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Clin Lung Cancer. 2017 Jan;18(1):60-67. doi: 10.1016/j.cllc.2016.10.003. Epub 2016 Oct 28.

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

Author information

1
Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA; Veterans Affairs Northern California Health Care System, Mather, CA. Electronic address: thli@ucdavis.edu.
2
Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
3
Division of Hematology/Oncology, Department of Internal Medicine, University of Massachusetts Medical School-Cancer Center of Excellence, Worcester, MA.
4
Department of Epidemiology, Albert Einstein College of Medicine, Bronx, NY.
5
Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA; Department of Public Health Sciences, University of California, Davis, Davis, CA.
6
Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.

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.

KEYWORDS:

EGFR wild type; Multiplex genotyping; Plasma circulating tumor DNA; Randomized phase 2 study; Second line

PMID:
27919627
PMCID:
PMC5497702
DOI:
10.1016/j.cllc.2016.10.003
[Indexed for MEDLINE]
Free PMC Article

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