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Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non-small-cell Lung Cancer.


ABSTRACT: BACKGROUND:Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non-small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype. PATIENTS AND METHODS:Patients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m2 provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2-17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression-free survival (PFS), which would be considered promising for future study if median PFS was ? 4.5 months. RESULTS:Of 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty-nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed-alone groups, respectively. In patients with EGFR wild-type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed-alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6-month PFS (45% vs. 29%, P = .26), and 12-month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm. CONCLUSION:In patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.

SUBMITTER: Li T 

PROVIDER: S-EPMC5497702 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non-small-cell Lung Cancer.

Li Tianhong T   Piperdi Bilal B   Walsh William V WV   Kim Mimi M   Beckett Laurel A LA   Gucalp Rasim R   Haigentz Missak M   Bathini Venu G VG   Wen Huiyu H   Zhou Kaili K   Pasquinelli Patricia B PB   Gajavelli Srikanth S   Sreedhara Meera M   Xie Xianhong X   Lara Primo N PN   Gandara David R DR   Perez-Soler Roman R  

Clinical lung cancer 20161028 1


<h4>Background</h4>Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non-small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype.<h4>Patients and methods</h4>Patients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m<sup>2</sup> provided intravenously on day 1) or pemetrexed followed by erlotinib  ...[more]

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