K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways

Background Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/ STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting. Methods This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated firstline immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS). Results Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/ STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings. Conclusions This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or

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“…patients with STK11m had a co-mutation in KRASm, which is largely consistent with the comutation frequencies reported previously [20,21,24,33].…”

Section: Plos Onesupporting

confidence: 91%

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

et al. 2020

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“…Additional genetic alterations detected by bulk tumor DNA-based analysis can co-exist with a primary targetable oncogenic "driver" alteration (e.g. oncogenic EGFR, ALK, BRAF, ROS1, KRAS and MET) and may help promote tumor progression and limit therapy response (Blakely et al, 2017;Kim et al, 2019;Scheffler et al, 2019;Yang et al, 2019). We queried scRNAseq transcripts from each cancer cell to identify somatic alterations, namely single nucleotide polymorphisms (SNPs), insertions/deletions (indels), and gene fusions (Figure 2A,2B,2C).…”

Section: Fig 1 Patient Characteristics and Experimental Overviewmentioning

confidence: 99%

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

Maynard

McCoach

Rotow

et al. 2019

Preprint

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“…The Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR) mutations play an important role in the pathogenesis of most lung adenocarcinomas and are, with rare exceptions, mutually exclusive, and vary by geography (1). KRAS is the most commonly mutated oncogene in nonsmall cell lung cancer (NSCLC), occurring mainly in lung adenocarcinomas (30%) and less frequently in squamous cell carcinoma (5%) (2,3) Treatments directed toward KRAS mutations are not available because of limited efficacy resulting from failure to inhibit the protein directly, or inhibit its downstream effectors (4).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib. Conclusions: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents.

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K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways

Cited by 185 publications

References 45 publications

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

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

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