FDA Grants Priority Review to Crizotinib for Pediatric ALK+ Anaplastic Large Cell Lymphoma


The FDA has granted a priority review to a supplemental new drug application for crizotinib in the treatment of pediatric patients with ALK-positive relapsed/refractory systemic anaplastic large cell lymphoma.

The FDA has granted a priority review to a supplemental new drug application (sNDA) for crizotinib (Xalkori) in the treatment of pediatric patients with ALK-positive relapsed/refractory systemic anaplastic large cell lymphoma (ALCL), according to an announcement from Pfizer, Inc.1

The sNDA is based on data from 2 trials: Study A8081013 (NCT01121588) and Study ADVL0912 (NCT00939770), which demonstrated encouraging antitumor activity with crizotinib in pediatric and adult patients with relapsed/refractory ALCL.

Under the Prescription Drug User Fee Act, the FDA must make a decision on the sNDA by January 2021. If approved, crizotinib would represent the first biomarker-driven agent for this type of pediatric lymphoma, according to the biopharmaceutical company.

“Today’s FDA filing exemplifies Pfizer’s commitment to broadening the use of biomarker-driven therapies in areas with significant needs, such as rare, pediatric cancers,” Chris Boshoff, MD, PhD, chief development officer of Oncology, Pfizer Global Product Development, stated in a press release. “Given [crizotinib’s] proven efficacy in ALK-positive lung cancer and activity seen in clinical trials investigating relapsed or refractory ALK- and ROS1-positive ALCL, if approved, [the agent] could represent an important step toward improving outcomes for children with this type of cancer.”

In Study A8081013, investigators set out to evaluate crizotinib at a continuous dose of 250 mg twice daily in patients with ALK-positive advanced malignancies beyond non–small cell lung cancer (NSCLC).

The primary end points of the trial include safety and overall response rate (ORR).2 Secondary end points are comprised of duration of response, plasma concentrations of the drug, overall survival, proportion of patients with each of the ALK genetic events, progression-free survival (PFS), and phosphorylation status of ALK in the tumor samples from surgery or biopsy before or after treatment.

A total of 44 patients were enrolled in the study; of these patients, 18 had lymphoma, 9 had inflammatory myofibroblastic tumors, and 17 had other tumors. Of the patients with lymphoma, 8 achieved complete responses (CRs) with the treatment, while 1 achieved a partial response (PR). The 2-year PFS rate with crizotinib in this subset was 63%.

With regard to safety, the most commonly experienced all-grade toxicities reported with crizotinib were diarrhea (45.5%) and vision disorders (45.5%).

In the phase 1/2 Study ADVL0912, investigators examined the toxicities and best dose of crizotinib in younger patients with solid tumors or ALCL that has relapsed following a period of improvement or has not responded to treatment.3

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

This trial enrolled a total of 26 pediatric patients with relapsed/refractory ALK-positive ALCL and 14 pediatric patients with metastatic or inoperable ALK-positive inflammatory myofibroblastic tumor. Those with ALCL were given crizotinib at doses of either 165 mg/m2 or 280 mg/m2.5

Results showed that those who received the agent at 165 mg/m2 experienced an ORR of 83%, with 5 of 6 patients achieving a CR; those who received the higher 280 mg/m2 dose experienced a higher ORR of 90%, with 16 of 20 patients achieving a CR and 2 reporting a PR.

Regarding safety, the most commonly reported adverse effect reported with crizotinib in the ALCL subgroups was decreased neutrophil count; this was reported in 33% of those who received the lower dose and 70% of those who were given the higher dose.

“Children with cancer and their families have been desperate for new and innovative medicines. We applaud Pfizer’s commitment to drug discovery and development to help address childhood cancers and continue to work together on behalf of patients with these cancers,” George Dahlman, chief executive officer of Children’s Cancer Cause, added in the release. “We look forward to potentially having a new biomarker-driven therapy for children with relapsed or refractory ALK-positive ALCL that may help improve these children’s lives.”

In May 2018, crizotinib was granted a breakthrough therapy designation from the FDA for the treatment of patients with relapsed/refractory ALK-positive ALCL. The agency also granted the designation to the kinase inhibitor for use in patients with NSCLC with MET exon 14 alterations who progress after receiving platinum-based chemotherapy.


  1. 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. September 23, 2020. Accessed September 23, 2020.
  2. An investigational drug, crizotinib (PF-02341066), is being studied in tumors, except non–small cell lung cancer, that are positive for anaplastic lymphoma kinase (ALK). Updated March 4, 2020. Accessed September 23, 2020.
  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. Updated June 9, 2020. Accessed September 23, 2020.
  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

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