Abstract
Purpose
KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown.
Methods
Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status.
Results
Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03–2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27–2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12–4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis.
Conclusion
Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.
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Associazione Italiana per la Ricerca contro il Cancro (AIRC), No. 15713 AIRC 2014.
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All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Comitato Etico Aziende Sanitarie (CEAS) Umbria approved the study (Approval Number: 4796/15/AV, 22 Jan 2015) to be conducted at Medical Oncology, Santa Maria della Misericordia Hospital, AOU of Perugia, Perugia, Italy (Deliberation Number: 1188, 9 Jul 2015). This article does not contain any studies with animals performed by any of the authors.
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Informed consent was obtained from all individual participants included in the study. Comitato Etico Aziende Sanitarie (CEAS) Umbria approved the study (Approval Number: 4796/15/AV 22 Jan 2015).
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Ricciuti, B., Brambilla, M., Cortellini, A. et al. Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancer. Clin Transl Oncol 22, 708–716 (2020). https://doi.org/10.1007/s12094-019-02175-y
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DOI: https://doi.org/10.1007/s12094-019-02175-y