chemotherapy or immunotherapy. The FDA also approved companion diagnostics (see Sidebar 34, p. 85), QIAGEN therascreen KRAS RGQ PCR kit (tumor tissue-based) and Agilent Resolution ctDx FIRST Assay (blood-based) to help identify patients with NSCLC carrying the KRAS G12C mutation. Both sotorasib and adagrasib bind to KRAS G12C protein and lock it in an inactive state thus blocking tumor growth. The FDA approval of adagrasib was granted after it was shown in a phase II clinical trial that 43 percent of the patients who received the targeted therapeutic had complete or partial tumor shrinkage and continued to respond for a median of 8.5 months without their cancer progressing (384). A critical finding from the clinical trial was that adagrasib was able to reach the brains of patients with NSCLC and shrink tumors that had metastasized to the brain (385). While additional research is needed to confirm therapeutic activity in the brain, these data are extremely encouraging considering recent findings that 27 to 42 percent of patients with NSCLC whose tumors harbor the KRAS G12C mutation may have central nervous system (CNS) metastases at diagnosis, and such metastases are associated with a poor prognosis (384). Another major advance against lung cancer during the 12 months covered in this report is the FDA approval of famtrastuzumab deruxtecan-nxki (Enhertu) for adult patients with surgically unremovable or metastatic NSCLC whose tumors have a type of mutation in the human epidermal growth factor receptor 2 (HER2) gene, called an activating mutation, as detected by an FDA-approved test, and who have received a prior systemic therapy. The FDA also approved Oncomine Dx Target Test (tissue-based) and Guardant360 CDx (blood-based) as companion diagnostics to test patients for activating HER2 mutations. HER2-mutated NSCLC, which accounts for three percent of all NSCLC cases, is associated with female sex, never-smoking history, and a poor prognosis. Furthermore, this type of NSCLC has a higher incidence of brain metastases than NSCLC without HER2 mutations or with other mutations (386,387). Milestones in the Journey to Target the Undruggable KRAS Decades of research led to the development and approval of sotorasib in May 2021 and adagrasib in 2022. The relationship between RAS genes and lung cancer was first described in 1983, and subsequent discoveries led to the evaluation of several KRAS targeted therapeutics that work directly (by inhibiting KRAS function) or indirectly (by blocking other proteins that carry out KRAS’s function in the cell). The first clinical trials investigating the efficacy of indirect KRAS inhibitors were carried out in the early 2000s. Since then, many KRAS inhibitors have been developed and tested but largely failed because of limited efficacy and/ or toxicity to normal tissues. Targeting KRAS with small molecular inhibitors has been particularly challenging because the three-dimensional form of the protein lacks an accessible or “druggable” pocket, posing a significant challenge to developing molecularly targeted drugs that are selective for the mutated protein. With the availability of deeper insights into the mutational landscape of lung cancer and breakthroughs in drug design, researchers were able to develop the first KRAS inhibitor, sotorasib (Lumakras), which was approved in May 2021 by FDA based on promising results from preclinical and clinical studies. In December 2022, FDA approved a second KRAS inhibitor, adagrasib (Krazati). FIGURE 16 1971 Signing of National Cancer Act 2001 Mouse models of KRAS mutant lung cancer are developed 1983 KRAS G12C and G12V mutants are cloned from lung and colon cancer cells 1987 High incidence of KRAS mutations is reported in colon cancer 1973 Kirsten rat sarcoma viruses shown to contain rat DNA sequences 1988 High frequency of KRAS mutations is described in pancreatic cancer 1993 Mutant KRAS is linked to colon tumor growth 1982 Human KRAS gene is cloned 2013 First inhibitor of KRAS G12C mutant is discovered 2019 Adgarisib shows antitumor activity in clinical trials 2005 Gene expression patterns associated with KRAS mutations in lung cancer are identified 2019 Sotorasib shows antitumor activity in clinical trials 2021 Sotorasib for treatment of KRAS G12C-carrying lung cancer 2020 2010 2000 1990 1980 1970 O N N F F N OH N N N O 2022 Adgarisib for treatment of KRAS G12C-carrying lung cancer CI N O F N N N N N O N STOP 1997 KRAS is essential for normal embryonic development in mice AACR Cancer Progress Report 2023 Advancing the Frontiers of Cancer Science and Medicine 84
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