Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors

Abstract

IMPORTANCETherapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET 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 NET have been disappointing.OBJECTIVE To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. DESIGN, SETTING, AND PARTICIPANTS This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. INTERVENTIONS Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. MAIN OUTCOMES AND MEASURESThe primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. RESULTSFollowing treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. CONCLUSIONS AND RELEVANCEIn this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies.

Evaluation of PD-L1 expression in a large set of gastroenteropancreatic neuroendocrine tumours and correlation with clinicopathological data

“…For receptors and markers, at least moderate expression (i.e., an IRS value of 6) is generally assumed to be necessary for their clinical utility as target structures. In our study, 25% of GEP-NEN tumours met this criterion for PD-L1, which is consistent with the percentage of responders in most studies of PD-L1 therapy [ [13] , [14] , [15] , [17] , [18] , [19] , [20] , 22 , 23 ].…”

“…Several anti-PD-1 antibodies such as cemiplimab, dostarlimab, nivolumab, and pembrolizumab and anti-PD-L1 antibodies such as atezolizumab, avelumab, and durvalumab have been approved, and many other inhibitors are under development, for the treatment of cancers including non-small cell lung cancer (NSCLC); head and neck squamous cell carcinoma; oesophagus, gut, colorectal, and renal clear cell carcinoma; bladder cancer; melanoma; Merkel cell carcinoma; and Hodgkin's lymphoma [9] , [10] , [11] , [12] . Trials examining the efficacy of these antibodies for GEP-NENs either alone or in combination with other therapies, however, have produced mixed results [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] . The inconsistencies may be due to the small numbers of patients included in the trials or to the substantial differences between studies in grading, localisation, and other clinicopathological characteristics of the tumours.…”

Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications

“…Despite a median PFS of 12.4 months, grade 3/4 toxicities were described in the 63% of the enrolled patients. Based on the evidence that anti-angiogenic agents such as bevacizumab may modulate the tumor immune microenvironment and decrease the expression of regulatory checkpoints on tumor-infiltrating lymphocytes ( 79 ), a single-arm, open-label, nonrandomized study has recently evaluated the association of bevacizumab with the anti-PD-L1 Ab atezolizumab in patients with advanced, progressive, well-differentiated NETs ( 71 ). Overall, 20 patients with panNETs and 20 patients with extra-pancreatic NETs have been enrolled, and an ORR of 20% and 15% has been recorded in the two cohorts.…”

Molecular factors, diagnosis and management of gastrointestinal tract neuroendocrine tumors: An update

“…The combination of the biological agents bevacizumab, an anti-VEGF monoclonal antibody, with atezolizumab, an anti-PD-L1 monoclonal antibody (against the protein programmed cell death-ligand 1), in patients with advanced NETs showed promising results that were compatible with other therapies[ 92 ].…”