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

Tianhong Li, Bilal Piperdi, William V. Walsh, Mimi Kim, Laurel A. Beckett, Rasim Gucalp, Missak Haigentz, Venu G. Bathini, Huiyu Wen, Kaili Zhou, Patricia B. Pasquinelli, Srikanth Gajavelli, Meera Sreedhara, Xianhong Xie, Primo N. Lara, David R. Gandara, Roman Perez-Soler

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalClinical Lung Cancer
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Pemetrexed
Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Disease-Free Survival
Genotype
Small Cell Lung Carcinoma
Erlotinib Hydrochloride
Neoplasms
Exanthema
Platinum

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Li, Tianhong ; Piperdi, Bilal ; Walsh, William V. ; Kim, Mimi ; Beckett, Laurel A. ; Gucalp, Rasim ; Haigentz, Missak ; Bathini, Venu G. ; Wen, Huiyu ; Zhou, Kaili ; Pasquinelli, Patricia B. ; Gajavelli, Srikanth ; Sreedhara, Meera ; Xie, Xianhong ; Lara, Primo N. ; Gandara, David R. ; Perez-Soler, Roman. / Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer. In: Clinical Lung Cancer. 2017 ; Vol. 18, No. 1. pp. 60-67.
@article{f643adb6e0814a84a9456b88f91e1ce3,
title = "Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer",
abstract = "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.",
author = "Tianhong Li and Bilal Piperdi and Walsh, {William V.} and Mimi Kim and Beckett, {Laurel A.} and Rasim Gucalp and Missak Haigentz and Bathini, {Venu G.} and Huiyu Wen and Kaili Zhou and Pasquinelli, {Patricia B.} and Srikanth Gajavelli and Meera Sreedhara and Xianhong Xie and Lara, {Primo N.} and Gandara, {David R.} and Roman Perez-Soler",
year = "2017",
month = "1",
day = "1",
doi = "10.1016/j.cllc.2016.10.003",
language = "English (US)",
volume = "18",
pages = "60--67",
journal = "Clinical Lung Cancer",
issn = "1525-7304",
publisher = "Elsevier",
number = "1",

}

Li, T, Piperdi, B, Walsh, WV, Kim, M, Beckett, LA, Gucalp, R, Haigentz, M, Bathini, VG, Wen, H, Zhou, K, Pasquinelli, PB, Gajavelli, S, Sreedhara, M, Xie, X, Lara, PN, Gandara, DR & Perez-Soler, R 2017, 'Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer', Clinical Lung Cancer, vol. 18, no. 1, pp. 60-67. https://doi.org/10.1016/j.cllc.2016.10.003

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; Piperdi, Bilal; Walsh, William V.; Kim, Mimi; Beckett, Laurel A.; Gucalp, Rasim; Haigentz, Missak; Bathini, Venu G.; Wen, Huiyu; Zhou, Kaili; Pasquinelli, Patricia B.; Gajavelli, Srikanth; Sreedhara, Meera; Xie, Xianhong; Lara, Primo N.; Gandara, David R.; Perez-Soler, Roman.

In: Clinical Lung Cancer, Vol. 18, No. 1, 01.01.2017, p. 60-67.

Research output: Contribution to journalArticle

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

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.

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