TY - JOUR
T1 - Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer
AU - Li, Tianhong
AU - Piperdi, Bilal
AU - Walsh, William V.
AU - Kim, Mimi
AU - Beckett, Laurel A.
AU - Gucalp, Rasim
AU - Haigentz, Missak
AU - Bathini, Venu G.
AU - Wen, Huiyu
AU - Zhou, Kaili
AU - Pasquinelli, Patricia B.
AU - Gajavelli, Srikanth
AU - Sreedhara, Meera
AU - Xie, Xianhong
AU - Lara, Primo N.
AU - Gandara, David R.
AU - Perez-Soler, Roman
N1 - Publisher Copyright:
© 2016
PY - 2017/1/1
Y1 - 2017/1/1
N2 - This randomized phase 2 study demonstrated promising clinical synergism between pemetrexed and intercalated erlotinib in patients with unselected nonsquamous non–small-cell lung cancer (NSCLC) as second-line therapy. EGFR (epidermal growth factor receptor) genotyping by Sequenom multiplex oncogenotyping assay was feasible in 79% of eligible patients using tumor DNA from either archival specimens and/or plasma. Because patients with EGFR-mutant NSCLC respond well to EGFR tyrosine kinase inhibitor monotherapy alone or in combination with bevacizumab, the combination might merit further evaluation as second-line or maintenance therapy against new standards in patients with EGFR wild-type advanced NSCLC. 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.
AB - This randomized phase 2 study demonstrated promising clinical synergism between pemetrexed and intercalated erlotinib in patients with unselected nonsquamous non–small-cell lung cancer (NSCLC) as second-line therapy. EGFR (epidermal growth factor receptor) genotyping by Sequenom multiplex oncogenotyping assay was feasible in 79% of eligible patients using tumor DNA from either archival specimens and/or plasma. Because patients with EGFR-mutant NSCLC respond well to EGFR tyrosine kinase inhibitor monotherapy alone or in combination with bevacizumab, the combination might merit further evaluation as second-line or maintenance therapy against new standards in patients with EGFR wild-type advanced NSCLC. 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.
KW - EGFR wild type
KW - Multiplex genotyping
KW - Plasma circulating tumor DNA
KW - Randomized phase 2 study
KW - Second line
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U2 - 10.1016/j.cllc.2016.10.003
DO - 10.1016/j.cllc.2016.10.003
M3 - Article
C2 - 27919627
AN - SCOPUS:85007426193
SN - 1525-7304
VL - 18
SP - 60
EP - 67
JO - Clinical lung cancer
JF - Clinical lung cancer
IS - 1
ER -