Lorvotuzumab Mertansine Well-Tolerated in Children at Adult Recommended Dose

A phase 2 study published in Cancer confirmed that lorvotuzumab mertansine (IMGN901) was well tolerated in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), or synovial sarcoma at the adult recommended phase 2 dose of 110 mg/m².

Lorvotuzumab mertansine is an antibody drug conjugate that links a potent antimitotic (DM1) via a disulfide linker to CD56-targeting antibodies (lorvotuzumab). However, though the CD56 target was confirmed to be expressed in the tumor types studied, the clinical efficacy of lorvotuzumab mertansine was limited.

“Perhaps with alternative [antibody drug conjugate] components targeting CD56, the clinical impact of such therapy could be enhanced for patients with targeted tumors,” the authors wrote.

Patients included in the study were aged 12 months to 30 years and had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine was administered at the adult recommended phase 2 dose of 110 mg/m² per dose intravenously on days 1 and 8 of 21-day cycles. Notably, dexamethasone premedication at 4 mg/m² per dose (maximum, 10 mg) the day before lorvotuzumab mertansine infusion was used.

Of note, the first 9 patients were enrolled at Children’s Oncology Group phase 1 and pilot consortium institutions for the monitoring of adverse events (AEs). Patients enrolled thereafter could be enrolled at any Children’s Oncology Group member institution in the US.

In total, 62 patients were enrolled in the phase 2 study. Thirty-five of the patients were male and the median age was 14.3 years (range, 2.8-29.9 years). Diagnoses included 17 patients with Wilms tumor, 17 with rhabdomyosarcoma, 12 with neuroblastoma, 10 with synovial sarcoma, 5 with MPNST, and 1 with pleuropulmonary blastoma.

Overall, 5 patients experienced 9 dose-limiting AEs, including hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). However, non-dose-limiting AEs of grade 3 or higher attributed to lorvotuzumab mertansine were rare.

“The adverse event profile of lorvotuzumab mertansine administered weekly for 2 of every 3 weeks at the adult maximum tolerated dose of 112 mg/m² in pediatric solid tumor patients was similar to the profile for adults,” the authors noted.

The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 μg/mL, 35 hours, and 27.9 μg/mL h, respectively.

On day 8, peripheral blood CD56+ leukocytes decreased by 71.9%. Importantly, 1 patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response.

“It is possible that the lack of efficacy in patients with solid tumors reflects limited delivery of the antimitotic payload to the cell, unfavorable delivery of the conjugate (due to either an inadequate dosing regimen or peritumoral factors), modifiers of CD56 binding/internalization such as CD56 isoforms with variable binding/internalization efficiencies, 30 altered intracellular processing of internalized lorvotuzumab mertansine, or tumor resistance to antimitotic agents such as DM1,” the authors explained.

Moving forward, the researchers recommended that future investigations focus on other factors involved in converting antibody drug conjugates targeting CD56 in relevant tumors in order to enhance tumor cytotoxicity.

Reference:

Geller JI, Pressey JG, Smith MA, et al. ADVL1522: A Phase 2 Study of Lorvotuzumab Mertansine (IMGN901) in Children With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma—A Children’s Oncology Group Study. Cancer. doi: 10.1002/cncr.33195