Significant Disease Control Achieved With Nivolumab/Temozolomide Combo in Neuroendocrine Tumors

“Although these are early data, we are encouraged by these findings. The depth of response is particularly impressive in some patients."

The combination of nivolumab (Opdivo) and temozolomide (Temodar) demonstrated promising efficacy in patients with neuroendocrine tumors (NETs), resulting in a disease control rate of 93%, according to interim results from a phase 2 trial.1

“Although these are early data, we are encouraged by these findings. The depth of response is particularly impressive in some patients,” lead study author Dwight H. Owen, MD, MS, assistant professor of medicine in the Division of Thoracic Medical Oncology at The Ohio State University Comprehensive Cancer Center–James in Columbus, told Targeted Therapies in Oncology. “In our interim analysis, we observed responses in patients with grades 2 and 3 tumors, including in 2 patients with very aggressive tumors with high Ki-67 [antigen expression] percentages [70% and 80%] and in patients with nonpancreatic NET.” Findings were presented in a poster released as part of the National Comprehensive Cancer Network (NCCN) 2020 Virtual Annual Conference.

Temozolomide is an NCCN-recommended treatment for patients with NETs and has an immunomodulatory impact on the lymphoid cells of patients with advanced cancers.1,2 The investigators sought to discover whether the addition of immunotherapy could boost efficacy results in patients with NETs.

A nonrandomized, 2-cohort, open-label trial was initiated at The Ohio State University Comprehensive Cancer Center to investigate the use of nivolumab and temozolomide in patients with advanced or metastatic NETs or recurrent or refractory small cell lung cancer (SCLC; NCT03728361). In the NET cohort, patients with any grade or primary site of disease were eligible to enroll regardless of PD-L1 expression or line of therapy, but disease progression within 12 months was required. The cohort was expected to enroll 28 patients, but the interim analysis focused on the first 15 patients treated; if 3 or more responses were seen, the cohort was able to proceed and complete enrollment.

The extensive-stage SCLC cohort included patients who were refractory or recurrent to platinum-based chemotherapy; any PD-L1 expression level was allowed, as was treated central nervous system (CNS) disease. The cohort planned to enroll a total of 25 patients if 2 or more responses were seen in the interim analysis. Investigators are currently reviewing the interim efficacy analysis for the SCLC cohort, according to Owen.

Patients initially received oral temozolomide at 200 mg/m2 for 5 days with nivolumab given at 480 mg intravenously every 4 weeks, but the investigators noted a higher-than-expected rate of hematologic malignancies in the first 13 patients treated, so the dose of temozolomide was reduced to 150 mg/m2.

After the first cycle, tumor imaging was completed every 8 weeks and tumor markers were assessed in the NET cohort every 4 weeks.

The primary end point of the trial was objective response rate by RECIST 1.1 criteria, and secondary end points included the incidence of adverse events, progression-free survival (PFS), CNS PFS, and overall survival (OS). The study also planned to conduct an exploratory biomarker analysis of PD-L1 expression and its impact on survival.

The median age of the first 15 patients treated in the NET cohort was 59 years (range, 41-78), and 60% of the participants were female. Ampullary tumors and those in the small bowel were the most commonly observed (47%), followed by bronchial tumors (33%). Three patients had Ki-67 expression above 20%. Most patients were being treated in the frontline setting (60%), although 2 patients were being treated in the third-line setting or beyond (13%).

After a median follow-up of 10.4 months, the median PFS was 10 months (95% CI, 5.6–not reached) and the median OS was not reached.

Three patients (20%) achieved a partial response, and 11 (73%) achieved stable disease, for a disease control rate of 93%. The partial responses were seen in patients with Ki-67 expression levels of 15%, 70%, and 80%. The responders each had a different primary tumor location and grade 2 or 3 tumors.

One dose-limiting toxicity of grade 3 bronchopulmonary hemorrhage was observed; grade 3/4 hematologic toxicities of neutropenia were observed in 3 patients and thrombocytopenia in 4.

Among the first 15 patients treated, serious adverse events of grade 3 dyspnea were reported in 2 patients, as were grade 3 abdominal pain, grade 3 cholangitis, and grade 3 ascites in 1 patient each. Investigators considered these events unrelated or unlikely to be related to study treatment. This toxicity profile was in line with the known safety profile for each agent and was improved with the reduced dose of temozolomide.

Enrollment in the NET cohort is continuing because the prespecified criteria were met for the study to continue in the cohort.

“We are looking forward to seeing the final analysis for this study and the results of our correlative studies to determine what patients are most likely to benefit from this treatment,” Owen commented.


1. Owen DH, Wei L, Goyal A, et al. A phase 2 trial of nivolumab and temozolomide in advanced neuroendocrine tumors (NETs): interim efficacy analysis. JNCCN. 2020;18(3.5):CLO20-054. doi:10.6004/jnccn.2019.7460

2. NCCN. Clinical Practice Guidelines in Oncology. Neuroendocrine and adrenal tumors, version 1.2019. Accessed May 26, 2020.