The objective of this study was to evaluate the efficacy and safety of dovitinib in patients with adenoid cystic carcinoma (ACC).
ACC patients with documented disease progression within the past 12 months were eligible. Patients received oral dovitinib (500 mg once daily for 5 consecutive days followed by a 2-day rest every week) until disease progression or unacceptable toxicities. The primary endpoint was the probability of 4-month progression-free survival (PFS). Metabolic response was evaluated with positron emission tomography (PET)/computed tomography (CT) scans performed at the baseline and after 8 weeks of treatment.
Between September 2011 and April 2013, 32 patients with metastatic and/or unresectable ACC were enrolled in this prospective, multicenter trial. The 4-month PFS probability was 80.4%, and the median PFS was 6.0 months (95% confidence interval, 4.4-7.6 months). Tumor shrinkage was observed in 22 patients (68.8%), and 1 patient had a confirmed partial response. The disease control rate was 96.9%. Among 26 patients with PET/CT scans both before and after treatment (at 8 weeks), the metabolic activity of ACC was reduced in 13 patients (50.0%), and 5 patients (19.2%) achieved a metabolic partial response, which was defined as a ≥25% reduction in maximum standardized uptake values. Common grade 3 and 4 adverse events were asthenia (50.0%) and neutropenia (25.0%).
Dovitinib shows modest antitumor activity in the treatment of ACC. Cancer 2015;121:2612–2617. © 2015 American Cancer Society.
Adenoid cystic carcinoma (ACC) is a rare variant of adenocarcinoma that occurs in secretory glands and particularly in salivary glands. The primary treatment for patients with ACC is surgical resection with or without postoperative radiotherapy according to the pathologic features.1 Although ACC is histologically low-grade and slow-growing, more than half of patients eventually have recurrent and/or metastatic disease.1-3
The natural course of metastatic disease with ACC is relatively indolent; however, most patients with metastatic disease ultimately die of their cancer.2-4 The role of systemic chemotherapy in ACC is very limited, and an objective response to any cytotoxic or molecular targeted agent is infrequent; the optimum regimen is unclear.5 Because of the rarity of ACC, there are few clinical trials investigating the efficacy of systemic chemotherapy.
Several lines of evidence suggest that fibroblast growth factor (FGF) signaling is associated with the progression of ACC in the salivary gland. FGF1, FGF2, and fibroblast growth factor receptor 1 (FGFR1) have been shown to be overexpressed in ACC and implicated in its carcinogenesis.6 DNA copy number increases at the loci for FGFR have also been observed in more than 60% of ACC tumor tissues, and this suggests an important role for this family of mitogens in ACC development.7 FGF stimulates the proliferation of ACC cell lines via upregulation of extracellular signal-regulated kinase and cyclin D1 and p21 signaling pathways.8
Dovitinib (TKI258) is a novel multikinase inhibitor targeting vascular endothelial growth factor receptors 1 to 3, FGFRs 1 to 3, fetal liver tyrosine kinase receptor 3, platelet-derived growth factor receptor b, and KIT.9, 10 On the basis of evidence suggesting a function for FGF signaling in ACC tumorigenesis and progression, a phase 2 study using dovitinib, an FGFR inhibitor, was planned. The purpose of this study was to evaluate the efficacy and safety of dovitinib in patients with unresectable and/or metastatic ACC.
MATERIALS AND METHODS
This open-label, multicenter, phase 2, single-arm study was conducted at 7 hospitals in Korea. This study was conducted in compliance with Good Clinical Practice, the guidelines of the International Conference on Harmonization, and the Declaration of Helsinki, and it was approved by the local institutional review boards of each hospital. Written informed consent was obtained from all patients before participation.
Patients ≥ 18 years of age with histologically or cytologically confirmed unresectable and/or metastatic ACC were eligible for this study. The progression of locally advanced or metastatic lesions needed to be documented on magnetic resonance imaging or computed tomography (CT) scans taken 2 to 12 months before study entry with comparison to a previous scan taken at any time in the past. Progression had to be documented according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.11 All toxicities from prior treatments needed to have resolved to grade 0 or 1 (per Common Terminology Criteria for Adverse Events [CTCAE] 3.0) before study entry; the last treatment for ACC needed to be at least 4 weeks before the baseline assessment. Patients needed to have measurable lesions according to RECIST 1.0.11 An Eastern Cooperative Oncology Group performance status of 0 to 1 and adequate hematologic, renal, and hepatic function were also required for study entry. Patients with previous active or passive immunotherapy, an intestinal obstruction, recent active upper gastrointestinal bleeding, a history of another malignant disease within the past 5 years (except for curatively treated basal cell carcinoma of the skin and cervical carcinoma in situ), or medically uncontrolled systemic disease were not eligible. Pregnant and lactating women were excluded.
Dovitinib was administered orally at 500 mg once daily for 5 consecutive days, and this was followed by a 2-day rest every week; each cycle consisted of 28 days.12 Dose modifications or delays in study drug administration were performed on the basis of the worst grade of toxicity according to the protocol. In brief, when grade 3 or 4 toxicities were first observed, dovitinib was discontinued until the toxicities were resolved to grade 1 or lower. Then, dovitinib was re-administered with 1 dose level reduction. A reduced dose of −1 dose level was 400 mg daily (5 days on, 2 days off), and a reduced dose of −2 dose level was 300 mg daily (5 days on, 2 days off). No more dose reductions to less than 300 mg were performed. When the administration of the study medication was delayed, all evaluations, including the tumor evaluation, adhered to the original schedule. When the administration of the study medication was either delayed for 3 weeks or more or the medication was discontinued because of toxicity, the patient was withdrawn from the study. The study medication was continued until disease progression, unacceptable toxicities, or withdrawal of consent.
Efficacy and Safety Assessment
Baseline assessments included a medical history, a physical examination, a complete blood count, serum chemistry with electrolytes, and CT scans. CT scans were performed every 8 weeks for response evaluation. Responses were assessed by investigators using RECIST 1.0.11 Because objective responses were very infrequent in ACC, we tried to test the utility of fusion [18F]fludeoxyglucose ([18F]FDG) positron emission tomography (PET)/CT scans as a surrogate for tumor responses. PET/CT scans were performed twice at the baseline and after 8 weeks of treatment. The maximum standardized uptake values (SUVmax) of all tumor lesions were analyzed. Metabolic responses were defined on the basis of the PET response criteria of the European Organization for Research and Treatment of Cancer.13 In brief, a metabolic complete response was defined as a complete resolution of [18F]FDG uptake within the tumor. A metabolic partial response (mPR) was defined as a reduction of >25% in SUVmax. Metabolic progressive disease (mPD) was defined as a >25% increase in SUVmax or the appearance of new [18F]FDG uptake in another region. Metabolic stable disease (mSD) was defined as neither a sufficient decrease to qualify for mPR nor a sufficient increase to qualify for mPD. Adverse events (AEs) were monitored and recorded according to CTCAE 3.0 during the treatment phase and for 28 days after the final dose of the study medication.
Because objective responses were very infrequent and stabilization of progressive disease suggests a true therapeutic effect, we selected progression-free survival (PFS) as a primary endpoint. The primary endpoint was the probability of PFS at 4 months. Secondary endpoints included the objective response rate, disease control rate, duration of response, metabolic response, and overall survival after the initiation of the study medication. The null hypothesis was that the true proportion of patients who remained progression-free at 4 months from study entry was at most 50% in prior studies,14-16 and the alternative hypothesis of this study was that the 4-month PFS rate would be >65% with an expected 15% improvement in the 4-months PFS. The study design required a minimum of 29 patients with 80% power, a type I error of 0.05, and a 1-sided hypothesis test. This sample size was based on the assumptions that patient survival would follow an exponential distribution and that no patients would be lost to follow-up. With an assumed dropout rate of 15%, the required number of patients was 33. PFS was defined as the time from the date of the first dose of medication to the date of disease progression or death. Overall survival was defined from the date of the first dose to the date of death. The probability of survival was estimated with the Kaplan-Meier method. Comparisons of survival between the different groups were made with log-rank tests. All analyses were performed with SPSS for Windows 19.0 (IBM Corporation, Armonk, NY).
Between September 2011 and April 2013, a total of 32 patients with metastatic and/or unresectable ACC were enrolled at 7 centers in South Korea. All patients received at least 1 cycle of dovitinib and were included in the efficacy and safety analyses. Baseline patient characteristics are summarized in Table 1. The median age was 53 years (range, 23-70 years), and 12 patients (37.5%) were male. The salivary gland was the most common primary site, and the lung was the most common metastatic site. By the censoring date (April 23, 2014), 21 progression events and 4 deaths had occurred, and the median length of follow-up was 14.4 months (range, 4.7-34.8 months). Two patients had received prior everolimus therapy.20
|Age, median (range), y||53 (23-70)|
|Sex, No. (%)|
|Disease status at original diagnosis, No. (%)|
|Previous treatment, No. (%)|
|Radiation therapy||25 (78.1)|
|ECOG performance status, No. (%)|
|Duration of disease, moa||56 (1-223)|
|Primary site, No. (%)|
|Oral cavity/oropharynx||11 (34.4)|
|Nasal cavity/nasopharynx||2 (6.3)|
|Paranasal sinus||2 (6.3)|
|Salivary gland||13 (40.6)|
|Site of metastasis, No. (%)|
|Lymph nodes||3 (9.4)|
- Abbreviation: ECOG, Eastern Cooperative Oncology Group.
- a From the date of the initial diagnosis to the initiation date of the trial.
The 4-month PFS probability was 80.4% (95% confidence interval [CI], 73.2%-87.6%), which satisfied the alternative hypothesis of a 4-month PFS rate > 65%. The median PFS duration was 6.0 months (95% CI, 4.4-7.6 months; Fig. 1). The median overall survival was not reached. According to RECIST, 1 patient (3.1%) achieved a confirmed partial response (PR), and 2 additional patients (6.3%) had an unconfirmed PR. The reasons for an unconfirmed PR were a new lesion and regrowth from the nadir. Thirty patients (93.8%) had stable disease (SD; Table 2). Tumor shrinkage was observed in 22 patients (68.8%; Fig. 2A), and SD for >6 months was observed in 15 patients. For 26 patients, the metabolic responses were assessable: 5 (19.2%) achieved mPR, 13 (50.0%) achieved mSD, and 8 (30.8%) had mPD (Fig. 2B). Among the 23 patients with radiologic SD, 11 patients (47.8%) showed declining SUVmax (Supplementary Figure 1). For the 23 patients with radiologic SD, the median PFS was 8.0 months (95% CI, 5.7-10.3 months) with mSD and 6.0 months (95% CI, 4.9-7.1 months) with mPD. There was a positive correlation between radiologic and metabolic responses (see Supplementary Table 1).
|Overall response (CR + PR)||1 (3.1)|
|Disease control rate (CR + PR + SD)||31 (96.9)|
- Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
- a The confirmation of PR or CR occurred at least 4 weeks after the response was noted. Among the 30 patients with SD, 2 patients had an unconfirmed PR.
|Adverse Event||All Grades (%)||Grade 3 or 4 (%)a|
|Neutropenia||12 (37.5)||8 (25.0)|
|Anemia||3 (9.4)||2 (6.3)|
|Thrombocytopenia||2 (6.3)||1 (3.1)|
|Asthenia||27 (84.4)||16 (50.0)|
|Myalgia||24 (75.0)||5 (15.6)|
|Neuropathy||6 (18.8)||1 (3.1)|
|Stomatitis||7 (21.9)||1 (3.1)|
|Infection||3 (9.4)||1 (3.1)|
|Nausea||17 (53.1)||2 (6.3)|
|Anorexia||12 (37.5)||6 (18.8)|
|Diarrhea||17 (53.1)||3 (9.4)|
|Skin reaction (rash, pruritus)||14 (43.8)||1 (3.1)|
|Hypercholesterolemia||5 (15.6)||3 (9.4)|
|Elevated liver enzymes||8 (25.0)||3 (9.4)|
|Hypertension||2 (6.3)||0 (0.0)|
|Dizziness||4 (12.5)||0 (0.0)|
|Headache||5 (15.6)||0 (0.0)|
|Weight loss||5 (15.6)||0 (0.0)|
|Cough||6 (18.8)||0 (0.0)|
|Dyspnea||6 (18.8)||0 (0.0)|
|Eye problems/lacrimation||8 (25.0)||0 (0.0)|
- a The infection was a grade 4 toxicity; otherwise, all toxicities were grade 3.
The median treatment duration was 5.0 months. A total of 199 cycles were administered to all the study patients. A median of 5 cycles was administered to each patient (range, 2-14 cycles; mean, 6.22 cycles). Table 3 summarizes AEs. The most common AEs of any grade were asthenia (84.4%), myalgia (75.0%), diarrhea (53.1%), and nausea (53.1%). The major treatment-related grade 3 and 4 AEs were asthenia (50.0%) and neutropenia (25.0%); most cases were manageable by dose modification. In all, 26 of 32 patients (81.3%) required dose reductions according to protocol-defined toxicities. The dose of dovitinib was reduced to 400 mg in 16 patients (50.0%) and to 300 mg in 10 patients (31.3%). Dovitinib was discontinued in 17 patients (53.1%) because of disease progression. Nine patients (28.1%) had their treatment discontinued because of AEs, and 4 (12.5%) had their treatment discontinued because of patient refusal. The reasons for patients' refusals were an economic cause for 1 patient and a referral to another hospital for 1 patient; the other 2 patients refused, regardless of AEs. For these 4 patients, 3 patients stopped dovitinib after 6 cycles, and 1 patient discontinued after 4 cycles. Treatment was still ongoing in 2 patients at the time of the analysis. There were no treatment-related deaths.
In this phase 2 study, we investigated the efficacy and safety of dovitinib in patients with unresectable ACC. Dovitinib showed modest antitumor activity; however, dovitinib at the current dose was poorly tolerated in many patients. The median PFS duration was 6.0 months, and the 4-month PFS probability was 80.4%. This study met the primary endpoint of a 4-month PFS rate > 65%. The disease control rate was 96.9%, and tumor shrinkage was observed in 68.8% of the patients. Furthermore, dovitinib reduced the metabolic activity of ACC, and 19.2% of the patients achieved mPR.
The antitumor activity of cytotoxic or other targeted agents in ACC seems to be primarily disease-stabilizing. With respect to this point, it is notable that 68.8% of the patients showed tumor shrinkage with dovitinib. The clinical efficacy of dovitinib for ACC in this study was more potent than that previously reported for other targeted agents. Imatinib, a c-kit tyrosine kinase inhibitor, failed to show a PR in the treatment of ACC.14, 17 Lapatinib, a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, resulted in SD for 15 of 19 patients with a median PFS of 3.5 months.15 Cetuximab18 and sunitinib19 also showed modest tumor stabilization in ACC. In our previous phase 2 study using everolimus in ACC,20 SD was observed in 79.4% of the patients, and tumor shrinkage within the SD criteria was observed in 44.1%. The median PFS was 11.2 months, and SD for >6 months was observed in 38.2% of the patients; this indicated a promising antitumor effect. Very recently, axitinib, an inhibitor of vascular endothelial growth factor receptor and c-kit, also showed promising antitumor activity in ACC.21 A confirmed PR to axitinib in ACC was observed in 3 patients (9.1%), and SD was found in 25 patients (75.8%).21 However, to date, no clear advantage of targeted agents over cytotoxic chemotherapy has been demonstrated in patients with ACC.
One of the major challenges in evaluating novel drugs for the treatment of advanced ACC is to determine whether the observed SD and survival rates reflect the protracted natural history of ACC or the antitumor effects of the drug.19 With this in mind, it would be helpful to use additional evaluations of molecular targeted agents in ACC to distinguish growth suppression by the molecular targeted agents and the slow natural history of ACC. Hence, we performed interim PET/CT assessments after 8 weeks of treatment. Interestingly, dovitinib reduced the metabolic activity of ACC as well as the radiologic tumor size on CT scans. An mPR to dovitinib was observed in 5 patients (19.2%). Similarly, everolimus also showed a metabolic response of 44.4% in our previous report,20 and this suggests tumor stabilization by chemotherapy. The use of PET in addition to conventional CT imaging may be helpful in differentiating tumor stabilization by chemotherapy and natural SD, especially in ACC patients with radiological SD.
Because of the rarity and highly varied natural history of ACC, judicious interpretation is needed to distinguish between growth suppression by chemotherapy and the slow tumor biology of ACC without chemotherapy. Novel clinical trial designs, such as biomarker-based studies or cross-trial comparisons of single-arm studies, need to be considered.
In this study, hyperphosphatemia, a common AE observed with more specific FGFR inhibitors, was not observed, and this was in line with other dovitinib trials.12, 22-25 In our study, the grade 3/4 toxicities were more common in comparison with other studies using dovitinib.12, 22-25 Grade 3/4 AEs included asthenia (50.0%) and neutropenia (25.0%). Most grade 3/4 toxicities were manageable by dose modification or supportive care, and there was no treatment-related mortality. Even though dovitinib showed promising antitumor activity, many patients discontinued treatment because of drug-related AEs (mainly fatigue). Wang et al26 suggested that dovitinib exposure may be dependent on ethnicity, and there was a difference in the frequency of grade 3 fatigue based on race: 20.0% in an Asian population24 versus 10.4% in a Western population.23 In this study, we chose a 5-day-on/2-day-off intermittent dosing schedule; however, the incidence of grade 3 fatigue remained high. Further careful efforts for asthenia should be made to adjust the dosing and scheduling of dovitinib to improve patients' tolerance.
In conclusion, dovitinib shows modest efficacy in the treatment of metastatic or unresectable ACC, and further clinical trials of novel combinations of dovitinib with biomarker analysis are warranted. Continued research based on collaborative efforts by multiple groups should be made to advance the treatment of ACC.
This work was supported in part by a research grant from Novartis.
CONFLICT OF INTEREST DISCLOSURES
Se-Hoon Lee reports grants and personal fees from Pfizer, grants from Astra-Zeneca, personal fees from Novartis, personal fees from Merck, personal fees from Roche, personal fees from Janssen, and personal fees from Astellas outside the submitted work. Yung-Jue Bang reports grants from Novartis during this study and outside the submitted work. The remaining authors have declared no conflicts of interest.
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. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg. 1986; 8: 177-184.
, et al. Clinicopathologic predictors and impact of distant metastasis from adenoid cystic carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 2003; 129: 1193-1197.
. Adenoid cystic carcinoma of the head and neck: predictors of morbidity and mortality. Arch Otolaryngol Head Neck Surg. 1999; 125: 149-152.
. Distant metastases of adenoid cystic carcinoma of the salivary glands and the value of diagnostic examinations during follow-up. Head Neck. 2002; 24: 779-783.
. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol. 2011; 12: 815-824.
, et al. Immunohistochemical study of overexpression of fibroblast growth factor-1 (FGF-1), FGF-2, and FGF receptor-1 in human malignant salivary gland tumours. J Pathol. 1996; 178: 429-436.
, et al. DNA copy number gains at loci of growth factors and their receptors in salivary gland adenoid cystic carcinoma. Clin Cancer Res. 2007; 13: 3133-3139.
. Effects of basic fibroblast growth factor on the proliferation of human salivary adenoid cystic carcinoma cell line ACC-2 and extracellular signal-regulated kinase, cyclin D1, p2waf/cip1 signaling pathway. Hua Xi Kou Qiang Yi Xue Za Zhi. 2008; 26: 118-120.
, et al. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res. 2005; 11: 3633-3641.
, et al. CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res. 2005; 11: 5281-5291.
, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205-216.
, et al. Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res. 2013; 19: 1257-1268.
, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999; 35: 1773-1782.
, et al. Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study. J Clin Oncol. 2005; 23: 585-590.
, et al. Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol. 2007; 25: 3978-3984.
, et al. Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: a phase II study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1993; 4: 785-788.
, et al. A phase II study of imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol. 2007; 43: 33-36.
, et al. Cetuximab in recurrent and/or metastatic salivary gland carcinomas: a phase II study. Oral Oncol. 2009; 45: 574-578.
, et al. A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC. Ann Oncol. 2012; 23: 1562-1570.
, et al. A multicenter phase II study of everolimus in patients with progressive unresectable adenoid cystic carcinoma. BMC Cancer. 2014; 14: 795.
, et al. Phase II study of axitinib in patients with progressive, recurrent/metastatic adenoid cystic carcinoma [abstract 6093]. Proc Am Soc Clin Oncol. 2014; 32(suppl): 5s.
, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2008; 14: 2075-2081.
, et al. Phase II results of dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res. 2014; 20: 3012-3022.
, et al. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br J Cancer. 2013; 109: 2309-2315.
, et al. Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin Cancer Res. 2011; 17: 7451-7461.
, et al. Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. J Clin Pharmacol. 2013; 53: 14-20.