Phase II trial of cabozantinib plus erlotinib in patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer with progressive disease on epidermal growth factor receptor tyrosine kinase inhibitor therapy

A California cancer consortium phase II trial (NCI 9303)

Karen L. Reckamp, Paul H. Frankel, Nora Ruel, Philip Mack, Barbara J. Gitlitz, Tianhong Li, Marianna Koczywas, Shirish M. Gadgeel, Mihaela C. Cristea, Chandra P. Belani, Edward M. Newman, David R Gandara, Primo N Lara

Research output: Contribution to journalArticle

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Abstract

Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8%) and 21 had stable disease (59.5%). A greater than 30% increase in tumor doubling time was observed in 79% of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32%) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted.

Original languageEnglish (US)
Article number132
JournalFrontiers in Oncology
Volume9
Issue numberMAR
DOIs
StatePublished - Jan 1 2019

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Neoplasms
Mutation
Therapeutics
Disease-Free Survival
cabozantinib
Erlotinib Hydrochloride
Amylases
Lipase
Vascular Endothelial Growth Factor A
Diarrhea
Carcinogenesis
Safety
Survival
Growth
Population

Keywords

  • EGFR
  • MET
  • Non-small cell lung cancer
  • RET
  • TKI resistance
  • VEGF

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase II trial of cabozantinib plus erlotinib in patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer with progressive disease on epidermal growth factor receptor tyrosine kinase inhibitor therapy : A California cancer consortium phase II trial (NCI 9303). / Reckamp, Karen L.; Frankel, Paul H.; Ruel, Nora; Mack, Philip; Gitlitz, Barbara J.; Li, Tianhong; Koczywas, Marianna; Gadgeel, Shirish M.; Cristea, Mihaela C.; Belani, Chandra P.; Newman, Edward M.; Gandara, David R; Lara, Primo N.

In: Frontiers in Oncology, Vol. 9, No. MAR, 132, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8{\%}) and 21 had stable disease (59.5{\%}). A greater than 30{\%} increase in tumor doubling time was observed in 79{\%} of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32{\%}) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted.",
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T1 - Phase II trial of cabozantinib plus erlotinib in patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer with progressive disease on epidermal growth factor receptor tyrosine kinase inhibitor therapy

T2 - A California cancer consortium phase II trial (NCI 9303)

AU - Reckamp, Karen L.

AU - Frankel, Paul H.

AU - Ruel, Nora

AU - Mack, Philip

AU - Gitlitz, Barbara J.

AU - Li, Tianhong

AU - Koczywas, Marianna

AU - Gadgeel, Shirish M.

AU - Cristea, Mihaela C.

AU - Belani, Chandra P.

AU - Newman, Edward M.

AU - Gandara, David R

AU - Lara, Primo N

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8%) and 21 had stable disease (59.5%). A greater than 30% increase in tumor doubling time was observed in 79% of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32%) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted.

AB - Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8%) and 21 had stable disease (59.5%). A greater than 30% increase in tumor doubling time was observed in 79% of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32%) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted.

KW - EGFR

KW - MET

KW - Non-small cell lung cancer

KW - RET

KW - TKI resistance

KW - VEGF

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U2 - 10.3389/fonc.2019.00132

DO - 10.3389/fonc.2019.00132

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JO - Frontiers in Oncology

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SN - 2234-943X

IS - MAR

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