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

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)
JournalClinical Lung Cancer
DOIs
StateAccepted/In press - Jun 19 2016

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

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

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, 19.06.2016.

Research output: Contribution to journalArticle

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. 2016.
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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 = "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",
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 = "2016",
month = "6",
day = "19",
doi = "10.1016/j.cllc.2016.10.003",
language = "English (US)",
journal = "Clinical Lung Cancer",
issn = "1525-7304",
publisher = "Elsevier",

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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 - 2016/6/19

Y1 - 2016/6/19

N2 - 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 - 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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DO - 10.1016/j.cllc.2016.10.003

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