Phase II Study of Reovirus with Paclitaxel (P) and Carboplatin (C) in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Have Kras or EGFR-activated Tumors.

TPS292 Background: Epidermal growth factor receptor (EGFR) dysregulation and Kras mutations occur commonly in NSCLC, both leading to downstream activation of Ras-dependent pathways. Kras mutations are associated with a worse prognosis, poorer benefits to chemotherapy, and resistance to EGFR tyrosine kinase inhibitor therapy. Targeting the Ras-dependent pathways is a major area of unmet therapeutic need in NSCLC. Reovirus is a naturally occurring virus with few pathogenic effects in humans which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. Cells that express high levels of EGFR are also susceptible to reovirus infection. In preclinical studies, reovirus has been shown to induce host immunity and cell cycle arrest, acting synergistically with standard cytotoxic agents. Encouraging results have come from 18 completed or ongoing phase I and II studies with ≥ 200 patients with advanced solid malignancies treated with reovirus, alone or in combination with chemotherapy. The adverse effects of reovirus have been predominantly mild to moderate flu-like symptoms. We have hypothesized those patients with EGFR-mutated, EGFR-amplified, or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and will exhibit response to treatment with reovirus. Methods: This is a Fleming single stage, single-arm, phase II study to evaluate the objective response rate and 6-month progression-free survival of reovirus in combination with P and C as first-line therapy in patients with metastatic NSCLC. Eligible patients are those with ECOG PS 0-2, adequate organ function, no prior systemic chemotherapy, and tumors with the specified genotype. Reovirus (3 × 1010 TCID50) will be administered intravenously daily on days 1-5, C (AUC 6) on day 1, and P (200 mg/m2) on day 1 of each 21-day cycle. Correlative studies testing for mitogen-activated protein kinase (MAPK) phosphorylation in tumor specimens will be performed to confirm the presence of an activated Ras/MAPK pathway. Thirty-six response-evaluable patients will be recruited. To date, we have enrolled and treated 7 patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncolytics Biotech Oncolytics Biotech