NCCN Adds Pedmark to Guidelines for Pediatric Solid Tumors

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for adolescent and young adult oncology have been updated to include Pedmark, a sodium thiosulfate injection, to assist in reducing the risk of ototoxicity associated with cisplatin use in pediatric patients with localized, non-metastatic solid tumors.¹

Pedmark was granted FDA approval in September 2022 for the prevention of platinum-induced ototoxicity for pediatric patients with localized non-metastatic solid tumors. Currently, this is the only FDA-approved therapy indicated to reduce the risk of ototoxicity in this patient population.

Safety and efficacy findings from 2 pivotal open-label, randomized phase 3 trials support the FDA approval of Pedmark in this patient population, including the SIOPEL 6 (NCT00652132) and COG ACCL0431 (NCT00716976) studies. Each trial looked to compare Pedmark combined with a cisplatin-based regimen with cisplatin-based regimen alone.

"It is great news that the NCCN guidelines have been updated to include Pedmark as an otoprotectant for pediatric patients receiving cisplatin. Pedmark will reduce hearing loss considerably and will therefore make a big difference to the quality-of-life of those patients who recieve it. Cisplatin induced hearing loss is permanent and bilateral and impacts all aspects of young people's lives. Adolescents particularly can feel isolated and unable to participate socially at a time in their life when socialising and gaining confidence in the world and interacting with others is so important," Peppy Brock, MD, PhD, of Great Ormond Street Hospital in London and international chair of the SIOPEL 6 trial, told Targeted Oncology^TM.

“The use of cisplatin chemotherapy, an indispensable treatment of choice in many pediatric cancer cases, can be toxic to the ears and frequently causes permanent and irreversible bilateral hearing loss. In fact, permanent hearing loss occurs in approximately 60 percent of children treated with cisplatin and can be as high as 90 percent,” said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals, in the press release. “We applaud NCCN for not only recognizing the importance of routine monitoring for hearing loss, which can have a profound impact on children’s learning and development at all ages, and also for providing a clear recommendation for the routine use of Pedmark, a recently approved FDA therapeutic that may help reduce this unfortunate treatment-related side effect. Moreover, the FDA has directed that Pedmark is not substitutable with other sodium thiosulfate products as part of the approved prescribing label.”

With the 5-year survival rate for pediatric patients now at 85% and higher due to treatment advances, there is a need to mitigate the impact that hearing loss can have on the learning and development of children. As a result, investigators are always looking for ways to recognize the importance of hearing loss.

COG ACCL0431 was a randomized, open-label study which evaluated Pedmark in 125 patients with newly diagnosed solid tumors.² Among the patients enrolled in the trial, 32 had germ cell tumor, 29 had osteosarcoma, 26 had neuroblastoma, 26 had medulloblastoma, 7 had hepatoblastoma, and 5 had other unspecified cancers.

A total of 104 patients were evaluable for the primary end point of incidence of hearing loss 4 weeks after the final cisplatin dose. The secondary end points of the trial consisted of change in hearing thresholds ranging from 500 hz to 8000 hz, event-free survival (EFS), overall survival (OS), and hearing loss among patients both carrying and not carrying 2 key gene mutations.

Among those enrolled, most patients were male (64%), and 29 were under the age of 5 years. Each patient was randomized and received an intravenous (IV) administration of sodium thiosulfate 16 mg/m2 over a duration of 15 minutes, 6 hours following each dose of cisplatin, or placebo.

In the control arm, 14 patients (28.6%; 95% CI, 16.6%-43.4%) had hearing loss after treatment with cisplatin in the sodium thiosulfate arm vs 31 patients (56.4%; 95% CI, 42.3%-69.7%; P = .00022). Patients given sodium thiosulfate were less likely to have hearing loss following cisplatin vs those in observation (odds ratio [OR], 0.31; 95% CI, 0.13-0.73; P = .0036). Additionally, a post hoc analysis examined 67 patients who were evaluable for the primary end point of the study. These findings revealed that 28% of patients had hearing loss in the sodium thiosulfate group vs 54% in the control group (P = .0015).

Looking at safety, 77% of patients in the sodium thiosulfate arm as well as in the control arm showed signs of hematologic toxicity (P = .95). Grade 3 or 4 hematological adverse events (AEs) that were the most common included neutropenia (66% vs 65%, respectively) in the experimental vs control arm. Further, the most common non-hematological AE was hypokalemia in 17% of patients who received sodium thiosulfate vs 12% of those in the observation alone arm.

Then, the phase 3 SIOPEL 6 trial assessed the efficacy of cisplatin and sodium thiosulfate vs cisplatin alone in 109 pediatric patients.³ Those enrolled received cisplatin at a dose of 80 mg/m² of the body-surface area administered over a 6-hour period. Sodium thiosulfate was also given at a dose of 20 mg/m² via IV administration over a 15-minute period at about 6 hours after the end of cisplatin treatment.

The primary end point of the trial was absolute hearing loss threshold. Secondary end points were response to preoperative chemotherapy, complete resection, complete remission, EFS, OS, safety, long-term renal clearance or glomerular filtration rate, and feasibility of central audiologic review.

Findings from this trial showed 33% of patients to have grade 1 or higher hearing loss in the cisplatin plus sodium thiosulfate arm vs 63% in the cisplatin-only arm, leading to a 48% reduction in the risk of hearing loss within the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% CI, 0.33-0.81; P = .002). At a median follow-up of 52 months, the 3-year OS rate was 98% (95% CI, 88%-100%) with cisplatin plus sodium thiosulfate vs 92% (95% CI, 81%-97%) with cisplatin-only. Patients in the combination arm had a 3-year EFS rate of 82% (95% CI, 69%-90%) compared with 79% (95% CI, 65%-88%) in the monotherapy arm.

For safety, AEs occurred in 57 patients in the cisplatin and sodium thiosulfate arm vs 52 in the cisplatin-only arm. The most common AEs were grade 3 infections, which was seen in 31% of the chemotherapy arm and 23% of the cisplatin plus sodium thiosulfate arm, and grade 3 febrile neutropenia, which occurred in 19% vs 14%, respectively.

The NCCN Guidelines for adolescent and young adult oncology has the goal of identifying issues specific to this patient population. Experts are always looking to provide new interventions unique to these patients, to educate physicians on the prevalence of cancer in pediatric and young adult patients, to discuss long-term consequences, to explain how to best manage patients to improve tolerance of treatment, and more.

REFERENCES:

1. Fennec pharmaceuticals announces updated NCCN clinical practice guidelines recommend PEDMARK® (sodium thiosulfate injection) to reduce the risk of cisplatin-induced hearing loss in pediatric patients. Fennec Pharmaceuticals, inc. January 25, 2023. Accessed January 26, 2023. https://yhoo.it/3JgxFTg

2. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomized, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74. doi:10.1016/ S1470-2045(16)30625-8

3. Brock PR, Maibahc R, Childs M, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med. 2018;378(25):2376-2385. doi:10.1056/NEJMoa1801109