Fam-trastuzumab deruxtecan-nxki is a type of molecularly targeted therapeutic called an antibody–drug conjugate. It comprises a cytotoxic agent, deruxtecan, attached to the HER2targeted antibody, trastuzumab (Herceptin), by a linker. When the antibody attaches to HER2 protein on the surface of lung cancer cells, the antibody–drug conjugate is internalized by the cells. This leads to deruxtecan being released from the linker and the antibody. Once free, the deruxtecan is toxic to the cancer cells, which ultimately die. The approval of fam-trastuzumab deruxtecan-nxki was primarily based on the results of a phase II clinical trial in which treatment with the HER2-targeted therapeutic shrank tumors in nearly 60 percent of the study participants (388). Among patients whose tumors shrank, the treatment kept their lung cancer at bay for nearly 9 months. While famtrastuzumab deruxtecan-nxki has previously been approved for the treatment of patients with HER2-driven breast and gastric cancers (4,389), this was the first approval of a HER2-targeted therapeutic for NSCLC and provides new hope for patients with NSCLC who carry an activating HER2 mutation. Like most cancer treatments, fam-trastuzumab deruxtecan-nxki can have adverse effects, some of which can be severe. One of the most concerning and, in the case of NSCLC, life threatening, is interstitial lung disease which causes stiffness in the lungs, making it difficult to breathe and get oxygen to the bloodstream. Therefore, FDA approved fam-trastuzumab deruxtecan-nxki with a warning for interstitial lung disease and recommends that patients being treated with the molecularly targeted therapeutic be monitored for signs and symptoms of interstitial lung disease, including cough, dyspnea (difficult or labored breathing), fever and other new or worsening respiratory symptoms. If interstitial lung disease is suspected, further testing and intervention must be considered. While FDA approvals of sotorasib, adagrasib and fam-trastuzumab deruxtecan-nxki are significant advances for patients with NSCLC, all stakeholders in public health need to work together to ensure that every patient has access to and benefits from the latest developments in precision cancer medicine. Patients with lung cancer who receive molecularly targeted therapies have better survival compared to those who do not receive targeted therapies (390,391). Unfortunately, according to recent data, many patients with advanced NSCLC do not receive appropriate molecular tests or the appropriate molecularly targeted treatments due to gaps in the delivery of clinical care (392,393). Targeting Cancers Based on a Common Genetic Feature, Not Tissue of Origin Chromosomal translocations that involve the RET gene and lead to the production of activating RET fusion proteins (see Sidebar 7, p. 30) are rare alterations observed mostly in patients with certain types of thyroid cancer and lung cancer (394). In 2020, FDA approved the RET-targeted therapeutic, selpercatinib (Retevmo), for treating patients with metastatic NSCLC and certain thyroid cancers that test positive for chromosomal translocations involving the RET gene (389). In solid tumors other than lung cancer and thyroid cancer, RET gene fusions are rarer, observed in less than one percent of patients (394). However, this is a distinct patient population since RET gene fusions are mutually exclusive of other genetic alterations and provide a unique opportunity for therapeutic intervention (394). A recent decision from FDA offers a new treatment option for these patients who until this approval had no molecularly targeted therapeutics available for their cancer. In September 2022, FDA expanded the approval of selpercatinib for the treatment of adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval of selpercatinib was based on the results of a phase I/II basket clinical trial (see Figure 14, p. 73) in which treatment with the RET-targeted therapeutic shrank tumors in nearly 44 percent of the study participants (395). Patients with a range of cancer Companion Diagnostics The effective use of anticancer therapeutics targeting defined cancer-driving molecular abnormalities often requires tests called companion diagnostics. Using tumor tissue or blood samples, companion diagnostic tests can identify whether a patient’s cancer has a specific genetic alteration or biomarker that is targeted by the drug. COMPANION DIAGNOSTICS: Are stringently tested for accuracy, sensitivity, and fidelity; Are regulated by the U.S. Food and Drug Administration; Accurately match patients with a specific therapy; Allow patients to receive a treatment to which they are most likely to respond; and Allow patients identified as very unlikely to respond to forgo treatment with the therapeutic and thus be spared the cost and adverse side effects. Adapted from (163). SIDEBAR 34 Advancing the Frontiers of Cancer Science and Medicine AACR Cancer Progress Report 2023 85
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