TY - JOUR
T1 - Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM
AU - Heipertz, Anna-Elisa
AU - Pajtler, Kristian W
AU - Pfaff, Elke
AU - Schramm, Kathrin
AU - Blattner-Johnson, Mirjam
AU - Milde, Till
AU - Jones, Barbara C
AU - Zuliani, Cecilia
AU - Hutter, Caroline
AU - Lohi, Olli
AU - Kattamis, Antonis
AU - Dachowska-Kalwak, Iwona
AU - Nilsson, Anna
AU - Gerber, Nicolas U
AU - Langenberg, Karin P S
AU - Goemans, Bianca
AU - Zwaan, C Michel
AU - Molenaar, Jan J
AU - Jäger, Natalie
AU - Dirksen, Uta
AU - Witt, Ruth
AU - Pfister, Stefan M
AU - Jones, David T W
AU - Kopp-Schneider, Annette
AU - Witt, Olaf
AU - van Tilburg, Cornelis M
PY - 2023/6
Y1 - 2023/6
N2 - PURPOSE: INFORM is an international pediatric precision oncology registry, prospectively collecting molecular and clinical data of children with recurrent, progressive, or very high-risk malignancies. We have previously identified a subgroup of patients with improved outcomes on the basis of molecular profiling. The present analysis systematically investigates progression-free survival (PFS) and overall survival (OS) of patients receiving matching targeted treatment (MTT) with the most frequently applied drug classes and its correlation with underlying molecular alterations.METHODS: A cohort of 519 patients with relapsed or refractory high-risk malignancies who had completed a follow-up of at least 2 years or shorter in the case of death or loss to follow-up was analyzed. Survival times were compared using the log-rank test.RESULTS: MTT with anaplastic lymphoma kinase (ALK), neurotrophic tyrosine receptor kinase (NTRK), and B-RAF kinase (BRAF) inhibitors showed significantly improved PFS (P = .012) and OS (P = .036) in comparison with conventional treatment or no treatment. However, analysis of the four most commonly applied MTT groups, mitogen-activated protein kinase (MEK- n = 19), cyclin-dependent kinase (CDK- n = 23), other kinase (n = 62), and mammalian-target of rapamycin (mTOR- n = 20) inhibitors, did not reveal differences in PFS or OS compared with conventional treatment or no treatment in patients with similar molecular pathway alterations. We did not observe differences in the type of pathway alterations (eg, copy number alterations, single-nucleotide variants, InDels, gene fusions) addressed by MTT.CONCLUSION: Patients with respective molecular alterations benefit from treatment with ALK, NTRK, and BRAF inhibitors as previously described. No survival benefit was observed with MTT for mutations in the MEK, CDK, other kinase, or mTOR signaling pathways. The noninterventional character of a registry has to be taken into account when interpreting these data and underlines the need for innovative interventional biomarker-driven clinical trials in pediatric oncology.
AB - PURPOSE: INFORM is an international pediatric precision oncology registry, prospectively collecting molecular and clinical data of children with recurrent, progressive, or very high-risk malignancies. We have previously identified a subgroup of patients with improved outcomes on the basis of molecular profiling. The present analysis systematically investigates progression-free survival (PFS) and overall survival (OS) of patients receiving matching targeted treatment (MTT) with the most frequently applied drug classes and its correlation with underlying molecular alterations.METHODS: A cohort of 519 patients with relapsed or refractory high-risk malignancies who had completed a follow-up of at least 2 years or shorter in the case of death or loss to follow-up was analyzed. Survival times were compared using the log-rank test.RESULTS: MTT with anaplastic lymphoma kinase (ALK), neurotrophic tyrosine receptor kinase (NTRK), and B-RAF kinase (BRAF) inhibitors showed significantly improved PFS (P = .012) and OS (P = .036) in comparison with conventional treatment or no treatment. However, analysis of the four most commonly applied MTT groups, mitogen-activated protein kinase (MEK- n = 19), cyclin-dependent kinase (CDK- n = 23), other kinase (n = 62), and mammalian-target of rapamycin (mTOR- n = 20) inhibitors, did not reveal differences in PFS or OS compared with conventional treatment or no treatment in patients with similar molecular pathway alterations. We did not observe differences in the type of pathway alterations (eg, copy number alterations, single-nucleotide variants, InDels, gene fusions) addressed by MTT.CONCLUSION: Patients with respective molecular alterations benefit from treatment with ALK, NTRK, and BRAF inhibitors as previously described. No survival benefit was observed with MTT for mutations in the MEK, CDK, other kinase, or mTOR signaling pathways. The noninterventional character of a registry has to be taken into account when interpreting these data and underlines the need for innovative interventional biomarker-driven clinical trials in pediatric oncology.
KW - Animals
KW - Humans
KW - Child
KW - Adolescent
KW - Antineoplastic Agents/adverse effects
KW - Proto-Oncogene Proteins B-raf/genetics
KW - Precision Medicine
KW - Neoplasm Recurrence, Local/drug therapy
KW - Receptor Protein-Tyrosine Kinases
KW - TOR Serine-Threonine Kinases
KW - Carcinoma
KW - Mitogen-Activated Protein Kinase Kinases
KW - Mammals
U2 - 10.1200/PO.23.00015
DO - 10.1200/PO.23.00015
M3 - Article
C2 - 37364231
SN - 2473-4284
VL - 7
JO - JCO Precision Oncology
JF - JCO Precision Oncology
M1 - e2300015
ER -