SPOTLIGHT that 73 percent of the treated patients responded to the drug combination and the response lasted, on average, for 22 months (433), bringing hope to patients with bladder cancer who otherwise have limited treatment options available. Research has shown that up to 60 percent of bladder cancers are characterized by elevated levels of a protein called nectin-4 (434). Enfortumab-vedotin-ejfv is an antibody–drug conjugate that comprises a cytotoxic agent, monomethyl auristatin E, attached by a linker to a nectin-4–targeted antibody. When the antibody attaches to nectin-4 on the surface of bladder cancer cells, the antibody–drug conjugate is internalized by the cells, which leads to release of monomethyl auristatin E from the linker and antibody. Once free, monomethyl auristatin is toxic to cancer cells. One of the new cancer types for which an ICI is now an approved treatment option is alveolar soft part sarcoma (ASPS). In December 2022, FDA approved the ICI atezolizumab (Tecentriq) for the treatment of adult and pediatric patients two years and older with ASPS that has spread to other parts of the body or cannot be removed by surgery. Alveolar soft part sarcoma is an extremely rare cancer that mainly affects adolescents and young adults, such as Isabella (Bella) Snow Fraser, p. 110 and Alexis Browning, p. 112. According to NCI, about 80 people are diagnosed with the disease in the United States each year. ASPS is a slow-growing cancer that forms in soft tissues such as muscle, fat, or nerves. Although the disease grows slowly, once metastatic, ASPS has poor outcomes. Chemotherapeutics have limited benefit and molecularly targeted therapeutics do not have lasting effectiveness against ASPS. Atezolizumab is a PD-L1-targeting ICI that has been approved previously for the treatment of patients with several cancer types, including liver cancer, melanoma, and lung cancer (see Figure 19, p. 106). The new FDA approval was based on data from a phase II clinical trial showing that about a quarter of the patients with ASPS responded to atezolizumab with some tumor shrinkage. Among patients who responded to the treatment, 67 percent had a response lasting at least six months, and 42 percent had a response lasting at least 12 months. The approval represents a significant advance for a rare disease as well as for pediatric patients with cancer, two research areas that require more intensive attention for continued progress. In March 2023, retifanlimab-dlwr (Zynyz) became the second new ICI approved by FDA during the 12 months covered by the report. It was approved for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma, a rare and aggressive form of skin cancer. Retifanlimab-dlwr targets the PD-1 brake on the surface of T cells, preventing T cells from attaching to the cells that can trigger the brake and deactivate them. The approval was based on the finding that treatment with retifanlimab-dlwr resulted in tumor shrinkage in more than half of the patients who received the treatment as part of a phase II clinical study. With this decision, retifanlimab-dlwr became the third ICI approved by the FDA for Merkel cell carcinoma (see Figure 19, p. 106). Immune checkpoint inhibitors have yielded extraordinary benefit for many patients, but they can have adverse effects (see Current Challenges in Cancer Immunotherapy, p. 125) particularly the induction of autoimmune-like conditions. This occurs because ICIs not only release the brake on cancer fighting immune cells but also some that recognize and injure normal tissues. To predict which patients are likely to experience adverse events and design treatments to combat these events without compromising the anticancer efficacy of the ICI, researchers must better understand why and how the adverse effects arise. This is an area of extensive research investigation. Another important area of scientific inquiry is to identify behavioral and clinical factors, such as diet, physical activity, gut microbiome composition, and optimal combinations with other therapeutic modalities that can boost the efficacy of ICIs and increase the number of patients who respond favorably to these lifesaving treatments. As documented in this report and in the past 12 editions of the AACR Cancer Progress Report, ICIs have transformed the clinical care of patients with a diverse array of cancer types including historically intractable diseases such as metastatic melanoma, lung cancer, and kidney cancer (436). While their use was initially limited to people with very advanced cancers that were no longer responding to standard treatments, checkpoint inhibitors are increasingly being approved as first-line—initial—treatments for patients. Recent data show that compared to the current standard treatments such as chemotherapy, ICI use in the first-line setting may improve survival for certain patients (437-439). Researchers are also evaluating how to best integrate the use of ICIs along with standard treatments such as surgery, radiation therapy, and/or chemotherapy in patients with early-stage cancer (440,441). One area of extensive research is the use of these therapeutics before initial surgery, known as neoadjuvant treatment, in people with locally advanced cancers that are largely restricted to their original location. The first neoadjuvant clinical trial with ICI was conducted in 2006, which provided the first safety Merkel cell carcinoma is a rare and aggressive form of skin cancer with a high risk for recurrence and metastasis. Researchers estimate that the current number of 3,000 new cases per year will increase to >3,250 cases per year by 2025 (435). AACR Cancer Progress Report 2023 Immunotherapy: Pushing the Frontier of Cancer Medicine 108
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