Targeting KRAS Mutations

KRAS oncogene, Pancreatic Cancer: KRAS oncogene, Pancreatic CancerOne maxim often repeated in baseball is that “singles win championships.” This acknowledges the fact that, although home runs are flashier, they are rarer, and the steady production of the more commonplace singles contributes more towards overall team goals. Recently, one such “single” has been delivered by researchers who have been attempting to treat cancers that have mutations to KRAS (Kirsten rat sarcoma viral oncogene homologue). KRAS has long been considered an undruggable target, meaning one for which therapeutics could not be developed because of the inherent challenges surrounding it. In a New England Journal of Medicine article, data were presented from the Phase I/II CodeBreaK 100 clinical trial (NCT03600883) by David S. Hong, MD, Deputy Chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center and colleagues (N Engl J Med 2023; doi: 10.1056/NEJMoa2208470). Recently, Oncology Times conducted an interview with Hong regarding the research. “These findings, although not a home run, are clearly very meaningful, and are a landmark in the attempt to treat cancers harboring this specific KRAS mutation,” Hong noted. KRAS Oncogene The Kirsten rat sarcoma viral oncogene homologue (KRAS) gene was first isolated and characterized in 1982 (Proc Natl Acad Sci USA 1982; doi: 10.1073/pnas.79.16.4848). Since then, mutations in KRAS have been found to be oncogenic drivers for a number of aggressive malignancies, such as non-small cell lung cancer, pancreatic ductal adenocarcinoma, and colorectal cancer. Importantly, cancers driven by mutated KRAS typically have poor clinical outcomes and high fatality rates. Despite the successes noted with targeted therapies in other molecularly driven malignancies, therapies targeting altered KRAS proteins have been incredibly unsuccessful, earning it the epithet “undruggable” (Signal Transduct Target Ther 2021; doi: 10.1038/s41392-021-00780-4). Functionally, the RAS family of proteins (including KRAS, HRAS, and NRAS) are regulatory G proteins that exert control over signal transduction functions. In these proteins, the interconversion of guanosine diphosphate and guanosine triphosphate functions as a “binary switch” between activated and inactivated forms of the proteins. KRAS controls numerous signaling cascades upon activation with a variety of different agents, such as calcium ions, chemokines, growth factors, or receptor tyrosine kinase. Among the pathways controlled by this important protein are the phosphoinositide 3-kinase–protein kinase B–mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway and the rapidly accelerated fibrosarcoma—mitogen-activated protein kinase—extracellular regulated protein kinases (Raf-MEK-ERK) signaling pathway, among others. These pathways are implicated in a number of malignancies, including pancreatic cancer. Pancreatic cancer is one of the most difficult malignancies to treat, often having poor clinical outcomes. When asked about the traditional therapies for this difficult disease, Hong replied, “Surgical procedures are sometimes employed; in addition, different chemotherapy combinations are often used as well. One of the frequently used regimens is the FOLFIRINOX combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. “Other used therapies include the liposomal irinotecan-leucovorin-fluorouracil and albumin-bound paclitaxel-gemcitabine combinations,” he noted. The use of these treatments, while conferring modest survival benefits, may not be suitable for everyone as the toxicities associated with them can be considerable, thus rendering them inappropriate for those who are older or have additional comorbidities. With the advent of newer therapies based on molecular biomarkers, treatments with lower toxicities have been applied to a number of malignancies, including pancreatic cancer. For example, patients with pretreated metastatic pancreatic ductal adenocarcinomas that have a germline BRCA mutation (BRCA1 or BRCA2) have been treated with the PARP inhibitor olaparib as a maintenance therapy. However, this therapy is relevant for only a small percentage of pancreatic cancer patients. Another therapy that has been applied to pancreatic cancer is the checkpoint inhibitor pembrolizumab. In May 2017, in a departure from their previous oncology approvals, the FDA granted accelerated approval to pembrolizumab for the treatment of solid tumors based not on the tissue, but upon the genetic characteristics of the disease. Specifically, the regulatory decision was for unresectable or metastatic solid tumors that were microsatellite instability-high or defective DNA mismatch repair-deficient, which constitutes roughly 1-2 percent of pancreatic ductal adenocarcinoma. KRAS Mutations Approximately 85 percent of pancreatic cancers have mutations in KRAS (Semin Oncol 2021; doi: 10.1053/j.seminoncol.2021.02.003). A majority of these anomalies are missense mutations that occur at one of three hotspots—glycine12 (G12), glycine13 (G13), or glutamine61 (Q61). Two of the most frequently encountered mutations in RAS-mutant pancreatic cancer are the G12D and G12V variants, which account for approximately 39 percent and 33 percent of all KRAS mutations in this disease state, respectively. In these variants, the glycine at position 12 of the wild-type KRAS is replaced with an aspartate (D) or valine (V) residue, respectively. In addition, approximately 17 percent of KRAS mutations in pancreatic ductal adenocarcinoma are the G12R variant, where the aforementioned glycine is replaced with an arginine. Finally, one altered form of KRAS that has the possibility of being therapeutically targeted is the G12C mutation, in which glycine12 is replaced by cysteine. “This KRAS mutation is present in about 1-2 percent of pancreatic cancers,” Hong observed. Sotorasib is an acrylamide derivative that irreversibly forms a covalent bond to a cysteine residue in a pocket that is only available when the G12C mutated form of the enzyme is in an “inactive guanosine diphosphate-bound conformation” (N Engl J Med 2021; doi: 10.1056/NEJMoa2103695). Thus, when this bond is formed, the enzyme is then locked in its inactive form. This binding can only occur in KRAS in which the glycine residue present in the wild-type form of the enzyme has been replaced by a cysteine residue (termed KRAS G12C). When KRAS is locked in the inactivated state, the downstream oncogenic signaling driving the malignancy is disrupted. CodeBreaK 100 The CodeBreaK 100 trial evaluated the use of sotorasib in patients having solid tumors with KRAS G12C mutations. Some of the initial patients included in this study had KRAS G12C-mutant non-small cell lung cancer. “The results from those patients have been presented previously,” Hong noted. This clinical trial also included patients with locally advanced or metastatic pancreatic cancer with locally confirmed KRAS G12C mutant disease. “In the Phase I portion of the trial, the main goals were to assess the safety of sotorasib, as well as to determine the recommended dosage for the Phase II portion of the trial,” Hong explained. In Phase II, the patients with pancreatic cancer were dosed at 960 mg sotorasib QD orally and the primary trial endpoint was the centrally assessed objective response. “This was defined as the patients having a complete or partial response,” he noted. “Efficacy assessments such as objective response, duration of response, time to objective response, progression-free survival, and overall survival were performed using the pooled Phase I and II patient populations.” In this analysis, there were a total of 38 patients—12 from Phase I and 26 from Phase II portions of this study. All of these patients had chemotherapy-treated metastatic pancreatic cancer. They had received a median of two previous lines of therapy with a range of 1-8 prior treatments. “Since this was not a placebo-controlled trial, all patients included in this analysis received sotorasib,” Hong noted. Eight patients showed a partial response to sotorasib, with three and five being Phase I and Phase II participants, respectively, affording a 21 percent objective response (95% CI: 10-37%). This analysis provided a median progression-free survival of 4.0 months (95% CI: 2.8-5.6 months) and a median overall survival of 6.9 months (95% CI: 5.0-9.1 months). A total of 16 patients had treatment-related adverse events and, of these, six patients had Grade 3 adverse events. “No new safety signals were obtained for sotorasib and, importantly, no adverse events led to death or treatment withdrawal,” Hong noted. “In this study, sotorasib did show anticancer activity against metastatic KRAS G12C-mutant pancreatic cancer and, importantly, no new safety signals were observed,” Hong stated. “Although our results were by no means a home run, they are an important milestone, as we did see some efficacy against heavily pretreated KRAS-mutant pancreatic cancer. For decades, KRAS was thought to be an undruggable target. Now in the CodeBreaK 100 study, we have seen activity against KRAS G12C-mutated pancreatic and non-small cell lung cancer.” Based on the results from the CodeBreaK 100 trial, the FDA approved the use of sotorasib in patients with KRAS G12C-mutant non-small cell lung cancer who had previously received at least one prior systemic therapy in May 2021. When asked about future directions for targeting KRAS-driven malignancies, Hong replied, “Within the CodeBreaK 100 trial, the use of sotorasib in combination with different drugs is being evaluated in additional cohorts of patients. Research is also currently ongoing to address some of the KRAS mutations, which occur more frequently in these malignancies.” Richard Simoneaux is a contributing writer.