Anetumab Ravtansine Does Not Improve PFS Vs Vinorelbinein Patients With MPM

Anetumab ravtansine did not show superior progression-free survival or overall survival in the second-line treatment setting for patients with mesothelin-expressing malignant pleural mesothelioma, according to results from the 15743 study.

Anetumab ravtansine (BAY 94–9343) demonstrated a manageable safety profile in patients with stage 4 mesothelin overexpressing malignant pleural mesothelioma (MPM), but did not show superiority to vinorelbine, missing the primary end point of the 15743 study (NCT02610140), according to results published in the Lancet Oncology.

“To our knowledge, this is the first clinical trial in relapsed malignant pleural mesothelioma including analysis of patients stratified by mesothelin expression and plasma cell-free DNA by next-generation sequencing to identify biomarkers of response or resistance to anetumab ravtansine. In this study, anetumab ravtansine was not superior to vinorelbine in terms of progression-free survival or overall survival in the second-line treatment setting for patients with mesothelin-expressing malignant pleural mesothelioma,” wrote the study authors led by Hedy L. Kindler, director of the Mesothelioma Program and medical director of Gastrointestinal Oncology at the University of Chicago.

In the second-line setting of MPM, few treatment options exist. To address the unmet need, the phase 2, randomized, open-label study aimed to assess the use of anetumab ravtansine vs vinorelbine in patients whose disease was unresectable locally advanced or metastatic after progression on frontline platinum-pemetrexed chemotherapy with or without bevacizumab (Avastin)/

Patients were enrolled across 76 hospitals in 14 countries. Enrollment was open to patients aged 18 years and older. Other requirements included an ECOG performance status of 0-1, progression on first-line platinum–pemetrexed chemotherapy with or without bevacizumab, measurable disease, a life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function.

A total of 589 patients were enrolled with 248 mesothelin-overexpressing patients randomly assigned to the 2 treatment groups. There were 166 patients randomly assigned to receive anetumab ravtansine given intravenously (IV) 6.5 mg/kg on day 1 of each 21-day cycle and 82 patients to receive IV vinorelbine at 30 mg/m2 once every week.

Treatment continued until centrally confirmed disease progression or until another reason was met for withdrawal from the study. Patients entered a follow-up phase in order to capture safety and end point data as required.

The primary end point was PFS with secondary end points including overall survival, objective response rate, disease control rate, duration of response, durable response rate, and number of treatment-emergent adverse events (TEAEs).

At a median follow-up of 4.0 months, 63% of patients (n = 105) treated with anetumab ravtansine versus 52% (n = 43) treated with vinorelbine at 3.9 months had disease progression or died. Median PFS was 4.3 months [95% CI, 4.1–5·2] compared to 4.5 months [4.1–5.8].

The most common grade 3 or worse adverse events (AEs) were neutropenia (1% for anetumab ravtansine and 39% for vinorelbine), pneumonia (4%, 7%), neutrophil count decrease (1%, 17%), and dyspnoea (6%, 4%).

Serious drug-related TEAEs occurred in 7% patients (n = 12) treated with anetumab ravtansine and 15% of patients (n = 11) treated with vinorelbine. Treatment-emergent deaths occurred with anetumab ravtansine in 6% of patients (n = 10) including pneumonia (2%), dyspnoea (1%), sepsis (1%), atrial fibrillation (1%), physical deterioration (1%), hepatic failure (1%), mesothelioma (1%), and renal failure (1%) with 1 patient having 3 events. One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).

Further studies are still needed to determine active treatments in relapsed mesothelin-expressing MPM.

“Post-hoc analyses suggested that plasma soluble mesothelin-related peptide and tissue mesothelin levels were associated with survival times in patients treated with anetumab ravtansine. Therefore, stratified therapy for malignant pleural mesothelioma might be feasible," wrote Kindler et al.

1. Kindler HL, Novello S, Bearz A, et al. Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomized, open-label phase 2 trial. Lancet Oncol. 2022; 23(4):540-552. doi:10.1016/S1470-2045(22)00061-4
2. Phase II anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma (MPM). Accessed April 11, 2022.
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