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Crizotinib effectively targets ALK pathway in pediatric cancers
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Crizotinib induced robust and sustained clinical responses in children with relapsed anaplastic large cell lymphoma and metastatic or unresectable inflammatory myofibroblastic tumors, according to a Children’s Oncology Group study.
These results highlight the role the ALK pathway plays in these rare diseases.
Patients with ALK-driven anaplastic large cell lymphoma and inflammatory myofibroblastic tumors have no known curative treatment options.
“Current clinical trial approaches in rare diseases are challenging,” Yael P. Mossé, MD, attending physician at Children’s Hospital of Philadelphia Cancer Center, and colleagues wrote. “Increased attention is being placed on the development of targeted agents for patients with cancers that share a molecular etiology to expedite clinical testing of potentially active drugs for rare indications.”
In a phase 1 dose-escalation trial, researchers evaluated crizotinib (Xalkori; Pfizer, EMD Serono) — an ALK-ROS1-MET small molecule inhibitor — for children with relapsed or refractory cancer. The agent appeared well tolerated at a recommended phase 2 dose of 280 mg/m², which is nearly twice the adult standard dose.
The researchers expanded phase 2 cohorts to include ALK-driven anaplastic large cell lymphoma and inflammatory myofibroblastic tumors.
The current analysis evaluates outcomes from 26 children with relapsed/refractory ALK-positive anaplastic large cell lymphoma — 20 of whom received the 280-mg/m2 dose — and 14 patients with metastatic or inoperable ALK-positive inflammatory myofibroblastic tumors, 12 of whom received the 280-mg/m2 dose.
Patients with anaplastic large cell lymphoma who received the recommended phase 2 dose demonstrated the highest overall responses rate (90%; 95% CI, 68-99), followed by patients with inflammatory myofibroblastic tumors (86%; 95% CI, 57-98), and patients with anaplastic large cell lymphoma who received 165 mg/m² (83%; 95% CI, 36-99.6).
Five patients (83%) with anaplastic large cell lymphoma who received the 165 mg/m² dose, 16 patients (80%) with anaplastic large cell lymphoma who received the recommended phase 2 dose and five patients (36%) with inflammatory myofibroblastic tumors achieved complete responses.
No patient with anaplastic large cell lymphoma who received 165 mg/m² achieved a partial response; however, two patients (10%) with anaplastic large cell lymphoma who received the recommended phase 2 dose and seven patients (50%) with inflammatory myofibroblastic tumors achieved partial responses.
Patients with anaplastic large cell lymphoma treated with 165 mg/m² received therapy for the longest duration (2.79 months; 95% CI, 0.31-not available), followed by patients with inflammatory myofibroblastic tumors (1.63 months; 95% CI, 0.55-2.3), and patients with anaplastic large cell lymphoma who received the recommended phase 2 dose (0.4 months; 95% CI, 0.18-1).
Twelve patients ceased protocol therapy to proceed to transplantation.
Levels of NPM-ALK decreased during therapy in most patients with anaplastic large cell lymphoma.
Decreased neutrophil counts presented as the most common grade 3 or grade 4 adverse events.
“The robust and sustained clinical responses to crizotinib in patients with relapsed or refractory ALK-driven anaplastic large cell lymphoma and inflammatory myofibroblastic tumors highlight the importance of this oncogene and the sensitivity to ALK inhibition in these diseases,” the researchers wrote. – by Kristie L. Kahl
Disclosures: Mossé reports research funding from Novartis. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
Back to TopStacey Zahler
This study of crizotinib activity against both ALK-positive anaplastic large cell lymphoma and inflammatory myofibroblastic tumors is the first to show such significant responses in a cohort of pediatric patients. Although the drug is FDA approved for non-small cell lung cancer, this study shows that other ALK-driven malignancies have rapid and profound response rates to crizotinib monotherapy. In both disease states, crizotinib appeared well tolerated overall with few grade 3 to grade 4 toxicities, and most patients achieved a partial or complete response by the end of the first month of therapy. Additionally, patients sustained response over a prolonged period of time. As the authors allude to, it will be important to look at long-term patient outcomes after stopping crizotinib therapy.
In an era where there is considerable effort to discover effective targeted therapies, these data are absolutely relevant and of high importance for pediatric cancer. Especially in a disease such as inflammatory myofibroblastic tumor — which is known to be chemotherapy resistant and is largely a surgical disease — crizotinib therapy could change the landscape of how we treat patients who have unresectable disease. Similarly, patients with relapsed/refractory anaplastic large cell lymphoma clearly benefit from an ALK-inhibiting agent.
It will be interesting to hear the results of an open COG trial that combines the intermediate dose of crizotinib with conventional chemotherapy for patients with newly diagnosed ALK-positive anaplastic large cell lymphoma. It will be important to know whether response rates are improved with upfront combination chemoimmunotherapy compared with chemotherapy alone.
It is impressive and exciting to see such robust responses from patients who have difficult-to-treat diseases. The goal of all our research on targeted therapies in cancer is to improve survival and achieve cure for these patients. Based on this data, we are certainly closer to doing just that.
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