Targeting mutations appears to be bearing fruit in the treatment of some difficult-to-treat tumors. For instance, in one study of adult-onset neuroblastoma, targeting ALK mutations in ALK-positive tumors demonstrated activity, even in patients who had not responded to their first ALK inhibitor. Of all the ALK inhibitors tested in this small series of patients, lorlatinib achieved the best results. These findings of a retrospective review of experience with adult-onset neuroblastoma at Memorial Sloan Kettering Cancer Center (MSK) were presented at the 2021 ASCO Annual Meeting.1
“ALK-targeted therapy appears to be a safe and effective option for adult-onset neuroblastoma and should be considered when making this diagnosis.”— Jessica Stiefel, MD
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“Adult-onset neuroblastoma is a rare cancer that is difficult to treat. Treatment is challenging because patients generally cannot tolerate the chemotherapy regimens used on children. ALK is an appealing drug target, and the use of an ALK inhibitor may be a well-tolerated option for these patients, improving response and time to disease progression. Our experience shows that development of resistance to one ALK inhibitor does not preclude the use of other agents within the same drug class. Overall, ALK-targeted therapy appears to be a safe and effective option for adult-onset neuroblastoma and should be considered when making this diagnosis,” said lead author Jessica Stiefel, MD, a pediatric hematologist/oncologist affiliated with MSK.
Neuroblastoma typically occurs in children, with a median onset at age 5, and is usually treated with chemotherapy and radiation. Adult-onset neuroblastoma is a rare disease that is biologically distinct from childhood neuroblastoma. Adults tend to be intolerant to the chemotherapy regimens used in children.
“Adult-onset neuroblastoma is metastatic, chemotherapy-resistant, and almost invariably fatal,” Dr. Stiefel explained. In the era of precision medicine, “the presence of ALK mutations in adult-onset neuroblastoma provides an opportunity for targeted therapy for a disease that is otherwise very challenging to treat,” she continued.
Over the past decade, a variety of ALK inhibitors have been developed for the treatment of ALK-mutated cancers, most notably lung cancer and lymphoma. Based on experience with ALK inhibitors in other ALK-positive tumors, Dr. Stiefel and colleagues reviewed the experience at MSK with ALK inhibitors in ALK-positive adult-onset neuroblastoma.
The retrospective review showed that 52 patients with adult-onset neuroblastoma were seen at MSK between 1979 and 2020. Between 2014 and 2020, review of electronic health records identified 23 patients with adult-onset neuroblastoma who were genetically sequenced; 14 (61%) were found to harbor ALK somatic mutations. Of the 14, 7 were treated with one or more U.S. Food and Drug Administration–approved ALK inhibitors, and these patients were the focus of Dr. Stiefel’s review. Response to ALK inhibitors was evaluated using the international neuroblastoma response criteria.
One patient was diagnosed with neuroblastoma as a teenager, and the other six had an onset at ages ranging from 28 to 68. Patients were treated with one to four prior regimens. Most had metastatic disease at diagnosis, and all had ALK mutations.
“Most of the patients had measurable disease at ALK inhibitor initiation and had received prior multimodality treatment including surgery, chemotherapy, and radiation,” stated Dr. Stiefel.
Overall, ALK inhibition was reported to be well tolerated, with a variety of effects. Dizziness, drowsiness, and hallucinations were reported in one patient each, and these effects resolved when the drug was stopped. Grade 1 nausea and vomiting were reported in six patients. Adverse events led to treatment discontinuation in four patients taking the kinase inhibitors crizotinib and alectinib.
“Lorlatinib was the best tolerated ALK inhibitor,” noted Dr. Stiefel. “No patient on lorlatinib required discontinuation due to adverse events, and one required a dose reduction.”
Median time to disease progression was 15.5 months. Median overall survival was 46.5 months (range, 17–74 months).
Initially, all seven patients responded to ALK inhibitors, but six discontinued therapy due to progressive disease or adverse events (three each). One responder is still in ongoing treatment and had positron-emission tomography–negative disease at 20.5 months after treatment initiation. Four patients treated with more than one ALK inhibitor were in ongoing response, and all were ultimately on lorlatinib after disease progression on other ALK inhibitors. Two patients had stable disease.
DISCLOSURE: Dr. Stiefel reported no conflicts of interest.
1. Stiefel J, Kushner BH, Basu EM, et al: ALK inhibitors for treatment of adult-onset neuroblastoma. 2021 ASCO Annual Meeting. Abstract 2001. Presented June 7, 2021.
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