Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial

Our plain-English summary of Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial, by G.V. Scagliotti, R. Gaafar, A.K. Nowak, et al (The Lancet. Respiratory Medicine, 2019).

The study

• Authors: G.V. Scagliotti, R. Gaafar, A.K. Nowak, T. Nakano, J. van Meerbeeck, S. Popat, N.J. Vogelzang, F. Grosso, R. Aboelhassan, M. Jakopovic, G.L. Ceresoli, P. Taylor, F. Orlandi, D.A. Fennell, S. Novello, A. Scherpereel, K. Kuribayashi, S. Cedres, J.B. Sørensen, N. Pavlakis, M. Reck, D. Velema, U. von Wangenheim, M. Kim, J. Barrueco, A.S. Tsao
• Journal: The Lancet. Respiratory Medicine
• Published: 2019;7(7):569-580
• Type of article: Randomized trial
• Cited by: 121 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma.

Methods: This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100.

Findings: Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5·3 months (IQR 2·8-7·3) in the nintedanib group and 5·1 months (2·7-7·8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6·8 months [95% CI 6·1-7·0]) and the placebo group (7·0 months [6·7-7·2]; HR 1·01 [95% CI 0·79-1·30], p=0·91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%]).

Interpretation: The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported.

Funding: Boehringer Ingelheim.

Copyright © 2019 Elsevier Ltd. All rights reserved.

In plain English

This double-blind, randomised, placebo-controlled phase 3 trial ran at 120 centres in 27 countries. From April 2016 to January 2018, 458 adults with unresectable malignant pleural mesothelioma, almost all epithelioid, who had had no chemotherapy for mesothelioma, were randomly assigned to pemetrexed plus cisplatin with nintedanib (229) or placebo (229). Previous asbestos exposure was reported by 62% of the nintedanib group and 66% of the placebo group. Time to disease worsening or death did not differ: median 6.8 months with nintedanib versus 7.0 with placebo (hazard ratio 1.01, 95% CI 0.79 to 1.30). Interim median overall survival was 14.4 months (95% CI 12.2 to 17.9) versus 16.1 (13.7 to 19.3), and did not differ significantly (hazard ratio 1.12, 95% CI 0.79 to 1.58). Among the 227 and 228 patients treated, severe neutropenia occurred in 32% versus 24%, and serious adverse events in 44% versus 39%. Exploratory analyses suggested baseline platelet count might predict benefit; the authors said this needs confirmation. The authors concluded the primary endpoint was not met and phase 2 findings were not confirmed. Boehringer Ingelheim funded the trial.

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: Double-blind, randomised, placebo-controlled phase 3 trial (the phase 3 part of the LUME-Meso trial)
• Who was studied: 458 adults with unresectable malignant pleural mesothelioma of epithelioid subtype who had not received previous systemic chemotherapy for the disease. They came from 541 patients screened between April 14, 2016, and Jan 5, 2018, at 120 centres in 27 countries, and were randomly assigned 229 to nintedanib and 229 to placebo. Of these, 227 and 228 received at least one dose. Fifteen patients with biphasic histology, enrolled before the protocol amendment, were also included.
• Exposure: Drug treatment: up to six 21-day cycles of pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1, with nintedanib 200 mg twice daily or matched placebo on days 2 to 21. Patients whose disease had not progressed then received nintedanib or placebo maintenance. Asbestos exposure was only recorded as a patient characteristic.
• Main results:
  • Investigator-assessed progression-free survival did not differ: median 6·8 months (95% CI 6·1–7·0) in the nintedanib group vs 7·0 months (6·7–7·2) in the placebo group; HR 1·01 (95% CI 0·79–1·30), p=0·914.
  • Independent central review gave consistent progression-free survival results: median 6·8 vs 6·8 months; HR 0·99 (95% CI 0·77–1·28).
  • Overall survival (interim analysis): 64 of 229 patients in the nintedanib group and 63 of 229 in the placebo group had died. Median overall survival was 14·4 months (95% CI 12·2–17·9) vs 16·1 months (13·7–19·3); HR 1·12 (95% CI 0·79–1·58), p=0·538.
  • Disease control was achieved in 208 (91%) nintedanib patients and 212 (93%) placebo patients. Objective response was 103 (45%) vs 98 (43%).
  • The most frequent grade 3 or worse adverse event in both groups was neutropenia: 73 (32%) of 227 nintedanib patients vs 54 (24%) of 228 placebo patients.
  • Serious adverse events occurred in 99 (44%) nintedanib patients vs 89 (39%) placebo patients. Pulmonary embolism was the only serious adverse event in at least 5% of either group: 13 (6%) vs seven (3%).
  • 26 (6%) of 455 treated patients died because of adverse events: nine (4%) in the nintedanib group and 17 (7%) in the placebo group.
  • Exploratory overall survival analysis by baseline platelet count: HR 0·53 (95% CI 0·30–0·92) for patients with a high platelet count and 2·04 (1·21–3·45) for patients with a low platelet count.
  • Previous asbestos exposure was reported by 141 (62%) patients in the nintedanib group and 150 (66%) in the placebo group. In the overall survival subgroup analysis, previous known asbestos exposure was one of three factors with an interaction p value of 0·1 or less.
• The authors' conclusion: The authors concluded that the primary endpoint of the phase 3 part was not met and that the phase 2 efficacy findings were not confirmed. They also stated that the results would not support further exploration of nintedanib with pemetrexed and cisplatin as first-line treatment.
• Limitations the authors state:
  • Interim overall survival data were immature at the time of the analysis.
  • There was no central pathological review to confirm patients' histology, and the protocol made no provision for switching to carboplatin if cisplatin was not tolerated.
  • The platelet count analyses were exploratory, with no formal statistical testing.
  • The white blood cell count subgroup analysis was limited by a low number of patients with a high count.

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: Pemetrexed (Alimta), Cisplatin, Chemotherapy, Pleural Mesothelioma, Platelet-Derived Growth Factor (PDGF), Unresectable, Epithelioid, ECOG Performance Status.

Related studies

• 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)
• 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)
• Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial — L.M. Krug, H.L. Kindler, et al. (2015)
• NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial — V. Gregorc, R.M. Gaafar, et al. (2018)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)

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