Safety and Clinical Activity Of Crizotinib In Patients With ALK-Rearranged Hematologic Malignancies

Crizotinib (Xalkori®) is an ALK inhibitor with proven efficacy in patients with ALK-rearranged advanced non-small cell lung cancer (NSCLC; Shaw AT et al, New Engl J Med 2013;368:2385–9). However, ALK rearrangement is implicated in other types of malignancy, including anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Here we assess the safety and anti-tumor activity of crizotinib in patients with advanced ALK-rearranged hematologic malignancies enrolled in an open-label phase 1b study (Pfizer; A8081013; NCT01121588).

ALK-positivity was confirmed by IHC for cases of ALCL; other malignancies required confirmation by FISH, PCR, or sequencing. Patients with brain metastases were eligible if neurologically stable for 2 weeks with no ongoing treatment requirement. Eligible patients received crizotinib 250 mg twice daily. Responses were assessed every 6 weeks using RECIST v1.1 or Revised Response Criteria for Malignant Lymphoma 2007 (Cheson criteria); best overall response was determined by RECIST or Cheson if only one assessment was available, and by Cheson criteria if both were available. Adverse events (AEs) were assessed using CTCAE v4.0.

Fifteen patients with advanced ALK-positive hematologic malignancies were enrolled; 14 with ALK-positive ALCL and one with ALK-positive DLBCL. At the data cutoff date of July 15, 2013, treatment was ongoing in 10 patients, and there were five discontinuations (1 due to early death, 1 due to global deterioration of health and 3 due to disease progression). Nine patients (60%) were male, and the median age was 25 years (range 15–37 years). Most patients were white (60%), with the remainder Asian. Two patients (13%) received prior radiation therapy. All patients received prior systemic therapy (median 2 lines [range 1–6]). ECOG performance status (ECOG PS) at baseline was 0 for 3 patients (20%), 1 for 7 patients (47%), 2 for 4 patients (27%), and 3 for 1 patient (7%). Median duration of treatment was 33 weeks (range 0.1–117 weeks). There were 9 confirmed responses (5 complete response [CR] and 4 partial response [PR]), for an objective response rate (ORR) of 60%. Additionally, 1 patient experienced stable disease (SD) of >12 months. Overall, the clinical benefit rate (CBR; CR + PR + SD) was 67%. AEs (all causality) were reported for all 15 patients and were predominantly of grade 1 or 2. The most common AEs were diarrhea (47% of patients), vomiting (47%, including 1 grade 3 event), visual impairment (40%), asthenia (27%), cough (27%), and neutropenia (27%, including 2 grade 3 events). Four patients experienced grade 4 events (abdominal pain, increased creatinine phosphokinase, lymphopenia, and multi-organ failure), and one of these patients also experienced a grade 5 event (central nervous system hemorrhage).

Crizotinib showed anti-tumor activity in advanced ALK-rearranged hematologic tumors. The high ORR (60%) and CBR (67%) with crizotinib in this cohort is consistent with the high response rates seen with crizotinib in ALK-rearranged advanced NSCLC, and the safety profile of crizotinib was also similar to previous clinical experience with crizotinib. These data suggest that ALK inhibition can be effective in patients with ALK-positive hematologic malignancy and further investigation may be warranted in this setting.

Gambacorti-Passerini:Pfizer: Research Funding. Off Label Use: Crizotinib is an ALK inhibitor which is indicated for use in ALK-positive advanced NSCLC. This study investigates the use of crizotinib in patients with ALK-positive malignancies other than NSCLC. Braiteh:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Pfizer: Research Funding. Taylor:1. Bayer HealthCare Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees; 1. Bayer HealthCare Pharmaceuticals, Inc.: Honoraria. Brega:Pfizer: Equity Ownership; Pfizer: Employment. Paolini:Pfizer: Equity Ownership; Pfizer: Employment. Selaru:Pfizer: Equity Ownership; Pfizer: Employment.