Abstract CT064: Trial of SBRT and in-situ gene therapy followed by nivolumab in metastatic non-small cell lung carcinoma (ENSIGN)
Authors: Bernicker Eric H. , Teh Bin S. , Butler Brian , Chang Jenny C. 
Published: July 2017

Abstract
The programmed death-1 (PD-1) pathway represents a major tumoral immune resistance mechanism. Although anti-PD-1 blockade with nivolumab has shown great promise in the treatment of metastatic squamous and non-squamous non-small cell lung carcinoma (NSCLC), only a minority of patients derive benefit. Viral vector-based gene therapy such as adenoviral vector-mediated herpes simplex virus tyrosine kinase (ADV/HSV-tk) plus (+) valacyclovir has been shown to induce antitumor immune activity by increasing natural killer cell proliferation and cytotoxicity, cytokine stimulatory activity, and lymphocytic infiltrate. Radiation therapy also augments endogenous antitumor immune responses and often leads to systemic responses at distant sites. This phenomenon, known as the abscopal effect, has been attributed to the induction and enhancement of antitumor immune responses. Based on these findings, we are conducting a Phase II window of opportunity trial of stereotactic body radiation therapy (SBRT) and ADV/HSV-tk in situ gene therapy followed by nivolumab in metastatic squamous or non-squamous NSCLC (NCT02831933). We hypothesize that ADV/HSV-tk + valacyclovir and SBRT will boost endogenous immune-mediated antitumor activity and neoantigen expression, thereby improving the response to nivolumab treatment. The primary endpoint is the objective response rate, and secondary endpoints are duration of response, overall and progression-free survival rates, and antitumor activity. Correlative studies include evaluation of abscopal effect and immune response. ADV/HSV-tk (5 x 1011 viral particles) will be injected intratumorally on Day 0. Valacyclovir (2 g orally 3 times/day) and SBRT (30 Gy; 6 Gy X 5 fractions) will be administered from Day 1 to Day 15 and Day 2 to Day 16, respectively. Nivolumab at a dose of 240 mg will be administered intravenously every 2 weeks starting on Day 17 of the study and continuing until disease progression or unacceptable toxicity. Male or female patients with histologically or cytologically confirmed metastatic squamous or non-squamous NSCLC that has progressed on or after platinum-based chemotherapy or on or after single agent immune checkpoint therapy will be eligible for enrollment. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab. Other eligibility criteria include Eastern Cooperative Oncology Group performance status of 0-1, life expectancy ≥ 6 months, evaluable or measurable disease (RECIST 1.1), target lesion of suitable diameter (at least 1 cm) for SBRT, and non-target lesion of at least 1 cm for abscopal effect evaluation. Twenty-nine patients will be enrolled, and enrollment is expected to begin in February 2017.
Citation Format: Eric H. Bernicker, Bin S. Teh, Brian Butler, Jenny C. Chang. Trial of SBRT and in-situ gene therapy followed by nivolumab in metastatic non-small cell lung carcinoma (ENSIGN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT064. doi:10.1158/1538-7445.AM2017-CT064