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Patients with malignant pleural mesothelioma (MPM) have very poor prognoses, and pemetrexed plus platinum is the standard first-line therapy. However, the second-line therapy for relapsed MPM remains controversial. A comprehensive search was performed to identify randomized controlled trials (RCTs) evaluating various second-line regimens in patients with relapsed MPM. Indirect comparisons of overall survival (OS) and progression-free survival (PFS) were performed using network meta-analysis. Surface under the cumulative ranking curve (SUCRA) values were used to rank the included treatments according to each outcome. Nivolumab alone or nivolumab plus ipilimumab provided significantly longer OS than placebo (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55-0.94 for nivolumab alone; HR: 0.54, 95% CI: 0.31-0.92 for nivolumab plus ipilimumab). The best SUCRA ranking for OS was identified for nivolumab plus ipilimumab (SUCRA: 90.8%). Tremelimumab, vorinostat, nivolumab alone, chemotherapy (CTX), asparagine-glycine-arginine-human tumor necrosis factor plus CTX, and nivolumab plus ipilimumab all produced noticeable PFS benefits compared with placebo. Nivolumab plus ipilimumab had the best PFS ranking (SUCRA: 92.3%). Second-line treatment with nivolumab plus ipilimumab provided the OS and PFS outcomes for patients with relapsed MPM.

In plain English

This was a systematic review and network meta-analysis, a method that combines separate trials to compare treatments indirectly. The authors searched medical databases and cancer conference abstracts through 12 August 2021 for randomized trials of second-line treatment for malignant mesothelioma that had returned after first-line pemetrexed-based chemotherapy. They included eight trials, in which more than 95% of patients had pleural mesothelioma. The study compared drug treatments; it did not study asbestos exposure. Compared with placebo, nivolumab alone (hazard ratio 0.72, 95% CI 0.55–0.94) and nivolumab plus ipilimumab (0.54, 95% CI 0.31–0.92) were associated with significantly longer overall survival. Other treatments showed no significant overall survival difference from placebo. Nivolumab plus ipilimumab ranked first for both overall survival and progression-free survival. Six treatments, including chemotherapy, were associated with longer progression-free survival than placebo. The authors noted that few trials were available, that the trials differed, that different chemotherapy drugs were pooled, and that safety and cost were not analyzed. They wrote that head-to-head trials are needed to confirm the results.

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: Systematic review and network meta-analysis of randomized controlled trials (indirect comparisons using hazard ratios and SUCRA rankings)
• Who was studied: Eight completed two-arm phase II or III randomized trials (11 publications) of adults with relapsed mesothelioma who had progressed after first-line pemetrexed-based therapy with a platinum agent. More than 95% of patients had pleural mesothelioma. Median age across trials was 62–71 years, and 73% to 85% were men. Databases (PubMed, Embase, ClinicalTrials.gov) and conference abstracts were searched through 12 August 2021.
• Exposure: Second-line treatments, not asbestos exposure: placebo, chemotherapy (single drugs such as gemcitabine, vinorelbine or doxorubicin, pooled as one group), NGR-hTNF plus chemotherapy, vorinostat, anetumab, pembrolizumab, tremelimumab, nivolumab alone, and nivolumab plus ipilimumab
• Main results:
  • Overall survival compared with placebo: nivolumab alone HR 0.72 (95% CI 0.55–0.94); nivolumab plus ipilimumab HR 0.54 (95% CI 0.31–0.92). Both were statistically significant.
  • Other active treatments (vorinostat, tremelimumab, pembrolizumab, anetumab, chemotherapy, NGR-hTNF plus chemotherapy) had hazard ratios below 1 for overall survival compared with placebo, but no significant benefit was shown. For example, chemotherapy had HR 0.79 (95% CI 0.53–1.18).
  • For overall survival, no significant differences were found between chemotherapy alone and other second-line treatments.
  • Nivolumab plus ipilimumab had significantly longer overall survival than vorinostat (HR 0.55, 95% CI 0.31–0.96).
  • Nivolumab plus ipilimumab had the highest ranking for overall survival (SUCRA 90.8%). Nivolumab alone was next (69.8%), and placebo ranked lowest (19.1%).
  • Progression-free survival compared with placebo was longer with six treatments: tremelimumab HR 0.81 (95% CI 0.68–0.96), vorinostat HR 0.75, nivolumab alone HR 0.61 (95% CI 0.48–0.78), chemotherapy HR 0.59 (95% CI 0.41–0.85), NGR-hTNF plus chemotherapy HR 0.56 (95% CI 0.37–0.85), and nivolumab plus ipilimumab HR 0.43 (95% CI 0.28–0.66).
  • For progression-free survival, nivolumab plus ipilimumab did better than nivolumab alone, but the difference was not statistically significant (HR 0.71, 95% CI 0.50–1.01).
  • Nivolumab plus ipilimumab had the highest ranking for progression-free survival (SUCRA 92.3%), and placebo ranked lowest (2.0%).
• The authors' conclusion: The authors concluded that patients with relapsed malignant pleural mesothelioma who received nivolumab alone or nivolumab plus ipilimumab had significantly longer overall survival than those who received placebo, and that nivolumab plus ipilimumab ranked best for overall and progression-free survival. They stated that the results need confirmation in head-to-head trials.
• Limitations the authors state:
  • Only a few studies met the inclusion criteria, so the meta-analysis was relatively small.
  • Differences (heterogeneity) between the included studies could not be avoided completely.
  • Different chemotherapy drugs (gemcitabine, vinorelbine, doxorubicin) were combined into one group.
  • Safety data could not be pooled because the trials reported adverse effects using different severity criteria.
  • Cost was not included in the analysis.
  • Some trials were open-label and were judged at high risk of performance bias.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Systematic Review, Meta-Analysis, Pemetrexed (Alimta), First-line Therapy, Second-Line Therapy, Overall Survival, Progression-Free Survival.

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