Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma

Abstract

Purpose: Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC.

Patients and methods: This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how MYB expression and genomic alterations relate to outcomes was conducted.

Results: Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician's discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1).

Conclusion: This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.

FIG 1.

(A) Waterfall plot of maximum percent change in tumor size from baseline as measured by Response Evaluation Criteria in Solid Tumor (RECIST). (B) Swimmer’s plot of time from start of therapy to time of last therapy, scan showing objective progression, or last known follow-up. (C) Kaplan-Meier estimate of progression-free survival as of May 11, 2018, defined as time from first dose until objective disease progression or death from any cause; vertical lines indicate censored events. (D) Longitudinal change in RECIST percentage from baseline. (E) Pre- and post-treatment images in a patient with a partial response. Green indicates patients with confirmed partial response. Blue indicates patients with stable disease or progression of disease as best response. TKI, tyrosine kinase receptor.

FIG 2.

Relationship between MYB expression and maximum tumor regression achieved. IHC, immunohistochemistry; RECIST, Response Evaluation Criteria in Solid Tumor.

FIG 3.

Integrated genomic and clinical response data. IHC, immunohistochemistry; RECIST, Response Evaluation Criteria in Solid Tumor. FISH, fluorescence in situ hybridization.

FIG A1.

Kaplan-Meier estimate of event-free survival as of May 11, 2018. An event was defined as Response Evaluation Criteria in Solid Tumors (RECIST) progression at any time point (including after study), initiation of new therapy, or death (whichever came first). Patients were otherwise censored at the last day of therapy (if still on study) or the last day of therapy on study if lost to follow-up.