In a single-institution phase II study reported in JAMA Oncology, Halperin et al found that the combination of atezolizumab and bevacizumab showed activity in treatment of advanced well-differentiated neuroendocrine tumors.

As stated by the investigators, “Therapies for patients with advanced well-differentiated [neuroendocrine tumors] have expanded but remain inadequate, with patients dying of disease despite recent advances in [neuroendocrine tumor] therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in [neuroendocrine tumors] have been disappointing.”

Study Details

The trial enrolled 40 patients with advanced, progressive grade 1 or 2 neuroendocrine tumors, including 20 with pancreatic neuroendocrine tumors and 20 with extrapancreatic neuroendocrine tumors, at The University of Texas MD Anderson Cancer Center between March 2017 and February 2019. Patients received bevacizumab at 15 mg/kg and atezolizumab at 1,200 mg on day 1 of 21-day cycles until disease progression or unacceptable toxicity. The median number of prior lines of therapy was four (range = 0–6) in patients with pancreatic neuroendocrine tumors and two (range = 0–3) in patients with extrapancreatic neuroendocrine tumors.

Responses

Objective response was observed in four patients with pancreatic neuroendocrine tumors (20%, 95% confidence interval [CI] = 5.7%–43.7%) and three patients with extrapancreatic neuroendocrine tumors (15%, 95% CI = 3.2%–37.9%). Median duration of response was 27 months (range = 11–38 months). Overall, five patients with pancreatic neuroendocrine tumors and none with extrapancreatic neuroendocrine tumors had PD-L1 expression in > 1% of tumor cells at baseline; objective response was observed in four of the five patients with PD-L1–positive tumors.  

Median progression-free survival was 14.9 months (95% CI = 4.4–32.0 months) in the pancreatic neuroendocrine tumor group and 14.2 months (95% CI = 10.2–19.6 months) in the extrapancreatic neuroendocrine tumor group. After median follow-up of 43.8 months (95% CI = 39.0–46.1 months), death had occurred in 12 patients with pancreatic neuroendocrine tumors and 6 with extrapancreatic neuroendocrine tumors. Median overall survival was 30.1 months (95% CI = 17.7-months to not reached) in the pancreatic neuroendocrine tumor group and not reached in the extrapancreatic neuroendocrine tumor group.

Adverse Events

The most common treatment-related adverse events of any grade were hypertension (55%), proteinuria (40%), fatigue (25%), increased alanine aminotransferase (23%), increases aspartate aminotransferase (23%), and hypothyroidism (23%). The most common grade ≥ 3 treatment-related adverse events included hypertension (10%) and proteinuria (3%). Adverse events led to discontinuation of treatment in two patients (5%), due to gastrointestinal hemorrhage in one and pain in one.  

The investigators concluded: “In this nonrandomized clinical trial, findings suggest that clinical responses in patients with [neuroendocrine tumors] may follow treatment with the combination of bevacizumab and atezolizumab, with a [progression-free survival] consistent with effective therapies.”

Daniel M. Halperin, MD, of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: This study was supported by the National Institutes of Health, an award from the Conquer Cancer Foundation of the American Society of Clinical Oncology, Genentech/Roche, and others. For full disclosures of the study authors, visit www.jamanetwork.com.