KRAS G12C inhibitors in metastatic colorectal cancer: a tale of two targets

Sotorasib is an irreversible inhibitor of the RAS guanosine triphosphatase (GTP)ase, specifically targeting the mutation involving glycine 12 to cysteine in the Kirsten rat sarcoma viral oncogene homolog (KRAS G12C). It works by covalently binding to a pocket in the switch 2 region, trapping KRAS G12C in an inactive state (1). In 2021, sotorasib has been granted accelerated approval for the treatment of pretreated locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults with KRAS G12C mutation by the Food and Drug Administration (FDA). The approval was supported by a Phase 1/2 clinical trial (NCT03600883) in 124 patients, which demonstrated an overall response rate (ORR) of 36% [95% confidence interval (CI): 28% to 45%] with a median response duration of 10 months (2).

In colorectal cancer (CRC), the KRAS G12C sequence variant is found in 3–4% and is associated with poor prognosis (3-5). Sotorasib as a single agent in patients with KRAS G12C-mutated metastatic CRC (mCRC) showed a moderate ORR of 9.7% (6). In the Phase 1 escalation study (2), sotorasib was administered at doses of 180, 360, 720 and 960 mg. The response rate in mCRC was higher with the daily 960 mg dose compared to all other doses combined. Three patients (12.0%) had a confirmed objective response and 20 patients (80.0%) had disease control in the 25 patients receiving the daily 960 mg dose. No responses were observed at the reduced dose levels.

Recently, additional results on distinct KRAS G12C inhibitors have been reported. Yaeger et al. observed that adagrasib (7) induced an ORR of 19% in 43 patients. In a Phase 1 dose-escalation basket study, divarasib achieved a confirmed partial response in 29.1% (95% CI: 17.6% to 42.9%) of 55 patients with mCRC (8).

Several studies have shown that both high levels of basally active epidermal growth factor receptor (EGFR) signaling and adaptive feedback leading to overactivation of EGFR-RAS-mitogen-activated protein kinases (MAPK) signaling following KRAS G12C inhibition, may be the essential mechanisms of primary resistance to KRAS G12C inhibitors (9,10). Thus, combining a KRAS G12C inhibitor with a monoclonal antibody against EGFR may be more effective in the clinic. The reactivation of MAPK signaling, mediated by EGFR, is an adaptive feedback mechanism that constitutes a primary and acquired resistance mechanism to B-Raf proto-oncogene (BRAF) inhibitors monotherapy in BRAF V600E mCRC (11). A dual BRAF-EGFR blockade with cetuximab and encorafenib improved overall survival (OS), progression-free survival (PFS) and responses in previously treated BRAF V600E mCRC patients compared with other chemotherapy options (12).

The Phase 1b trial published by Kuboki et al. in 2024 (13) is designed to evaluate the safety and efficacy of the combination. Of sotorasib plus panitumumab in refractory mCRC and KRAS G12C mutation, utilizing a planned dose de-escalation scheme. The KRAS G12C was confirmed by local molecular testing. The study includes two cohorts: a dose exploration cohort and an expansion cohort. Patients were enrolled in the United States and Japan from June 24, 2020, to December 21, 2021. The primary objectives for both cohorts were safety and tolerability. Safety was measured by the occurrence of adverse events and dose limiting toxicities (DLTs) within the first 4 weeks. The initial doses explored (level 1) were sotorasib 960 mg orally, once daily (OD) and panitumumab 6 mg/kg, once every two weeks (Q2W), which are the standard doses of both drugs. Secondary endpoints included efficacy and pharmacokinetics.

In all, 48 patients (eight in the dose-finding cohort and 40 in the extension cohort) were treated. No DLTs were observed in the exploration cohort. Thus, all the patients in both cohorts received dose level 1. Treatment-related adverse events (TRAEs) of any grade and grade ≥3 and of any grade occurred in 13 (27%) and 45 (94%) patients, respectively. The most common grade 3 TRAEs were rash (6%), acneiform dermatitis (4%) and hypomagnesemia (4%). Nevertheless, no TRAEs led to discontinuation of sotorasib, although panitumumab was discontinued in one patient.

In the dose-finding cohort, one KRAS-G12C inhibitor-naive had a confirmed partial response (ORR =12.5%; 95% CI: 0.3% to 52.7%). The disease control rate (DCR) was 75.0% (95% CI: 34.9% to 96.8%). Five patients had received prior sotorasib treatment as single drug and 80% achieved stable disease. In the expansion cohort, the ORR was 30% (95% CI: 16.6% to 46.5%), with a DCR of 92.5% (95% CI: 79.6% to 98.4%). The duration of response was 5.3 months (95% CI: 2.8 to 7.4 months). Of note, the response evaluation was based on investigator assessment. With a median follow-up of 16.7 months, the median PFS was 5.7 months (95% CI: 4.2 to 7.7 months), and the median OS was 15.2 months (95% CI: 12.5 to not estimable). Regardless of primary tumor location (left or right), sotorasib plus panitumumab showed similar efficacy. No data have been reported regarding other clinical factors, as sex, time from initial diagnosis of metastases, number of metastatic sites, or presence of liver metastases.

The exploratory endpoints included an assessment of genomic alterations at baseline, based on a comprehensive analysis of circulating-free DNA (cfDNA). The KRAS G12C sequence variant was found in 41 out of 43 patients, although with a very low variant allelic frequency (VAF; 0.0009 to 0.5810). Concurrent genomic alterations, which may condition the potential response to anti-EGFR and/or sotorasib, were found in PIK3CA (28%), EGFR (26%), BRAF non-V600 (19%) and ARID1A (14%). Although the number of patients is limited, the authors suggest that the presence of alterations in BRAF or ARID1A could be associated with worse PFS, but do not provide data regarding other alterations found in cfDNA. Finally, pharmacokinetic analysis showed that sotorasib exposure was similar in all patients, enrolled at centers in Japan or the United States.

The efficacy and safety and efficacy results of sotorasib combined with panitumumab have been reinforced and validated in other Phase 1/2 clinical trials evaluating other combinations of KRAS G12C inhibitors and anti-EGFR agents. In the Phase 1/2 trial KRYSTAL-1, adagrasib and cetuximab were evaluated in 32 patients (7). TRAEs of grade 3 or higher were reported in 16%. Cetuximab was discontinued due to toxicity in 16%. The ORR was 46% (central review), with a median PFS of 6.9 months. Combining divarasib and cetuximab in a Phase 1 study (14) achieved a response rate (determined by the investigator) of 62.5% in 24 patients who have not received prior treatment with another KRAS G12C-targeting agent. The median PFS was 8.1 months. TRAEs resulted in 4 patients (13.8%) having to reduce the dose of divarasib, with no discontinuations. Cetuximab was suspended in one patient (3.4%).

Approximately 88% of patients in the adagrasib-cetuximab study (7) and 77.3% of patients in the divarasib-cetuximab study (14) showed a reduction in KRAS G12C VAF with the treatment, based on serial cfDNA analysis, but these assessments were performed at different time points. Future studies could analyze whether early and serial evaluation of KRAS G12C VAF in cfDNA would aid in titrating the appropriate dose of the specific inhibitor in combination with anti-EGFR for each patient.

Moreover, data from randomised Phase 3 trial (CodeBreaK 300) confirmed that sotorasib plus panitumumab resulted (15) in longer PFS than standard treatment (regorafenib or trifluridine/tiparacil) in chemorefractory mCRC (median number of previous lines =2). In this trial, sotorasib was evaluated at two doses, (960 mg OD in 53 patients and 240 mg OD in 53 patients) in combination with panitumumab (6 mg/kg Q2W). Patients were included form 76 sites across 12 countries. Radiologic assessment was performed by blinded independent central review. The median PFS was 5.6 months (95% CI: 4.2 to 6.3 months), 3.9 months (95% CI: 3.7 to 5.8 months) and 2.2 months (95% CI: 1.9 to 3.9 months) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and control groups, respectively. The hazard ratio (HR) for PFS (primary end point) in the 960-mg sotorasib plus panitumumab group as compared with the control group was 0.49 (95% CI: 0.30 to 0.80; P=0.006), and the HR for the 240-mg sotorasib plus panitumumab group was 0.58 (95% CI: 0.36 to 0.93; P=0.03). The ORR was 26.4% (95% CI: 15.3% to 40.3%), 5.7% (95% CI: 1.2% to 15.7%), and 0% (95% CI: 0.0% to 6.6%) in the 960-mg sotorasib plus panitumumab, 240-mg sotorasib plus panitumumab, and control groups, respectively. However, no formal comparison of doses of sotorasib 960 vs. 240 mg was made. At the time of publication, the data on OS were not mature. The HRs in the sotorasib plus panitumumab group as compared with the control group were 0.77 and 0.91 for the 960 and 240 mg subgroups respectively.

In the various trials with KRAS G12C inhibitors, the proportion of women appears to be higher (ranging from 50% to 73%) than in other trials conducted in mCRC in the third or subsequent lines (16-19): CORRECT, 38–40%; RECOURSE, 39–38%; SUNLIGHT, 49.6–54.5%; FRESCO2, 39–47%. These discrepancies could be explained by differences in the incidence of KRAS G12C mutations or in the prognosis of this mutation according to gender (20). It remains to be seen whether the efficacy of anti-KRAS G12C drugs will differ according to gender. In the subgroup analysis of the CodeBreaK 300 (15), the HR for PFS in the female cohort was 0.35 (95% CI: 0.17 to 0.73) in the 960-mg sotorasib plus panitumumab group as compare with the control group and 0.63 (95% CI: 0.31 to 1.27) in the 240-mg sotorasib plus panitumumab group as compared with the control group.

Phase 1b trial results presented by Kuboki et al. (13) suggest that effectively blocking KRAS G12C in mCRC is “a tale of two targets”. Moreover, Phase 3 results support the combination of sotorasib 960 mg plus panitumumab as a new treatment option in mutated KRAS G12C chemo refractory mCRC patients. The doublet of KRAS G12C and EGFR blockade is also currently being studied in an earlier line of treatment in randomized trials CodeBreaK 301 (ClinicalTrials.gov; NCT06252649) and KRYSTAL-10 (ClinicalTrials.gov; NCT04793958) in mCRC and even in the pre-operative setting in resectable KRAS G12C CRC (ClinicalTrials.gov; NCT05845450).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-48/coif). J.M.P. received honoraria and support for attending meetings and travel from Bristol-Myers Squibb, Merck Sharp & Dohme Corp, and Merck. M.V.A. received contracts from AMGEN (Research contract, personal fees) and ROCHE (Research contract, Institutional); consulting fees from AMGEN, SERVIER, and SANOFI; payment from MSD, Bristol-Myers, and Merck; support for attending meetings and travel from Merck, SERVIER, and AMGEN; and is the member on Advisory Board from AMGEN, SERVIER, and MERCK. The authors have no other conflicts of interest to declare.

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References

1. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019;575:217-23. [Crossref] [PubMed]
2. 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]
3. Fakih M, Tu H, Hsu H, et al. Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer. Oncologist 2022;27:663-74. [Crossref] [PubMed]
4. 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.
5. Osterlund E, Ristimäki A, Kytölä S, et al. KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer. Front Oncol 2022;12:826073. [Crossref] [PubMed]
6. 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]
7. 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]
8. Sacher A, LoRusso P, Patel MR, et al. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. N Engl J Med 2023;389:710-21. [Crossref] [PubMed]
9. Amodio V, Yaeger R, Arcella P, et al. EGFR Blockade Reverts Resistance to KRAS(G12C) Inhibition in Colorectal Cancer. Cancer Discov 2020;10:1129-39. [Crossref] [PubMed]
10. Ryan MB, Coker O, Sorokin A, et al. KRAS(G12C)-independent feedback activation of wild-type RAS constrains KRAS(G12C) inhibitor efficacy. Cell Rep 2022;39:110993. [Crossref] [PubMed]
11. Corcoran RB, André T, Atreya CE, et al. Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer. Cancer Discov 2018;8:428-43. [Crossref] [PubMed]
12. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol 2021;39:273-84. [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. Desai J, Alonso G, Kim SH, et al. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nat Med 2024;30:271-8. [Crossref] [PubMed]
15. 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]
16. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303-12. [Crossref] [PubMed]
17. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015;372:1909-19. [Crossref] [PubMed]
18. Prager GW, Taieb J, Fakih M, et al. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med 2023;388:1657-67. [Crossref] [PubMed]
19. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet 2023;402:41-53. [Crossref] [PubMed]
20. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRAS (G12C) Somatic Mutations across Race, Sex, and Cancer Type. N Engl J Med 2021;384:185-7. [Crossref] [PubMed]