Anetumab Ravtansine Shows Promise in Mesothelin-Expressing Solid Tumors

Raffit Hassan, MD

The investigational antibody-drug conjugate (ADC) anetumab ravtansine showed promising antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors, according to findings from a phase I study published in the Journal of Clinical Oncology.

The evaluable 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.

The ADC anetumab ravtansine links an anti-mesothelin antibody to maytansinoid DM4. 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.

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 et al wrote in their conclusion.

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