Comparison of 3 Randomized Clinical Trials of Frontline Therapies for Malignant Pleural Mesothelioma

Abstract

IMPORTANCE Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments. OBJECTIVETo directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021. MAIN OUTCOMES AND MEASURES Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT. RESULTS A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, −0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048). CONCLUSIONS AND RELEVANCEThis comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial.Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the (continued)

Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability

“…Messori et al found that nivolumab plus ipilimumab or pembrolizumab monotherapy showed a small but significant survival benefit, but not durvalumab plus pemetrexed plus cisplatin, compared to standard of care treatment (pemetrexed plus cisplatin) [96]. However, Meirson et al [97] and Kerrigan et al [98] reported no survival benefit for nivolumab plus ipilimumab or either a single agent alone compared to bevacizumab plus cisplatin plus pemetrexed or single-agent chemotherapy. MMe patients in these trials were not stratified by their MSI status or tumor mutation burden.…”

Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects

“…For instance, the median overall survival after treatment with nivolumab plus ipilimumab was consistent between epithelioid histology tumors (18.7 months) and nonepithelioid tumors (18.1 months) (73). Nevertheless, a recent comparative effectiveness study was conducted to compare the 3 main clinical trials of first line setting for MPM: the SoC cisplatin and pemetrexed (MPS), nivolumab and ipilimumab (CM73) and bevacizumab combined with the SoC (MAPS) (74). Through an accurate reconstruction of Kaplan-Meier curves, no significant improvements in terms of overall survival was detected for one treatment over the other.…”

“…Through an accurate reconstruction of Kaplan-Meier curves, no significant improvements in terms of overall survival was detected for one treatment over the other. Moreover, potential biases on censored patients have been detected, leading to hesitations that should be further investigated and clarified to strengthen the reliability of the study (74). As well as that, another study aimed at comparing individual patient data reconstructed retrospectively from 4 clinical trials: the same considered in the other study and durvalumab combined with SoC.…”

Butein-instigated miR-186-5p-dependent modulation of TWIST1 affects resistance to cisplatin and bioenergetics of Malignant Pleural Mesothelioma cells

“…MPM exhibits long clinical latency and significant resistance to therapy, with the latter impacting only to a limited extent the natural history of the disease. As a result, prognosis for MPM patients results in poor PFS and OS [1,7,8] . The mainstay of MPM treatment is still represented, for first-line or inoperable patients, by cisplatin and antifolate [1,9] .…”