FDA Grants Crizotinib Breakthrough Designation for MET+ NSCLC and ALK+ ALCL


The FDA has granted crizotinib a breakthrough therapy designation for the treatment of patients with metastatic non–small cell lung cancer with MET exon 14 alterations, and for use in patients with relapsed/refractory ALK+ anaplastic large cell lymphoma.

Mace Rothenberg, MD

The FDA has granted crizotinib (Xalkori) a breakthrough therapy designation for the treatment of patients with metastatic non—small cell lung cancer (NSCLC) with MET exon 14 alterations who progress after receiving platinum-based chemotherapy. The agency also granted the designation to the kinase inhibitor for use in patients with relapsed/refractory ALK+ anaplastic large cell lymphoma (ALCL).

The breakthrough designation will expedite the development and review of crizotinib in these settings. The kinase inhibitor is currently approved by the FDA for the treatment of patients with ALK- or ROS1-positive metastatic NSCLC.

“Biomarker-driven therapies have changed the way we treat cancer, helping to ensure that patients receive the right medicine for their disease,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

“These breakthrough therapy designations for Xalkori exemplify our commitment to precision medicine development and delivering medicines that have the potential to transform the lives of patients whose cancers carry these genomic alterations.”

The breakthrough designation for MET-positive NSCLC is based on an expansion cohort from the phase I PROFILE 1001 study (NCT00585195).1 The cohort included 21 patients with MET exon 14—altered NSCLC who had been treated with crizotinib at a starting dose of 250 mg twice daily. The median age was 68 years (range, 53-87). Sixty-two percent of the patients were former smokers and 32% were never smokers. Sixteen patients had adenocarcinoma, 3 patients had sarcomatoid carcinoma, 1 had adenosquamous carcinoma, and 1 had squamous cell carcinoma. Three patients were treatment-naïve, 12 had received one prior line of therapy, and 6 had received ≥2 prior lines of therapy.

Among 18 evaluable patients, there were 8 (44%) partial responses and 9 (50%) cases of stable disease. No patients had progressive disease.

The majority of drug-related adverse events (AEs) were grade 1/2. There was 1 case of grade 3 edema and 1 case of grade 3 bradycardia. No grade 4 AEs occurred.

“Crizotinib has clinically meaningful antitumor activity in patients whose lung cancers harbor MET exon 14 alterations,” lead investigator Alexander Drilon, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said when presenting the findings at the 2016 ASCO Annual Meeting.

The breakthrough designation for ALCL was based on 2 trials. The first was the multicenter, single-arm, open-label phase Ib Study A8081013 (NCT01121588), which examined crizotinib at 250 mg twice daily in patients with ALK-positive advanced malignancies other than NSCLC.2

The study included 44 patients, comprising 18 with lymphoma, 9 with inflammatory myofibroblastic tumors (IMTs), and 17 with other tumors. Among patients with lymphoma, there were 8 complete responses and 1 partial response. The 2-year progression-free survival rate was 63% in the lymphoma group.

Across the population, the most common all-grade AEs related to treatment were diarrhea (45.5%) and vision disorders (45.5%).

The second study, which was conducted by the Children’s Oncology Group, was Study ADVL0912 (NCT00939770).3 The trial examined crizotinib in 26 pediatric patients with relapsed/refractory ALK-positive ALCL and 14 pediatric patients with metastatic or inoperable ALK-positive IMT.

Patients with ALCL received crizotinib at doses of 165 mg/m2 or 280 mg/m2. The ORRs in these 2 treatment arms were 83% (5 of 6 patients had a complete response) and 90% (16 of 20 patients had a complete response and 2 had a partial response), respectively.

The most frequently reported all-grade AE in the ALCL groups was a decrease in neutrophil count, which occurred in 33% of patients receiving the lower dose and 70% of patients receiving the higher dose.


  1. Drilon AE, Camidge DR, Ou S-H, et al. Efficacy and safety of crizotinib in patients (PTS) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol 2016 34:15_suppl, 108-108.
  2. 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.
  3. 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 Oct 1;35(28):3215-3221. doi: 10.1200/JCO.2017.73.4830.
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