In a phase I trial reported in the Journal of Clinical Oncology, Hassan et al found evidence of activity of the anti–mesothelin antibody-drug conjugate anetumab ravtansine in patients with advanced solid tumor types known to express the tumor-differentiation antigen mesothelin. The agent consists of an anti–mesothelin antibody linked to the tubulin inhibitor maytansinoid DM4.

Study Details

The trial, performed in eight centers in the United States, enrolled 148 patients with multiple types of advanced or metastatic solid tumors. In the dose-escalation phase, 45 patients received anetumab ravtansine at 0.15 to 7.5 mg/kg once every 3 weeks. In the dose-expansion phase, 103 patients with advanced recurrent ovarian cancer or malignant mesothelioma received one of three dose regimens.

Dose-Escalation Phase

The maximum tolerated dose was 6.5 mg/kg every 3 weeks. Dose-limiting toxicities were observed in one of six patients in the 6.5 mg/kg group (grade 3 increase in aspartate aminotransferase). Dose-limiting toxicities at other dose levels included grade 3 hypertension, grade 3 hyponatremia, grade 3 peripheral neuropathy, grade 4 keratitis/keratopathy, and grade 4 increases in serum lipase and amylase. 

Responses

In the dose-expansion phase, patients with advanced recurrent ovarian cancer or malignant mesothelioma received 6.5 mg/kg of the agent every 3 weeks (n = 32), 1.8 mg/kg once per week (n = 35), or 2.2 mg/kg once per week (n = 36).

Among the total population of 148 patients with mesothelioma or ovarian, pancreatic, lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. In the dose-expansion phase, objective response rates were 16%, 9%, and 6% in the 6.5 mg/kg, 1.8 mg/kg, and 2.2 mg/kg cohorts, with respective disease control rates of 65%, 54%, and 64%. The highest objective response (31%) and disease control rates (75%) were observed in the 6.5 mg/kg once-every-3-weeks mesothelioma subgroup. Activity of the agent was associated with higher tumor mesothelin expression levels.

Adverse Events

The most common drug-related adverse events of any grade among across the three regimens tested in the dose-expansion cohorts were fatigue (54%–63%), nausea (46%–58%), diarrhea (33%–53%), anorexia (25%–50%), vomiting (14%–39%), and peripheral sensory neuropathy (19%–37%). Treatment-related grade ≥ 3 adverse events were observed in 19% to 29% of patients, and no drug-related deaths were reported.

The recommended phase II dose and schedule was determined to be 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week.

The investigators concluded, “Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.”

Raffit Hassan, MD, of the Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bayer HealthCare Pharmaceuticals and by the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.