An international group of researchers led by Winship Cancer Institute of Emory University, Children’s Hospital of Philadelphia (CHOP) and the New Approaches to Neuroblastoma Therapy (NANT) Consortium has shown that the targeted therapy lorlatinib is safe and effective in treating high-risk neuroblastoma.
The findings, published today in Nature Medicine, have led to a major amendment in a phase 3 Children’s Oncology Group (COG) clinical trial, which has incorporated lorlatinib for newly diagnosed ALK-driven high-risk neuroblastoma, as well as a planned amendment to the European phase 3 trial in collaboration with the International Society of Paediatric Oncology European Neuroblastoma (SIOPEN).
“The profound clinical responses seen in this trial, in a highly therapy-resistant, relapsed pediatric cancer population, allows us to now offer lorlatinib into frontline care for newly diagnosed patients with ALK mutated or amplified neuroblastoma, a population known to have inferior survival with standard-of-care, high-risk therapy,” said the study’s first author and co-chair of the trial Kelly Goldsmith, MD, Co-Leader of the Discovery & Developmental Therapeutics Program at Winship Cancer Institute of Emory University, Director of the Neuroblastoma/MIBG Therapy Program at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and associate professor of pediatrics at Emory University School of Medicine. “This trial will truly change the paradigm of clinical care and improve outcomes for our neuroblastoma patients.”
After screening numerous anti-ALK agents, researchers discovered in preclinical tests that lorlatinib, an ALK and ROS-1 inhibitor, surpassed results seen with crizotinib. Leveraging that data, the researchers were able to test the safety, tolerability, and anti-tumor activity of lorlatinib in a first-in-child NANT Consortium Phase 1 trial in children, adolescents and adults with ALK-driven refractory/relapsed neuroblastoma.
In the phase 1 NANT trial, researchers found that lorlatinib given alone or in combination with chemotherapy was safe and tolerable in pediatric, adolescent, and adult patients with relapsed/refractory ALK-driven neuroblastoma. Lorlatinib demonstrated clinical activity across patients of all ages harboring the three neuroblastoma-specific hotspot ALK mutations, including patients who had previously received other ALK inhibitors.
Approximately 30% of patients under the age of 18 responded to the drug, and approximately 67% of patients over 18 responded. Patients under the age of 18 had a better response in combination with chemotherapy, with 63% of patients responding to the combined treatment. The researchers noted that younger patients treated with lorlatinib alone – particularly those with amplification of an oncogene called MYCN – had fewer responses compared to older patients. They suspect this could reflect the heterogeneity within the tumor in these patients and indicate that for patients with MYCN mutations, lorlatinib alone will be insufficient, but holds promise when given in combination with chemotherapy. Swiftly moving this drug upfront for the subset of patients with ALK alterations provides an opportunity to go after a key driver of this disease to prevent relapse.
The safety profile of lorlatinib across all ages was similar in scope and grade to those reported in studies examining lorlatinib in non-small cell lung cancer. The neuroblastoma patients using lorlatinib also experienced weight gain and increased circulating lipids, but those were manageable with supportive care and diet management.
To read the full results of the trial, click here.