In a phase I clinical trial, the investigational antibody-drug conjugate (ADC) anetumab ravtansine (BAY 94-9343; Bayer) shows promising antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors.

Mesothelin is a tumor differentiation antigen. It is frequently overexpressed in tumors including mesothelioma, ovarian, pancreatic, and lung adenocarcinomas. In contrast, mesothelin shows limited expression in nonmalignant tissues. [1]

In vitro, anetumab ravtansine demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. Furthermore, antitumor efficacy of anetumab ravtansine correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models

The study findings were published in the Journal of Clinical Oncology.

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The purpose of the study was to evalkuate the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.

In the clinical trial the evaluable patient population included 148 patients with mesothelioma or ovarian, pancreatic, non—small cell lung, or breast cancers. Among these patients, there were 11 partial responses (PRs), 1 complete response (CR), and 66 patients with stable disease. The investigators also considered the ADC to have a manageable safety profile.

“The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies,” first author Raffit Hassan, MD, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, and coinvestigators wrote.

Mechanism of action
The antibody-drug conjugates anetumab ravtansine, also known as BAY 94-9343, links a fully human immunoglobulin G1 anti-mesothelin antibody to the maytansine derivative tubulin inhibitor DM4 through a reducible disulfide linker. The drug–antibody ratio or DAR of anetumab ravtansine is 3.2. [2]

After binding to mesothelin on tumor cells, anetumab ravtansine is internalized and the disulfide linker is cleaved, releasing the DM4 payload. DM4 subsequently binds to tubulin; this disrupts microtubule polymerization, resulting in cell cycle arrest and apoptosis.[2][3][4]

The release of DM4 into the tumor microenvironment leads to bystander killing of neighboring dividing cells. Preclinical studies have shown that anetumab ravtansine was highly cytotoxic to mesothelin-expressing mesothelioma and pancreatic, non–small-cell lung, and ovarian cancer cell lines.[2][3][4]

In vivo, anetumab ravtansine had robust antitumor activity in mesothelioma, pancreatic, and ovarian xenografts with mesothelin expression derived from patients with cancer.

Dose escalation study
The multicenter dose-escalation/expansion, open-label phase I study accrued 148 adult patients across several solid tumor types between September 2011 and June 2015. The majority of patients had mesothelioma (n = 64) or ovarian cancer (n = 64). Other tumor types included breast cancer (5), non—small cell lung cancer (2), pancreatic cancer (9) and other (4).

The mean age was 60 years and 64% of patients were female. The ECOG performance status was 0 for 44 patients, 1 for 99 patients, and unknown for 5 patients. The mean time since diagnosis was 40.2 months. The mean number of prior systemic anticancer treatment regimens was 3.5.

The initial dose-escalation phase enrolled 45 patients across 10 cohorts. It was determined that the maximum-tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Subsequently, in the dose-expansion cohorts, 32 patients were enrolled in the 6.5 mg/kg once-every-3-weeks group, 35 in the 1.8 mg/kg once-per-week group, and 36 in the 2.2 mg/kg once-per-week group.

Among patients with ovarian cancer there was 1 CR, 4 PRs, and 29 patients with stable disease. In patents with mesothelioma, there were 6 PRs and 26 patients with stable disease. High levels of tumor mesothelin expression were associated with clinical activity of anetumab ravtansine.

Adverse events
Overall, fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy were the most frequently reported drug-related adverse events. There were no deaths related to study treatment.

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 55%, 57%, and 61% of the 6.5-, 1.8-, and 2.2-mg/kg doses, respectively. Serious TEAEs occurred in 39%, 31%, 42%, respectively.

Among the group receiving the 6.5-mg/kg dose, drug-related peripheral sensory neuropathy was observed in 32% of patients; however, only 1 of the events was grade 3. Infusion-related reactions were uncommon.

“Anetumab ravtansine is being investigated as a potential treatment option for patients with mesothelin-expressing solid tumors, who currently have very limited treatment options. This phase I study showed that anetumab ravtansine was well tolerated in these patients, leading to the initiation of several phase II studies across multiple tumor types including mesothelioma, non—small cell lung cancer, cholangiocarcinoma, and pancreatic adenocarcinoma,” Hassan wrote in his conclusion.

Clinical trials
Click on the link for an overview of clinical trials.

Reference
[1] Hassan R, Blumenschein Jr GR, Moore KN, et al. First-in-human, multicenter, phase I dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors [published online March 26, 2019]. J Clin Oncol. doi: https://doi.org/10.1200/JCO.19.02085
[2] Golfier S, Kopitz C, Kahnert A, et al. Anetumab ravtansine: A novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 13: 1537-1548,2014
[3] Chen H, Lin Z, Arnst KE, Miller DD, Li W. Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2017;22(8):1281. Published 2017 Aug 1. doi:10.3390/molecules22081281
[4] Chalouni C, Doll S. Fate of Antibody-Drug Conjugates in Cancer Cells. J Exp Clin Cancer Res. 2018;37(1):20. Published 2018 Feb 6. doi:10.1186/s13046-017-0667-1

Featurted image: Nurse discussing a clinical trial with a patients. Photo courtesy © 2016 – 2020 Fotolia/Adobe. Used with permission.