Phase 1 study of EGFR-antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives

Julie E. Bauman, Umamaheswar Duvvuri, Sufi Thomas, William E. Gooding, David A. Clump, Brian Karlovits, Ahmad Wehbe, Frank R. Miller, Seungwon Kim, Malabika Sen, Dwight E. Heron, Jennifer R. Grandis, Athanassios Argiris

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

BACKGROUND: Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT. METHODS: Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2. RESULTS: When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS–related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens. CONCLUSIONS: In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.

Original languageEnglish (US)
Pages (from-to)3881-3889
Number of pages9
JournalCancer
Volume124
Issue number19
DOIs
StatePublished - Oct 1 2018

Keywords

  • antisense
  • cetuximab
  • epidermal growth factor receptor (EGFR)
  • head and neck cancer
  • oligonucleotide
  • phase 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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