The second generation ALK inhibitor ceritinib (Zykadia) showed encouraging antitumor activity in pediatric patients with ALK-positive refractory or recurrent malignancies, according to a multicenter phase I study.
The recommended dose for expansion (RDE) of ceritinib was set at 510 mg/m2 fasted or 500 mg/m2 fed, given to 55 patients, reported Johannes Schulte, MD, of Charité-Universitätsmedizin Berlin in Germany and colleagues.
Overall response rates with ceritinib were 75% in patients with anaplastic large cell lymphoma (ALCL; six out of eight patients), 70% in patients with inflammatory myofibroblastic tumor (IMT; seven out of 10), 20% in patients with neuroblastoma (six out of 10). out of 30), and 14% in those with other tumors (one out of seven), they noted in Lancet Oncology.
The drug’s safety profile was consistent with that seen in adult patients, the authors added.
“Our data support the idea that ALK inhibitors should be considered in therapeutic strategies for pediatric patients with malignancies with genetic ALK changes,” Schulte and team wrote.
“These next-generation ALK inhibitors with a higher therapeutic index than the first-generation inhibitors will hopefully overcome resistance in neuroblastoma and destroy resting neoplastic cells, reducing the risk of relapse after treatment discontinuation,” wrote Laurence Brugieres, MD, of Gustave Roussy Cancer Center in Villejuif, France, and colleagues, in an accompanying commentary.
The study was conducted at 23 academic sites in 10 countries and included patients aged 1 to 18 years diagnosed with advanced or metastatic ALK-positive malignancy that had progressed despite standard therapy, or for which no effective standard therapy exists.
Of the 83 patients in the study (median age 8 years), 67 had metastatic disease at study entry. Forty patients were enrolled in the dose-escalation group and 43 were enrolled in the dose-expansion group. All had received at least one prior treatment with antineoplastic therapy (55% had received one or two, while 35% had received at least three), 63% had undergone surgery and 43% had received radiotherapy.
The primary outcome of this study was the determination of the maximum tolerated dose, or RDE, of ceritinib under fasted and fed conditions. Secondary outcomes included overall response rate, disease control rate, duration of response, progression-free survival, and safety.
Disease control rates were 53% for patients with neuroblastoma, 80% for those with IMT, 88% for those with ALCL, and 43% for those with other tumors.
The median duration of response in the six neuroblastoma patients who had a confirmed complete or partial response and who were treated with the fasted or fed RDE was 15 months and was not reached in the six responding patients with ALCL, the seven patients with IMT or a patient with a different tumor type.
Fifty percent of patients with neuroblastoma had a sustained response at 12 months, as did 80% of patients with IMT and 67% with ALCL.
Among the responders, disease progression was reported in three patients with neuroblastoma and one each with IMT and ALCL.
The safety of the drug in the pediatric population “was consistent with the known safety profile established in adult patients, consisting primarily of gastrointestinal toxicity and elevated aminotransferases,” Schulte and colleagues reported.
The most common adverse reactions of any grade were vomiting (87% of patients), diarrhea (78%), alanine aminotransferase increased (65%), aspartate aminotransferase increased (59%), nausea (57%), and abdominal pain (51%). Grade 3 or 4 adverse reactions were reported in 81% of patients, primarily elevations in alanine aminotransferase (46%) and aspartate aminotransferase (33%).
There were 14 deaths during the study, of which 12 were on treatment: 10 were due to disease progression (neuroblastoma), one was due to sepsis and one was due to intractable hypotension.
“While ALK inhibitors are generally tolerated in children, ongoing and future studies should determine the appropriate duration of therapy needed to treat these diseases, and test whether ALK inhibitors are associated with long-term toxic effects. term in children,” the editors concluded. .
Mike Bassett is a staff writer who focuses on oncology and hematology. He is based in Massachusetts.
This study was sponsored by Novartis.
Schulte reported no disclosures. Several co-authors reported industry relationships.
Brugieres serves on an advisory board for Takeda.