Bridging the Gap: Advancing Drug Approval for Young Patients Battling Cancer

In the field pediatric oncology, every advancement counts, especially for patients facing rare and severe conditions like Constitutional Mismatch Repair Deficiency (CMMRD), a lethal cancer predisposition syndrome. CMMRD is characterized by early-onset synchronous and metachronous multiorgan cancers including central nervous system tumors, most frequently high-grade gliomas. Our recent case report entitled "A precision immuno-oncology approach for four malignant tumors in two siblings afflicted with CMMRD syndrome," sheds light on the challenges and successes in managing this complex condition. But beyond the intricacies of our case lies a broader narrative – one that underscores the pressing need for expedited drug approval processes tailored to young patients.

Understanding CMMRD: Unraveling the Complexity

CMMRD is caused by biallelic germline mutations in mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. In our case report, we describe the clinical journey of two siblings with CMMRD, each navigating a distinct cancer spectrum despite sharing the same genetic predisposition, two heterozygous mutations in the PMS2 gene. We revealed the nuanced variations in phenotypic manifestations, emphasized the importance of accurate diagnosis accompanied by a comprehensive molecular genetic examination, as well as the essential role of surveillance and early cancer detection in individuals affected by CMMRD (1).

Immuno-Oncology: A Beacon of Hope

Amid the therapeutic challenges posed by CMMRD-associated tumors, our research highlights the pivotal role of immune checkpoint inhibitors (ICI; used as off label in both described patients) in prolonging survival for young patients. By leveraging the uniform hypermutation characteristic of CMMRD tumors, we employed precision immuno-oncology strategies, including the use of nivolumab (PD-1 blocking antibody), to combat lethal gliomas and B-cell lymphoma. These findings not only underscore the efficacy of ICI treatments but also advocate for their early integration into pediatric oncology protocols.

Urgent Action Needed: Closing the Drug Approval Gap

While our case offers promise, it also underscores a larger systemic issue: the lag in drug approval for pediatric populations. Coppes et al, 2022, and Vassal et al, 2023 in their articles elucidates the persistent disparities in accessing innovative drugs for young patients. Despite strides in regulatory frameworks and trial methodologies, the gap between adult and pediatric drug approval remains glaring, prolonging the wait for life-saving therapies (2,3).

As summarized by Vassal et al, 2023 (3), since the introduction of the EU Pediatric Medicine Regulation in 2007, only 16 new molecular entities have gained approval for treating pediatric malignancies. Among these, half are designated for diseases responsible for a combined 5.4% of childhood cancer-related deaths. The gap between initial marketing authorization in adults and subsequent approval for pediatric malignancies averaged 6.4 years. Notably, the development of anti-cancer drugs for children has primarily followed trends in the adult market, leaving significant unmet needs unaddressed in pediatric oncology.

A Call to Action: Collaboration and Innovation

In confronting these challenges, collaboration becomes the strongest ally. Initiatives like the Institute for Advanced Clinical Trials (I-ACT) for Children or Accelerate defend the cause of pediatric drug development, rallying stakeholders from regulatory agencies to biopharmaceutical companies. Through advocacy, innovative trial designs, and concerted efforts, organizations mentioned above strive to expedite drug approval processes, ensuring timely access to vital treatments for young patients, however, this process is more advanced in US than in EU and it still is quite an easy for pharma industry to get a waiver for pediatric development. For such ultra rare diseases like ours, it is almost impossible to organize and perform standard clinical trials required for standard regulatory approval, making reimbursement of such treatments difficult in many countries. Different path should be exploited in order to have life saving treatment funded through standard health care.

Conclusion: Navigating the Path Forward

As patients and researchers advocates, we stand at a pivotal juncture – one that demands collective action and unwavering commitment. Our case on CMMRD illuminates the possibilities of precision medicine in pediatric oncology, but its impact extends far beyond individual cases. It underscores the urgency of reforming drug approval processes, empowering young patients with timely access to transformative therapies, reflecting individual patient´s and his tumor biology. Together, let us bridge the gap and pave the way for a brighter future for pediatric oncology.

1. Durno C, Ercan AB, Bianchi V, Edwards M, Aronson M, et al. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance. J Clin Oncol Off J Am Soc Clin Oncol. 2021 Sep 1;39(25):2779–90.

2. Coppes MJ, Jackson C, Connor EM. I-ACT for Children: helping close the gap in drug approval for adults and children. Pediatr Res. 2023 Jun;93(7):1786–7.

3. Vassal G, de Rojas T, Pearson ADJ. Impact of the EU Paediatric Medicine Regulation on new anti-cancer medicines for the treatment of children and adolescents. Lancet Child Adolesc Health. 2023 Mar;7(3):214–22.