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Cited by 527Colorectal Cancer Treatments and StudiesColorectal Cancer Surgical TreatmentsLung Cancer Treatments and Mutations

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C

Open access
Yaeger, Rona, Weiss, Jared, Pelster, Meredith S., Spira, Alexander I., Barve, Minal, Ou, Sai-Hong I., Leal, Ticiana A., Bekaii-Saab, Tanios S. +7 more·2023·New England Journal of Medicine
DOI 10.1056/nejmoa2212419PMC PMC9908297
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Abstract

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

Integrity signals

Registry

Crossref · 10.1056/nejmoa2212419

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 44 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Adagrasib has demonstrated clinical activity in previously treated patients with multiple tumor types, including colorectal cancer.

    “Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer.”
    • Also stated in: § CONCLUSIONS · hedged
      “Preliminary data indicate clinical activity in pretreated patients across nine tumor types with KRAS G12C mutations, including those with colorectal cancer, non–small-cell lung cancer, pancreatic and biliary-tract cancers, and other gastrointestinal and nongastrointestinal cancers.8”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    Combining a KRAS G12C inhibitor with an EGFR antibody could be an effective clinical strategy.

    “Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.”
    • Also stated in: § CONCLUSIONS · hedged
      “Preclinical studies have shown that combining an antibody against EGFR with a KRAS G12C inhibitor could be an effective clinical strategy to mitigate EGFR reactivation.24”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    Adagrasib is an oral small-molecule covalent inhibitor of KRAS G12C that irreversibly and selectively binds the mutant protein in its inactive GDP-bound state.

    “Adagrasib (MRTX849) is an orally available, small-molecule covalent inhibitor of KRAS G12C that irreversibly and selectively binds the mutant protein in its inactive, GDP-bound state.8,20”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] source
    • cites [20] source
  • Premisecitation

    No therapy specifically targeting KRAS G12C protein has been approved for colorectal cancer.

    “Currently, no therapies that specifically target KRAS G12C protein have been approved for the treatment of colorectal cancer.13,19”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] source

      The EGFR resistance section discusses KRAS mutations and resistance to anti-EGFR treatment, but does not address therapies specifically targeting KRAS G12C. Searches for “G12C,” KRAS inhibitors, and approval status found no passage in our copy establishing whether such a therapy was approved for colorectal cancer. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [19] source
  • Premisecitation

    In colorectal cancer, the KRAS G12C allele is associated with worse survival than other KRAS mutations and KRAS wild-type tumors.

    “KRAS mutations have historically been considered to be “undruggable,” and retrospective series of clinical data suggest that the presence of the KRAS G12C allele is associated with worse survival outcomes than other KRAS mutations in patients with colorectal cancer.12,17”
    • Also stated in: § DISCUSSION · plain
      “KRAS G12C mutations occur in approximately 3 to 4% of patients with metastatic colorectal cancer and are associated with shorter survival than are other KRAS mutations and KRAS wild-type tumors.10–12,17,28”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [12] source
    • cites [17] source

      The Abstract reports worse overall survival for patients with KRAS G12C colorectal cancer than for an internal cohort with other KRAS mutations. It does not report a survival comparison with KRAS wild-type tumors; that comparator appears in the supplied claim but not in the verbatim citing sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] source

      The letter’s GENIE analysis reports the frequency of KRAS G12C in colorectal cancer and differences by sex and race (page not provided). Our copy does not report survival outcomes or compare KRAS G12C with other KRAS mutations or KRAS wild-type tumors for survival; searches for those comparisons found no passage addressing them. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [11] source
    • cites [28] source
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Premisecitation

    Early adagrasib monotherapy data in KRAS G12C colorectal cancer are promising, but RAS-MAPK pathway reactivation may occur through EGFR-mediated adaptive feedback.

    “Although early data from a study of adagrasib monotherapy are promising in patients with colorectal cancer with KRAS G12C mutations,22 reactivation may occur in the RAS–MAPK signaling pathway because of adaptive feedback mediated by epidermal growth factor receptor (EGFR).23,24”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [22] source
      Experimental — accuracy not yet measured
    • cites [23] source
      Experimental — accuracy not yet measured
    • cites [24] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Adagrasib has favorable pharmacokinetic properties, including a 23-hour half-life, dose-dependent pharmacokinetics, and CNS penetration.

    “Adagrasib has favorable pharmacokinetic properties, including a long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration.8,21,22”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [8] source

      The Results section on in vivo treatment (page unavailable) reports that MRTX849, also called adagrasib, had a prolonged half-life after oral administration in mice. It does not give a 23-hour drug half-life or report CNS penetration. Its dose-dependent findings concern target modification and antitumor effects, not pharmacokinetics. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [21] source
    • cites [22] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    KRAS G12C occurs in 3 to 4% of colorectal cancer patients and impairs GTP hydrolysis, shifting KRAS to its active GTP-binding state.

    “The KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in 3 to 4% of patients with colorectal cancer and impairs GTP hydrolysis, which shifts KRAS to the active GTP-binding state to drive protumorigenic effector signaling.8,10–12”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [8] source

      The Introduction states that KRASG12C occurs in colon adenocarcinoma and that codon 12 mutations impair GAP-stimulated GTP hydrolysis, leaving RAS predominantly active and GTP-bound. It does not give the claimed 3–4% prevalence in colorectal cancer patients. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] source

      The mutation-distribution paragraph reports KRAS G12C in 234 of 7,402 patients with colorectal cancer (3.2%), supporting the 3–4% figure. The paper does not address impaired GTP hydrolysis, the active GTP-bound state, or effector signaling. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [11] source
    • cites [12] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cetuximab is an anti-EGFR monoclonal antibody indicated for RAS wild-type metastatic colorectal cancer, as monotherapy or with chemotherapy.

    “Cetuximab is an anti-EGFR monoclonal antibody that is indicated for the treatment of RAS wild-type metastatic colorectal cancer, either as monotherapy or in combination with chemotherapy.13”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Metastatic colorectal cancer treatment is moving toward biomarker-selected strategies, but options are limited to BRAF V600E-directed agents and PD-1 antibodies for high microsatellite instability or mismatch-repair deficiency.

    “The therapeutic landscape of metastatic colorectal cancer is moving toward biomarker-selected strategies. However, options are limited to agents directed at tumors carrying BRAF V600E mutations and to antibodies against programmed death 1 (PD-1) in patients with high microsatellite instability or mismatch-repair deficiency.13,26,27”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [13] source

      The review’s immune checkpoint section links response in metastatic colorectal cancer to MSI-H or dMMR tumors, and its EGFR-related pathway section discusses treatment for BRAF-mutant tumors. But the claim that biomarker-selected options are limited to those two groups is too narrow: the review also recommends anti-EGFR treatment for patients with RAS-wild-type, BRAF-wild-type tumors and discusses HER2-targeted treatment for HER2-positive metastatic colorectal cancer. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] source
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Keeping adagrasib exposure continuously above a target threshold inhibits KRAS-dependent signaling throughout the dosing interval and is predicted to maximize antitumor activity.

    “Maintaining continuous adagrasib exposure above a target threshold allows for the inhibition of KRAS-dependent signaling for the duration of the dosing interval and is predicted to maximize antitumor activity.8,20”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] source

      The Discussion (page not supplied) says durable inhibition of KRAS-dependent signaling is important for maximizing therapeutic response. It does not establish an adagrasib exposure threshold that ensures inhibition throughout a dosing interval. The Results on temporal signaling (page not supplied) also report ERK signaling recovery in partially sensitive models despite repeat dosing. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [20] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Emerging data suggest that acquired resistance to KRAS G12C inhibitors in colorectal cancer largely involves MAPK signaling reactivation.

    “Emerging data suggest that potential mechanisms of acquired resistance to KRAS G12C inhibitors in colorectal cancer largely include reactivation of MAPK signaling, and future analyses from this trial and others will help to clarify these mechanisms.37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] source

      The Results and Discussion (page not provided) identify acquired alterations in the RTK–RAS–MAPK pathway after adagrasib treatment, including alterations in patients with colorectal cancer. However, the paper does not establish that MAPK signaling reactivation accounts for most acquired resistance in colorectal cancer specifically; its resistance data also concern adagrasib rather than KRAS G12C inhibitors generally. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    The results show activity of combined KRAS and EGFR inhibition in colorectal cancer, consistent with preclinical observations.

    “These results show the activity of combined KRAS and EGFR inhibition in patients with colorectal cancer, a finding that is consistent with preclinical observations.24”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Maintaining disease control may improve quality of life because disease progression is associated with deterioration in health-related quality of life across several cancer types, including metastatic colorectal cancer.

    “Maintaining disease control may translate into improved quality of life for patients, because disease progression is associated with deterioration in health-related quality of life across several cancer types, including metastatic colorectal cancer.34”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TP53 and PIK3CA are commonly mutated in colorectal cancer and have been postulated to affect treatment response and sensitivity to KRAS inhibition.

    “TP53 and PIK3CA are commonly mutated in colorectal cancer and have been postulated to potentially affect treatment response and sensitivity to KRAS inhibition.35,36”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [35] source

      The Results (Mutational profile analysis; page unavailable) report frequent TP53 (70%) and PIK3CA (23%) mutations in the colorectal cancer cohort. The Discussion links KRAS mutation—not TP53 or PIK3CA mutation—to reduced response to EGFR inhibitors. Our copy does not support the attributed claim about TP53 or PIK3CA affecting treatment response or sensitivity to KRAS inhibition. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [36] source

      In the section “PIK3CA mutation and colorectal cancer precision medicine” (page unavailable), the paper reports PIK3CA mutations in 10–20% of colorectal cancers and discusses their potential effect on treatment response. It does not address TP53, and its discussion of reduced sensitivity concerns anti-EGFR antibodies, not KRAS inhibition. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adagrasib and sotorasib are both selective covalent KRAS G12C inhibitors, but they differ pharmacologically, including half-life, dose-dependent exposure, and potential CNS penetration.

    “Adagrasib and sotorasib are both selective covalent inhibitors of KRAS G12C, but pharmacologic differences between the two drugs have been reported, including half-life (5 hours for sotorasib and 23 hours for adagrasib), dose-dependent exposure with adagrasib, and potential CNS penetration with adagrasib.22,29”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [22] source

      The Results > PK section reports a 23.0-hour mean half-life for adagrasib and increasing exposure with increasing doses; the Introduction describes it as a selective covalent KRAS G12C inhibitor with CNS penetration. Our copy does not give sotorasib’s five-hour half-life or establish the stated comparison between the drugs. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [29] source

      The Abstract (Background) and Discussion identify sotorasib as a selective, covalent KRAS G12C inhibitor. Results (Pharmacokinetics; page unavailable) report its mean elimination half-life as 5.5 hours, consistent with the cited 5-hour figure. Our copy does not address adagrasib’s selectivity, half-life, dose-dependent exposure, or potential CNS penetration, so it does not establish the comparison between the drugs. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    All patients had prior fluoropyrimidine-based chemotherapy, and most had also received oxaliplatin, irinotecan, or both.

    “All the patients had previously received fluoropyrimidine-based chemotherapy; the majority had also received oxaliplatin, irinotecan, or both.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the combination-therapy cohort, grade 3 or 4 treatment-related adverse events occurred in 5 patients (16%), with none in more than one patient.

    “Five patients (16%) had grade 3 or 4 treatment-related adverse events, with none occurring in more than 1 patient.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the combination-therapy cohort, no treatment-related adverse events led to adagrasib discontinuation, and all 5 patients who discontinued cetuximab continued adagrasib.

    “No treatment-related adverse events led to the discontinuation of adagrasib. All 5 patients continued to receive adagrasib after the discontinuation of cetuximab.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In the monotherapy cohort, median age was 59 years and 50% of patients were women.

    “The median age of the patients was 59 years (range, 29 to 79), and 50% of the patients were women (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the 43 clinically evaluable monotherapy patients, objective response was 23% by blinded independent central review and 19% by investigator assessment.

    “Of the 43 patients who received adagrasib monotherapy in the clinically evaluable population, the response was 23% (95% confidence interval [CI], 12 to 39) according to blinded independent central review and 19% (95% CI, 8 to 33) according to investigator assessment (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the monotherapy cohort, no treatment-related adverse events led to treatment discontinuation and no grade 5 treatment-related events occurred.

    “No treatment-related adverse events led to treatment discontinuation, and no grade 5 treatment-related events occurred.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    By the same cutoff date, 32 patients had received adagrasib plus cetuximab, with median follow-up of 17.5 months and median treatment duration of 7.3 months.

    “By the same data-cutoff date, 32 patients had received adagrasib plus cetuximab (median follow-up, 17.5 months; median duration of treatment, 7.3 months [range, 0.0 to 24.0]).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Median prior systemic therapy lines were three; median interval from last systemic therapy to enrollment was 42 days in monotherapy and 53 days in combination therapy.

    “The median number of previous lines of systemic therapy was three; the median interval between the last systemic therapy and trial enrollment was 42 days in the monotherapy cohort and 53 days in the combination-therapy cohort.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the monotherapy cohort, 29 patients (66%) started subsequent anticancer therapy.

    “At the data-cutoff date, 29 patients (66%) had started subsequent anticancer therapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In the combination-therapy cohort, median age was 60 years and 53% were women.

    “The median age of the patients was 60 years (range, 41 to 74), and 53% were women.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In the monotherapy cohort, median follow-up was 20.1 months and median treatment duration was 5.9 months.

    “The median duration of follow-up was 20.1 months, and the median duration of treatment was 5.9 months (range, 0.6 to 23.8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Exploratory analyses showed no apparent association between co-occurring TP53 or PIK3CA mutations and response to adagrasib, though interpretation was limited by small sample size.

    “Exploratory analyses of tumor molecular profiles showed that co-occurring mutations in TP53 and PIK3CA had no apparent association with the response to adagrasib, but interpretation was limited by the small sample size.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In this trial, 6 monotherapy patients (14%) had progressive disease as best response, while no combination-therapy patient did.

    “In our trial, 6 patients (14%) had progressive disease as the best response with adagrasib monotherapy; no patient had progressive disease as the best response with adagrasib plus cetuximab.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All patients had prior fluoropyrimidine-based therapy with oxaliplatin, irinotecan, or both, and most had received a VEGF inhibitor before enrollment.

    “All the patients had received previous fluoropyrimidine-based therapy with oxaliplatin, irinotecan, or both, and most had received an inhibitor of vascular endothelial growth factor before enrollment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All patients provided written informed consent.

    “All the patients provided written informed consent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The trial was conducted according to the Declaration of Helsinki and ICH Good Clinical Practice guidelines.

    “The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation guidelines for Good Clinical Practice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The protocol was approved by all necessary ethics committees and institutional review boards at each trial site.

    “The protocol (available with the full text of the article at NEJM.org) was approved by all the necessary ethics committees and institutional review boards at each trial site.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Adding cetuximab to adagrasib may enhance KRAS-dependent signaling inhibition or overcome adaptive feedback, delaying resistance and improving outcomes.

    “Combining cetuximab with adagrasib may enhance the inhibition of KRAS-dependent signaling or overcome adaptive feedback to delay resistance and improve outcomes.25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Trial oversight was provided by the sponsor, investigators, local and central institutional review boards, and an independent data and safety monitoring committee.

    “Trial oversight was provided by the sponsor, investigators, local institutional review boards, a central institutional review board, and an independent data and safety monitoring committee.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Third-line options for metastatic colorectal cancer are limited to regorafenib and trifluridine-tipiracil, which extend median overall survival by less than 2 months over placebo and have low response rates and short progression-free survival.

    “Third-line treatment options are limited to regorafenib and trifluridine–tipiracil, which have extended median overall survival by less than 2 months over placebo and have been associated with a low response rate (<2%) and median progression-free survival of approximately 2 months, outcomes that highlight the need for new approaches.15,16”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] source
    • cites [16] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Data were collected by investigators and analyzed by sponsor-employed statisticians.

    “The data were collected by the investigators and analyzed by statisticians employed by the sponsor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    This trial provides clinical evidence that KRAS G12C can be targeted in metastatic colorectal cancer, with activity for adagrasib as monotherapy and with cetuximab in heavily pretreated patients.

    “In this trial, we provide clinical evidence that KRAS G12C can be targeted in metastatic colorectal cancer, with activity observed for adagrasib as monotherapy and in combination with cetuximab in heavily pretreated patients (i.e., in those who had received a median of three previous lines of therapy, the majority of whom had disease that was resistant to previous therapies).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a recent phase 1b study, sotorasib plus panitumumab produced a confirmed response of 30% in pretreated KRAS G12C colorectal cancer patients, compared with 10% for sotorasib monotherapy.

    “Early clinical data support this hypothesis, and in a recent phase 1b study of sotorasib in combination with the EGFR-targeting monoclonal antibody panitumumab, a confirmed response of 30% was reported in pretreated patients who had colorectal cancer with a KRAS G12C mutation,32 as compared with 10% for sotorasib monotherapy.30”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] source
    • cites [30] source

  • May combine two claims.

    Interpretationown data

    In this phase 1-2 trial, both adagrasib monotherapy and adagrasib plus cetuximab produced reversible toxic effects in most patients and no new safety concerns.

    “In this phase 1–2 trial of adagrasib as monotherapy and in combination with cetuximab, both treatments produced reversible toxic effects in the majority of patients and resulted in no new safety concerns.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Adagrasib's biologic activity appeared greater when combined with cetuximab, supporting ongoing clinical investigation.

    “The biologic activity of adagrasib appeared to be even greater in combination with cetuximab and supports ongoing clinical investigation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The monotherapy and combination-therapy cohorts are sufficiently comparable that observed differences in activity can suggest enhanced benefit from combination therapy.

  • May combine two claims.

    Study design and conductown data

    Documented disease progression on prior therapy was not a specific enrollment criterion, though the population had poor prognostic features and no standard-of-care option.

    “The documentation of disease progression while patients were receiving previous therapy was not a specific enrollment criterion for these cohorts; however, this was a patient population with poor prognostic features and for whom no standard-of-care treatment option was available.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a recent phase 2 sotorasib trial, pretreated metastatic KRAS G12C colorectal cancer patients had a 10% response rate and median response duration of 4.2 months.

    “In a recent phase 2 trial of sotorasib, a response of 10% was observed, with a median response duration of 4.2 months in pretreated patients with metastatic colorectal cancer with mutant KRAS G12C.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

  • May combine two claims.

    Interpretationown data

    Adagrasib plus cetuximab did not produce synergistic toxic effects, and observed treatment-related adverse events were consistent with those of each treatment alone.

    “The combination of adagrasib plus cetuximab did not produce synergistic toxic effects, and observed treatment-related adverse events were consistent with those reported for each treatment alone.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The monotherapy and combination-therapy cohorts are sufficiently comparable that observed differences in activity can suggest enhanced benefit from combination therapy.
39 of 39

  • The paper relies on this without support.

    The monotherapy and combination-therapy cohorts are sufficiently comparable that observed differences in activity can suggest enhanced benefit from combination therapy.

    “The nonrandomized design does not allow for direct comparisons between cohorts.”

  • The paper relies on this without support.

    At least 95% plasma clearance of the KRAS G12C mutant allele reflects depth of ctDNA response.

    “which suggests a greater depth of ctDNA response for the combination.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Patients who previously received single-agent adagrasib therapy showed no additional responses when subsequently treated with adagrasib plus cetuximab combination therapy.

    “In contrast, patients who previously received single-agent adagrasib therapy showed no additional responses when subsequently treated with adagrasib plus cetuximab combination therapy20.”

    From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [20]

    The Results > Clinical Activity section reports that six patients crossed over from adagrasib monotherapy to adagrasib plus cetuximab. It directs readers to supplementary Table S5 for their response outcomes, but our copy does not state whether those patients had additional responses. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The duration of response and progression-free survival of CRC patients treated with sotorasib or adagrasib were lower than those in NSCLC patients.

    “The duration of response (DOR) and progression-free survival (PFS) of CRC patients treated with sotorasib or adagrasib were also lower than those in NSCLC patients (Table 1) [48].”

    From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [48]

    The Results (Clinical Activity; page not provided) report duration of response and progression-free survival for colorectal cancer patients receiving adagrasib. The Discussion also reports response duration for colorectal cancer patients receiving sotorasib. Our copy gives no corresponding outcomes for NSCLC patients, so it does not establish that either measure was lower in colorectal cancer. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Dual KRAS and EGFR inhibition shows promise in treating KRAS-mutant colorectal cancer.

    “While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge.”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [5]

    The Discussion reports activity for combined KRAS G12C and EGFR inhibition in heavily pretreated colorectal cancer, and describes a 46% response with adagrasib plus cetuximab. This supports the treatment's promise, but the cited trial studied the KRAS G12C subtype, not KRAS-mutant colorectal cancer generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Responses to KRAS and EGFR dual targeting in KRAS-mutant CRC are often short-lived, with most patients relapsing within months due to acquired resistance.

    “While KRAS and EGFR dual targeting holds promise in KRAS-mutant CRC, responses are often short-lived; most patients relapse within months due to acquired resistance.”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [5]

    The Results (Clinical Activity; page unavailable) report a median response duration of 7.6 months and median progression-free survival of 6.9 months with adagrasib plus cetuximab, supporting the point that benefit can be limited to months. The Discussion describes acquired-resistance mechanisms as emerging possibilities requiring further study; it does not establish that most patients relapsed within months *because of* acquired resistance. The trial also concerns KRAS G12C-mutant colorectal cancer, not all KRAS-mutant colorectal cancer. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The most common treatment-related adverse events with sotorasib plus panitumumab (rash, acneiform dermatitis, hypomagnesemia) are also in accordance with that shown with adagrasib-cetuximab and anti-EGFR therapies for the treatment of metastatic colorectal cancer in general.

    “The most common treatment-related adverse events with sotorasib plus panitumumab (rash, acneiform dermatitis, hypomagnesemia) are also in accordance with that shown with adagrasib-cetuximab and anti-EGFR therapies for the treatment of metastatic colorectal cancer in general. 18,21”

    From Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial (2024) · cites this paper as [18]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Cites

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5 of the 41 references couldn’t be matched to a known paper.

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Authors
Yaeger, R., Weiss, J., Pelster, M. S., Spira, A. I., Barve, M., Ou, S.-H. I., Leal, T. A., Bekaii-Saab, T. S., Paweletz, C. P., Heavey, G. A., Christensen, J. G., Velastegui, K., Kheoh, T., Der-Torossian, H., & Klempner, S. J.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.Y.); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill (J.W.); Sarah Cannon Research Institute, Tennessee Oncology, Nashville (M.S.P.); Virginia Cancer Specialists, NEXT Oncology–Virginia, Fairfax (A.I.S.); US Oncology Research, the Woodlands (A.I.S.), and Mary Crowley Cancer Research, Dallas (M.B.) — both in Texas; the University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange (S.-H.I.O.), and Mirati Therapeutics, San Diego (J.G.C., K.V., T.K., H.D.-T.) — all in California; the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta (T.A.L.); Medical Oncology, Mayo Clinic, Phoenix, Arizona (T.S.B.-S.); Belfer Center for Applied Cancer Science and the Department of Medical Oncology, Dana–Farber Cancer Institute (C.P.P., G.A.H.), and the Department of Medicine, Division of Hem...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2023-01-05
Volume
388
Issue
1
Pages
44-54
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2212419
PMC
PMC9908297
OpenAlex
W4312094576
Cited by
527
References
41
Citations by year
2026: 117 · 2025: 157 · 2024: 167 · 2023: 86
FWCI
42.87
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Memorial Sloan Kettering Cancer Center (P30 CA 008748 to MSK)
  • Mirati Therapeutics, Inc.
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
adagrasib, cetuximab, KRAS G12C, colorectal cancer, metastatic colorectal cancer, KRAS inhibitors, anti-EGFR monoclonal antibody, combination therapy, oral small-molecule inhibitor, treatment-related adverse events, progression-free survival, objective response rate, heavily pretreated patients, drug safety and tolerability
MeSH terms
Cetuximab, Acetonitriles, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Piperazines, Pyrimidines, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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