Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer

David E. Gerber, Mark A. Socinski, Joel W. Neal, Heather A. Wakelee, Keisuke Shirai, Lecia V. Sequist, Rachel P. Rosovsky, Rogerio C. Lilenbaum, Bruno R. Bastos, Chao Huang, Melissa L. Johnson, Paul J. Hesketh, Deepa S. Subramaniam, Martin F. Dietrich, Feng Chai, Yunxia Wang, Julia Kazakin, Brian Schwartz, Joan H. Schiller, Julie R. BrahmerRonan J. Kelly

Research output: Contribution to journalArticle

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Abstract

Background: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). Materials and methods: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. Results: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. Conclusion: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

Original languageEnglish (US)
Pages (from-to)44-49
Number of pages6
JournalLung Cancer
Volume117
DOIs
StatePublished - Mar 1 2018

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Non-Small Cell Lung Carcinoma
Disease-Free Survival
Drug Therapy
docetaxel
gemcitabine
Pemetrexed
Alopecia
Oncogenes
Nausea
Fatigue
Neoplasms
Research Personnel
Mutation
Survival
ARQ 197
Erlotinib Hydrochloride
Therapeutics

Keywords

  • Adenocarcinoma
  • MET
  • Small molecule
  • Targeted therapy
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer. / Gerber, David E.; Socinski, Mark A.; Neal, Joel W.; Wakelee, Heather A.; Shirai, Keisuke; Sequist, Lecia V.; Rosovsky, Rachel P.; Lilenbaum, Rogerio C.; Bastos, Bruno R.; Huang, Chao; Johnson, Melissa L.; Hesketh, Paul J.; Subramaniam, Deepa S.; Dietrich, Martin F.; Chai, Feng; Wang, Yunxia; Kazakin, Julia; Schwartz, Brian; Schiller, Joan H.; Brahmer, Julie R.; Kelly, Ronan J.

In: Lung Cancer, Vol. 117, 01.03.2018, p. 44-49.

Research output: Contribution to journalArticle

Gerber, DE, Socinski, MA, Neal, JW, Wakelee, HA, Shirai, K, Sequist, LV, Rosovsky, RP, Lilenbaum, RC, Bastos, BR, Huang, C, Johnson, ML, Hesketh, PJ, Subramaniam, DS, Dietrich, MF, Chai, F, Wang, Y, Kazakin, J, Schwartz, B, Schiller, JH, Brahmer, JR & Kelly, RJ 2018, 'Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer', Lung Cancer, vol. 117, pp. 44-49. https://doi.org/10.1016/j.lungcan.2018.01.010
Gerber, David E. ; Socinski, Mark A. ; Neal, Joel W. ; Wakelee, Heather A. ; Shirai, Keisuke ; Sequist, Lecia V. ; Rosovsky, Rachel P. ; Lilenbaum, Rogerio C. ; Bastos, Bruno R. ; Huang, Chao ; Johnson, Melissa L. ; Hesketh, Paul J. ; Subramaniam, Deepa S. ; Dietrich, Martin F. ; Chai, Feng ; Wang, Yunxia ; Kazakin, Julia ; Schwartz, Brian ; Schiller, Joan H. ; Brahmer, Julie R. ; Kelly, Ronan J. / Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer. In: Lung Cancer. 2018 ; Vol. 117. pp. 44-49.
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title = "Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer",
abstract = "Background: KRAS mutations are identified in approximately 25{\%} of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). Materials and methods: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. Results: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95{\%} CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95{\%} CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. Conclusion: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.",
keywords = "Adenocarcinoma, MET, Small molecule, Targeted therapy, Tyrosine kinase inhibitor",
author = "Gerber, {David E.} and Socinski, {Mark A.} and Neal, {Joel W.} and Wakelee, {Heather A.} and Keisuke Shirai and Sequist, {Lecia V.} and Rosovsky, {Rachel P.} and Lilenbaum, {Rogerio C.} and Bastos, {Bruno R.} and Chao Huang and Johnson, {Melissa L.} and Hesketh, {Paul J.} and Subramaniam, {Deepa S.} and Dietrich, {Martin F.} and Feng Chai and Yunxia Wang and Julia Kazakin and Brian Schwartz and Schiller, {Joan H.} and Brahmer, {Julie R.} and Kelly, {Ronan J.}",
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T1 - Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer

AU - Gerber, David E.

AU - Socinski, Mark A.

AU - Neal, Joel W.

AU - Wakelee, Heather A.

AU - Shirai, Keisuke

AU - Sequist, Lecia V.

AU - Rosovsky, Rachel P.

AU - Lilenbaum, Rogerio C.

AU - Bastos, Bruno R.

AU - Huang, Chao

AU - Johnson, Melissa L.

AU - Hesketh, Paul J.

AU - Subramaniam, Deepa S.

AU - Dietrich, Martin F.

AU - Chai, Feng

AU - Wang, Yunxia

AU - Kazakin, Julia

AU - Schwartz, Brian

AU - Schiller, Joan H.

AU - Brahmer, Julie R.

AU - Kelly, Ronan J.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Background: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). Materials and methods: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. Results: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. Conclusion: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

AB - Background: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). Materials and methods: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. Results: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. Conclusion: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

KW - Adenocarcinoma

KW - MET

KW - Small molecule

KW - Targeted therapy

KW - Tyrosine kinase inhibitor

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