Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial

Our plain-English summary of Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial, by D.A. Fennell, C. Porter, J. Lester, et al (EClinicalMedicine, 2022).

The study

• Authors: D.A. Fennell, C. Porter, J. Lester, S. Danson, P. Taylor, M. Sheaff, R.M. Rudd, A. Gaba, S. Busacca, L. Nixon, G. Gardner, L. Darlison, C. Poile, C. Richards, P.W. Jordan, G. Griffiths, A. Casbard
• Journal: EClinicalMedicine
• Published: 2022;48:101432
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Currently, there is no US Food and Drug Administration approved therapy for patients with pleural mesothelioma who have relapsed following platinum-doublet based chemotherapy. Vinorelbine has demonstrated useful clinical activity in mesothelioma, however its efficacy has not been formally evaluated in a randomised setting. BRCA1 expression is required for vinorelbine induced apoptosis in preclinical models. Loss of expression may therefore correlate with vinorelbine resistance.

Methods: In this randomised, phase 2 trial, patients were eligible if they met the following criteria: age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, histologically confirmed pleural mesothelioma, post platinum-based chemotherapy, and radiological evidence of disease progression. Consented patients were randomised 2:1 to either active symptom control with oral vinorelbine versus active symptom control (ASC) every 3 weeks until disease progression, unacceptable toxicity or withdrawal at an initial dose of 60 mg/m2 increasing to 80 mg/m2 post-cycle 1. Randomisation was stratified by histological subtype, white cell count, gender, ECOG performance status and best response during first-line therapy. The study was open label. The primary endpoint was progression-free survival (PFS), measured from randomisation to time of event (or censoring). Analyses were carried out according to intention-to-treat (ITT) principles. Recruitment and trial follow-up are complete. This trial is registered with ClinicalTrials.gov, number NCT02139904.

Findings: Between June 1, 2016 and Oct 31, 2018, we performed a randomised phase 2 trial in 14 hospitals in the United Kingdom. 225 patients were screened for eligibility, of whom 154 were randomly assigned to receive either ASC + vinorelbine (n = 98) or ASC (n = 56). PFS was significantly longer for ASC+vinorelbine compared with ASC alone; 4.2 months (interquartile range (IQR) 2.2-8.0) versus 2.8 months (IQR 1.4-4.1) for ASC, giving an unadjusted hazard ratio (HR) of 0·60 (80% CI upper limit 0.7, one-sided unadjusted log rank test p = 0.002); adjusted HR 0.6 (80% CI upper limit 0.7, one-sided adjusted log rank test p < 0.001). BRCA1 did not predict resistance to ASC+vinorelbine. Neutropenia was the most common grades 3, 4 adverse events in the ASC +vinorelbine arm.

Interpretation: Vinorelbine plus ASC confers clinical benefit to patients with relapsed pleural mesothelioma who have progressed following platinum-based doublet chemotherapy.

Funding: This study was funded by Cancer Research UK (grant CRUK A15569).

© 2022 The Authors.

In plain English

This randomised, open-label phase 2 trial ran in 14 UK hospitals from June 2016 to October 2018. It enrolled 154 patients with malignant pleural mesothelioma whose disease had progressed after platinum-based chemotherapy. Of these, 98 were randomly assigned to active symptom control (ASC) plus oral vinorelbine and 56 to ASC alone. Most patients in both groups had an asbestos history. Median progression-free survival was 4.2 months with vinorelbine versus 2.8 months with ASC alone (unadjusted hazard ratio 0.60, one-sided 80% confidence interval upper limit 0.7, p=0.0022). Median overall survival did not differ significantly: 9.3 versus 9.1 months. Disease control was 65.3% versus 48.2% (p=0.06). BRCA1 status did not predict progression-free survival, but it was unknown for half the patients. Severe neutropenia (low neutrophils, a type of white blood cell) occurred in 12 of 96 vinorelbine patients versus none of 51 ASC patients. The authors concluded that vinorelbine showed modest but statistically significant activity with an acceptable safety profile. They urged caution because of the less strict statistical threshold (alpha 0.2), no central scan review, and no blinding or placebo.

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: Multicentre, open-label, 2:1 randomised phase 2 trial
• Who was studied: 154 patients with histologically confirmed pleural mesothelioma that had progressed after platinum-based chemotherapy, enrolled at 14 UK hospitals between June 1, 2016 and Oct 31, 2018 (225 screened). 98 were randomised to ASC plus vinorelbine and 56 to ASC alone. Median age was 71 (range 42 to 83) and 81% were male. An asbestos history was recorded for 80 of 98 in the vinorelbine arm and 47 of 56 in the ASC arm.
• Exposure: Treatment studied: oral vinorelbine at 60 mg/m2 on days 1, 8 and 15 of a 21-day cycle, rising to 80 mg/m2 from cycle 2, added to active symptom control. It was compared with active symptom control alone.
• Main results:
  • Median progression-free survival was 4.2 months (IQR 2.2 to 8.0) in the ASC+vinorelbine arm versus 2.8 months (IQR 1.4 to 4.1) in the ASC arm.
  • The unadjusted hazard ratio for progression-free survival was 0.60 (one-sided 80% CI upper limit 0.7), with an unadjusted one-sided log rank p-value of 0.0022. The adjusted hazard ratio was 0.6 (adjusted p less than 0.001).
  • Median overall survival did not differ significantly between arms: 9.3 months with ASC+vinorelbine versus 9.1 months with ASC.
  • Partial response occurred in 3 (3%) ASC+vinorelbine patients and 1 (2%) ASC patient. The disease control rate was 65.3% versus 48.2% (p = 0.06).
  • BRCA1 expression was detected in 51/154 (33.1%) patients and 26/154 (17%) were BRCA1 negative. Status was missing for 77/154 (50%). Low BRCA1 expression did not predict progression-free survival.
  • Grade 3 or higher neutropenia occurred in 12/96 (13%) patients in the ASC+vinorelbine arm versus 0/51 in the ASC arm. Fatigue of any grade occurred in 50/96 (52%) versus 11/51 (22%).
  • Two (2%) patients in the ASC+vinorelbine arm had fatal serious adverse events causally related to treatment (pneumonia and lower respiratory tract infection). One patient in the ASC arm had a fatal serious adverse event (lower respiratory tract infection).
• The authors' conclusion: The authors concluded that the VIM trial showed modest but statistically significant activity in relapsed malignant mesothelioma, with an acceptable safety profile compared with active symptom control. They also concluded that BRCA1 expression does not predict progression-free survival.
• Limitations the authors state:
  • Caution is needed because the improvement in progression-free survival was 1.4 months, an alpha of 0.2 was used, and scans were not centrally reviewed.
  • The trial was not double blind or placebo controlled, which may have influenced the assessment of efficacy and safety.
  • BRCA1 could be assessed in only 50% of the trial population.
  • The study was not powered for overall survival.
  • 29% of patients received immunotherapy after the study, a likely source of crossover bias.
  • The non-epithelioid group was small, so the benefit seen in that group was not significant. This was an unplanned, post-hoc analysis.
  • Quality of life and cost-effectiveness data were not collected.

Topics

Medical terms in this study, explained in our Lexicon: Vinorelbine, Pleural Mesothelioma, Chemotherapy, Mesothelioma, Apoptosis, Performance Status, Disease Progression, Histological Subtype.

Related studies

• Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres — D. Fennell, D. Griffiths, et al. (2023)
• Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial — D.A. Fennell, S. Ewings, et al. (2021)
• Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial — H.L. Kindler, S. Novello, et al. (2022)
• 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)
• 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)
• A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol — X. Elharrar, D. Barbolosi, et al. (2016)

Browse return to medical research.