The first time FDA approved the use of two molecularly targeted therapeutics as a combination treatment for cancer was in January 2014 (67). The approval was for the use of dabrafenib (Tafinlar) and trametinib (Mekinist) for treating patients with metastatic melanoma that tests positive for activating BRAF V600E and BRAF V600K mutations. The two therapeutics target different components of the BRAF signaling pathway. Dabrafenib targets altered BRAF proteins containing V600 mutations, while trametinib targets MEK1 and MEK2, which are two proteins that mediate the function of BRAF. By blocking both BRAF and MEK, the combination therapy can more completely and effectively shut down the signaling pathway. The combination was approved after it was shown to almost double the length of time before disease progression compared with dabrafenib alone (403). In March 2023, the same combination of molecularly targeted therapeutics was approved for pediatric patients one year of age and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of dabrafenib and trametinib for pediatric patients who are unable to swallow pills. Brain and other nervous system tumors are the second most diagnosed cancers in children. Low-grade glioma is the most common type of pediatric brain cancer. Research has demonstrated that BRAF signaling pathway activation is common in pediatric low-grade gliomas. Therefore, the March approval of dabrafenib and trametinib combination therapy brings hope to many parents and families whose children are diagnosed with the disease. FDA approved the combination therapy based on data from a clinical trial showing that a significantly higher percentage of patients who received dabrafenib and trametinib had their tumors shrink compared to those who received the standard of care chemotherapy (47 percent vs. 11 percent, respectively) (404). Patients treated with dabrafenib and trametinib also had a 69 percent lower risk of disease progression, with a progression-free survival of 20 months, compared to seven months among patients receiving chemotherapy (404). The FDA approval of a second combination therapy during the 12 months covered in the report provides a new and first of a kind treatment option for certain patients with colorectal cancer. The combination of tucatinib (Tukysa) and trastuzumab (Herceptin), both HER2-targeted therapeutics, was approved by FDA in January 2023 for patients with HER2positive unresectable or metastatic colorectal cancer that has progressed following at least two standard treatments, including chemotherapy. To be eligible to receive the new combination, patients’ tumors must also not have driver mutations in the RAS group of genes. Colorectal cancer is the second most common cause of cancer death in the United States. An estimated 153,020 people are expected to be diagnosed with colorectal cancer in the United States in 2023 (28). Excessive production of the HER2 protein which leads to tumor cell multiplication, invasion, and metastasis is found in approximately three to five percent of patients with metastatic colorectal cancers (405) such asthat of Brian Beck, p. 92. The approval of the tucatinib and trastuzumab combination for this patient population was based on a phase II clinical trial which showed that 38 percent of patients who received the drug combination had their tumors shrink or disappear (406). Considering that prior treatment options for patients with HER2positive colorectal cancer that has returned or started growing again after receiving standard treatments were not very effective, the approval of tucatinib and trastuzumab represents a significant breakthrough for this subset of patients with metastatic colorectal cancer. Ongoing studies are evaluating whether addition of tucatinib and trastuzumab to standard treatment regimens could be used earlier on as the initial treatment for metastatic HER2positive colorectal cancer. Adding Precision to the Treatment of Blood Cancers Cancers that arise in blood-forming tissues, such as the bone marrow, or in cells of the immune system, are called blood cancers, or hematologic cancers. In the 12 months covered by this report, FDA has made numerous decisions that are transforming the lives of patients with a wide array of hematologic cancers (see Sidebar 37, p. 94). Acute myeloid leukemia (AML) is the most commonly diagnosed leukemia in the United States, with 20,380 new cases anticipated in 2023 (28). AML has only 32 percent overall 5-year relative survival rate, the lowest among leukemias (5). Research has substantially increased our understanding of the biology of AML, in particular the different types of genetic mutations that promote AML development. This knowledge is fueling the emergence of molecularly targeted therapeutics for defined groups of patients with the disease. One of the genes known to be mutated in about seven to 14 percent of AML cases is IDH1 (407). Mutation in IDHI gene results in an altered IDH1 protein, which can drive cancer formation by interfering with normal cellular maturation and promote uncontrolled cell multiplication. This knowledge led to the development of ivosidenib (Tibsovo), the first therapeutic to target IDH1, which was approved by FDA in 2018. In December 2022, FDA approved a second IDH1-targeted agent, olutasidenib (Rezlidhia), for adult patients with AML that has not responded to or has relapsed after other treatments, and that harbors an IDH1 mutation as detected by an FDAapproved test. At the same time that the molecularly targeted therapeutic was approved, FDA also approved the companion diagnostic, Abbott RealTime IDH1 Assay, to identify patients with AML with an IDH1 mutation. continued on page 94 Advancing the Frontiers of Cancer Science and Medicine AACR Cancer Progress Report 2023 91
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