FDA Approves Crizotinib for Pediatric and Young Adult ALK+ Anaplastic Large Cell Lymphoma

The FDA has approved crizotinib (Xalkori) for the treatment of pediatric patients 1 year of age and older and young adults with ALK-positive relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL).¹

The regulatory decision was based on data from Study ADVL0912 (NCT00939770), which showed encouraging antitumor activity with crizotinib in pediatric and adult patients with relapsed/refractory ALCL.²

“We are proud to deliver the first biomarker-driven therapy for children and young adults with ALCL. [Crizotinib] offers a meaningful new treatment option for young patients with relapsed or refractory ALK-positive ALCL,” Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, stated in a press release. “[Crizotinib] transformed the treatment of ALK-positive non-small cell lung cancer as the first biomarker-driven therapy for that disease, and this approval is a notable milestone in our journey to continue to follow the science to address cancers with significant unmet need.”

In the open-label, multicenter, single-arm phase 1/2 Study ADVL0912, investigators evaluated the toxicities and optimal dose of crizotinib in younger patients with solid tumors or ALCL that has relapsed after a period of improvement or has not responded to treatment.³

The primary end points of this trial focused on identifying the maximum-tolerated dose of the agent, as well as determining the recommended phase 2 dose. Investigators also set out to characterize the pharmacokinetics of crizotinib in pediatric patients with refractory disease.⁴ Key secondary end points were to define the antitumor activity of the drug in the phase 1 portion of the research, to evaluate the relationship between ALK positivity crizotinib response, the relationship between minimal residual disease status and response, to understand the palatability of the oral formulation of the agent, and to assess potential alterations in bone growth in the patient population.

A total of 121 patients were enrolled to the trial; this included 26 pediatric patients with relapsed/refractory, systemic ALK-positive ALCL who had previously received at least 1 systemic treatment. Patients who received crizotinib experienced an ORR of 88%. Of the 23 patients who achieved a response to treatment, 39% continued to respond for at least 6 months, while 22% continued to respond for at least 12 months.

Regarding safety, the toxicity profile of the agent in children and young adults with ALK-positive ALCL proved to be comparable to its use in those with ALK-positive and ROS1-positive non–small cell lung cancer. The most frequently reported toxicities included diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough and pruritis.

Additionally, the most common adverse effect determined to be grade 3 or higher in severity comprised neutropenia, lymphopenia and thrombocytopenia. Sixty-two percent of patients experienced grade 4 neutropenia, while 35% reported grade 4 lymphopenia, and 19% experienced grade 4 thrombocytopenia. Just under half of all study participants, or 46%, experienced visual disorders with crizotinib; 65% of those with ALCL reported this toxicity.

“Crizotinib represents an exciting new development in the treatment of this disease,” Meghan Gutierrez, chief executive officer at the Lymphoma Research Foundation, added in the release. “Researchers have made significant progress in our understanding of ALCL, which we hope will continue to improve treatment strategies and the options for children with ALCL. Today’s news builds upon this progress and provides hope to pediatric patients with ALCL and their loved ones.”

References

1. Pfizer's Xalkori (crizotinib) approved by FDA for ALK-positive anaplastic large cell lymphoma in children and young adults. News release. Pfizer Inc. January 14, 2021. Accessed January 14, 2021. http://bit.ly/35YmdaL.
2. FDA accepts supplemental new drug application for Pfizer’s Xalkori (crizotinib) for the treatment of pediatric ALK-positive anaplastic large cell lymphoma. News release. Pfizer Inc. January 14, 2021. Accessed September 23, 2020. https://bit.ly/2RRX75J.
3. Gambacorti-Passerini C, Orlov S, Zhang L, et al. Long-term effects of crizotinib in ALK-positive tumors (excluding NSCLC): a phase 1b open-label study. Am J Hematol. 2018;93:607-614. doi:10.1002/ajh.25043
4. Crizotinib in treating younger patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. ClinicalTrials.gov. Updated June 9, 2020. Accessed September 23, 2020. https://clinicaltrials.gov/ct2/show/NCT00939770.
5. Mossé YP, Voss SD, Lim MS, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children's Oncology Group study. J Clin Oncol. 2017;35(28):3215-3221. doi:10.1200/JCO.2017.73.4830