Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial

Our plain-English summary of Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial, by H.L. Kindler, S. Novello, A. Bearz, et al (The Lancet. Oncology, 2022).

The study

• Authors: H.L. Kindler, S. Novello, A. Bearz, G.L. Ceresoli, J.G.J.V. Aerts, J. Spicer, P. Taylor, K. Nackaerts, A. Greystoke, R. Jennens, L. Calabrò, J.A. Burgers, A. Santoro, S. Cedrés, P. Serwatowski, S. Ponce, J.P. Van Meerbeeck, A.K. Nowak, G. Blumenschein, J.M. Siegel, L. Kasten, K. Köchert, A.O. Walter, B.H. Childs, C. Elbi, R. Hassan, D.A. Fennell
• Journal: The Lancet. Oncology
• Published: 2022;23(4):540-552
• Type of article: Randomized trial
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab.

Methods: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.

Findings: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).

Interpretation: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.

Funding: Bayer Healthcare Pharmaceuticals.

Copyright © 2022 Elsevier Ltd. All rights reserved.

In plain English

This was a randomised, open-label phase 2 trial, not a study of asbestos exposure. It was run at 76 hospitals in 14 countries in adults whose inoperable malignant pleural mesothelioma had progressed after first-line platinum–pemetrexed chemotherapy, with or without bevacizumab. Of 589 patients enrolled between December 2015 and May 2017, 248 whose tumours showed high mesothelin levels were randomly assigned to anetumab ravtansine (166) or vinorelbine chemotherapy (82). Median progression-free survival was 4.3 months (95% CI 4.1 to 5.2) with anetumab ravtansine and 4.5 months (4.1 to 5.8) with vinorelbine (hazard ratio 1.22, 0.85 to 1.74). Median overall survival was 9.5 months (8.3 to 12.3) versus 11.6 months (8.6 to 13.1). Anetumab ravtansine was not superior on either measure. Grade 3 or 4 treatment-emergent adverse events (not necessarily caused by treatment) occurred in 78 of 163 treated patients (48%) on anetumab ravtansine and 53 of 72 (74%) on vinorelbine. Treatment-emergent deaths numbered ten (6%) versus one (1%); one of the ten was considered drug-related. The authors concluded that anetumab ravtansine had a manageable safety profile and was not superior to vinorelbine.

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: Open-label, randomised (2:1), active-controlled phase 2 drug trial comparing two treatments for relapsed mesothelioma; not an asbestos exposure study
• Who was studied: Adults with unresectable locally advanced or metastatic malignant pleural mesothelioma that had progressed on first-line platinum–pemetrexed chemotherapy (with or without bevacizumab), with mesothelin overexpression, at 76 hospitals in 14 countries. 589 were enrolled between Dec 3, 2015, and May 31, 2017; 248 were randomly assigned (166 to anetumab ravtansine, 82 to vinorelbine).
• Exposure: The exposure was treatment, not asbestos: intravenous anetumab ravtansine (an antibody–drug conjugate targeting mesothelin) 6.5 mg/kg once every 3 weeks, versus intravenous vinorelbine 30 mg/m2 once every week. No asbestos exposure or fiber type was studied.
• Main results:
  • Progression-free survival (the primary endpoint): median 4.3 months (95% CI 4.1 to 5.2) with anetumab ravtansine vs 4.5 months (4.1 to 5.8) with vinorelbine; hazard ratio 1.22 (0.85 to 1.74); log-rank p=0.86. Anetumab ravtansine was not superior.
  • Overall survival at the final analysis (April 6, 2018): median 9.5 months (95% CI 8.3 to 12.3) with anetumab ravtansine vs 11.6 months (8.6 to 13.1) with vinorelbine; hazard ratio 1.07 (0.76 to 1.51); log-rank p=0.66. Anetumab ravtansine was not superior.
  • No complete responses occurred in either group. Partial responses occurred in 16 of 166 patients (9.6%) on anetumab ravtansine vs 6 of 82 (7.3%) on vinorelbine.
  • Grade 3 or 4 treatment-emergent adverse events occurred in 78 (48%) of 163 treated patients on anetumab ravtansine vs 53 (74%) of 72 treated patients on vinorelbine. Grade 3 or worse neutropenia occurred in one (1%) of 163 vs 28 (39%) of 72.
  • Treatment-emergent deaths occurred in ten (6%) of 163 patients on anetumab ravtansine and one (1%) on vinorelbine (pneumonia). One of the two sepsis deaths in the anetumab ravtansine group was considered study drug related.
  • Stopping treatment because of treatment-emergent adverse events was more frequent with anetumab ravtansine: 45 (28%) of 163 vs 13 (18%) of 72.
  • In a post-hoc subgroup analysis, patients on anetumab ravtansine in mesothelin expression quartiles 2 to 4 had longer progression-free survival than those in quartile 1. This was not seen in patients on vinorelbine.
  • In blood samples from 47 patients treated with anetumab ravtansine, BAP1 was the most frequently mutated gene. It was found in 4 of 14 patients whose best response was progressive disease (29%), 1 of 19 with stable disease (5%), and none with a partial response.
• The authors' conclusion: The authors concluded that anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine, and that further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors state that interpreting the mesothelin and soluble mesothelin-related peptide findings could be complicated by tumour heterogeneity, differences in tumour load and peptide shedding, and immunohistochemistry results coming from a single lesion.
  • Somatic mutations were detected in only 51% of patients using the custom gene panel.
  • The authors state that they do not have a thorough understanding of why the study was negative.
  • Patients previously treated with immunotherapy drugs were not enrolled.

Topics

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

Medical terms in this study, explained in our Lexicon: Vinorelbine, Mesothelin, Pleural Mesothelioma, Unresectable, Platinum-Pemetrexed, Chemotherapy, Bevacizumab, Performance Status.

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• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• 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)
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