NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial

Our plain-English summary of NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial, by V. Gregorc, R.M. Gaafar, A. Favaretto, et al (The Lancet. Oncology, 2018).

The study

• Authors: V. Gregorc, R.M. Gaafar, A. Favaretto, F. Grossi, J. Jassem, A. Polychronis, P. Bidoli, M. Tiseo, R. Shah, P. Taylor, S. Novello, A. Muzio, A. Bearz, L. Greillier, F. Fontana, G. Salini, A. Lambiase, M. O'Brien
• Journal: The Lancet. Oncology
• Published: 2018;19(6):799-811
• Type of article: Randomized trial
• Cited by: 69 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment.

Methods: NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m2 intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000-1250 mg/m2 intravenously), vinorelbine (25 mg/m2 intravenously or 60 mg/m2 orally), doxorubicin (60-75 mg/m2 intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266).

Findings: Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1-24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2-9·9] in the NGR-hTNF group vs 8·0 months [6·6-8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75-1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related.

Interpretation: The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis.

Funding: MolMed.

Copyright © 2018 Elsevier Ltd. All rights reserved.

In plain English

This randomised, double-blind, placebo-controlled phase 3 drug trial did not study asbestos exposure. It enrolled 400 patients with malignant pleural mesothelioma that had progressed after first-line chemotherapy (pemetrexed-based in all but one) at 41 centres in 12 countries from 2010 to 2013. Patients received weekly NGR-hTNF, a drug aimed at tumour blood vessels, or placebo. Each was added to care chosen by their doctor, usually single-drug gemcitabine or vinorelbine. Median overall survival was 8.5 months with NGR-hTNF and 8.0 months with placebo (hazard ratio 0.94, 95% CI 0.75 to 1.18; p=0.58), so the trial did not meet its primary endpoint. Progression-free survival also did not differ significantly. In patients starting second-line treatment less than 4.8 months (the median) after first-line therapy, survival was longer with NGR-hTNF (hazard ratio 0.68, 95% CI 0.49 to 0.95). The authors said all such analyses should be taken as descriptive only. Grade 3 or worse adverse events during the study occurred in 136 (70%) of 193 patients given NGR-hTNF and 118 (61%) of 193 given placebo. No treatment-related deaths were reported. The authors concluded these hypothesis-generating findings deserve a confirmatory 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: Randomised, double-blind, placebo-controlled phase 3 drug trial (NGR015)
• Who was studied: 400 adults with malignant pleural mesothelioma that had progressed after first-line chemotherapy (a pemetrexed-based regimen for all but one patient). They were recruited at 41 sites in 12 countries between April 2010 and January 2013.
• Exposure: No asbestos exposure was studied. The intervention was weekly intravenous NGR-hTNF 0.8 µg/m² (n=200) or placebo (n=200), each given with best investigator choice: single-drug chemotherapy or supportive care only.
• Main results:
  • All patients but one had previously been treated with a pemetrexed-based regimen. The one exception, in the NGR-hTNF group, had received gemcitabine plus carboplatin.
  • Investigators selected chemotherapy for 381 (95%) of the 400 patients: gemcitabine for 211 (53%), vinorelbine for 159 (40%) and doxorubicin for 11 (3%).
  • Overall survival, the primary endpoint, did not differ significantly between groups. Median overall survival was 8.5 months (95% CI 7.2 to 9.9) in the NGR-hTNF group and 8.0 months (6.6 to 8.9) in the placebo group; hazard ratio 0.94, 95% CI 0.75 to 1.18, p=0.58.
  • Progression-free survival did not differ significantly between groups: hazard ratio 0.95 (95% CI 0.78 to 1.17). Median progression-free survival was 3.4 months in the NGR-hTNF group and 3.0 months in the placebo group, p=0.65.
  • For subgroup analysis, the treatment-free interval was split at its median for the whole trial population, 4.8 months (n=398).
  • In the short treatment-free-interval subgroup, overall survival was longer with NGR-hTNF than with placebo (hazard ratio 0.68, 95% CI 0.49 to 0.95, p=0.020).
  • In the long treatment-free-interval subgroup, overall survival did not differ significantly between groups (hazard ratio 1.30, 95% CI 0.93 to 1.81, p=0.12).
  • Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of 193 patients given NGR-hTNF and 118 (61%) of 193 given placebo.
  • Infusion-related chills were reported in 104 (54%) of 193 patients given NGR-hTNF and 23 (12%) of 193 given placebo.
  • No treatment-related deaths were reported in either group.
• The authors' conclusion: The authors concluded that the study did not meet its primary endpoint. They said the hypothesis-generating subgroup findings deserve a confirmatory randomised trial, because patients who rapidly progress after first-line treatment have a poor prognosis.
• Limitations the authors state:
  • Chemotherapy choice was left to investigators, and the resulting mix of chemotherapy treatments might have prevented adequate comparison between groups.
  • Disease progression was not centrally reviewed by radiologists, either at study entry or during treatment.
  • Multiple subgroup analyses raise the chance of false-positive findings.
  • The trial was not powered for subgroup analyses, which the authors said should be taken as descriptive only.

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: Pleural Mesothelioma, Prognosis, Chemotherapy, Histological Subtype, Sarcomatoid, Performance Status, Pemetrexed (Alimta), Gemcitabine.

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