Vascular Endothelial Growth Factor Receptor Inhibitors for Recurrent or Metastatic Adenoid Cystic Carcinoma: A Systematic Review and Meta-Analysis

Abstract

Importance: There is no systemic therapy for recurrent or metastatic adenoid cystic carcinoma (ACC) approved by the US Food and Drug Administration.

Objective: To examine the efficacy, safety, and tolerability of vascular endothelial growth factor receptor (VEGFR) inhibitors in recurrent or metastatic ACC.

Data sources: PubMed, Embase, and Cochrane Library were systematically searched for studies of VEGFR inhibitors in recurrent or metastatic ACC from database inception to August 31, 2023.

Study selection: Inclusion criteria were prospective clinical trials of recurrent or metastatic ACC treated with VEGFR inhibitors, reporting at least 1 outcome of interest specifically for ACC. Of 1963 identified studies, 17 (0.9%) met inclusion criteria.

Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guideline was followed to extract data. Data were pooled using a random-effects generalized linear mixed model with 95% CIs.

Main outcomes and measures: The primary efficacy outcome was best overall response to VEGFR inhibitors, including objective response, stable disease, or progressive disease (PD). Safety and tolerability outcomes included incidence of grade 3 or higher adverse events, rates of exit from trial due to PD or drug-related toxic effects, and dose reduction rate (DRR).

Results: A total of 17 studies comprising 560 patients with recurrent or metastatic ACC treated with 10 VEGFR inhibitors were included. The objective response rate was 6% (95% CI, 3%-12%; I2 = 71%) and stable disease was the most frequent best overall response (82%; 95% CI, 74%-87%; I2 = 67%). The 6-month disease control (defined as objective response and stable disease) rate was 54% (95% CI, 45%-62%; I2 = 52%). The rate of grade 3 or higher adverse events was 53% (95% CI, 42%-64%; I2 = 81%) and of DRR was 59% (95% CI, 40%-76%). Most patients (57%; 95% CI, 44%-70%; I2 = 83%) continued therapy until PD; 21% (95% CI, 15%-28%; I2 = 62%) of patients suspended therapy for toxic effects. In subgroup analysis by specific VEGFR inhibitor, the objective response rate was 14% (95% CI, 7%-25%; I2 = 0%), stable disease rate was 76% (95% CI, 63%-85%; I2 = 0%), proportion treated until PD was 61% (95% CI, 14%-94%; I2 = 94%), and DRR was 78% (95% CI, 66%-87%; I2 = 39%) with lenvatinib. Corresponding axitinib results were objective response rate of 8% (95% CI, 4%-15%; I2 = 0%) and stable disease rate of 85% (95% CI, 72%-92%; I2 = 69%), with 73% (95% CI, 63%-82%; I2 = 0%) of patients treated until PD, and the DRR was 22% (95% CI, 12%-38%; I2 = 77%). Rivoceranib had the highest objective response rate (24%; 95% CI, 7%-57%) but high heterogeneity among studies (I2 = 95%) and the lowest rate of patients who continued therapy until PD (35%; 95% CI, 20%-55%; I2 = 90%).

Conclusions and relevance: This systematic review and meta-analysis found that VEGFR inhibitors were associated with high rates of disease stabilization in recurrent or metastatic ACC. Of 10 included VEGFR inhibitors, lenvatinib and axitinib were associated with the best combined and consistent efficacy, safety, and tolerability profiles, substantiating their inclusion in treatment guidelines.

Figure 1.. Flowchart of Study Screening and Selection

ACC indicates adenoid cystic carcinoma.

Figure 2.. Response Associated with Vascular Endothelial Growth Factor Receptor Inhibitors for Recurrent or Metastatic Adenoid Cystic Carcinoma

Diamonds indicate pooled results. ^aCalculated using the random-effects generalized linear mixed model.

Figure 3.. Disease Activity Associated With Vascular Endothelial Growth Factor Receptor Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma

Diamonds indicate pooled results. ^aCalculated using the random-effects generalized linear mixed model.

Figure 4.. Safety and Tolerability of Vascular Endothelial Growth Factor Receptor Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma

Safety was measured as rate of grade 3 or higher adverse events (AEs). Tolerability was calculated as the proportion of patients who discontinued treatment because of toxic effects. ^aCalculated using the random-effects generalized linear mixed model.