KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials

Erman Akkus a,b\*, Nejat Emre Oksuz a,b, Enes Erula,b

AnkarvesitFaculficintfdclclgynkarary AnkaraivrsitaneeserchstitAnkararky

ARTICLEINFO

ABSTRACT

Keywords:
Metastatic colorectal cancer
KRAS mutation
KRAS G12C
RAS inhibitor
Anti-EGFR

Background: 1-2% of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation.This study aims to pool theresults of available clinicaltrials of KRAS-G12Cinhibitors,comparing monotherapy and combinations.

Methods:A systematicliterature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts.PhaseI-I-IItrialsthat investigatedaKRAS-G12Cinhibitorinpatients withmCRCwereincludedThe primary endpoints were objective response rate (ORR) and progression-free survival (PFS).Pooled proportions and comparative subgroup analysesformonotherapy andcombinationswere presented withtherandomeffects model.

Results:96patientswithpreviouslytreatedmCRCin14studycohortstreatedwithnefsotorasib,adagrasi divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9% 0 95%CI 20.7-48.4) (I^{2}; 87.1), which is significantly higher than monotherapy [16.7% (95%{CI}; 8.3-27.3) (\boldsymbol{I}^{2};73.2)] \mathbf{\left(p=0.045\right)} .Median PFS was significantly longer with the combination [5.7 months( 95%CI : 4.47.1) (\boldsymbol{I}^{2}, :80.8) vs. 4.2 months 95%CI{:} 3.64.7) (\boldsymbol{I}^{2};0.0) 办 \mathbf{p}{=}0.027] ， Grade 3-4treatment-related adverse events(TRAEs)were significantly more frequent withthe combination [32.8% 95%CI; 26.4-39.6) (I^{2}{:}42.5) Vs. 16.5% 95%CI; 4.9-33.1) (I^{2}) 84.2), \mathbf{p}=0.047] .Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.

Conclusion:This analysis suggests that KRAS-G12Cinhibitorsincombinationwithanti-EGFRagents mayprovide a doubled ORRand1.5-month FSbenefit compared to monotherapyin previously treated mCRC patients,but withadoubledgrade4TRAEsincluding skintoxicitiparonychiaandhpomagnsmiareatment rf erences should be individualized in these highly pretreated patients.

1.Introduction

Colorectal cancer(CRC)is the third mostcommon cancer and the second most common cause of cancer mortality worldwide,with nearly 2 million new cases annually (Morgan et al., 2023; Siegel et al., 2023). The burden is expected to increase to 3.2 million new cases by 2040 (Morgan et al., 2023). Nearly 20% of the patients have metastatic disease at diagnosis (Biller and Schrag,2021).Among patients with metastatic CRC (mCRC), 40% have activating mutations in KRAS. Of those, G12D (30%36%) ,G12V (20%-22%) ,and G13D (15%-18%) arethe most common mutations,whereas KRAS-G12C represents approximately 3% of activating mutations (Pellatt et al., 2024).

RAS was considered untargetable for years,however, recent advancementshaveenabledoncologists totargetRASwiththedevelopment of mutation-specific, pan-KRAS,and pan-RAS inhibitors (Sahin et al., 2024). In non-small cell lung cancer (NSCLC), KRAS-G12C is the most common variant (40%) among the observed KRAS mutations, representing 10-13% of advanced non-squamous NSCLC (Lim et al., 2023).Sotorasib and adagrasib received approvals in 2021 and 2022, respectively,and are recommended for advanced/metastatic NSCLC harboring KRAS-G12C in the second line and beyond (Hendriks et al., 2023).AlthoughKRAS-G12Cmutations constitute a smallpercentage of KRAS mutations in mCRC,its inhibitors were most investigated and are the first agents among RAS inhibitors entering the treatment algorithm

Identificationofstudies

MEDLINE:

(sotorasib[Title/Abstract])AND(colorectal[Title/Abstract]), n=67 (adagrasib[Title/Abstract])AND(colorectal[Title/Abstract]), n=48 of mCRC ((NCCN), 2024). Second-line and subsequent treatment options for KRAS-mutant mCRC include chemotherapies, anti-angiogenic agents, trifluridine-tipiracil with or without bevacizumab,regorafenib, and fruquintinib(Cervantes et al.,2023).However,available options provide limited benefits with considerable toxicity in the third line. Biomarker-directed therapies,including KRAS-G12C inhibitors, are additionally recommended in second-line or beyond ((NCCN),2024; Cervantes and Martinelli, 2024),with promising efficacy.TheFood and Drug Administration (FDA) has recently approved KRAS-G12C inhibitors (sotorasib in 2025 and adagrasib in 2024) in combination with anti-epidermal growthfactorreceptor(anti-EGFR)agents (cetuximab, panitumumab) because of the increased efficacy with the combination ((NCCN), 2024).

Fig. 1.PRISMA flow diagram of search strategy and study selection.

Despite the promising advancement and approval of combinations, the studies of KRAS-G12C inhibitors are mainly phaseI and II studies with small sample sizes.The studiesincluded highly pretreated patients, including 4 or moreprevious lines.Toxicity and symptom palliation are major concerns in this pretreated patient group,affecting the treatment preferences.Therefore,this study aimstopool theefficacy and toxicity results of available clinical trials of KRAS-G12C inhibitors in mCRC, comparing monotherapy and combinations to reach a perspective to assist daily practice treatment preferences.

2.Methods

2.1.Literature search and study selection

A systematic literature search was conducted in the MEDLINE database andEuropeanSociety of Medical Oncology(ESMO)/American Society of Clinical Oncology (AsCO) meeting abstracts, in compliancewithPreferredReportingItemsforSystematicReviews andMetaAnalyses (PRISMA) guidelines(Page et al., 2021) (Fig. 1). An unstructured literature search was conductedto detectKRAS-G12Cinhibitors investigated in mCRC(Deming, 2025). Sotorasib (AMG 510), adagrasib (MRTX849),divarasib(GDC-6036),and olomorasib(LY3537982)were determined as agents that had reported clinical trials in mCRC.The searchstrategiesof(sotorasib[Title/Abstract]）AND (colorectal [Title/Abstract]), (adagrasib[Title/Abstract]) AND (colorectal [Title/Abstract]), (divarasib[Title/Abstract]) AND (colorectal [Title/Abstract]),(olomorasib[Title/Abstract]) AND (colorectal [Title/Abstract]),AMG 510[Title], MRTX849[Title], GDC-6036[Title], LY3537982[Title] were used in the MEDLINE database. Eight agent names were separately used for the search in the meeting source engines of ESMO and ASCO websites (sotorasib,AMG 510, adagrasib,MRTX849, divarasib,GDC-6036,olomorasib,LY3537982).

Phase I, II, and II trials that investigated one of the KRAS-G12C inhibitors in metastatic colorectal cancer as monotherapy or combined with othersystemic treatments were eligible.Only trials writtenin Englishwereincluded.Prospectiveandretrospectiveobservational studies, in-vitro and computational studies,preclinical studies, case reports,reviews,letters, correspondences, approval reports, expert opinions, and guidelines were excluded.

2.2. Data extraction and endpoints

The titles and abstracts of the studieslistedbased on the search strategy were screened accordingtoinclusion-exclusioncriteria.Thefull texts/meeting dataofstudieswere assessedindependentlyby tworesearchers (E.A. and N.E.O.) to extract data.Any discrepancies between the reviewers were resolved through the assessment of the third author (E.E.) and the final consensus. If the trial was a basket trial, data for only patients with mCRC were extracted.Thefollowing datawere recorded: Study name, first author and publication year, phase of the trial, drug and dosage,sample size,median age,percentageofmales,percentagef Eastern Cooperative Oncology Group performance scores (ECOG-PS), lines of previous treatment, complete,partial response and stable disease rates,objective response rate (ORR),disease control rate (DCR), median follow-up duration, median progression-free survival (PFS), median overall survival(Os), rate of treatment-related adverse events (TRAE) (any grade and grade 3-4) and most common adverse events.

The primary endpoints were ORR and PFS, and the secondary endpoint was TRAEs.The studies’ characteristics, efficacy, and toxicity results were presented. ORR, PFS, and TRAEs were pooled and compared between monotherapy and combinations by subgroup differences.

2.3.Risk of bias assessment

The ROB-ME tool (Page et al., 2023) was used to assess the risk of bias due to missing evidence in primary endpoints. The tool contains foursteps:Step1is selecting and defining themeta-analyses that will be assessed.Step 2 is completing the study matrix for missing results.Step 3 considers the potential for missing studies across the systematic review.Step 4 assesses the risk of bias due to missing evidence in the meta-analysis.The key for results in the ROB-ME tool is given in Table S1.

Modified Cowley's criteria (Alsinbili, 2023), a scoring method to assess the risk of bias in single-arm trials,was additionally utilized. It included a total of 13 criteria,each is scored by 2 for satisfactory reporting,1 for partialreporting, and 0 for no reporting.The total score of 24-26/26 is grouped as“low risk of bias", 20-23/26 as“moderate risk of bias", and <20/26 as “high risk of bias"(Table 1).

2.4.Statistical analyses

Continuous variables werepresented asmedian(range)forindividual study data and median [95% Confidence Interval (CI)] for pooled analyses. Categorical variables were presented as the percentage forindividual study data and the percentage 95% CI) for pooled analyses.The meta-analyses of ORR and TRAEs were performed using the proportion method andFreeman-Tukey transformation(Freeman and Tukey,1950). Meta-analysis of the PFS and subgroup analyses were performedby using theinversevariance method.All analyses were calculated and reported according to the random effects model.All p-values were based on a 2-tailed test of significance (\mathbf{p}=0.05) .Higgins' I square statistics (I^{2}) was used to quantify the degree of heterogeneity between the studies (Higgins et al., 2003). The analyses and visualization were performed using R Version 4.4.2, RStudio, and MedCalc Statistical Software version 22.026(MedCalc Software Ltd, Ostend, Belgium).

3.Results

3.1.Studies and characteristics

The systematic literature search according to the search strategy yielded 306 records. After the exclusion of 292 records,a total of 14 reports (9 arefull-text publications and5are meeting abstracts/presentations) were included (Desai et al., 2024; Fakih et al.,2024;Fakih et al.,2022;Fakih et al.,2023;Heist et al.,2024;Hollebecque et al., 2024;Hong et al.,2020;Hong et al.,2023;Kuboki et al.,2024;Ouet al., 2022; Sacher et al., 2023; Yaeger et al., 2025; Yaeger et al., 2024; Yaegeret al.,2023).3of the meeting abstracts were utilizedforupdated survival results (Fakih et al., 2024;Heist et al.,2024;Yaeger et al., 2025).A total of 596 patients were included in the studies (Fig.1, PRISMAdiagram).14 treatment arms and patient cohorts were formed from the included studies (Table 2). 6 of those (42.9%) weremonotherapy and 8 (57.1\ %) werecombinationtreatments.9 (64.3%) were phase I, 2 (14.3%) were phase II, 1 (7.1\ %) was phase I-Il, and 2 (14.3%) were phase IlItrial arms.The trialswerereported between 2020 and 2024. All trials included patients who received at least 1 previous line of treatment in the metastatic setting.Patients who received only1 previous line of treatment constitute a small percentage and minority in the trials. The trials and characteristics, including efficacy results, are presented in Table 2.

3.2.Risk of bias assessment results

Step1 of the ROB-ME tool for risk of bias assessment was defined in relevant sections of this study.Step 2(result matrixfor the risk of bias assessment) is presented in Table1.Step 3 was concluded as“We were likely to have found all eligible studies regardless of their results". In

Fig.2.a)bjetiveresponserate(ORR andb)Diseae controlrate DCR)withKAS-G12Cinhibitorsinpreviouslytreated mCRC

Fig3Objctiveepnerataodin tthntheraAbitraAGCibtoronre

Step 4, the “Risk of bias judgment”was “Low”for ORR and “Some concerns"for PFS and TRAEs.Scores and bias groups of the studies according to the modified Cowley's criteria scoring are shown in Table 1. Five study arms had a moderate risk, and the remaining had a low risk of bias.

3.3.Eficacy

3.3.1.Objective response rate (ORR)

When all treatments were pooled regardless of monotherapy or combinations,KRAS-G12Cinhibitors provided an ORR of 26.3% 0 95% CI: 17.3-36.6) (\boldsymbol{I}^{2}) 86.06% (Fig. 2a). The disease control rate (DCR) was 73.9% C 95% CI: 73.8-88.4) (I^{2}{:}60.53\ %) (Fig. 2b). In the subgroup analysis for ORR,monotherapies provided an ORR of 16.7% (95%{CI} 8.3-27.3) (I^{2}; ：73.21),whereas ORR with combination treatments was 33.9% 95%CI : 20.7-48.4) (I^{2}; 87.13) (Figs. 3a and 3b). The subgroup difference was statistically significant (\mathtt{p}=0.045) ,revealing a higher ORR with the combination.

3.3.2.Progression-free survival (PFS)

The median PFS was 5.1 months( 95% CI: 4.2-6.0) (\boldsymbol{I}^{2}; 77.51)when all treatments were pooled,regardless of monotherapy or combinations (Fig. \mathbf{4}\mathbf{a}_{,}^{~\tiny~} 0.ThemedianPFSwith monotherapyKRAS-G12Cinhibitors was 4.2 months (95 %CI: 3.6-4.7) \scriptstyle(I^{2}:0.0) (Fig. 4b).With combinations, the median PFS was 5.7 months 95% CI: 4.4-7.1) (I^{2}; 80.8) (Fig. 4c). The subgroup difference was statistically significant (\mathbf{p}=0.027) ,suggesting longer PFS with the combination.

3.4.Treatment-relatedadverseevents(TRAEs)

TRAEs of KRAS-G12C inhibitors as monotherapy and in combination were presented in Tables 3 and 4.Adding anti-EGFR agents to the KRASG12C inhibitors caused a different specific toxicity profile than monotherapy, such as hypomagnesemia and skin disorders. Grade 3-4 TRAEs were observed in 16.5% 95\ %CI; 4.9-33.1) (I^{2}; ：84.26)with monotherapy, whereas the frequency of grade 3-4 TRAEs was 32.8% e 95% CI: 26.4-39.6) (I^{2}{:}42.57) with the combination (Figs. 5a and 5b). The subgroup difference was statistically significant (\mathtt{p}=0.047) ,suggesting highergrade 3-4 toxicity with the combination.Subgroup differences of ORR, PFS, and TRAEs are summarized in Figs. 6a, 6b,and 6c.

4.Discussion

This study pooled the currently available data on KRAS-G12C inhibitors in mCRC.The results further support improved ORR and PFS by adding anti-EGFR agents to KRAS-G12C inhibitors,however, with an increasedrateofgrade3-4TRAEs.

Therecommendedfirst-linetreatment of RAS-mutantmCRC is

a

g.4.Progresion-fre suivalPwihlAnibtotherayKAinibto dAGCiibiti on treatments.

doublet or triplet chemotherapy with or without bevacizumab (Cervantes et al., 2023). The options for second-line and beyond treatment include chemotherapies,anti-angiogenic agents likebevacizumab, ramucirumab, or aflibercept, trifluridine-tipiracil with or without bevacizumab,regorafenib,fruquintinib, and biomarker-directed therapies. Considering theefficacy andtoxicity of these available treatment options,KRAS-G12C inhibitors are likely to have a more efficacious and less toxic profile in similar patient groups as a precision treatment, as shown in our study.KRAS-G12C inhibitor and anti-EGFR combinations provided an ORR of 33.9% a median PFS of 5.7 months,and 32.8% of grade 3-4 TRAEs. On the other hand, in the SUNLIGHT trial, patients who had received no more than two previous chemotherapy regimens forthetreatmentofmCRCwererandomizedtotrifluridine-tipiracilwith or without bevacizumab(Prager et al., 2023).Median PFS was 5.6 vs 2.4 months (HR: 0.44; 95% CI, 0.36{-}0.54 D \begin{array}{r}{\mathbf{p}<0.001_{*}^{*}}\end{array} 0,showing the superiority of the combination.ORR,on the other hand,was 6.1% and 1.2% respectively.Grade >=3 adverse eventswerereported in 72.4% and 69.5% of the patients.In the CORRECT trial, regorafenib was compared with the best supportive care in previously treated mCRC (Grothey et al., 2013).Median PFS was 1.9 vs.1.7 months,and ORR was 1% and 0.4% 54% of the patients had grade3-4 adverseevents.In the FRESCO-2 trial, patients who received a median of 4 lines of previous systemictherapyformetastaticdiseasewererandomized tofruquintinib vs.placebo(Dasari et al.,2023).ORR was 2% and themedianPFSwas 3.7months withthefruquintinib.Grade3 or worse adverseevents occurred in 63% of patients.When these data of currently recommended treatmentswere considered,thepromisingefficacy and toxicity results ofKRAS-G12C inhibitors compared to other available options emphasize the testing for targets and precision treatment of patients with mCRC.

Thepreclinical modelsshowed that the selectiveinhibition ofKRASG12CinCRCencounters a treatment resistance through theupstream reactivation of the epidermal growth factor receptor (EGFR) pathway (Amodio et al.,2020).Thus, the synergistic activity of concomitant KRAS-G12C and EGFR inhibitionhas been rationalized and investigated, and thereby,KRAS-G12C inhibitors are approved only in combination with anti-EGFR agents according to the efficacy results.However,as shown in our analysis, grade 3-4 TRAEs are also doubled by adding anti-EGFR agents toKRAS-G12Cinhibitors.These trials included highly pretreated patients.Patients havehigher comorbidity and accumulated treatment toxicities at this stage andhavethepotentialtoexperience morephysical and psychological symptoms throughout the treatment, which can negatively impact quality of life (Karlekar et al.,2023). Therefore, toxicity and quality of life are one of major concerns. Although overall survival results are not mature and trials are not phase III trials except one, our analysis showed that KRAS-G12C inhibitors as monotherapy showed an ORR of 16.7% a median PFS of 4.2, and 16.5% of grade 3-4 TRAEs.These results favor KRAS-G12Cinhibitors when compared with other currently recommended treatment options, as mentioned above.Monotherapy withKRAS-G12C inhibitors maybe considered for patientsfor whom toxicity is a major concern.Additionally,combination treatment creates specific toxicities,such as skin disorders, that should be taken into account. Thus, treatment preferences should beindividualized forpatients with mCRC inlater lines.For example,inpatientsforwhom thetumorshrinkageisthetreatment aim for palliation,the combination may be the option since it provides a higher ORR.As a note, dose-dependent response rates were observed, especially with sotorasib,where the high dose ( 960~mg VS 240~mg, is more effective when combined with panitumumab,yet with slightly increased toxicity (Fakih et al.,2023). ORR rates were 26.4% and 5.7% respectively.Grade3and 4 TRAEs were observed in 35.8% and 3.8% with 960~mg while 30% and 0% with 240~mg

Despite the promising results with KRAS-G12C inhibitors, only around 1{-}2% of mCRC patients have the mutation (Sahin et al., 2024). Therefore,only a small percentage of patients may benefit from these treatments. On the other hand, pan-KRAS [ PF-07934040 (NCT06447662), QTX3034 (NCT06227377), LY4066434 (NCT06607185)] and pan-RAS inhibitors [RSC-1255 (NCT04678648), RMC-6236 （ NCT06445062), YL-17231 (NCT06096974, NCT06078800)] are under development and investigation(Isermann et al., 2025;Sahin et al.,2024).Since any activating RAS mutations are observed in 40% of the patients with mCRC, more patients may benefit from RAS inhibitors in the near future.Moreover,ctDNA assessments during the disease course and progression may provide higher detection rates of target mutations and may identify features of acquired resistance, such as RTK amplifications/fusions,EGFR amplification, secondary mutations inKRAS,KRASamplification, and mutations/fusions in other MAPK pathway genes (Yaeger et al.,2024).Whether testing additionalmutations and ctDNA evaluations couldrefine theuse of combination versus monotherapy may be a future research area.

Finally,the availability,accessibility,and cost of the KRAS-G12C inhibitors, as other novel treatments, is a major issue globally. In 2024, sotorasibwas priced at US844.65 perday and Adagrasib was priced at US885.96 per day(Brazel and Nagasaka,2024).The 2023 update of the ESMO Global Consortium Study on the availability,out-of-pocket costs,andaccessibility of cancer medicines revealed that in lower-middle and low-income countries,even 40% of traditional chemotherapy agents deemed essential in the World Health Organization(WHO)Essential Medicine List are only available atfullcost to patients (Cherny et al., 2025). Therefore, cost and insurance coverage are other parameters for treatment preference for an individual patient and region.

This study has some strengths and limitations. Since the studies of KRAS-G12C inhibitors are mainly phase I and II studies and have small sample sizeswithheterogeneous results (as seenin theheterogeneity test results of our analyses), our study provides a pooled average estimate of efficacy and toxicity to assist daily practice.As far as weknow, this is the first meta-analysis on KRAS-G12C inhibitors in mCRC.As limitations, since most of the trials are phase I and single-arm trials, missing results cause a bias in the analyses.Although the efficacy and toxicity data were extractedfor only patients with mCRC in all trials including phase I-basket trials,some meta-analyses did not include all studies because of missing data.Combining early-phase trials with more mature phase II or II studies with different designs, including varying dosage ranges,causes a limitation.Since the available data comes mainly from phase I and II trials, the comparison between monotherapy and combinations is performed as a subgroup analysis. The characteristics of the patient populations in the trials are similar,however,confounding effects are probable. Some of the data was obtained from meeting abstracts and presentations, which limits the assessment.

5.Conclusion

This study reassures that KRAS-G12C inhibitors are efficacious targeted treatment options in previouslytreatedmCRCpatients andmaybe prioritized in patients who have received prior treatment with fluoropyrimidine-,oxaliplatin-,and irinotecan-based chemotherapy when the target mutation is detected.Combination with anti-EGFR agents provides a significantly higher response rate and progression-free survival thanmonotherapiesbut at thecost of higher grade 3-4 adverse events.Treatment preferences should beindividualized accordingto the needs of these pretreated patients. Overall survival data are promising, and future advancements in inhibiting RAS may continue to shape the treatment algorithm of mCRC.

Authorcontributions

EA formed the study's conception and design. EA, NEO, and EE collected the data, and EA performed the analysis. EA,NEO and EE wrote the draft and revised versions of the manuscript and approved the final manuscript.

Declaration of CompetingInterest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

None.

Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.critrevonc.2025.104741.

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Erman Akkus, MD is a Clinical Medical Oncology Fellow and Internal Medicine Consultant at Ankara University Faculty of Medicine,Department of Medical Oncology,Tirkiye, practicingas anMDfornine years and withexperienceinclinicaland laboratoryprojects and publications in renowned journals. His focus is gastrointestinal malignancies.

Nejat Emre Oksiz, MD is a Clinical Medical Oncology Fellow and Internal Medicine Consultant at Ankara University Faculty of Medicine,Department of Medical Oncology, Tirkiye.

Enes Erul, MD is a Clinical Medical Oncology Fellow and Internal Medicine Consultant at Ankara University Faculty of Medicine,Department of Medical Oncology,Tuirkiye.