Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status

Our plain-English summary of Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status, by P. Baverel, L. Roskos, M. Tatipalli, et al (Clinical and Translational Science, 2019).

The study

• Authors: P. Baverel, L. Roskos, M. Tatipalli, N. Lee, P. Stockman, M. Taboada, P. Vicini, K. Horgan, R. Narwal
• Journal: Clinical and Translational Science
• Published: 2019;12(5):450-458
• Type of article: Randomized trial
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Tremelimumab, an anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that enhances T-cell activation, was evaluated in a randomized, double-blind, placebo-controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. A population pharmacokinetic (PK) model adequately described the PK data. Three factors (sex, C-reactive protein, and baseline tumor size) were identified as statistically significant PK predictors (P < 0.05 on clearance). A positive association between exposure and OS was observed. However, an association between key baseline factors with OS (regardless of treatment) and imbalances in prognostic factors favoring patients with higher exposure (upper vs. lower PK quartile) was seen. Taken together, these results suggest that the exposure OS relationship observed for tremelimumab in mesothelioma is likely spurious rather than a true association of exposure with efficacy.

© 2019 MedImmnue. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

In plain English

This article reported a post hoc analysis of the DETERMINE trial, a randomized, placebo-controlled trial of the drug tremelimumab in previously treated patients with unresectable pleural or peritoneal malignant mesothelioma. Here, "exposure" means the level of drug in patients' blood, not asbestos. In the trial, median survival was 7.72 months with tremelimumab and 7.29 months with placebo. Among 376 treated patients with drug-level data, split into quarters of 94, survival was longer at higher drug levels: a median of 4.93 months (95% CI 3.86 to 6.68) in the lowest quarter and 14.9 months (95% CI 12.5 to 18.6) in the highest. However, the lowest quarter did worse than placebo. Patients with higher drug levels more often had features linked to longer survival regardless of treatment, such as better performance status, lower EORTC risk, lower C-reactive protein, smaller tumors and female sex. Sex, C-reactive protein and tumor size were also statistically linked to drug levels. The authors concluded that the apparent link between drug level and survival was spurious. MedImmune funded the analysis, and several authors were its employees.

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: Post hoc exposure-response analysis of a randomized, double-blind, placebo-controlled phase IIb trial (DETERMINE), using population pharmacokinetic modeling and Kaplan-Meier survival plots
• Who was studied: Patients with unresectable pleural or peritoneal malignant mesothelioma who had received one or two previous systemic treatments. The trial randomized 382 patients to tremelimumab and 189 to placebo. Of the 382 in the tremelimumab arm, 376 had drug-level (PK) data. The article does not give the countries or dates.
• Exposure: The drug tremelimumab, an anti-CTLA-4 antibody, given at 10 mg/kg every 4 weeks for seven doses and then every 12 weeks, compared with placebo. Drug exposure was measured as the modeled steady-state area under the concentration curve (AUCss) and split into quartiles. Asbestos exposure was not studied.
• Main results:
  • Overall survival was similar in the two arms of the intention-to-treat population: median 7.72 months with tremelimumab versus 7.29 months with placebo. The hazard ratio was 0.92 (95% CI 0.76 to 1.12, P = 0.408).
  • Among tremelimumab-treated patients, the highest drug-exposure quartile (n = 94) had a median overall survival of 14.9 months (95% CI 12.5 to 18.6).
  • The lowest exposure quartile (n = 94) had a median overall survival of 4.93 months (95% CI 3.86 to 6.68). This was worse than placebo (7.29 months), which the authors took to suggest confounding.
  • Regardless of treatment, patients with ECOG performance status 0 survived longer than those with ECOG 1 (median 11 to 13 versus 5 to 7 months). Longer survival was also seen with EORTC low-risk status (median 10 versus 6 months), lower C-reactive protein, and female sex.
  • Patients in the highest exposure quartile had more favorable prognostic factors than those in the lowest quartile: low CRP, female, low tumor burden, ECOG 0, and low-risk EORTC.
  • Higher baseline tumor size, higher CRP and male sex were associated with significantly lower tremelimumab exposure (P less than 0.05). The authors did not find these differences clinically relevant (less than 30% effect on AUCss).
  • Antidrug antibodies were found after baseline in 15 (4%) of 377 evaluable patients in the tremelimumab arm and in 6 (3.2%) of 188 in the placebo arm. These antibodies had no apparent effect on drug levels.
• The authors' conclusion: The authors concluded that the apparent relationship between tremelimumab exposure and overall survival in mesothelioma was spurious. In their view, it reflected imbalances in baseline disease factors across exposure groups and the links between those factors and drug clearance, rather than a true effect of exposure on efficacy.
• Limitations the authors state:
  • The authors did not run a multivariate Cox regression model. They gave as reasons the presence of time-dependent predictors such as exposure and collinearity between predictors.
  • The authors stated that their map of relationships among survival, drug levels and baseline factors ignored correlations among the risk factors, for simplicity.

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: Overall Survival, Tremelimumab, Unresectable, Malignant Mesothelioma, Confounding, Monoclonal Antibody, Mesothelioma.

Related studies

• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial — M. Maio, A. Scherpereel, et al. (2017)
• High liposomal doxorubicin tumour tissue distribution, as determined by radiopharmaceutical labelling with (99m)Tc-LD, is associated with the response and survival of patients with unresectable pleural mesothelioma treated with a combination of liposomal doxorubicin and cisplatin — O. Arrieta, L.A. Medina, et al. (2014)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study — L. Calabrò, A. Morra, et al. (2018)
• Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study — L. Calabrò, A. Morra, et al. (2015)
• Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study — L. Calabrò, G. Rossi, et al. (2021)

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