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Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancer

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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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Acknowledgements

Associazione Italiana per la Ricerca contro il Cancro (AIRC), No. 15713 AIRC 2014.

Author information

Author notes

  1. B. Ricciuti and M. Brambilla are the co-first authors.

Authors and Affiliations

  1. Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, University of Perugia, via Dottori, 1, 06156, Perugia, Italy

    B. Ricciuti, A. De Giglio, V. Ludovini, S. Baglivo, G. Metro & R. Chiari

  2. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, University of Milan, Milan, Italy

    M. Brambilla

  3. Medical Oncology, Department of Biotechnological and Applied Clinical Sciences, St. Salvatore Hospital, University of L’Aquila, L’Aquila, Italy

    A. Cortellini & C. Ficorella

  4. Division of Pathology and Histology, Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy

    A. Sidoni & G. Bellezza

  5. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy

    L. Crinò

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Correspondence to B. Ricciuti.

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Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical approval

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.

Informed consent

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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