Pulmonary Toxicity Associated With Concurrent Lorlatinib and Anti-GD2 Monoclonal Antibody Therapy in Patients With Neuroblastoma.
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BACKGROUND: The anaplastic lymphoma kinase (ALK) inhibitor lorlatinib demonstrated safety without pulmonary toxicity in early-phase trials in patients with neuroblastoma. Lorlatinib is being tested with chemotherapy and immunotherapy in the Children's Oncology Group study ANBL1531. However, pulmonary toxicity was noted in patients receiving lorlatinib concurrently with anti-disialoganglioside 2 (GD2) monoclonal antibody (mAb) dinutuximab on the trial. METHODS: After IRB approval, we performed a retrospective review on patients with neuroblastoma treated with lorlatinib and anti-GD2 mAbs from 9/2020 to 11/2024. Before 11/2023, lorlatinib was given concurrently with anti-GD2 mAbs; after 11/2023, it was withheld during mAb immunotherapy. RESULTS: Twenty-nine patients received lorlatinib with naxitamab (n = 12), dinutuximab (n = 11), or both (n = 6). Eight, 8, and 13 patients received lorlatinib with chemoimmunotherapy, mAbs, and both, respectively. Twenty of the 29 patients were treated with a total of 160 cycles before 11/2023, and 4 developed ≥grade 3 pulmonary toxicity. Severe respiratory failure with hemodynamic instability and the need for mechanical ventilation and extracorporeal membrane oxygenation occurred in two patients. The other two patients experienced hypoxia, wheezing, or cough, both managed with supportive care. All four recovered to <grade 3 toxicity. Three continued with lorlatinib alone or between cycles of mAbs without further >grade 2 pulmonary toxicities. Fifteen of the 29 patients were treated with 64 combined cycles after 11/2023, but none developed ≥grade 3 pulmonary toxicity. CONCLUSIONS: Concurrent use of lorlatinib with anti-GD2 mAbs may be associated with severe pulmonary toxicities. Temporarily withholding lorlatinib during immunotherapy appeared to mitigate this risk.