Anti-PD-(L)1 for KRAS-mutant advanced non-small–cell lung cancers: a meta-analysis of randomized–controlled trials

Landre, Thierry; Justeau, G.; Assié, Jean-Baptiste; Chouahnia, Kader; Davoine, Claire; Taleb, Chérifa; Chouaïd, C.; Duchemann, Boris

doi:10.1007/s00262-021-03031-1

Cited by 45 publications

(55 citation statements)

References 20 publications

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“…A recent registry study from the Netherlands reported no difference in OS for PD-L1 high patients receiving first-line pembrolizumab monotherapy but the fraction of patients where KRAS mutations status had been assessed and reported to the registry was uncertain and could only be approximated (at around 75%) [37]. However, a meta-analysis of randomized controlled trials showed a significant OS benefit for KRAS MUT patients in first-line immunotherapy with or without chemotherapy vs. chemotherapy alone [44], which is in line with the current study. Among these, the retrospective analysis of the phase 3 study KEYNOTE042 indicated a clear trend towards better OS in the KRAS MUT group when comparing first-line pembrolizumab versus platinum-containing chemotherapy (28 vs 11 months) than for the patients with KRAS WT (15 vs 12 months) [43], albeit only 301 out of 782 patients were molecularly assessed for KRAS status among which 69 KRAS MUT cases were identified.…”

Section: Discussionmentioning

confidence: 99%

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

Eklund

Wiel

Fagman

et al. 2021

Preprint

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BackgroundPembrolizumab, a humanized antibody targeting Programmed Cell Death 1 (PD-1), is used as first-line therapy for patients with metastatic Non-Small Cell Lung Cancer (NSCLC) expressing Programmed Death Ligand 1 (PD-L1). However, not all PD-L1 expressing patients respond to pembrolizumab. Thus, there is an urgent need to identify new predictive biomarkers for response to immune checkpoint blockade (ICB) therapy. KRAS mutational status has been suggested to affect treatment outcome, but no clear consensus could be drawn for previous studies.MethodsAll consecutive patients diagnosed between 2016-2018 with metastatic NSCLC (stage IV) in the region of West Sweden with molecular characterization available were included in this multi-centers retrospective study. Primary study outcome was overall survival (OS). Baseline patients’ characteristics, histology type, mutational status, PD-L1 expression and first-line treatment were collected from patient charts and the Swedish Lung Cancer registry.ResultsOut of 580 stage IV NSCLC patients, 35.5% harbored a mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet, KRASMUT (n = 219) is a significant (p = 0.001) negative factor for survival with median OS 9 months vs KRASWT 14 months. Patients on KRAS mutational status and PD-L1 expression levels had a significant better OS in KRASMUT with increased PD-L1 expression (p = 0.036) but not for KRASWT. On first-line ICB, KRASMUT had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status and Performance Status (PS) 0-1 were independent prognostic factors for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016 and HR 0.398, 95 % CI 0.165-0.963, p =0.041).ConclusionsKRAS mutations combined with PD-L1high is a better predictive marker for response to first-line monotherapy with pembrolizumab than only PD-L1high in patients with metastatic NSCLC.

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Section: Discussionmentioning

confidence: 99%

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

Eklund

Wiel

Fagman

et al. 2021

Preprint

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“…More recently, another metanalysis was performed on six rst-and second-line studies which compared an anti-PD-(L)1 with or without chemotherapy to chemotherapy alone: the authors found that in 386 KRAS-mutant patients, the anti-PD-(L)1 plus chemotherapy prolonged OS (HR 0.59 [95% CI, 0.49-0.72]; p < 0.00001) compared to chemotherapy alone, regardless the treatment line; moreover, OS of mutated KRAS was signi cantly longer than wild type KRAS (p = 0.001) (Landre et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Impact of KRAS mutations on clinical outcomes of patients with advanced non-squamous non-small cell lung cancer receiving anti PD1/PDL1 therapy.

Veccia¹,

Dipasquale²,

Kinspergher³

et al. 2022

Preprint

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PurposeTo evaluate the impact of KRAS mutations on response and survival outcomes in mutated vs wild type KRAS advanced non squamous non small cell lung cancer patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy. Patients and methodsWe retrospectively identified 119 patients, most of which (58%) were wild type. For each patient we evaluated overall survival (OS), progression free survival (PFS) and disease control rate (DCR). An exploratory analysis was performed among mutated patients to investigate the impact of specific KRAS mutations on response and survival outcomes. ResultsAfter a median follow-up of 10.3 months, the median OS was 14.9 months (95% CI 7.6 – 22.7) in wild type KRAS patients vs 14.7 months (95% CI 8.0 – 19.5) in mutated KRAS patients; p-value=0.529. No differences were also detected between two groups in terms of PFS and DCR. Patients with pG12C KRAS mutation reported survival and response outcomes that were not statistically different from those of patients with other KRAS mutations. ConclusionOur data confirmed that KRAS mutational status is not associated with survival and response outcomes in advanced non squamous NSCLC patients treated with immunotherapy alone or combined to chemotherapy.

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“…Immunotherapy with or without chemotherapy was significantly associated with prolonged OS (HR 0.59, 95% CI: 0.49-0.72, P<0.00001) and PFS (HR 0.58, 95% CI: 0.43-0.78, P=0.0003) compared to chemotherapy alone in patients with KRAS-mutant NSCLC. Survival for KRAS mutated patients was longer than for KRAS wild-type patients (P=0.001) (103).…”

Section: Use Of Agents Acting Outside Krasmentioning

confidence: 99%

“…A recent meta-analysis considered randomised-trial data comparing first-or second-line anti-PD-(L)1 with or without chemotherapy versus chemotherapy alone for KRAS-mutant advanced NSCLC (103). The authors analysed three first-line clinical trials (IMpower-150, KEYNOTE-189 and KEYNOTE-042) and three secondline trials (Oak, Poplar and CheckMate-057) that involved 1, 313 NSCLCs (386 with the KRAS mutation and 927 without this mutation).…”

Section: Use Of Agents Acting Outside Krasmentioning

confidence: 99%

The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target—a narrative review

Spagnuolo¹,

Maione²,

Gridelli³

2022

Transl Lung Cancer Res

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Background and Objective: The genetic nature of cancer provides the rationale to support the need for molecular diagnosis and patient selection for individualised antineoplastic treatments that are the best in both tolerability and efficacy for each cancer patient, including non-small cell lung cancer (NSCLC) patients.Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent the prevalent oncogenic driver in NSCLC, being detected in roughly one-third of cases and KRAS G12C is the most frequent mutation found in approximately 13% of patients.Methods: This paper gives an overview of the numerous scientific efforts in recent decades aimed at KRAS inhibition.

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Anti-PD-(L)1 for KRAS-mutant advanced non-small–cell lung cancers: a meta-analysis of randomized–controlled trials

Cited by 45 publications

References 20 publications

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

Impact of KRAS mutations on clinical outcomes of patients with advanced non-squamous non-small cell lung cancer receiving anti PD1/PDL1 therapy.

The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target—a narrative review

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