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Crizotinib—New Standard of Care in Inflammatory Myofibroblastic Tumors?

Authors:

Katrina Mountfort, Medical Writer, Touch Medical Media, UK
Tim Sheldrick, Account Director and Advisory Editor, Touch Medical Media, UK

    Insights into crizotinib research for inflammatory myofibroblastic tumors presented at American Association for Cancer Research Annual Meeting, Chicago, IL, US, April 14–18 2018.

    Inflammatory myofibroblastic tumors (IMTs) are a group of rare soft tissue sarcomas that occur mostly in children and adolescents, and are generally found in the abdomen, lung, and retroperitoneum.1 They are usually benign tumors made up of cells called myofibroblastic spindle cells. They may be asymptomatic; may be associated with nonspecific respiratory symptoms, fever, or pain; and can lead to organ dysfunction, and death. IMTs may recur and become locally invasive and/or metastasize to other parts of the body. The management of these tumors can be challenging because there are no established treatment protocols; they are normally removed surgically but complete resection is often not possible because of the proximity of the tumors to vital organs.2

    Approximately half of IMTs express anaplastic lymphoma kinase (ALK) protein,2,3 making ALK inhibition a promising therapeutic approach. Four tyrosine kinase inhibitors—crizotinib (Xalkori®, Pfizer, New York, NY, US), ceritinib (Zykadia®, Novartis, Basel, Switzerland), alectinib (Alcensa, Roche, Basel, Switzerland), and brigatinib (Alunbrig®, Takeda, Osaka, Japan)—are currently approved for ALK-positive non-small-cell lung cancer (NSCLC) and several others are in clinical development.4 A number of studies have suggested that crizotinib may be also beneficial in IMTs.5–7 As a result, the National Comprehensive Cancer Network recommends the off-label use of crizotinib as a treatment for ALK-positive IMTs.8

    Data from the EORTC 90101 clinical trial, which was presented at the American Association for Cancer Research (AACR) Meeting, on April 14–18, 2018, and simultaneously published in Lancet Respiratory Medicine,9 has shown that crizotinib is a safe and effective treatment option for patients with IMTs. The phase II single-arm study recruited 35 primarily adult patients (age range 15–78 years) from eight European countries across 13 sites. All had with locally confirmed advanced or metastatic IMTs. Of these, 20 were confirmed centrally to have IMTs and received crizotinib 250 mg twice daily. The trial included patients both ALK-positive and ALK-negative IMTs, the latter comprising a nonrandomized, nonhistorical, internal control. However, the small number of patients with ALK-negative tumors did not provide adequate statistical power to compare treatment effects across the two groups.

    Among the 12 evaluable patients with ALK-positive IMTs who received crizotinib, the primary endpoint, objective response rate (ORR), was 50%, including two complete responses, four partial responses, and stable disease in five patients. Among the seven evaluable patients with ALK-negative IMTs, the ORR was 14.3%. The disease control rate was 100% in patients with ALK-positive IMTs, and 85% in those with ALK-negative tumors. At data cut-off, on November 9, 2017, the median duration of response among the patients with ALK-positive IMTs was 9.0 months. Of these, four patients are still responding and are continuing to receive treatment. The 1-year progression-free survival (PFS) rate was 73.3% and the 2-year PFS rate was 48.9%. Both the 1-year and 2-year overall survival rates were 81.8%.9 The benefits in patients with ALK-IMTs can be explained by the fact that ALK positivity was defined in the study as at least 15% of tumor cells showing an ALK rearrangement on fluorescence in situ hybridization and/or immunohistochemistry. This may have misclassified some patients with ALK-negative disease. Another possibility is that some ALK-negative IMTs are driven by rearrangement of the ROS1 gene,10 which is also targeted by crizotinib.

    Toxicities were as expected for crizotinib; the most common treatment-related adverse events were nausea (55%), fatigue (45%), blurred vision (45%), vomiting (35%), and diarrhea (35%). There were eight serious adverse events in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation. Only one patient discontinued treatment due to toxicity.

    The trial is limited by the fact that it is a noncomparative, single-arm study with a small number of patients. However, given the rarity of the disease, a more definitive, randomized, comparative trial is not feasible.11

    In a press release, lead investigator Patrick Schöffski, MD, MPH, of Leuven Cancer Institute at University Hospitals Leuven, said: “Our data in predominantly adult patients with IMTs, combined with recently published data for children with this disease suggest that crizotinib should be considered the standard-of-care for patients with ALK-positive IMT who cannot be treated with surgery.”11

    Together with data from the recent Children’s Oncology Group study, in which crizotinib showed a response rate of 86% in 14 pediatric patients with metastatic or inoperable ALK-positive IMTs,12 as well as the PROFILE 1013 study, which investigated crizotinib in ALK-positive advanced malignancies other than NSCLC and found a response rate of 67% in nine patients with IMTs, including one complete response,13 a growing body of evidence supports Schöffski’s statement, and it seems likely that crizotinib will become the standard of care in this patient population.

    The success of crizotinib in IMTs is one of several emerging new indications for the drug. A number of recent studies have shown that crizotinib is beneficial to patients with ALK-positive lymphomas,12,13 which have led to its breakthrough designation by the US Food and Drug Administration for the treatment of patients with ALK-positive relapsed or refractory systemic anaplastic large cell lymphoma.14 In addition, preclinical data suggest potential benefits in breast cancer.15 These studies open the door to new research investigating new patient populations whose tumors carry genomic alterations and may benefit from molecularly targeted therapies.

    References

    1. Coffin CM, Watterson J, Priest JR, et al. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19:859–72.
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    11. AACR. Crizotinib Yielded a High Objective Response Rate for Adult Patients With ALK-positive Inflammatory Myofibroblastic Tumor. Available at: www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1173#.Wy4cXKdKiUk (accessed June 20, 2018).
    12. Mosse 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;35:3215–21.
    13. 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;93:607–14.
    14. Pfizer. Pfizer’s XALKORI® (crizotinib) Receives FDA Breakthrough Therapy Designation in Two New Indications. Available at: http://press.pfizer.com/press-release/pfizers-xalkori-crizotinib-receives-fda-breakthrough-therapy-designation-two-new-indic (accessed June 20, 2018).
    15. Bajrami I, Marlow R, van de Ven M, et al. E-cadherin/ROS1 inhibitor synthetic lethality in breast cancer. Cancer Discov. 2018;8:498–515.

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