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Cited by 72Lung Cancer Treatments and MutationsProtein Kinase Regulation and GTPase SignalingCancer Genomics and Diagnostics

Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes

Open access
Palma, Gabriela, Khurshid, Faisal, Lu, Kevin, Woodward, Brian, Husain, Hatim·2021·npj Precision Oncology
DOI 10.1038/s41698-021-00237-5PMC PMC8630042
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Abstract

Cancers harboring mutations in the Kirsten rat sarcoma homolog (KRAS) gene have been associated with poor prognosis and lack of targeted therapies. KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer (NSCLC) with KRAS G12C mutations harbored at approximately 11–16%. Research into KRAS-driven tumors and analytical chemistry have borne a new class of selective small molecules against the KRAS G12C isoform. Phase II data for sotorasib (AMG510) has demonstrated a 37.1% overall response rate (ORR). Adagrasib (MRTX849) has demonstrated a 45% ORR in an early study. While single agent efficacy has been seen, initial data suggest combination approaches are an opportunity to improve outcomes. Here, we present perspectives on the initial progress in targeting KRAS G12C, examine co-mutations evident in KRAS G12C NSCLC, and comment on potential future combinatorial approaches including SHP2, SOS1, MEK, EGFR, mTOR, CDK, and checkpoint blockade which are currently being evaluated in clinical trials. As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of a prior therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the chemistry, co-mutation landscape, and early clinical outcomes of selective KRAS G12C inhibitors in NSCLC, focusing on sotorasib and adagrasib. It highlights single-agent activity, frequent co-alterations such as STK11/KEAP1, and ongoing combination strategies to overcome adaptive resistance.

Key findings

  • KRAS G12C occurs in approximately 11–16% of NSCLC and about 13% of NSCLC in the cited genomic analyses; other frequencies include 3–5% of colorectal cancers and 1–2% of other cancer types.
  • In the phase II sotorasib NSCLC cohort (n = 126; 124 response-eligible), ORR was 37.1% (43 partial responses, 3 complete responses), DCR 80.6%, median duration of response 10.0 months, median PFS 6.8 months, and updated median OS 12.5 months; sotorasib received US FDA approval on May 28, 2021.
  • In KRYSTAL-01, adagrasib at 600 mg twice daily in combined phase I/Ib and II NSCLC cohorts (n = 51) produced 45% PR, 51% SD, and 96% DCR; half-life was ~24 h, with 85% of all enrolled patients experiencing AEs, 30% grade 3–4, and 2% grade 5.
  • Co-alterations in KRAS G12C NSCLC frequently include TP53, STK11, KEAP1, and CDKN2A; exploratory analyses reported sotorasib ORR 50% in KRAS G12C/STK11-mutant patients without KEAP1 mutation (n = 22) versus 23% in triple KRAS G12C/STK11/KEAP1 mutants (n = 13), and adagrasib ORR 64% in KRAS G12C/STK11 co-altered patients (n = 14) versus 33% in STK11 wild-type patients (n = 30).

Methods

  • Narrative review/perspective synthesizing published preclinical data, clinical trial results, and structural modeling of KRAS G12C; no primary patient enrollment or systematic review methodology is reported.
  • Data sources include cBioPortal NSCLC datasets for co-alteration landscape (n = 560), published phase I/II/III trials of sotorasib and adagrasib, and other emerging KRAS G12C, SHP2, SOS1, MEK, EGFR, CDK4/6, mTOR, and checkpoint inhibitor studies.
  • Structural modeling used UCSF ChimeraX to depict sotorasib binding to KRAS G12C in the GDP-bound state and to map residues near the Switch II pocket.

Limitations

  • The paper states that cross-trial comparisons have the caveat that patient characteristics differ between trials.
  • The paper states that patients with active brain metastases were excluded from initial sotorasib and adagrasib trials, leaving a lack of data on CNS penetration and requiring further studies.
  • Evident from the text: this is a narrative review relying on published trials, conference abstracts, and press releases, with several exploratory subgroup analyses based on small patient numbers and no formal systematic search or meta-analysis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41698-021-00237-5

Cites

Statistics

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Claims the paper makes

0 of 117 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Based on non-small cell lung cancer datasets within cBioPortal, the landscape of KRAS G12C mutated tumors includes a complex landscape of co-altered genes.

    “Based on non-small cell lung cancer datasets within cBioPortal, the landscape of KRAS G12C mutated tumors includes a complex landscape of co-altered genes (Fig. 3)25,26.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401 (2012). source

      Not checked in the free run.

    • cites [26] Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using cBioPortal. Sci. Signal. 6, p11 (2013). source

      Not checked in the free run.

  • Findingcitation

    Frequently co-altered genes in KRAS G12C mutated NSCLC include TP53, STK11, KEAP1, and CDKN2A.

    “Frequently co-altered genes include TP53, STK11, KEAP1, and CDKN2A.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401 (2012). source

      Not checked in the free run.

    • cites [26] Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using cBioPortal. Sci. Signal. 6, p11 (2013). source

      Not checked in the free run.

  • Findingown data

    In the authors' structural model, Val9, Lys16, Gln61, Glu63, Arg68, His95, Tyr96, and Gln99 are in proximity to bound sotorasib.

    “We observed in our structural model the proximity of Val9, Lys16, Gln61, Glu63, Arg68, His95, Tyr96, and Gln99 to bound sotorasib (Fig. 2).”
    Quote in the paperSubstantial claim
  • Premisecitation

    In mutant-KRAS tumor cells, inhibition of SOS1 led to a 50% reduction in phospho-ERK.

    “In mutant-KRAS tumor cells, inhibition of SOS1 led to a 50% reduction in phospho-ERK.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Hillig, R. C. et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad. Sci. USA 116, 2551–2560 (2019). source

      Not checked in the free run.

  • Premisecitation

    RAS requires modification with C15 farnesyltransferase when localized in the plasma membrane.

    “In order for RAS to maintain its functionality, the molecule requires a modification with C15 farnesyltransferase when localized in the plasma membrane3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 15
  • May combine two claims. 49

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

    Findingown data

    The authors modeled KRAS G12C and presented areas of binding of sotorasib at the allosteric pocket under the Switch II loop region in the GDP-bound state of KRAS using ChimeraX software.

    “We have modeled KRAS G12C and presented areas of binding of the medicine sotorasib at the allosteric pocket under the Switch II loop region (Fig. 2) in the GDP-bound state of KRAS using ChimeraX software from UCSF13,14.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Goddard, T. D. et al. UCSF ChimeraX: meeting modern challenges in visualization and analysis. Protein Sci. 27, 14–25 (2018). source

      Not checked in the free run.

    • cites [14] Canon, J. et al. The Clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity. Nature 575, 5581 (2019). source

      Not checked in the free run.

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

    Premisecitation

    The KRAS protein includes a G domain and a C-terminal membrane targeting region, and once activated through guanine nucleotide exchange factors it can affect pathways including PI3K, mTOR, RAF/MEK/ERK, and other downstream cell cycle pathways.

    “The protein includes two major binding regions including the G domain and the C terminal membrane targeting region which, once activated through guanine nucleotide exchange factors (GEFs), have the ability to further affect many pathways including PI3K, mTOR, RAF/MEK/ERK, and other downstream cell cycle pathways4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Nagasaka, M. et al. KRAS G12C game of thrones: which direct KRAS inhibitor will claim the iron throne? Cancer Treat. Rev. 84, 101974 (2020). source

      Not checked in the free run.

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    Premisecitation

    Farnesyltransferase inhibitors yielded preclinical responses but limited responses in clinical trials.

    “This modification was the target of an active pipeline of farnesyltransferase inhibitors and yielded preclinical responses however limited responses in clinical trials12.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Berndt, N., Hamilton, A. D. & Sebti, S. M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer 11, 775–791 (2011). source

      Not checked in the free run.

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    Premisecitation

    KRAS binds tightly with GTP (with picomolar affinity in vivo) in the main binding pocket, and its features sterically inhibit many treatments from reversing the strong binding affinity for GTP.

    “KRAS binds tightly with GTP (with picomolar affinity in vivo) in the main binding pocket, and its features sterically inhibit many treatments from reversing the strong binding affinity for GTP4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Nagasaka, M. et al. KRAS G12C game of thrones: which direct KRAS inhibitor will claim the iron throne? Cancer Treat. Rev. 84, 101974 (2020). source

      Not checked in the free run.

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

    Premisecitation

    Within a subgroup analysis, both Caucasian and African American populations can be more often diagnosed with KRAS G12C NSCLC than Asian populations; white females harbor KRAS G12C NSCLC mutations more often than their male counterparts; and Asian males more frequently have NSCLC G12C mutations than Asian females.

    “Within a subgroup analysis of those who are more frequently diagnosed with KRAS G12C NSCLC, both Caucasian and African American populations can be more often diagnosed than Asian populations. Interestingly, white females harbor KRAS G12C NSCLC mutations more often than their male counterparts. This trend is opposite for Asian populations, as Asian males more frequently have NSCLC G12C mutations11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Nassar, A. H., Adib, E. & Kwiatkowski, D. J. Distribution of KRAS G12C somatic mutations across race, sex, and cancer type. N. Engl. J. Med. 384, 185–187 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Binding at the allosteric pocket under the Switch II loop region inhibits RAS activity by blocking SOS-mediated nucleotide exchange and altering the affinity of KRAS for GDP versus GTP.

    “Binding at this pocket has been found to inhibit RAS activity by blocking SOS-mediated nucleotide exchange and altering the affinity of KRAS for GDP versus GTP nucleotide.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Patricelli, M. P. et al. Selective Inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6, 316–329 (2016). source

      Not checked in the free run.

    • cites [16] Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). source

      Not checked in the free run.

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

    Premisecitation

    GTPase activating proteins hydrolyze GTP to shift GTP-bound RAS to GDP-bound RAS, reducing cell growth when GTP is bound to RAS and serving as a functional control mechanism of proliferation.

    “To cause the shift in state of GTP-bound RAS into GDP-bound RAS, GTPase activating proteins (GAPs) hydrolyze GTP Fig. 1 leading to a reduction in cell growth seen when GTP is bound to RAS and serving as a functional control mechanism of proliferation5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Liu, P. Y., Wang, Y. J. & Li, X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm. Sin. B 9, 871–879 (2019). source

      Not checked in the free run.

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    Premisecitation

    Pre-clinical mouse models (CDX and PDX) showed a total response rate of 65% across tumors, and specifically a response rate of 75% in NSCLC models.

    “Pre-clinical mouse models (CDX and PDX) also showed a total response rate of 65% across tumors, and specifically a response rate of 75% in NSCLC models20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Janne P. A., Papadopoulos K., Ou I., Rybkin I. & Johnson M. A phase 1 clinical trial evaluating the pharmacokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRAS G12C inhibitor, in advanced solid tumors. AACR-NCI-EORTC (2019).

      Not checked in the free run.

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

    Premisecitation

    KRAS mutations appear in approximately 97% of pancreatic adenocarcinomas and 52% of colorectal cancers, and some responses have been seen in these tumor types albeit with varying consistency.

    “Among other types of cancers, KRAS mutations appear in approximately 97% of pancreatic adenocarcinomas, 52% of colorectal cancers, and some responses have been seen in these tumor types albeit with varying consistency3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014). source

      Not checked in the free run.

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    Premisecitation

    Small molecules bind irreversibly with high specificity to the mutant cysteine at exon 12, leading to preferential GDP binding over GTP.

    “Small molecules bind irreversibly with high specificity to the mutant cysteine at exon 12, leading to preferential GDP binding over GTP16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). source

      Not checked in the free run.

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

    Premisecitation

    A genomic analysis of KRAS mutations in NSCLC showed that a G>A transition is increasingly seen in never smokers, while a G>T transversion is commonly seen in current and former smokers diagnosed with lung cancer.

    “A genomic analysis of KRAS mutations in NSCLC showed that a G>A transition has been increasingly seen in those who have never smoked, while a G>T transversion is commonly seen in current and former smokers who are diagnosed with lung cancer6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Riely, G. J. et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin. Cancer Res. 14, 5731–5734 (2008). source

      Not checked in the free run.

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

    Premisecitation

    KRAS mutations are less common in lung squamous cell carcinoma (<1-5%) and small cell lung cancer (1-2%).

    “In comparison, KRAS mutations are less common in lung squamous cell carcinoma (<1–5%) and small cell lung cancer (1–2%)7–10.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Guan, J. L. et al. KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann. Surg. Oncol. 20, 1381–1388 (2013). source

      Not checked in the free run.

    • cites [8] Thunnissen, F. B. et al. Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development. Lung Cancer 75, 156–160 (2012). source

      Not checked in the free run.

    • cites [9] Brose, M. S. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002).

      Not checked in the free run.

    • cites [10] Murakami H. et al. A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan). ASCO 2017; Chicago, IL, USA 2017. (ASCO Annual Meeting Abstracts, Chicago, 2017).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The KRAS protein oscillates between the inactive GDP-bound form and the active GTP-bound form.

    “The KRAS protein oscillates between the inactive form of GDP-RAS and the active form of GTP-RAS1–3.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-Specific Inhibitor. Cell 172, 578–589 (2018). source

      Not checked in the free run.

    • cites [2] Arbour, K. C. et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 334–340 (2018). source

      Not checked in the free run.

    • cites [3] Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Modifications to ARS-853 gave rise to ARS-1620, which targeted the His95 amino acid on KRAS G12C; ARS-1620 had higher potency and preclinical efficacy and produced a better conformational response than its predecessor.

    “Modifications were made to this small molecule inhibitor, giving rise to ARS-1620, which targeted the His95 amino acid on KRAS G12C. ARS-1620 also proved to have a higher potency and preclinical efficacy and produced a better conformational response than its predecessor1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-Specific Inhibitor. Cell 172, 578–589 (2018). source

      Not checked in the free run.

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    Premisecitation

    In xenografts and preclinical models, the precursor tool compound MRTX1257 showed promising results, leading to development of MRTX849.

    “In xenografts and preclinical models, a precursor tool compound MRTX1257 showed promising results, leading to development of MRTX84918,19.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Marx M. A. et al. Structure-based drug discovery of MRTX1257, a selective, covalent KRAS G12C inhibitor with oral activity in animal models of cancer. American Association for Cancer Research, 18, 5 Supplement (2020). source

      Not checked in the free run.

    • cites [19] Hallin, J. et al. The KRAS G12C inhibitor MRTX849 Provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SOS1 has been labeled as a potential oncogenic driver, with the capability of tumorigenesis in vivo and the ability to activate both the RAS protein through a RAS-GEF and Myc target genes, as well as increase phosphorylation of MEK.

    “SOS1 has been labeled as a potential oncogenic driver, with the capability of tumorigenesis in vivo and the ability to activate both the RAS protein through a RAS-GEF (guanine nucleotide exchange factor) and Myc target genes, as well as increase phosphorylation of MEK22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Cai, D., Choi, P. S., Gelbard, M. & Meyerson, M. Identification and characterization of oncogenic SOS1 Mutations in lung adenocarcinoma. Mol. Cancer Res. 17, 1002–1012 (2019). source

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    Premisecitation

    SHP2 activation enables resistance mechanisms to MEK inhibitor therapy and enhances expression of signaling upstream from KRAS.

    “In addition, SHP2 activation enables resistance mechanisms to MEK inhibitor therapy and enhances expression of signaling upstream from KRAS21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Mai, T. T. & Lito, R. A treatment strategy for KRAS-driven tumors. Nat. Med. 24, 902–904 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In KRYSTAL-01, a phase I/Ib and II trial (n = 79) to investigate the efficacy of adagrasib, the majority of patients were included in the dosage cohort of 600 mg taken twice daily, although doses up to 1200 mg twice daily were evaluated.

    “In KRYSTAL-01 (NCT #03785249), a phase I/Ib and II trial (n = 79) to investigate the efficacy of adagrasib, the majority of patients were included in the dosage cohort of 600 mg taken twice daily, although doses up to 1200 mg twice daily were evaluated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

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    Premisecitation

    In the combined cohort of 18 patients with colorectal cancer who received 600 mg twice daily, 17% achieved partial response, while 78% achieved stable disease for a total disease control rate of 94%.

    “In the combined cohort of 18 patients with colorectal cancer who received 600 mg twice daily (n = 18), 17% achieved PR, while 78% achieved SD for a total disease control rate of 94%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

      Not checked in the free run.

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    Premisecitation

    In colorectal cancer, 3 of 42 patients achieved partial response (ORR 7.1%) and another 28/42 achieved stable disease (DCR 73.8%).

    “In colorectal cancer, 3 of 42 patients achieved PR (ORR 7.1%) and another 28/42 achieved SD (DCR 73.8%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020). source

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    Premisecitation

    In the cases of fatal events, one patient experienced cardiac failure and another experienced pneumonitis.

    “In the cases of fatal events, one patient experienced cardiac failure and another experienced pneumonitis35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

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    Premisecitation

    Dose escalation of sotorasib ranged from 180 mg to 960 mg, and responses were seen in all dose levels evaluated.

    “Dose escalation ranged from 180 mg to 960 mg, and responses were seen in all dose levels evaluated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Amgen. Amgen Announces First Clinical Data Evaluating Novel Investigational KRASG12C Inhibitor AMG 510 At ASCO 2019. News Releases. https://www.amgen.com/media/news-releases/2019/06/amgen-announces-first-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-amg-510-at-asco-2019/ (2019).

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    Premisecitation

    The mean elimination half-life of sotorasib was determined to be 5.5 h.

    “The mean elimination half-life of the drug was determined to be 5.5 h.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Amgen. Amgen Announces First Clinical Data Evaluating Novel Investigational KRASG12C Inhibitor AMG 510 At ASCO 2019. News Releases. https://www.amgen.com/media/news-releases/2019/06/amgen-announces-first-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-amg-510-at-asco-2019/ (2019).

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    Premisecitation

    Of the 59 patients, 34 were treated at 960 mg with an ORR of 35.3% and DCR of 91.2%.

    “Of the 59 patients, 34 were treated at 960 mg with an ORR of 35.3% and DCR of 91.2%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical combinations of mTOR inhibitors with MEK inhibitors yielded severe adverse effects, and have prompted preclinical trials to test the substitution of a MEK inhibitor with the KRAS G12C inhibitor ARS-1620, in combination with an mTOR inhibitor (everolimus) and an IGF-1R inhibitor (linsitinib).

    “Clinical combinations of mTOR inhibitors with MEK inhibitors yielded severe adverse effects, and have prompted preclinical trials to test the substitution of a MEK inhibitor with the KRAS G12C inhibitor ARS-1620, in combination with an mTOR inhibitor (everolimus) and an insulin-like growth factor 1 receptor (IGF-1R) inhibitor (linsitinib)55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Moore, C. et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci. Transl. Med. 11, 1–16 (2019).

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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Clinical utility in previously untreated NSCLC and in other cancer types such as colorectal cancer will likely require greater efficacy than that seen to-date with KRAS G12C inhibitor monotherapy.

    “Clinical utility in previously untreated NSCLC and in other cancer types such as colorectal cancer will likely require greater efficacy than that seen to-date with KRAS G12C inhibitor monotherapy.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    28 patients with diagnosed cancers other than NSCLC or colorectal cancer were evaluated, with four reaching partial response and 17/28 achieving stable disease.

    “28 patients with diagnosed cancers other than NSCLC or colorectal cancer were evaluated, with four reaching PR and 17/28 achieving SD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the combined Phase I/Ib and Phase II NSCLC cohorts of patients (n = 51) receiving 600 mg twice daily, 45% achieved partial response while 51% achieved stable disease for a DCR of 96%.

    “In the combined Phase I/Ib and Phase II NSCLC cohorts of patients (n = 51) receiving 600 mg twice daily, 45% achieved PR while 51% achieved SD for a DCR of 96%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

      Not checked in the free run.

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    Premisecitation

    In 2020, updated results of 59 evaluable NSCLC patients showed 19/59 achieved partial response (32.2% ORR) and 33/59 achieved stable disease (88.1% DCR).

    “In 2020, updated results of 59 evaluable NSCLC patients were presented and 19/59 achieved PR (32.2% ORR) and 33/59 achieved SD (88.1% DCR).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020). source

      Not checked in the free run.

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    Premisecitation

    Median duration of response was 10.0 months and median progression-free survival was 6.8 months.

    “Median duration of response was 10.0 months and median progression-free survival was 6.8 months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] B., Li. Sotorasib for KRAS G12C. World Conference on Lung Cancer (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within the NSCLC cohort, median progression-free survival was 6.3 months, and within the colorectal cancer cohort progression-free survival was 4.0 months.

    “Within the NSCLC cohort, the median progression-free survival (PFS) was 6.3 months, and within the colorectal cancer cohort the PFS was 4.0 months28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combining all enrolled patients for safety analyses, 85% of patients enrolled in the clinical trial experienced adverse events, with 30% experiencing grades 3-4, and 2% experiencing grade 5 adverse events.

    “Combining all enrolled patients for safety analyses, 85% of patients enrolled in the clinical trial experienced AEs, with 30% experiencing grades 3–4, and 2% experiencing grade 5 adverse events.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the updated analysis of the 126-patient Phase II NSCLC cohort, the overall response rate remained at 37.1% although one of the partial responses converted to a complete response.

    “In the updated analysis, the overall response rate remained at 37.1% although one of the partial responses converted to a complete response.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Skoulidis, F. et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 384, 2371–2381 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with other types of tumors (non-NSCLC, non-CRC) who were administered 600 mg twice daily (n = 6), ORR was determined to be 67% with one response unconfirmed and all patients remaining on treatment at data cutoff.

    “In patients with other types of tumors (non-NSCLC, non-CRC) who were administered 600 mg twice daily (n = 6), ORR was determined to be 67% with one response unconfirmed and all patients remaining on treatment at data cutoff.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase II and Phase III development proceeded with the 960 mg dose, although the sponsor has announced they will conduct a randomized study of sotorasib 240 mg versus sotorasib 960 mg as part of a US FDA post-marketing requirement.

    “Phase II and Phase III development proceeded with the 960 mg dose, although the sponsor has announced they will conduct a randomized study of sotorasib 240 mg versus sotorasib 960 mg as part of a US FDA post-marketing requirement34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Staff, The ASCO Post. Updated information on sotorasib dose-comparison study. The ASCO Post. https://ascopost.com/news/april-2021/updated-information-on-sotorasib-dose-comparison-study/ (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Through both knockout and inhibition of SHP2, SOS1 can be inhibited and RAS/MAPK is restricted in oncogenic proliferation.

    “Through both knockout and inhibition of SHP2, SOS1 can be inhibited and RAS/MAPK is restricted in oncogenic proliferation56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Nichols, R. J. et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat. Cell Biol. 20, 1064–1073 (2018). source

      Not checked in the free run.

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

    Premisecitation

    This data was granted FDA priority review on February 16, 2021, and the phase 3 clinical study comparing the efficacy of sotorasib versus docetaxel for patients with KRAS G12C-mutant NSCLC is actively ongoing.

    “This data was granted FDA priority review on February 16, 2021 and the phase 3 clinical study comparing the efficacy of sotorasib versus docetaxel for patients with KRAS G12C-mutant NSCLC is actively ongoing30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Amgen. Study to Compare AMG 510 “Proposed INN Sotorasib” With Docetaxel in Non Small Cell Lung Cancer (NSCLC) (CodeBreak 200). ClinicalTrials.gov. NIH U.S. National Library of Medicine https://www.clinicaltrials.gov/ct2/show/NCT04303780 (2021).

      Not checked in the free run.

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

    Premisecitation

    The half-life of adagrasib was determined to be approximately 24 h.

    “The half-life of adagrasib was determined to be ~24 h.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Janne. P. A. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRAS G12C Mutation From a Phase 1/2 Study. AACR-NCI-EORTC (2020).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preliminary results for the phase I study of sotorasib presented in 2019 showed a partial response in 5 of 10 patients with KRAS G12C-mutant NSCLC and 4 patients achieved stable disease for a 90% disease control rate by investigator review.

    “Preliminary results for the phase I study presented in 2019 showed a partial response (PR) for sotorasib in 5 of 10 patients with KRAS G12C-mutant NSCLC and 4 patients achieved stable disease (SD) for 90% disease control rate by investigator review.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Amgen. Amgen Announces First Clinical Data Evaluating Novel Investigational KRASG12C Inhibitor AMG 510 At ASCO 2019. News Releases. https://www.amgen.com/media/news-releases/2019/06/amgen-announces-first-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-amg-510-at-asco-2019/ (2019).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a more mature Phase II cohort presented in 2021, 126 patients with previously treated NSCLC were enrolled, 124 of which were response eligible by central review; results demonstrated an ORR of 37.1%, including 43 partial responses and 3 complete responses, and a disease control rate of 80.6%.

    “In a more mature Phase II cohort presented in 2021, 126 patients with previously treated NSCLC were enrolled and presented, 124 of which were response eligible by central review. Results demonstrated an ORR of 37.1%, including 43 partial responses and 3 complete responses. Disease control rate was 80.6%29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] B., Li. Sotorasib for KRAS G12C. World Conference on Lung Cancer (2021).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The described benefit of SHP2 and KRAS G12C inhibition supports further investigation of a combination therapy approach to prevent upregulation of upstream pathways.

    “The described benefit of SHP2 and KRAS G12C inhibition supports further investigation of combination therapy approach to prevent upregulation of upstream pathways24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Ryan, M. B. et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS G12C inhibition. Clin. Cancer Res. 26, 1633–1643 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent overall survival data for sotorasib is favorable, with an overall survival of 12.5 months including second and third line and beyond patients receiving benefit.

    “Recent overall survival data has been favorable with an overall survival of 12.5 months including second and third line and beyond patients receiving benefit.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Skoulidis, F. et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 384, 2371–2381 (2021). source

      Not checked in the free run.

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

    Premisecitation

    Relay Therapeutics has developed RLY-1971, an oral SHP2 inhibitor, and is investigating the drug as a monotherapy in a phase I clinical trial.

    “Relay Therapeutics has developed RLY-1971, an oral SHP2 inhibitor, and is investigating the drug as a monotherapy in a phase I clinical trial58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Therapeutics, Relay. RLY-1971 in subjects with advanced or metastatic solid tumors. ClinicalTrials.gov. NIH U.S. National Library of Medicine, https://clinicaltrials.gov/ct2/show/NCT04252339 (2020).

      Not checked in the free run.

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

    Premisecitation

    Similar histological transformations have been observed after EGFR inhibitor therapy.

    “Similar histological transformations have been observed after EGFR inhibitor therapy65.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Marcoux, N. et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes. J. Clin. Oncol. 37, 278–285 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations occurred at the cysteine residue of G12 and in exon 13.

    “Alterations also occurred at the cysteine residue of G12, as well as in exon 13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Awad M., et al. LB002- Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. AACR (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CodeBreaK 100, patients with checkpoint therapy within 3 months had an ORR of 34.4% and median OS of 11.7 months, compared to an ORR of 39.7% and not evaluable OS in patients with more than 3 months between checkpoint inhibition and sotorasib.

    “Patients whom have had checkpoint therapy within 3 months had overall response of 34.4% and median overall survival of 11.7 months, compared to 39.7% and not evaluable in patients that had more than 3 months between checkpoint inhibition and sotorasib.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Skoulidis, F. et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 384, 2371–2381 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In JUNIPER, median OS was similar between abemaciclib and erlotinib in KRAS mutant advanced NSCLC, and the difference was statistically insignificant.

    “The outcome showed a similar median OS between the two therapies, which was statistically insignificant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Goldman, J. W. et al. A randomized phase III study of abemaciclib versus erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPER. Front. Oncol. 10, 1–12 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of 23 NSCLC and 7 CRC patients treated with adagrasib, 42% experienced multiple resistance mutations following treatment, while the rest experienced a single resistance mutation.

    “42% of this cohort experienced multiple resistance mutations following treatment, while the rest of patients experienced a single resistance mutation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Awad M., et al. LB002- Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. AACR (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A tool SHP2 inhibitor compound developed by Revolution Medicine is RMC-4550, which showed significant in vivo results when targeting KRAS G12C H358 and MIAPaCa-2 xenograft models both in terms of potency and sensitivity.

    “A tool SHP2 inhibitor compound developed by Revolution Medicine is RMC-4550, which showed significant in vivo results when targeting KRAS G12C H358 and MIAPaCa-2 xenograft models both in terms of potency and sensitivity56.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Nichols, R. J. et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat. Cell Biol. 20, 1064–1073 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Patients with KRAS-mutant NSCLC with STK11/LKB1 co-occurring mutation may have higher responses and may have attenuated responses to immune checkpoint therapy.

    “Data suggesting that patients with KRAS-mutant NSCLC with STK11/LKB1 co-occurring mutation may have higher responses and may have attenuated responses to immune checkpoint therapy36.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Skoulidis, F. et al. STK11/LKB1 Mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Disco. 8, 822–835 (2018). source

      Not checked in the free run.

    • Rests on an assumption: KRAS G12C/STK11 co-mutated NSCLC has poor prognosis with chemotherapy or immunotherapy and is an area of unmet need.

  • May combine two claims.

    Premisecitation

    In preclinical studies, KRAS G12C direct inhibitors upregulated a pro-inflammatory tumor microenvironment and enhanced anti-tumor T cell activity.

    “In preclinical studies, KRAS G12C direct inhibitors were noted to upregulate a pro-inflammatory tumor microenvironment and enhance anti-tumor T cell activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The PFS, ORR, and DCR differences favoring abemaciclib were statistically significant, demonstrating clinical activity of CDK4/6 inhibition in KRAS exon 12 and exon 13 NSCLC.

    “These latter three values were statistically significant, demonstrating clinical activity of CDK4/6 inhibition within KRAS exon 12 and exon 13 NSCLC patients62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Goldman, J. W. et al. A randomized phase III study of abemaciclib versus erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPER. Front. Oncol. 10, 1–12 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Patients with active brain metastases were excluded from both initial trials for sotorasib and adagrasib, providing a lack of data on how the small molecule inhibitors penetrate the central nervous system.

    “It is important to note that patients with active brain metastases were excluded from both initial trials for both sotorasib and adagrasib, providing a lack of data on how the small molecule inhibitors penetrate the central nervous system.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Jacobio and AbbVie are jointly developing two oral small molecule SHP2 inhibitors including JAB-3068 and JAB-3312 which are being evaluated as monotherapies and in combination with a KRAS G12C inhibitor.

    “Jacobio and AbbVie are jointly developing two oral small molecule SHP2 inhibitors including JAB-3068 and JAB-3312 which are being evaluated as monotherapies and in combination with a KRAS G12C inhibitor59.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Jacobio Pharmaceuticals Group Co., LTD. Jacobio Pipeline. http://en.jacobiopharma.com/intro/17.html (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients acquired on-target amplifications of KRAS G12C and off-target alterations of BRAF, NRAS, MEK, and gene fusions.

    “Patients further acquired on-target amplifications of KRAS G12C and off-target alterations of BRAF, NRAS, MEK, and gene fusions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Awad M., et al. LB002- Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. AACR (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Favorable ORR, DOR, PFS, and a favorable toxicity profile relative to current standards in the previously treated setting demonstrate high potential utility of sotorasib in clinical care.

    “Favorable ORR, DOR, PFS, and a favorable toxicity profile relative to current standards in the previously treated setting demonstrate high potential utility in clinical care.”
    Quote in the paperSubstantial claim
56 of 56

  • The paper relies on this without support.

    KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer.

    “KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer (NSCLC) with KRAS G12C mutations harbored at approximately 11–16%.”

  • The paper relies on this without support.

    KRAS G12C mutations are harbored in approximately 11–16% of NSCLC patients.

    “KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer (NSCLC) with KRAS G12C mutations harbored at approximately 11–16%.”

  • The paper relies on this without support.

    As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of prior therapy.

    “As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of a prior therapy.”

  • The paper relies on this without support.

    Somatic mutations block the reversible nature of the KRAS gene, creating a constitutively bound RAS-GTP complex and a resulting conformational change.

    “Somatic mutations block the reversible nature of this gene, creating a constitutively bound RAS-GTP complex and resulting conformational change.”

  • The paper relies on this without support.

    G12C mutations make up about 13% of NSCLC, 3–5% of colorectal cancers, and 1–2% of other cancer types.

    “G12C mutations make up about 13% of NSCLC, 3–5% of colorectal cancers, and 1–2% of other cancer types.”

  • The paper relies on this without support.

    Cancers harboring RAS mutations have remained genomically untargetable more than 30 years after the initial discovery of the oncogene, and attempts to target KRAS directly or through downstream mechanisms have been met with limited efficacy in clinical trials.

    “Cancers harboring RAS mutations have remained genomically untargetable more than 30 years after the initial discovery of the oncogene, and attempts to target KRAS directly or through downstream mechanisms have been met with limited efficacy in clinical trials.”

  • The paper relies on this without support.

    Earlier attempts to target KRAS focused on molecules that bind directly to RAS, inhibit interaction with its activator SOS or its effector RAF, affect downstream signaling (such as MEK inhibitors), act on synthetically lethal pathways, and affect binding at the plasma membrane (such as farnesyltransferase inhibitors), and none of these mechanisms have resulted in approvals for KRAS G12C mutant CAn

    “Earlier attempts to target KRAS have focused on molecules that bind directly to RAS, inhibit interaction with its activator SOS or its effector RAF, affect downstream signaling (i.e., MEK inhibitors), act on synthetically lethal pathways, and affect binding at the plasma membrane (i.e., farnesyltransferase inhibitors). Unfortunately, none of these mechanisms have resulted in approvals for these”

  • The paper relies on this without support.

    Decreased binding affinity to the downstream RAF protein target contributed anti-tumor effects.

    “Decreased binding affinity to the downstream RAF protein target contributed anti-tumor effects.”

  • The paper relies on this without support.

    ARS-853 was one of the first developed mutant-specific, covalent small molecule inhibitors to demonstrate proficiency in targeting KRAS G12C and locking it into a GDP-bound state, and had robust cellular activity against KRAS G12C in the low micromolar range.

    “One of the first developed mutant specific, covalent small molecule inhibitors to demonstrate proficiency in targeting KRAS G12C and locking it into a GDP-bound state was ARS-853 by Wellspring Biosciences and had robust cellular activity against KRAS G12C in the low micromolar range.”

  • The paper relies on this without support.

    Direct inhibition of KRAS G12C was validated by ARS-1620, but the identification of improved inhibitors suitable for clinical testing proved difficult.

    “Direct inhibition of KRAS G12C was validated by ARS-1620, but the identification of improved inhibitors suitable for clinical testing proved difficult.”

  • The paper relies on this without support.

    KRAS G12C/STK11 co-mutated NSCLC has poor prognosis with chemotherapy or immunotherapy and is an area of unmet need.

    “as this disease subset has poor prognosis with chemotherapy or immunotherapy and is an area of unmet need.”

  • The paper relies on this without support.

    Immunotherapy with checkpoint inhibitors is standard of care for front-line management in KRAS mutated NSCLC.

    “Immunotherapy with checkpoint inhibitors remain a standard of care for front line management in KRAS mutated NSCLC.”

  • The paper relies on this without support.

    The SOS1 catalytic domain affects the EGFR/MAPK pathway.

    “A novel investigation into KRAS G12C therapeutic approaches has yielded a new target of the SOS1 catalytic domain that affects the EGFR/MAPK pathway.”
13 of 13

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Inconsistent identifier for the SOS1 inhibitor

    Minor

    The discussion calls the inhibitor BI-3046, while the cited reference names BI-3406 alongside BI 1701963. The identifiers differ by transposed digits.

  • Inconsistent identifier for the Janssen KRAS G12C inhibitor

    Minor

    The prose names the Janssen inhibitor JNJ-74699147, but Table 1 names it JNJ-74699157. The identifiers differ by one digit.

2 of 2

The citation lists haven’t been fetched yet

References 63 · Cited by 72

Research works printed but not linked: 5

  1. Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019). · DOI · Paper page
  2. B., Li. Sotorasib for KRAS G12C. World Conference on Lung Cancer (2021).
  3. Revolution Medicines. Translating frontier oncology targets to outsmart cancer: corporate review Q2 2021. Revolution Medicines, (2021).
  4. Peng S. B. et al. Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C Inhibitor. Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C Inhibitor. AACR Annual Meeting (2021). · DOI
  5. Globe Newswire. Guardant Health Announces Collaboration With Amgen to Develop a Global Liquid Biopsy Companion Diagnostic for AMG 510 KRAS G12C Inhibitor. Press Releases. Guardant Health, Inc., 2020. https://investors.guardanthealth.com/press-releases/press-releases/2020/Guardant-Health-Announces-Collaboration-With-Amgen-to-Develop-a-Global-Liquid-Biopsy-Companion-Diagnostic-for-AMG-510-KRAS-G12C-Inhibitor/default.aspx (2021).

Authors
Palma, G., Khurshid, F., Lu, K., Woodward, B., & Husain, H.
Affiliations
University of California San Diego (US)
Corresponding author
Husain, Hatim
ORCID
Venue
npj Precision Oncology
Publisher
Springer Science and Business Media LLC
Published
2021-11-29
Volume
5
Issue
1
Pages
98-98
ISSN
2397-768X (ISSN-L)
DOI
10.1038/s41698-021-00237-5
PMC
PMC8630042
OpenAlex
W3215936267
Semantic Scholar
5b8cd2eacadeb918b332ba735ca7e7a5b060292a
Cited by
72
References
63
Citations by year
2026: 11 · 2025: 14 · 2024: 17 · 2023: 15 · 2022: 15
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Precision Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
KRAS G12C, non-small cell lung cancer, KRAS inhibitors, sotorasib, adagrasib, co-occurring mutations, SHP2, SOS1, MEK, EGFR, mTOR, cyclin-dependent kinases, immune checkpoint blockade, combination therapy, targeted therapy

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