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Anetumab Ravtansine vs Vinorelbine in Relapsed Mesothelin-Positive Advanced Malignant Pleural Mesothelioma


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In the phase II ARCS-M trial reported in The Lancet Oncology, Hedy L. Kindler, MD, FASCO, and colleagues found that the antimesothelin antibody–tubulin inhibitor conjugate anetumab ravtansine did not improve progression-free survival vs vinorelbine as second-line treatment for patients with relapsed, mesothelin-positive, advanced malignant pleural mesothelioma.

Hedy L. Kindler, MD, FASCO

Hedy L. Kindler, MD, FASCO

The open-label trial included 248 patients from sites in 14 countries with unresectable locally advanced or metastatic disease that had progressed on first-line platinum/pemetrexed therapy with or without bevacizumab. They were randomly assigned 2:1 between December 2015 and May 2017 to receive anetumab ravtansine at 6.5 mg/kg on day 1 of 21-day cycles (n = 166) or vinorelbine at 30 mg/m² once every week (n = 82). Treatment continued until disease progression or unacceptable toxicity. Mesothelin overexpression was defined as 2+ or 3+ mesothelin membrane staining intensity on ≥ 30% of viable tumor cells on immunohistochemistry. The primary endpoint was progression-free survival on blinded central radiology review in the intention-to-treat population.

Progression-Free Survival

At primary progression-free survival analysis (data cutoff in May 2017), median follow-up was 4.0 months (interquartile range [IQR] = 1.4–5.5 months) in the anetumab ravtansine group and 3.9 months (IQR = 1.4–5.4 months) in the vinorelbine group. Median progression-free survival was 4.3 months (95% confidence interval [CI] = 4.1–5.2 months) in the anetumab ravtansine group vs 4.5 months (95% CI = 4.1–5.8 months) in the vinorelbine group (hazard ratio [HR] = 1.22, 95% CI = 0.85–1.74, P = .86).

At the time of the final efficacy analysis (data cutoff in April 2018), with median follow-up of 8.6 months (IQR = 4.3–15.3 months) in the anetumab ravtansine group and 8.7 months (IQR = 3.5–14.3 months) in the vinorelbine group, 68% vs 59% of patients had died. Median overall survival was 9.5 months (95% CI = 8.3–12.3 months) with anetumab ravtansine vs 11.6 months (95% CI = 8.6–13.1 months) with vinorelbine (HR = 1.07, 95% CI = 0.76–1.51, P = .66). In an exploratory analysis with data cutoff in July 2019, death had occurred in 77% of the anetumab ravtansine group vs 72% of the vinorelbine group (HR = 0.98, 95% CI = 0.72–1.34).

KEY POINTS

  • Anetumab ravtansine did not improve progression-free survival vs vinorelbine.
  • Median progression-free survival was 4.3 vs 4.5 months.

Adverse Events

Grade ≥ 3 adverse events occurred in 48% of patients in the anetumab ravtansine group vs 74% of the vinorelbine group. The most common in the anetumab ravtansine group were alanine aminotransferase increase (6%), dyspnea (6%), and infusion-related reaction (5%). The most common in the vinorelbine group were neutropenia (39%) and decreased neutrophils (17%). Grade ≥ 3 pneumonia occurred in 4% vs 7% of patients.

Serious drug-related adverse events occurred in 7% vs 15% of patients, most commonly infusion-related reaction (1%) in the anetumab ravtansine group and neutropenia and pneumonia (3% each) in the vinorelbine group. One death in the anetumab ravtansine group, due to sepsis, was considered related to treatment.

The investigators concluded, “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.”

Dr. Kindler, of the Section of Hematology/Oncology, University of Chicago, and Dean A. Fennell, PhD, of Leicester Cancer Research Centre, University of Leicester, are the corresponding authors for The Lancet Oncology article.

Disclosure: The study was funded by Bayer Healthcare Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.

 


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