The Pharmacologic Inhibition of KRAS Mutants as a Treatment for Cancer

Therapeutic Principles and Clinical Results

Background: Mutations of the KRAS oncogene are found in up to 20% of all cancers, and particularly in non–small-cell lung cancer (NSCLC) (20–40%) and colorectal cancer (CRC) (30–50%). Inhibitors of specific KRAS mutants have recently become available and are now a part of routine care.

Methods: This review is based on articles published in the past 5 years that were retrieved by a selective search in PubMed for clinical trials of the pharmacological inhibition of KRAS.

Results: Sotorasib and adagrasib have already been approved, on the basis of two randomized phase III trials, as specific inhibitors of the KRAS^G12C mutant for palliative second-line treatment. Compared to standard chemotherapy with docetaxel, both drugs significantly prolonged progression-free survival (PFS): 5.6 months (95% confidence interval [4.3; 7.8]) for sotorasib versus 4.5 [3.0; 5.7] for docetaxel, and 5.5 months [4.5; 6.7] for adagrasib versus 3.8 [2.7; 4.7] for docetaxel. Sotorasib was also found to cause fewer severe adverse drug events (33%, versus 40% with docetaxel). The most common ones were diarrhea and elevated liver enzymes. For already treated CRC, sotorasib combined with the anti-epidermal growth factor receptor (anti-EGFR) antibody panitumumab was found, in a randomized phase III trial, to prolong progression-free survival significantly compared to standard therapy with triflurdin/tipiracil or regorafenib (5.6 months [4.2; 6.3] versus 2.2 months [1.9; 3.9]), while also improving patients’ quality of life. Approval by the European Medicines Agency is pending. Further KRAS and pan-RAS inhibitors are now in early clinical development.

Conclusion: Pharmacological KRAS inhibition is a promising new approach to the treatment of many kinds of cancer.

Cite this as: Kasper S, Sebastian M: The pharmacologic inhibition of KRAS mutants as a treatment for cancer: Therapeutic principles and clinical results. Dtsch Arztebl Int 2024; 121: 163–7. DOI: 10.3238/arztebl.m2025.0002

The KRAS (Kirsten rat sarcoma virus) gene is one of several oncogenes that play a key role in the development of many types of cancer. Activating mutations of this gene lead to the activation of downstream signaling pathways; they promote proliferation, inhibit programmed cell death, and mediate resistance to anticancer treatment (see Figure). KRAS is one of the most commonly mutated oncogenes in solid tumors, with KRAS mutations being present in as many as 20% of such tumors. Their prevalence varies widely depending on the tumor type: for example, they are present in 85–90% of pancreatic ductal adenocarcinomas (PDAC), in 30–50% of colorectal carcinomas (CRC), and in 20–40% of non-small cell lung carcinomas (NSCLC) (1). The localization of the mutation within the KRAS gene varies widely as well. The G12D mutation is found most often in PDAC, the G12D and G12V mutations in CRC, and the G12C mutation in NSCLC (2). The various KRAS mutations appear to have different prognostic implications depending on the underlying tumor disease.

Figure

The intracellular RAS signal transduction pathway

For example, patients with KRAS^G12C-mutated CRC in metastatic disease have a shorter progression-free (PFS) and overall survival (OS) under palliative chemotherapy than those with other KRAS mutations (9.4 versus 10.8 months and 21.1 months versus 27.3 months, respectively). In contrast, the KRAS^G12C mutation in NSCLC seems not to lead to worse outcomes (3, 4, 5).

The pharmacologic inhibition of KRAS

The direct pharmacological inhibition of the KRAS protein with targeted small-molecule drugs was found to be exceedingly difficult, because suitable drugs for the molecule’s complex binding pockets were hard to find (6). Recently, however, specific orally administered inhibitors of certain KRAS mutations, such as KRAS^G12C, have been developed and successfully tested clinically. In addition to the specific inhibitors of the KRAS isoforms, pan-KRAS and pan-RAS inhibitors are now available that inhibit not only KRAS, but also the other members of the RAS family (HRAS, NRAS) (7, 8, 9, 10).

The KRAS^G12C mutation

The prevalence of the KRAS^G12C mutation varies widely across tumor types. In NSCLC, this specific isoform is the most common KRAS mutation, present in an estimated 8.9% of patients (11). It is much rarer in gastrointestinal tumors such as appendiceal carcinoma (3.9%), CRC (3.2%), CUP (“cancer of unknown primary”) syndrome (1.6%), PDAC (1.3%), small bowel carcinoma (1.4%), and hepatobiliary tumors (<1%) , and very rare in gynecological, urogenital, and hematological neoplasms (all <1%).

Clinical data on KRAS^G12C inhibitors in NSCLC

Sotorasib was the first orally administered KRAS^G12C inhibitor that could irreversibly block the mutant protein (12). In the single-arm Phase II CodeBreaK 100 trial in patients with previously treated NSCLC, a PFS of 6.7 months [5.3; 8.2] and an OS of 12.5 months [10.0; 17.8] were observed (13, 14). Although this trial was conducted without a control arm, these results led to the provisional approval of the drug by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), on condition that a confirmatory phase III study be conducted. In the subsequent randomized phase III CodeBreaK 200 trial, sotorasib was tested against standard second-line chemotherapy with docetaxel (15). The primary endpoint of this trial, PFS, was significantly longer with sotorasib (5.6 months [4.3; 7.8]) than with docetaxel (4.5 months [3.0; 5.7]), but longer OS was not found. Another noteworthy finding in this trial was the lower rate of ADR of grade 3 or above (33% in patients taking sotorasib and 40% in patients taking docetaxel). The main adverse drug reactions of sotorasib were diarrhea and elevated liver function tests; those of docetaxel were neutropenia, fatigue, and fever in neutropenia. The efficacy of sotorasib was also recently shown in an observational study involving a less stringently selected cohort, including patients with brain metastases (16). In this study, PFS was 4.8 months [3.9; 5.9] and OS was 9.8 months [6.5; not reached]. The cost of treatment with 960 mg qd sotorasib is approximately 4,800 euros. In addition to sotorasib, the KRAS^G12C -specific inhibitor adagrasib was also recently approved by the EMA and the FDA for the palliative second-line treatment of patients with advanced NSCLC who have a KRAS^G12C mutation. Approval was based on data from the randomized phase III KRYSTAL-12 trial of adagrasib versus docetaxel. The findings were presented at the American Society of Clinical Oncology (ASCO) in 2024 and have not yet been published in full (17). PFS was significantly longer under adagrasib (5.5 months [4.5; 6.7]) than under docetaxel [2.7; 4.7]. Adagrasib was also shown to be associated with a higher quality of life and fewer lung cancer symptoms than docetaxel (18). The rate of higher-grade adverse drug reactions (ADR) was similar with the two drugs: 47% under adagrasib (mainly diarrhea, nausea, and vomiting) and 45.7% under docetaxel (mainly anemia, asthenia, and diarrhea). Data on overall survival have not yet been released. Adagrasib is not yet available in Germany, but it is expected that the cost of treatment with 600 mg of adagrasib bid will be similar to that of sotorasib.

Other specific KRAS^G12C inhibitors, such as divarasib, are still in the early stages of clinical testing (19). Further trials now in progress involve KRAS^G12C inhibitors in combination with immunotherapeutic, cytostatic, or other targeted drugs.

Clinical data on KRAS^G12C inhibitors in colorectal cancer

In CRC, the specific KRAS^G12C mutation is rarer than in NSCLC, affecting only about 3% of patients. Yet in CRC, unlike in NSCLC, KRAS^G12C is associated with a poorer outcome than other KRAS mutations. Retrospective analyses showed that patients with KRAS^G12C had significantly shorter PFS (9.4 versus 10.8 months) and OS (21.1 versus 27.3 months) than patients with other KRAS mutations when given systemic chemotherapy for palliative treatment. New therapeutic strategies are urgently needed for these patients in particular (3). In early clinical trials, patients with CRC had lower response rates to the specific KRAS^G12C inhibitors sotorasib, adagrasib, and divarasib than patients with NSCLC, and combination therapies with other targeted drugs were therefore investigated directly (19, 20, 21). Thus, patients with chemotherapy-refractory CRC underwent trials of KRAS^G12C inhibitors combined with the epithelial growth factor receptor (EGFR) antibodies cetuximab or panitumumab. This type of combination therapy achieved higher response rates and longer median PFS times than monotherapy. In the phase II CodeBreaK 101 trial, the combination of sotorasib and panitumumab yielded a response rate of 33% with a median PFS and OS of 5.7 months [4.2; 7.7] and 15.2 months [12.5; not reached], respectively (22). The combination of adagrasib and cetuximab was investigated in the phase I/II KRYSTAL-1 trial (21): there was a 46% response rate with a median PFS of 6.9 months [5.4; 8.1]. In a phase Ib trial, the combination of divarasib and cetuximab yielded a 62.5% response rate with a median PFS of 8.1 months [5.5; 12.3] (23) (eTable).

Table

Randomized phase III trials of KRASG12C inhibitors

eTable

Early trials of KRASG12C inhibitors

On the basis of these data, the randomized phase III CodeBreaK 300 trial was set up to compare the combination of sotorasib and panitumumab with standard treatment [either trifluridine/tipiracil (oral chemotherapy) or regorafenib (a multitarget tyrosine kinase inhibitor)] in patients with previously treated metastatic CRC who had a KRAS^G12C mutation (2 4).

In this trial, sotorasib was given in two different doses (960 mg and 240 mg). 160 patients were included, and the trial achieved its primary endpoint (PFS). A significant prolongation of median PFS was achieved with sotorasib (960 mg) and panitumumab (5.6 months; [4.2; 6.3]) compared to standard treatment with either trifluridine/tipiracil or regorafenib (2.2 months; [1.9; 3.9]), with a higher response rate (26% versus 0%) (Table) (24). The rate of higher-grade ADR was 35.8% in the combination arm with sotorasib and panitumumab (mainly skin side effects, hypomagnesemia and diarrhea), and 43.1% in the standard treatment arm (mainly hematotoxicity, nausea and diarrhea). It was shown with standardized questionnaires that patients who received sotorasib and panitumumab had a better quality of life as well (25). These data led to FDA approval of the combination of sotorasib and panitumumab in the USA. The potential utility of KRAS^G12C inhibitors in earlier lines of therapy is now being investigated. In the ongoing randomized phase III KRYSTAL-10 trial, adagrasib combined with cetuximab is being compared with standard FOLFIRI (irinotecan, folinic acid and 5-fluorouracil) or FOLFOX (oxaliplatin, folinic acid and 5-fluorouracil) chemotherapy, each optionally in combination with a VEGF antibody, in patients with metastatic CRC who had progressive disease after first-line chemotherapy. Sotorasib together with panitumumab in combination with the FOLFIRI protocol in first-line treatment is now being tested in the randomized phase III CodeBreaK 301 study against the standard FOLFIRI chemotherapy in combination with bevacizumab-awwb. Safety data and initial efficacy data for this type of combination therapy are already available for patients with chemotherapy-refractory disease (eTable) (26).

Clinical data on KRAS^G12C inhibitors in pancreatic cancer and other gastrointestinal tumors

KRAS mutations are present in 85–90% of pancreatic carcinomas; the specific KRAS^G12C mutation is present in 1–2%. The KRAS^G12C mutation is also rarely present in other, less common gastrointestinal tumors, such as biliary tract carcinoma (BTC), appendiceal carcinoma, or small bowel carcinoma. Early screening is nevertheless worthwhile because of the availability of specific KRAS^G12C inhibitors and the often limited therapeutic options for these rare diseases. Patients with PDAC or other types of tumor were also included in the early clinical trials of sotorasib, adagrasib, and divarasib (eTable). In patients with previously treated pancreatic cancer, the response rates were 21% for sotorasib and 33% for adagrasib (27, 28). No entity-specific response rates have been reported for divarasib to date; the objective response rate (ORR) in the Basket study was 36%, but many of these patients had pancreatic or biliary tract cancer (19). Adagrasib yielded a 41.7% response rate, with a progression-free survival of 8.6 [2.7; 11.3] months and an overall survival of 15.1 [8.6; not reached] months, in patients with previously treated biliary tract cancer.

Development of resistance to KRAS^G12C inhibitors

Primary and acquired resistance are common problems with targeted therapies. For example, resistance-conferring genetic alterations have been identified by sequential analysis of tumor tissue or circulating DNA (cfDNA) for all three KRAS^G12C inhibitors mentioned above, either as monotherapy or in combination with EGFR antibodies (23, 29, 30). In addition to other acquired KRAS or NRAS mutations, genetic alterations in downstream signaling pathways and in receptor tyrosine kinases such as EGFR or fibroblast growth factor receptor (FGFR) were also frequently detected. In order to overcome these resistance mechanisms, various drug combinations are now under investigation in phase I trials.

Clinical data on pan-RAS inhibitors

The pan-RAS inhibitor RMC-6236 blocks KRAS, NRAS, and HRAS in their active conformation and is thus what is called a RAS-on inhibitor. It has been tested in a phase I trial in various tumor diseases with evidence of a KRAS mutation (RMC-6236–001/NCT05379985) (9, 31). The response rate was 38% in patients with previously treated NSCLC (N = 40) and 20% in patients with pancreatic cancer (N = 46).

Overview

The pharmacological inhibition of KRAS mutants is a new therapeutic approach for solid tumors. Because of the special conformation of this protein molecule, suitable inhibitors block it effectively could not be developed for many years. Recently, however, it has been possible to synthesize specific inhibitors for certain subtypes, such as the KRAS^G12C mutation, and test them clinically. Some of these inhibitors have already been approved and have rapidly become a part of routine oncological practice. As with many other targeted therapies, acquired resistance mediated by new genetic changes is a problem, and combination therapies are now being studied as a way to overcome it.

Conflict of interest statement

SK states that he and his institution have received financial support from Amgen, Roche, Lilly, GSK, MerckHealthcare, Novartis, J&J, Daiihi-Sankyo, BMS, MSD, and AstraZeneca. He has also served as a paid consultant for Amgen, BMS, MSD, Roche, AstraZeneca, Oncowissen.de, Daiichi-Sankyo, Takeda, Lilly, Beigene, and Novartis and has received payment from these companies for continuing medical education events. He has received reimbursement of scientific meeting participation fees from Amgen, BMS, MSD, Takeda, and Beigene. He is a member of the trial steering committee at Amgen and the CRC task force of the German Cancer Society’s Medical Oncology Working Group (Arbeitsgemeinschaft Internistische Onkologie, AIO).

MS states that his institution has received funding from AstraZeneca. He has personally served as a paid consultant for, and has received payment for continuing medical education events and the like from, the following companies: AstraZeneca, Sanofi, Merck, Novartis, Boehringer-Ingelheim, Pfizer, Takeda, Pierre-Fabre, Daiichi-Sankyo, Regeneron, and Gilead. He has received reimbursement of scientific meeting participation fees and/or travel expenses from Takeda, Merck, and Pfizer.

Submitted on 7 August 2024, revised version accepted on 6 January 2025

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Stefan Kasper

Information on CME

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