and continue in the long term, or they can appear months or even years later. Health care providers and researchers are investigating different approaches to make chemotherapeutics safer for patients. Areas of ongoing investigation include designing modifiable chemotherapeutics, e.g., with “on” and “off” switches, that are selectively delivered to tumors while sparing healthy tissue; evaluating less aggressive chemotherapy regimens which can allow patients the chance of an improved quality of life without compromising survival; and identifying biomarkers such as circulating tumor DNA to correctly predict which patients will or will not benefit from chemotherapy, among other approaches (381-383). Notably, due to complex reasons, the United States is amid a significant chemotherapeutic shortage. The situation is affecting many patients and disrupting clinical research nationwide. It is imperative that all stakeholders in health care come together and identify ways to address these shortages at the earliest possible time (see Addressing Cancer Drug Shortages, p. 158). Advances in Treatment with Molecularly Targeted Therapy Remarkable advances in our understanding of the biology of cancer, including the identification of numerous genetic mutations that fuel tumor growth, set the stage for a new era of precision medicine, an era in which the standard of care for many patients is changing from a one-size-fits-all approach to one in which greater understanding of the individual patient and the characteristics of his or her cancer dictates the best treatment option for the patient (see Understanding the Path to Cancer Development, p. 24). Therapeutics directed to molecules influencing cancer cell multiplication and survival target tumor cells more precisely than cytotoxic chemotherapeutics, which generally target all rapidly dividing cells, and thereby limit damage to healthy tissues. The greater precision of these molecularly targeted therapeutics tends to make them more effective and less toxic than cytotoxic chemotherapeutics. As a result, they are not only saving the lives of patients with cancer, but also allowing these individuals to have a higher quality of life. Unfortunately, because of multilevel barriers to health care, there are disparities in the utilization of molecularly targeted treatments among patients from racial and ethnic minorities and other medically underserved populations (13). It is vital that ongoing research and future public health policies are aimed to ensure equitable access to precision cancer medicine including tumor genetic testing and the receipt of molecularly targeted therapeutics for all patients. In the 12 months spanning August 1, 2022, to July 31, 2023, FDA approved seven new molecularly targeted anticancer therapeutics (see Table 3, p. 77). During this period, FDA also approved nine previously approved molecularly targeted anticancer therapeutics for treating additional types of cancer. Expanding Treatment Options for Patients with Lung Cancer Lung cancer is the second most diagnosed cancer in both men and women and the most common cause of cancer death. More than 127,000 deaths are estimated to occur from the disease in 2023 in the United States (28). Decades of basic and translational research have significantly increased our understanding of the genetic changes that drive lung cancer growth and have fueled the development of therapeutics that target these changes (see Figure 1, p. 14) (28). Two recent FDA decisions have the potential to drive more progress against lung cancer because they have provided new molecularly targeted therapeutic options for certain patients with the disease. About 81 percent of lung cancers diagnosed in the United States are classified as non–small cell lung cancers (NSCLC) and approximately 25 percent of patients with NSCLC carry mutations in the gene that is responsible for producing KRAS, an essential protein needed for growth and survival of normal lung cells, but which can contribute to cancer if mutated (28,384). Mutated KRAS represents one of the most common genetic alterations responsible for the development and progression of human cancers. Patients with NSCLC harboring KRAS mutations often develop resistance to standard treatments such as chemotherapy, radiation therapy, and immunotherapy, and only 25 percent of these patients live five years or more after diagnosis (438). The most common KRAS mutation in patients with NSCLC is known as KRAS G12C, an alteration that is more frequently found in individuals who smoke currently or have smoked previously. The G12C mutation causes KRAS protein to prefer an “on” or “active” state, leading to uncontrollable cell growth that can form tumors. Historically, KRAS has been considered an undruggable target because of the difficulties in designing a therapeutic that could selectively bind and inhibit KRAS in cancers. Despite major breakthroughs in selective targeting of a range of other genetic drivers of NSCLC, no effective treatment options were available for patients with KRAS G12C until two years ago. Thanks to enhanced understanding of KRAS biology and unprecedented progress in structural biology and drug development, in May 2021, sotorasib (Lumakras) became the first ever molecularly targeted therapeutic approved by the FDA for the treatment of patients with NSCLC with the KRAS G12C mutation (see Figure 16, p. 84) (4). In December 2022, FDA approved a new molecularly targeted therapeutic, adagrasib (Krazati), for adult patients with locally advanced or metastatic NSCLC that has the KRAS G12C mutation, as determined by an FDA-approved test, and who have received at least one prior systemic treatment such as Advancing the Frontiers of Cancer Science and Medicine AACR Cancer Progress Report 2023 83
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