Vinblastine/Methotrexate Fails to Demonstrate Activity for NF1-PN in Pediatric and Young-Adult Patients

Findings from a phase 2 study show vinblastine/methotrexate did not demonstrate activity for neurofibromatosis type 1 with plexiform neurofibromas (NF1-PN) in pediatric and young-adult patients, despite being well-tolerated.

There are currently limited effective therapies for the treatment of NF1-PN, leading researchers to evaluate the activity and safety of vinblastine and methotrexate (conventional cytotoxic chemotherapies) given on a metronomic schedule in pediatric and young-adult patients in this phase 2 trial.

Patients ≤25 years of age with progressive and/or inoperable NF1-PN received vinblastine at 6 mg/m² and methotrexate at 30 mg/m² weekly for 26 weeks, followed by every 2 weeks for 26 weeks. The primary trial end point was objective response rate.

Overall, 25 patients were enrolled, of whom, 23 were evaluable for toxicities and tumor responses. The median age of participants was 6.6 years. The most frequent target PN location was head and neck (44%), followed by the trunk (35%). Of the 14 tumors with any involvement of the neck, 9 (64%) had airway involvement. Of the 9 participants with airway involvement, 5 (56%) had associated functional impairments at enrollment.

Overall, 14 (61%) of the 23 evaluable patients completed protocol therapy. Of the 9 (39%) patients that did not complete protocol therapy, 3 (13%) progressed on therapy (weeks 13, 14, and 40), 1 withdrew due to progression of a low-grade glioma (week 14), and 5 withdrew from therapy due to patient/caregiver choice (weeks 1, 12, 14, 17, 36); only 1 participant withdrew for low-grade intolerable adverse events (grade 1 neuropathy).

On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval, 16.9 to 64.9). Overall, 2 (25%) of 8 patients with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index.

A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 (46%) participants had progressive disease on or by the end of therapy.

Researchers noted that vinblastine/methotrexate was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation.

“Overall, although vinblastine/methotrexate was generally well-tolerated, it did not demonstrate activity for NF1-associated PN. At present, given the recent successes of mitogen-activated protein kinase inhibitors, as well as emerging data with other targeted therapies, we believe that vinblastine/methotrexate does not warrant further evaluation in children with NF1 and progressive and/or inoperable PN,” researchers concluded.

Source:

Kotch C, Wagner K, Broad JH, et al. Cancers (Basel). 2023 May 5;15(9):2621. doi:10.3390/cancers15092621.