Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901

Our plain-English summary of Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901, by A.Z. Dudek, X. Wang, L. Gu, et al (Clinical Lung Cancer, 2020).

The study

• Authors: A.Z. Dudek, X. Wang, L. Gu, S. Duong, T.E. Stinchcombe, R. Kratzke, H. Borghaei, E.E. Vokes, H.L. Kindler
• Journal: Clinical Lung Cancer
• Published: 2020;21(6):553-561.e1
• Type of article: Randomized trial
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS).

Patients And Methods: Eligible patients with unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression, stratified by number of cycles (< 6 or 6), cis- or carboplatin containing regimen, and histology. Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months.

Results: A total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049).

Conclusion: Maintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

In plain English

This was a randomized phase II trial (CALGB 30901) in people with malignant pleural mesothelioma that could not be removed by surgery. Their disease had not worsened after 4 to 6 cycles of pemetrexed with cisplatin or carboplatin. Of 72 patients enrolled at 30 sites from December 2010, 53 were randomized to continued (maintenance) pemetrexed or to observation. The trial closed early in July 2016 because of slow accrual. 49 eligible patients (27 pemetrexed, 22 observation) were analyzed. Median progression-free survival was 3.4 months on pemetrexed and 3 months on observation (hazard ratio 0.99, 95% CI 0.51 to 1.90). Median overall survival was 16.3 months on pemetrexed and 11.8 months on observation (hazard ratio 0.86, 95% CI 0.44 to 1.71). Thirty-three of the 49 patients were recorded as having had asbestos exposure. In a statistical model, asbestos exposure was associated with shorter overall survival. On pemetrexed there were no grade 5 events and one grade 4 event. The authors concluded that maintenance pemetrexed did not add benefit over observation. They named slow accrual, early closure and small sample size as the 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: Randomized phase II clinical trial (CALGB 30901) of maintenance pemetrexed versus observation, with 1:1 randomization
• Who was studied: Patients with unresectable malignant pleural mesothelioma whose disease had not progressed after 4 to 6 cycles of pemetrexed plus cisplatin or carboplatin. 72 were enrolled at 30 sites in the United States from December 2010 to July 2016. 53 were randomized (27 to pemetrexed, 26 to observation), and 49 eligible patients (27 pemetrexed, 22 observation) were analyzed.
• Exposure: The treatment studied was maintenance pemetrexed, 500 mg/m2 every 3 weeks until progression, compared with observation. Asbestos exposure was recorded only as a yes/no baseline characteristic, with no fiber type or dose given.
• Main results:
  • Median progression-free survival (the primary endpoint) was 3 months on observation (95% CI 2.6 to 11.9 months) and 3.4 months on pemetrexed (95% CI 2.8 to 9.8 months).
  • The hazard ratio for progression-free survival, pemetrexed compared with observation, was 0.99 (95% CI 0.51 to 1.90; P = .9733).
  • Median overall survival was 11.8 months on observation (95% CI 9.3 to 28.7) and 16.3 months on pemetrexed (95% CI 10.5 to 26.0), with a hazard ratio of 0.86 (95% CI 0.44 to 1.71; P = .6737).
  • Best response: on the pemetrexed arm, 1 of 27 patients (3.7%) had a complete response and 2 of 27 (7.4%) a partial response, a response rate of 11.1%. There were no responses among 21 evaluable observation patients.
  • Among the 27 patients on pemetrexed there were no grade 5 events. The only grade 4 toxicity was a decreased neutrophil count in 1 patient (4%).
  • Asbestos exposure was recorded for 33 of 49 patients (67.3%): 14 of 22 on observation and 19 of 27 on pemetrexed.
  • In a Cox model of overall survival, several factors were associated with higher risk of shorter overall survival. These included exposure to asbestos (hazard ratio 4.689, 95% CI 1.873 to 11.742, P = .001, compared with no exposure), ECOG performance status 1 versus 0, younger age, histology, absence of chest pain, and shorter duration of initial symptoms.
  • In an exploratory analysis of baseline samples from 33 patients (16 observation, 17 pemetrexed), a higher soluble mesothelin-related peptide (SMRP) level was associated with worse progression-free survival (hazard ratio 1.86, 95% CI 1.00 to 3.46, P = .049). The interaction between treatment and biomarker was not significant, so SMRP did not indicate which patients would benefit from pemetrexed.
• The authors' conclusion: The authors concluded that, in unselected patients with mesothelioma, continuing maintenance pemetrexed after initial platinum and pemetrexed therapy does not provide additional benefit over observation.
• Limitations the authors state:
  • The authors' main stated limitations were slow accrual leading to premature closure, and small sample size.
  • The original design sought a 67% improvement in median progression-free survival. It was amended in January 2015 to seek a 100% improvement so that a smaller number of patients would be needed.
  • The biomarker (SMRP and osteopontin) analysis was exploratory and needs prospective validation in a larger group.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, Progression-Free Survival, Unresectable, Disease Progression, Carboplatin, Histology, confidence interval.

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• LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma — G.V. Scagliotti, R. Gaafar, et al. (2017)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
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• Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma — D.C. Christoph, B.R. Asuncion, et al. (2012)
• Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma — L.M. Krug, A.J. Wozniak, et al. (2014)

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