of death compared to those who received standard chemotherapy during the course of the clinical study (409). Quizartinib can cause several cardiac adverse effects and is therefore available only through a restricted program. At the same time that the FDA made the decision about quizartinib, it expanded the use of the LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic to identify patients with FLT3 ITD mutation–positive AML who are eligible for treatment with the new molecularly targeted therapeutic. Myeloid/lymphoid neoplasm (MLN) with fibroblast growth factor receptor 1 (FGFR1) rearrangement is a rare, aggressive disease characterized by higher-than-normal levels of certain white blood cells. MLNs do not respond well to standard chemotherapy and can rapidly progress to AML (410). FGFR1 is a cell surface protein that stimulates cellular proliferation upon binding with specific extracellular molecules. In rare instances, the FGFR1 gene fuses with another gene (an alteration known as a genetic rearrangement) resulting in a fusion protein that drives the development of MLNs. Pemigatinib (Pemazyre) inhibits the function of FGFR1 to suppress the growth of FGFR1-driven cancers (410) and in August 2022, it was approved by FDA for adults with MLNs with FGFR1 rearrangement who have not responded to or have relapsed after other treatments. The approval was based on results from a phase II clinical trial that showed that 79 percent of patients had a complete response to pemigatinib. Therefore, the FDA approval of pemigatinib for adult patients with relapsed or refractory MLNs with FGFR1 alteration is a major milestone for the treatment of patients who are diagnosed with the disease. Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed blood cancer in the United States. In 2023, 77,240 people in the United States are expected to be newly diagnosed with the disease (28). Notably, NHL encompasses many different types of cancer, most of which arise in immune cells called B cells. Two molecularly targeted therapeutics, recently approved by FDA for treating different subtypes of NHL arising in B cells— pirtobrutinib (Jaypirca) and zanubrutinib (Brukinsa)—target a protein called Bruton tyrosine kinase (BTK). BTK was first identified in 1993. Since its discovery, the role of BTK has been studied extensively in blood cancers and inflammatory diseases. Researchers have found that BTK is a key component of a signaling pathway that promotes the survival and expansion of NHL B cells. Consequently, BTK inhibitors have revolutionized the treatment of NHL arising in B-cells, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL) as well as certain inflammatory diseases (411). Ibrutinib was the first BTK inhibitor approved by FDA. The approval, in 2013, was for the treatment of patients with relapsed and refractory mantle cell lymphoma (MCL). While the approval of ibrutinib was a major milestone in personalized treatment for B-cell cancers, researchers soon discovered that in patients on continuous treatment with BTK-targeted therapy, cancer cells can acquire mutations in the BTK gene that render the therapeutic ineffective. Since then, newer and more sophisticated BTK inhibitors with improved specificities and thus reduced toxicities have been developed to mitigate the challenge of acquired resistance (see Sidebar 35, p. 87). Pirtobrutinib (Jaypirca) is a new BTK targeted therapeutic that FDA approved in January 2023 for treating MCL. The agent was approved for patients with relapsed or refractory MCL that has not responded to or has relapsed after another treatment, including a BTK inhibitor. Pirtobrutinib has a unique mechanism of action that makes it effective even against mutated forms of BTK that are resistant to other BTK-targeted therapeutics (412). The approval of pirtobrutinib was based on results from a phase I/II clinical trial, which showed that 50 percent of MCL patients treated with the molecularly targeted therapeutic had tumor shrinkage, with 13 percent having their tumors disappear. Zanubrutinib, another BTK-targeted therapeutic, was approved for treating patients with MCL in November 2019 (413). In January 2023, FDA approved zanubrutinib for treating adults who have CLL or SLL, which are slow-growing types of NHL. CLL and SLL are essentially the same disease but have different names depending on where in the body the NHL cells accumulate. CLL cells are found mostly in the blood and bone marrow, whereas SLL cells are found mostly in the lymph nodes. The approval of zanubrutinib to treat CLL and SLL was based on results from two phase III clinical trials. The first trial which evaluated the efficacy of zanubrutinib in previously untreated patients with CLL/SLL showed that patients who received zanubrutinib lived a longer time without their cancer worsening compared with patients who received standard treatments. In the second trial, which compared zanubrutinib to ibrutinib in CLL/SLL patients whose disease did not respond to or came back after prior treatments, a greater percentage of patients receiving zanubrutinib were alive during the course of the study with no growth of their cancer, compared to patients taking ibrutinib (414). FDA APPROVALS OF BTK INHIBITORS FOR RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA 2013 ibrutinib 2017 acalabrutinib 2019 zanubrutinib 2023 pirtobrutinib continued on page 98 Advancing the Frontiers of Cancer Science and Medicine AACR Cancer Progress Report 2023 95
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