Lorlatinib appears effective, safe for high-risk, ALK-driven advanced neuroblastoma
Key takeaways:
- About one-third of children and two-thirds of adults with relapsed or refractory neuroblastoma responded to single-agent lorlatinib.
- Adverse events including weight gain appeared manageable.
Lorlatinib appeared safe and showed potential efficacy among a cohort of patients with relapsed or refractory, ALK-driven, high-risk neuroblastoma, results of a phase 1 trial showed.
The findings, published in Nature Medicine, support the rapid translation of lorlatinib (Lorbrena, Pfizer) into active phase 3 trials for this patient population, researchers concluded.
Rationale and methodology
“This study is the culmination of decades of work that began at CHOP [Children’s Hospital of Philadelphia] with our initial discovery of ALK mutations in neuroblastoma in 2008,” Yael P. Mossé, MD, professor in the department of pediatrics at the cancer center at CHOP, said in a press release. “The difficulties we experienced in targeting ALK with crizotinib [Xalkori, Pfizer] in neuroblastoma motivated us to find a more potent ALK inhibitor.”
The ongoing first-in-child study evaluated lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma.
Researchers enrolled patients to one of three cohorts, including lorlatinib alone for children (n = 25), lorlatinib alone for adults (n = 15) and lorlatinib in combination with topotecan/cyclophosphamide for children. (n = 9).
Safety, pharmacokinetics and recommended phase 2 dose served as primary endpoints. Secondary endpoints included response rate and 123I-metaiodobenzylguanidine response.
Findings
Common adverse events among the overall population included hypertriglyceridemia in 90%, hypercholesterolemia in 79% and weight gain in 87%. Neurobehavioral adverse events occurred most often among adults and resolved with dose hold or reduction.
Researchers recommended a phase 2 single-agent dose of lorlatinib of 115 mg/m² for children and a single-agent dose of 150 mg for adults.
Results among patients evaluable for efficacy showed a response rate of 30% among children assigned single-agent lorlatinib, 67% among adults assigned the single agent and 63% among children assigned combination treatment.
Moreover, 48% of responders experienced 123I-metaiodobenzylguanidine complete responses.
Implications
“We started testing lorlatinib in the lab in 2013 and, as a result of this clinical trial, lorlatinib has now moved upfront in a pivotal [Children’s Oncology Group] phase 3 trial, which will hopefully support eventual FDA approval of this treatment,” Mossé said in the release. “This serves as a paramount example across all pediatric cancers of forward and reverse translation, where we learn from the science and from our patients and make decisions in real-time to fast-track development of new agents when there is potential for substantive impact.”
References:
- Goldsmith KC, et al. Nat Med. 2023;doi:10.1038/s41591-023-02297-5.
- Researchers find lorlatinib to be safe and effective treatment for high-risk neuroblastoma (press release). Available at: https://news.emory.edu/stories/2023/04/winship_researchers_find_lorlatinib_to_be_safe_and_effective_treatment_for_high-risk_neuroblastoma/story.html. Published April 3, 2023. Accessed May 2, 2023.
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