Precision medicine in metastatic colorectal cancer: targeting KRAS G12C mutation

Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer-related death worldwide, with 153,020 new cases and 52.550 deaths in the United States annually (1). Approximately 50% of patients will develop metastatic spread during the course of the disease, the most frequent sites being the liver, lungs and peritoneum. With the exception of a minority of cases with oligometastatic disease that is amenable to complete surgical resection, treatment is mainly palliative in intent. Despite recent advances in systemic therapy, median patient survival does not exceed 30 months (2). First- and second-line systemic treatments consist of chemotherapy with fluoropyrimidine-based doublets or triplets plus targeted therapy with monoclonal antibodies directed against the vascular endothelial growth factor (bevacizumab, aflibercept) or the epidermal growth factor receptor (EGFR) (cetuximab or panitumumab). For patients progressing to or not tolerating these agents, third-line therapies include antiangiogenic, multitargeted tyrosine-kinase inhibitors (regorafenib, fruquintinib) or bio-chemotherapy with trifluridine-tipiracil plus bevacizumab (3). These third-line and beyond treatment options are not biomarker-directed and have yielded limited efficacy.

Mutations in the rat sarcoma viral (RAS) genes are among the most common oncogenic events in CRC. RAS are small membrane-bound guanine nucleotide-binding proteins playing a crucial role in different signaling pathways. In fact, RAS genes participate in modulating cell growth, differentiation, migration and survival. They are also involved in several mechanisms of neoplastic initiation, tumor progression and resistance to targeted agents. The RAS family of oncogenes includes three variants: Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), and Harvey rat sarcoma viral oncogene homolog (HRAS), all of them located in 12p. Nearly 45% of metastatic CRC present with KRAS mutations, mainly in exon 2 (codon 12 in 80% and codon 13), and less frequently in exons 3 and 4 (4). Mutations in NRAS are uncommon (5–10% of CRC). Determination of RAS mutational status plays a crucial role in the treatment decision-making process of patients with metastatic CRC. KRAS mutation defines a population of patients with both poor intrinsic prognosis and lack of benefit (or even deleterious effect) with anti-EGFR agents. Until recently, different mutations in KRAS have been considered equivalent in terms of prognostic and predictive implications. In the last years, however, the discovery of the possibility to target KRAS glycine-to-cysteine mutation at codon 12 (G12C) has changed this clinical scenario. The KRAS G12C mutation is found in only 2–4% of metastatic CRC and shows scarce geographic variation (United States, Japan or North Europe) in mutational rates. Both genders are equally affected, there is a 60% predominance for left-sided tumors, and no differences in stage at presentation or metastatic pattern have been described. Several retrospective investigations have reported that this mutation is associated with a more aggressive disease, unfavorable response to conventional chemotherapy, and inferior long-term survival in comparison with other non-G12C KRAS mutations. In a series of 111 patients, 62% and 36% could receive second and third lines of therapy, respectively (5). A distinct molecular profile has been described with high rate of EGFR activation at baseline, more common phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA) mutation and diminished profile of immune expression (6).

Since the identification of RAS genes in 1982, KRAS has been considered an undruggable target. The inhibition of KRAS has been troublesome due to the lack of actionable pockets on its surface. Furthermore, the development of direct KRAS inhibitors has failed because of the increased affinity of guanosine triphosphate (GTP) and guanosine diphosphate (GDP) to KRAS and augmented intracellular concentrations of both molecules. In contrast, recent research has initiated some success given the chance to target KRAS by means of low-weight organic molecules with high affinity for this protein, and the recognition of two pockets on the KRAS surface, mainly the Switch II one situated over the Switch II loop in the GDP of KRAS G12C (7). A breakthrough was accomplished with the development of specific covalent inhibitors designed against KRAS G12C mutation such as sotorasib and adagrasib, that are administered orally. Table 1 shows the results of completed clinical trials involving selective KRAS G12C inhibitors.

The safety and antitumor activity of sotorasib was tested in a phase I study including a cohort of patients with pretreated KRAS G12C mutated metastatic CRC. Objective response rates (ORR) were observed in 7.1%, stable disease (SD) in 71.8%, and median progression-free survival (mPFS) was 4.0 months (8). The most common adverse events were diarrhea, fatigue and nausea. In a phase II expansion cohort, ORR were observed in 10%, SD in 73%, mPFS was 4 months, and median overall survival (mOS) was 10.6 months (9). In a phase I trial, adagrasib monotherapy demonstrated ORR in 19%, mPFS was 5.6 months and mOS 19.8 months, with a similar toxicity profile (10). Grade 3–4 adverse events occurred in 34% of patients (mainly diarrhea and emesis). Among the KRAS G12C inhibitors available to date, the efficacy of single agents as sotorasib or adagrasib in CRC has resulted significantly inferior to that observed in non-small cell lung cancer. This lower response rate is similar to the results employing other inhibitors of the mitogen-activated protein kinase (MAPK) pathway. The intrinsic resistance is probably derived from key differences in the tumor biology of CRC. The redundancy of KRAS signaling, with subsequent stimulation of several feedback processes, parallels the need for double inhibition to target B-rapidly accelerated fibrosarcoma (BRAF) V600E mutation in CRC (11). This implies that inhibition of a RAS-BRAF-MAPK pathway that is overstimulated requires a concomitant EGFR blockade.

It has been shown that KRAS G12C mutation in metastatic CRC still depends on the EGFR signal pathway. In fact, activation of EGFR decreases the efficacy of KRAS G12C direct inhibition. In this setting, targeted therapy with monoclonal antibodies directed against the EGFR in combination with low-molecular weight, oral KRAS G12C inhibitors (dual blockade) constitute a promising treatment approach. In the KRYSTAL-1 trial, the combination of adagrasib plus cetuximab showed an ORR of 46%, mPFS of 6.9 months, and mOS of 13.4 months. The disease-control rate (DCR) was 100% (10). In a phase 3 trial, 160 patients with refractory CRC with mutated KRAS G12C were randomized to be given sotorasib (960 mg) plus panitumumab, sotorasib (240 mg) plus panitumumab, or the investigator’s selection of third-line trifluridine-tipiracil or regorafenib. After a median follow-up of 7.8 months, PFS was significantly improved, with mPFS of 5.6, 3.9, and 2.2 months, respectively. The treatment effect of both doses of the combination on PFS in different prespecified subgroups showed no significant correlations. ORRs were 26.4%, 5.7%, and 0, respectively. Treatment-related, grade 3 or higher toxicity was seen in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related adverse events and hypomagnesemia were the most frequent toxic effects associated with the experimental arm of sotorasib-panitumumab (12).

The recent publication by Kuboki et al. in Nature Medicine (13) confirms previous data and reinforces the safety and benefit with a combination of an oral, small molecule inhibiting KRAS G12C plus an anti-EGFR monoclonal antibody for patients with refractory KRAS G12C-mutated metastatic CRC. The authors report a dose-exploration cohort (8 patients) and a dose-expansion cohort (40 patients) of the phase 1b substudy of the CodeBreaK 101 trial with sotorasib plus panitumumab. The primary endpoints included safety and tolerability. Secondary endpoints were clinical efficacy and pharmacokinetics. In addition, exploratory baseline biomarkers were tested. Adverse events of any grade and grade 3 or more were seen in 94% and 27%, respectively. The most common ones were dermatologic, in the form of skin rash and acneiform dermatitis. No treatment-related grade 4 or 5 adverse events were seen nor led to termination of either agent. No dose-limiting toxicities were detected. There were no significant differences in sotorasib pharmacokinetics between monotherapy and the combination, suggesting no clinically relevant drug interactions. The confirmed ORR in the dose-expansion cohort was 30%, mPFS was 5.7 months and mOS was 15.2 months. These results are in line with and confirm previous reports with the same combination of sotorasib plus panitumumab or the analogous combination of adagrasib plus cetuximab. No direct comparison of results can be made between the CodeBreak 101 study and the KRYSTAL-1 data because of differences in trial design, previous treatment lines, patient profile, and sample size. However, these results support the concept that sotorasib and adagrasib work synergistically with the anti-EGFR monoclonal antibodies, as observed in preclinical studies (4,7). Efficacy results are significantly better with the combination of drugs (in comparison with either monotherapy) or in patients not previously exposed to a KRAS G12C inhibitor (dose-expansion cohort). In a subgroup analysis, objective responses were reported in 44.4% of Japan patients vs. 25.8% of patients from the United States. Response rates and median PFS were similar, independently of the sidedness of the primary tumor. The most prevalent gene alterations in baseline cell-free DNA were adenomatous polyposis coli gene (APC) (84%), tumor protein 53 (TP53) (74%), mothers against decapentaplegic homolog 4 (SMAD4) (33%), PIK3CA (28%) and EGFR (26%). Other co-alterations, such as those in non-V600E BRAF or AT-rich interactive domain-containing protein 1A (ARID1A) were associated with shorter PFS. This finding is in line with other reports involving these genetic alterations in the resistance to EGFR blockade and merits future biomarker studies.

Trials are ongoing with sotorasib plus panitumumab and adagrasib plus cetuximab in KRAS G12C-mutated CRC (14). Confirmatory randomized studies should refine the role of these combinations in metastatic CRC from advanced lines of therapy to the frontline treatment. Furthermore, KRAS-GTP inhibitors and other next-generation molecules could increase response rates and overcome some mechanisms of resistance to directed therapy (15). Other clinical trials in progress are investigating new KRAS G12C inhibitors as JAB-21822, BI 1823911, LY3537982, JDQ443 or GDC-6036 either as single agents or in combination with other drugs (14). Direct pan-RAS or pan-KRAS inhibitors work independently of the mutated allele and have shown activity also in RAS wild type patients. Preclinical results and early clinical data are promising (16). In addition, several investigational molecules are being tested in combination with KRAS G12C inhibitors. Alongside the use of specific inhibitors and their combinations, new approaches to interfere with RAS signaling are under evaluation: targeting cell membrane localization through farnesyltransferase inhibition, sarcoma (Src) homology region 2-containing protein tyrosine phosphatase 2 inhibitors, son of sevenless homolog 1 (SOS1) inhibitors, and blocking KRAS signaling pathways downstream, such as the MAPK-rapidly accelerated fibrosarcoma (RAF)-extracellular signal-regulated kinase (ERK) cascade (4). Other promising avenue is the combination of KRAS G12C inhibition with immune checkpoint blockade therapy (17). Future investigation should better delineate which is the most effective treatment approach for mutant KRAS G12C metastatic CRC patients.

Optimal treatment strategy for patients with metastatic CRC is evolving. The discovery and progressive definition of the molecular landscape of the disease has been cornerstone. The identification of several tumor molecular targets has resulted in the development of directed drugs, thus initiating the era of precision medicine for the individual patient (18). In the first- and second-line setting, therapeutic algorithms now rely on a molecular stratification for RAS (KRAS and NRAS), BRAF V600E and high microsatellite instability/DNA mismatch repair genetic alterations. In latter lines of therapy, a relatively small but growing proportion of patients may benefit from additional molecular testing for targetable alterations such as human epidermal growth factor receptor 2 (HER2) amplification, neurotrophic tropomyosin receptor kinase (NTRK) or rearranged during transfection (RET) fusions and now KRAS G12C mutations. The next steps will be to integrate the current knowledge of tumor gene alterations, microenvironment profile of protein expression, host immune mechanisms, and application of this information in a personalized treatment approach through all treatment lines. Newer, more precise prognostic and predictive parameters could help clinicians in choosing the most appropriate treatment approach for each patient with metastatic CRC.

Acknowledgments

Funding: None.

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References

1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
2. Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA 2021;325:669-85. [Crossref] [PubMed]
3. Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34:10-32. [Crossref] [PubMed]
4. Ciardiello D, Maiorano BA, Martinelli E. Targeting KRAS(G12C) in colorectal cancer: the beginning of a new era. ESMO Open 2023;8:100745. [Crossref] [PubMed]
5. Ciardiello D, Chiarazzo C, Famiglietti V, et al. Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM). ESMO Open 2022;7:100567. [Crossref] [PubMed]
6. Henry JT, Coker O, Chowdhury S, et al. Comprehensive Clinical and Molecular Characterization of KRAS (G12C)-Mutant Colorectal Cancer. JCO Precis Oncol 2021;5:PO.20.00256.
7. Ottaiano A, Sabbatino F, Perri F, et al. KRAS p.G12C Mutation in Metastatic Colorectal Cancer: Prognostic Implications and Advancements in Targeted Therapies. Cancers (Basel) 2023;15:3579. [Crossref] [PubMed]
8. Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 2020;383:1207-17. [Crossref] [PubMed]
9. Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRAS(G12C) mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 2022;23:115-24. [Crossref] [PubMed]
10. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med 2023;388:44-54. [Crossref] [PubMed]
11. Ji J, Wang C, Fakih M. Targeting KRAS (G12C)-Mutated Advanced Colorectal Cancer: Research and Clinical Developments. Onco Targets Ther 2022;15:747-56. [Crossref] [PubMed]
12. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. N Engl J Med 2023;389:2125-39. [Crossref] [PubMed]
13. Kuboki Y, Fakih M, Strickler J, et al. Sotorasib with panitumumab in chemotherapy-refractory KRAS(G12C)-mutated colorectal cancer: a phase 1b trial. Nat Med 2024;30:265-70. [Crossref] [PubMed]
14. Available online: https://clinicaltrials.gov
15. Qunaj L, May MS, Neugut AI, et al. Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer. Front Oncol 2023;13:1252516. [Crossref] [PubMed]
16. Kim D, Herdeis L, Rudolph D, et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 2023;619:160-6. [Crossref] [PubMed]
17. Zhang Z, Rohweder PJ, Ongpipattanakul C, et al. A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell 2022;40:1060-1069.e7. [Crossref] [PubMed]
18. Ciardiello F, Ciardiello D, Martini G, et al. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin 2022;72:372-401. [Crossref] [PubMed]