KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315)

Sebastian, Martin; Eberhardt, Wilfried; Hoffknecht, Petra; Metzenmacher, Martin; Wehler, Thomas; Kokowski, Konrad; Alt, Jürgen August; Schütte, Wolfgang; Büttner, Reinhard; Heukamp, Lukas C.; Jänicke, Martina; Fleitz, A.; Zacharias, Stefan; Dille, Stephanie; Hipper, A.; Sandberg, Marlen; Weichert, Wilko; Groschek, Matthias; Heyde, E. von der; Rauh, Jacqueline; Dechow, Tobias; Thomas, Michael; Griesinger, Frank

doi:10.1016/j.lungcan.2021.02.005

Cited by 54 publications

(62 citation statements)

References 39 publications

(48 reference statements)

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“…Regarding survival in patients with KRAS wt and KRAS mut tumours, our results are consistent with other studies [ 5 , 6 , 7 , 8 , 9 , 23 ]. Moreover, we found no significant differences in PFS or OS between patients with KRAS wt, KRAS G12C, and KRAS non-G12C mutated tumours or among patients with G12C, G12V, G12D, and G12A mutated tumours, which agrees with other studies [ 2 , 13 , 16 , 24 , 25 , 26 , 27 ]. However, worse survival in patients with KRAS mutated tumours (as one group) compared to KRAS wt, as well as in patients with KRAS G12C compared to patients with KRAS non-G12C mutations, have also been reported [ 2 , 10 , 11 , 28 ].…”

Section: Discussionsupporting

confidence: 92%

“…KRAS hot spot mutations are clustered on codon 12 and 13 in exon 2 and codon 61 in exon 3 [ 15 ]. The most common mutation subtypes in KRAS mutated lung adenocarcinoma are the codon 12 transversion mutations (substitution of a purine with a pyrimidine nucleotide, or opposite) G12C (39%) and G12V (18–21%), followed by the transition mutations (substitution of a purine by a purine, or a pyrimidine with a pyrimidine) G12D (14–18%) and G12A (10–11%) [ 1 , 2 , 16 ]. While KRAS transversion mutations are associated with a history of smoking, KRAS transition mutations are more common in never-smokers [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

Wahl

Dai

Emdal

et al. 2021

Cancers

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Background: due to emerging therapeutics targeting KRAS G12C and previous reports with conflicting results regarding the prognostic impact of KRAS and KRAS G12C in non-small cell lung cancer (NSCLC), we aimed to investigate the frequency of KRAS mutations and their associations with clinical characteristics and outcome. Since mutation subtypes have different preferences for downstream pathways, we also aimed to investigate whether there were differences in outcome according to mutation preference for the Raf, PI3K/Akt, or RalGDS/Ral pathways. Methods: retrospectively, clinicopathological data from 1233 stage I–IV non-squamous NSCLC patients with known KRAS status were reviewed. KRAS’ associations with clinical characteristics were analysed. Progression free survival (PFS) and overall survival (OS) were assessed for the following groups: KRAS wild type (wt) versus mutated, KRAS wt versus KRAS G12C versus KRAS non-G12C, among KRAS mutation subtypes and among mutation subtypes grouped according to preference for downstream pathways. Results: a total of 1117 patients were included; 38% had KRAS mutated tumours, 17% had G12C. Among KRAS mutated, G12C was the most frequent mutation in former/current smokers (45%) and G12D in never smokers (46%). There were no significant differences in survival according to KRAS status, G12C status, among KRAS mutation subtypes or mutation preference for downstream pathways. Conclusion: KRAS status or KRAS mutation subtype did not have any significant influence on PFS or OS.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

Wahl

Dai

Emdal

et al. 2021

Cancers

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“…Additionally, these characteristics were also described in patients without the three main actionable drivers (Triple WT cohort) and the overall cohort of patients with advanced NSCLC (All Advanced NSCLC cohort). Patients in the G12C cohort had demographic and clinical characteristics similar to those in the overall group of patients with advanced NSCLC; however, higher proportions of past or present smokers and nonsquamous cell carcinoma histology were observed in the G12C cohort, as has recently been reported based on data from the CRISP registry of German patients [29]. These findings are consistent with earlier studies in smaller populations showing that KRAS mutations, specifically the p.G12C mutation, are highly prevalent among current or former smokers, and that this mutation is associated with a high rate of brain metastases [18,20,30,31].…”

Section: Discussionsupporting

confidence: 61%

A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease

Spira

Aggarwal

et al. 2021

Lung Cancer

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The KRAS p.G12C mutation, prevalent in non-small-cell lung cancer (NSCLC), has only recently become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS p.G12C in patients with advanced NSCLC. Materials and Methods: Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different mutation profiles (KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011 to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed. Results: Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma histology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver mutations, but non-driver co-mutations were common (STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C patients, median (95 % CI) rwOS was 12.0 (9.6-15.3), 9.5 (8.1-13.1), and 6.7 (5.9-10.7) months after first, second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4-5.8), 4.0 (2.8-5.3), and 3.1 (2.4-4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts. Conclusion:The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need for more effective novel treatments.Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; CGDB, clinico-genomic database; CGP, comprehensive genomic profiling; EGFR, epidermal growth factor receptor; EHR, electronic health records; FH-FMI, Flatiron Health-Foundation Medicine; G12C, patients with KRAS p.G12C mutated NSCLC included in study; KEAP1, Kelch-like ECH-associated protein 1 oncogene; KRAS, Kirsten rat sarcoma viral oncogene homolog; KRAS p.G12C, codon 12 glycine-tocysteine substitution of KRAS; MET, mesenchymal-epithelial transition; NGS, next-generation sequencing; NSCLC, non-small-cell lung cancer; NTRK1-3, neurotrophic tyrosine kinases 1-3 gene; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RAS, rat sarcoma viral oncogene homolog; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged-during-transfection gene; ROS1, ROS proto-oncogene 1; rwOS, real-world overall survival; rwPFS, real-world progression-free survival; STK11/LKB1, serine/threonine kinase 11, liver kinase B1; TP53, tumor protein p53; Triple WT, KRAS/EGFR/ALK wild-type; VEGF, vascular endothelial growth factor.

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“…Noteworthy, recent studies focused on KRAS p.G12C mutation incidence exclude the EGFR-positive NSCLC population. 20 Therefore, whether these patients could benefit from a KRAS inhibitor as a second-line treatment or concomitant to first-line EGFR-TKI is completely unexplored.…”

Section: Discussionmentioning

confidence: 99%

KRAS p.G12C mutation occurs in 1% of EGFR-mutated advanced non-small-cell lung cancer patients progressing on a first-line treatment with a tyrosine kinase inhibitor

et al. 2021

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Background: KRAS is mutated in w30% of non-small-cell lung cancer (NSCLC) but it has also been identified as one of the mechanisms underlying resistance to tyrosine kinase inhibitors (TKIs) in EGFR-positive NSCLC patients. Novel KRAS inhibitors targeting KRAS p.G12C mutation have been developed recently with promising results. The proportion of EGFR-positive NSCLC tumours harbouring the KRAS p.G12C mutation upon disease progression is completely unexplored. Materials and methods: Plasma samples from 512 EGFR-positive advanced NSCLC patients progressing on a first firstline treatment with a TKI were collected. The presence of KRAS p.G12C mutation was assessed by digital PCR. Results: Overall, KRAS p.G12C mutation was detected in 1.17% of the samples (n ¼ 6). In two of these cases, we could confirm that the KRAS p.G12C mutation was not present in the pre-treatment plasma samples, supporting its role as an acquired resistance mutation. According to our data, KRAS G12C patients showed similar clinicopathological characteristics to those of the rest of the study cohort and no statistically significant associations between any clinical features and the presence of the mutation were found. However, two out of six KRAS G12C tumours harboured less common EGFR driver mutations (p.G719X/p.L861Q). All KRAS G12C patients tested negative for the presence of p.T790M resistance mutation. Conclusions: The KRAS p.G12C mutation is detected in 1% of EGFR-positive NSCLC patients who progress on a first line with a TKI. All KRAS G12C patients were negative for the presence of the p.T790M mutation and they did not show any distinctive clinical feature.

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KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315)

Cited by 54 publications

References 39 publications

The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease

KRAS p.G12C mutation occurs in 1% of EGFR-mutated advanced non-small-cell lung cancer patients progressing on a first-line treatment with a tyrosine kinase inhibitor

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