Clinical evidence demonstrating the effectiveness of systemic therapy for advanced salivary duct carcinoma (SDC) is lacking because of the disease’s rarity. We assessed the efficacy and toxicity of trastuzumab plus docetaxel in patients with locally advanced and/or recurrent or metastatic human epidermal growth factor receptor 2–positive SDC.

This was a single-center, single-arm, open-label, phase II study in Japan. The patients received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Docetaxel 70 mg/m2 was administrated every 3 weeks. The primary end point was the overall response rate; the secondary end points included the clinical benefit rate, progression-free survival, overall survival, and toxicity. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry (Identification No. UMIN000009437).

Fifty-seven eligible patients with SDC were enrolled. The overall response rate was 70.2% (95% CI, 56.6% to 81.6%), and the clinical benefit rate was 84.2% (95% CI, 72.1% to 92.5%). Median progression-free and overall survival times were 8.9 months (95% CI, 7.8 to 9.9 months) and 39.7 months (95% CI, not reached), respectively. The most frequent adverse event was anemia (52 patients [91%]), followed by a decreased WBC count (51 patients [89%]) and neutropenia (50 patients [88%]). The most frequently observed grade 4 adverse event was a decreased neutrophil count (34 patients [60%]). Grade 3 febrile neutropenia was reported in eight patients (14%). No grade 2 or greater adverse events of heart failure or left ventricular ejection fraction decline to less than 50% occurred.

Our data show encouraging efficacy of trastuzumab plus docetaxel therapy in patients with human epidermal growth factor receptor 2–positive SDC, with a manageable toxicity profile.

Salivary gland carcinoma (SGC) is an uncommon cancer, accounting for 0.2% of all malignancies and 8% of head and neck cancers; its incidence is 1.0 to 1.2 per 100,000 population per year.1,2 Salivary duct carcinoma (SDC) is one of the most aggressive SGCs; according to the WHO classification, it is pathologically defined as an epithelial malignancy resembling high-grade mammary ductal carcinoma.3 SDC accounts for 1% to 4% of all SGCs1,2,4; however, recent studies reported a higher incidence, suggesting that SDC is not as rare as previously thought.3,5 The median overall survival (OS) and 5-year OS in patients with SDC who underwent definitive treatment were reported to be 3 to 4 years and 30% to 40%, respectively.3-10 The prognosis of SDC has not improved,4 largely because of distant failure.4,5,8,9 The largest retrospective study of systemic therapy in patients with advanced SDC to date involved 18 patients treated with carboplatin plus paclitaxel and reported an objective response rate (ORR) of 39%.11 Therefore, the development of a novel treatment strategy is warranted.

Approximately 80% to 90% of patients with SDC are positive for the androgen receptor (AR), and 30% to 40% are positive for the human epidermal growth factor receptor 2 (HER2).3,5,9,10,12-15 Both biomarkers are used for an accurate histopathologic diagnosis and are being explored as potential therapeutic targets.3,5,7-10,12-16 Among 400 histologic types of cancers, SDC had the highest frequency of HER2 gene alterations (32%).7 Trastuzumab is a humanized murine monoclonal antibody against HER2; its efficacy and safety have been well established in HER2-positive breast17-19 and gastric20 cancers. Several studies evaluating the efficacy of trastuzumab in other HER2-positive cancers are ongoing.21-24 HER2-targeted therapies for patients with SGC were first described in 2003.25 In a clinical trial of 13 patients with HER2-overexpressing SGC, only one patient showed a partial response (PR) to trastuzumab monotherapy.25 In contrast, there are 21 case reports of trastuzumab combined with taxanes in patients with HER2-positive SGC, and the cumulative response rate of 46 available patients was 67% (Data Supplement).5,6,9,16 These results underscore the need for the assessment of trastuzumab plus taxanes in a prospective study.

Therefore, we conducted a prospective phase II study to examine the efficacy and safety of combined androgen blockade (CAB; leuprorelin acetate plus bicalutamide) or trastuzumab plus docetaxel combination therapy in patients with locally advanced (LA) and/or recurrent or metastatic (RM) AR- or HER2-positive SGC, respectively, stratified by biomarker status. Because this study included two treatment approaches, we deemed it appropriate to report the outcome of each treatment separately. The results of the CAB study portion were recently pulished26; herein, we describe the outcomes pertaining to the anti-HER2 therapy.

Study Design and Patients

This was a single-institution, open-label, single-arm, phase II study. Patients who met the following criteria were enrolled: RM or unresectable LA HER2-positive SGC; unresectable tumor meeting at least one of the following conditions: primary lesion, T4b; cervical lymph node metastasis, N2c or N3 (International Union Against Cancer TNM, seventh edition); or cervical lymph node metastasis invading the carotid artery; age ≥ 20 years; Eastern Cooperative Oncology Group performance status of 0 to 2; adequate organ function; at least a 2-week interval from the previous treatment; measurable lesion(s) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; at least a 3-month life expectancy; and ability to provide written consent. There were no restrictions on the number or type of previous systemic treatments, except for trastuzumab. The main exclusion criterion was prior exposure to trastuzumab. The full inclusion and exclusion criteria are described in the study protocol (Data Supplement).

This study was conducted in accordance with the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Review Board of the International University of Health and Welfare Mita Hospital. All patients provided written informed consent. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry in Japan (Identification No. UMIN000009437). The study protocol is provided in the Data Supplement.

Histopathologic Analyses

All tumors were histopathologically reviewed and confirmed by an expert pathologist (T.N.), according to the criteria of the 2017 WHO Classification of Head and Neck Tumors.3 All primary tumors or, in some cases, RM lesions were also assessed for their HER2 and AR status, as described elsewhere.12,14 Briefly, HER2 positivity was defined by an immunohistochemistry score of 3+ or gene amplification confirmed by fluorescence in situ hybridization, according to the ASCO/College of American Pathologists guidelines for breast cancer.27

Procedures

The patients received a loading dose of intravenous trastuzumab 8 mg/kg, followed by a dose of 6 mg/kg administered at day 1 every 3 weeks. Docetaxel was administered intravenously at day 1 every 3 weeks at a dose of 70 mg/m2. The starting dose of docetaxel was reduced to 55 mg/m2 in patients ≥ 75 years of age.28 All patients were scheduled to receive six cycles of the combination treatment and could continue to receive trastuzumab with or without docetaxel beyond the six cycles of treatment until disease progression; the development of unacceptable adverse events (AEs), as described in the study protocol (Data Supplement); or the withdrawal of consent. Although other antitumor therapies were not permitted before disease progression or the completion of the six cycles of the study treatment, radiation therapy and/or other drug therapy were allowed thereafter.

A CBC and serum biochemistry data were obtained on day 1 of every cycle. The left ventricular ejection fraction (LVEF) was assessed at baseline (within 14 days before treatment initiation), every third successive cycle thereafter within the study treatment, and every 3 months after the study treatment period.

AEs were recorded by an investigator at baseline and at each visit, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0. The docetaxel dose was reduced to 55 mg/m2 and then to a minimum dose of 45 mg/m2 if the following toxic effects were observed: febrile neutropenia, grade 4 thrombocytopenia, grade 3 or greater nonhematologic toxicity except for nausea and vomiting, grade 2 or greater peripheral sensory neuropathy, and a delay in docetaxel administration of 8 days or more. Other reasons for a dose reduction were decided at the discretion of the investigator. Docetaxel therapy was discontinued if an additional dose reduction was required. In cases of discontinuation of docetaxel therapy, trastuzumab monotherapy was continued.

Outcomes

Tumor assessments by computed tomography and/or magnetic resonance imaging were performed within 4 weeks before treatment initiation and repeated every 6 weeks until disease progression, death, or 2 years after the treatment initiation; after 2 years, tumor assessments were performed every 3 months in surviving patients. The response was determined according to the RECIST, version 1.1, by a medical image interpretation specialist (H.O.) at a different institution.

The primary end point was the ORR, which was defined as the proportion of patients achieving a complete response (CR) or a PR. The secondary end points included the clinical benefit rate (CBR), progression-free survival (PFS), OS, and safety during the six cycles of the study treatment. The CBR was defined as the proportion of patients who achieved a CR, PR, or stable disease for 24 weeks or more. PFS was defined as the time from enrollment to disease progression or death from any cause. Patients who received anticancer drugs other than trastuzumab or docetaxel and those who received radiotherapy for target lesions were censored for the PFS analysis. OS was defined as the time from enrollment to death from any cause or the last follow-up.

Safety parameters included AEs of any grade, the tolerability of the trastuzumab plus docetaxel combination, and the relative dose-intensity (RDI) of docetaxel within the six cycles of the study treatment. The RDI was calculated as the ratio of the actual to the planned dose-intensity in milligrams per meters squared per week.

Statistical Analysis

Efficacy and safety analyses were conducted in all patients who received at least one dose of the study regimen. The ORR and CBR were determined along with the corresponding two-sided 95% CIs computed using the modified Wald method. PFS and OS were analyzed using the Kaplan-Meier method and are expressed as median values and corresponding 95% CIs. To better characterize the efficacy of trastuzumab and docetaxel we used the logistic regression and the Cox proportional hazards model to perform additional analyses of the primary and secondary end points according to selected clinicopathologic factors, including age; sex; Eastern Cooperative Oncology Group performance status; RM versus LA disease; presence of visceral metastasis; HER2 immunohistochemistry (3+ v 2+), HER2 gene (amplified v not amplified), and AR status; presence of previous chemotherapy, taxane, docetaxel, or paclitaxel exposure; and docetaxel RDI (< v ≥ 0.7). All statistical analyses were two sided, and P < .05 was considered statistically significant. We used the Statistical Package for the Social Sciences (SPSS) for Windows version 24 (SPSS, Chicago, IL) for all statistical analyses.

Patients

A total of 67 patients with SDC were screened between March 16, 2012, and July 7, 2017. After excluding 10 patients who did not meet the inclusion criteria, 57 patients were included in the efficacy and safety analyses (Fig 1). The accrual of patients to the study was completed on July 7, 2017. The data cutoff date was November 30, 2017.

The patient characteristics are listed in Table 1 (with additional details in the Data Supplement). Eight patients (14%) had LA disease, and 49 patients (86%) had RM disease. Chemotherapy had been previously administered in 20 patients (35%), and seven patients (12%) had a history of exposure to docetaxel.

Table

TABLE 1. Baseline Characteristics of the Participants

Efficacy

At the time of the data cutoff, the median follow-up period for all patients was 28 months (range, 3.6 to 69 months). A confirmed CR was achieved in eight patients (14.0%). A total of 32 patients (56.1%) showed a PR, 14 (24.6%) had stable disease, and three (5.3%) had progressive disease (Table 2). The independently assessed ORR was 70.2% (95% CI, 56.6% to 81.6%), and the CBR was 84.2% (95% CI, 72.1% to 92.5%). Representative scans of patients who achieved a CR or PR are provided in the Data Supplement. Tumor shrinkage was observed in 54 patients (94.7%; Figs 2A and 2B).

Table

TABLE 2. Treatment Efficacy

We observed a median PFS time of 8.9 months (95% CI, 7.8 to 9.9 months) and median OS time of 39.7 months (95% CI, not reached; Table 2 and Fig 3). The 1-year PFS rate was 25.6% (95% CI, 13.4% to 39.6%), and the 1-, 2-, and 3-year OS rates were 89.0% (95% CI, 77.1% to 94.9%), 70.2% (95% CI, 55.3% to 81.0%), and 58.3% (95% CI, 41.5% to 71.7%), respectively (Fig 3).

Of the 18 patients without PFS events, four sustained a response by the time of the data cutoff at 5, 13, 36, and 39 months after the initiation of the study treatment (Figs 2B and 2C). Of the remaining 14 patients, 10 were censored as a result of the initiation of radiotherapy and two were censored as a result of the administration of other antitumor drugs and surgery. All eight patients with LA disease were alive at the data cutoff. Thirty-nine patients (68.4%) experienced disease progression events (Figs 2B and 2C); new lesions developed in 23 patients (40.4%), including seven patients (12.3%) with CNS metastases, and disease progression in pre-existing target or nontarget lesions was seen in 16 patients (28.1%). Additional analyses of the associations between treatment outcomes and clinicopathologic factors showed no statistically significant differences, except that the ORR and CBR were significantly lower when the RDI of docetaxel was less than 0.7 (Data Supplement). Notably, patients who were previously exposed to docetaxel or paclitaxel had similar treatment outcomes to those of taxane-naïve patients (Data Supplement).

Safety

Table 3 provides a summary of the AEs (see Data Supplement for more details). All 57 patients experienced at least one AE during the six cycles of the study treatment. The most common AEs of any grade were anemia (n = 52; 91%), a decreased WBC count (n = 51; 89%), and neutropenia (n = 50; 88%). Grade 3 or 4 AEs were observed in 51 patients (89%), and 35 patients (61%) experienced grade 4 AEs, but no deaths occurred. The most frequent grade 4 AE was neutropenia (n = 34; 60%). Grade 3 febrile neutropenia was reported in eight patients (14%). Only one to three patients each showed other nonhematologic treatment-related grade 3 or 4 AEs. No left ventricular systolic dysfunction of grade 3 or greater, heart failure of grade 2 or greater, or LVEF decline to less than 50% during the six cycles of the study treatment was seen.

Table

TABLE 3. Adverse Events

Treatment Administration

Of the total of 57 patients, 48 (84%) completed six cycles of trastuzumab and docetaxel therapy (Fig 1). The reasons for treatment discontinuation before the completion of the six cycles were disease progression (n = 1; 1.8%), patient refusal (n = 2; 3.5%), and AEs (n = 6; 11%), including prolonged neutropenia (n = 4; 7.0%), drug-induced pneumonitis (n = 1; 1.8%), and edema of the lower extremities (n = 1; 1.8%). Among patients who completed six cycles of the study treatment, docetaxel dose reduction was observed in eight patients (14%) and was a result of febrile neutropenia in four patients (7.0%), prolonged neutropenia in three patients (5.3%), and edema in one patient (1.8%). The mean RDI of docetaxel in all patients was 0.95 (range, 0.43 to 1.06). Trastuzumab was not discontinued in any of the patients as a result of AEs.

Of the 49 patients with RM disease, 44 (90%) continued trastuzumab and docetaxel combination therapy or trastuzumab monotherapy, three (6%) received radiotherapy, two (4%) received other antitumor drug therapies, and two (4%) underwent surgery after the study treatment. All patients with LA disease (n = 8) received radiotherapy after more than six cycles of the study treatment with the aim of locoregional disease control. At the time of the data cutoff, three patients were still receiving trastuzumab plus docetaxel therapy, and 12 patients were receiving maintenance trastuzumab monotherapy. The median number of cycles of trastuzumab and docetaxel combination therapy in all patients was 10.5 (range, three to 36 cycles); that of trastuzumab monotherapy was 21 cycles (range, three to 92 cycles).

The results from this phase II trial showed an encouraging efficacy of trastuzumab plus docetaxel combination therapy in patients with HER2-positive SDC, with a manageable toxicity profile. To the best of our knowledge, this is the first prospective analysis of the combination of an HER2-targeted drug and chemotherapy in the largest number of patients with HER2-positive SDC to date.

On the basis of the results of prospective and small-scale phase II trials on SDC, doublet or triplet chemotherapy with platinum and/or taxanes has been the most common treatment of patients with LA or RM SDC.6,9,16 Although a retrospective study of carboplatin plus paclitaxel in patients with advanced SDC reported an ORR of 39%,11 we found an ORR of 70.2% (95% CI, 56.6% to 81.6%) for trastuzumab plus docetaxel. However, this must be interpreted with caution because our study was a nonrandomized trial and the sample size was not predefined. The differences in study design, eligibility, and patient characteristics should be considered as potential biases. In fact, HER2 status could be one of the biases because the HER2 status of the patients in the carboplatin plus paclitaxel report was unavailable,11 although the HER2 status does not significantly affect the survival of patients with SDC.9,10,12-14

Significantly lower ORR and CBR were observed when the RDI of docetaxel was less than 0.7, suggesting that the response might be dependent on docetaxel therapy. Given that no previous studies have assessed the effects of docetaxel alone in LA or RM HER2-positive SDC and our study was a single-arm study, a randomized clinical trial is needed to provide evidence that docetaxel in combination with trastuzumab has greater effect than docetaxel alone in patients with HER2-positive SDC.

We recently reported that the response rate of CAB was 41.7% in 36 patients with AR-positive SGC.26 CAB had a relatively mild toxicity profile and was therefore considered to be a promising treatment option for patients with unresectable AR-positive SGC. In patients with SDC coexpressing HER2 and AR, accounting for 25% to 35% of patients,12-14 it should be considered whether trastuzumab plus docetaxel therapy or CAB should be used as first-line treatment in a randomized crossover trial. Additional studies are warranted to better establish the role of combination therapy including trastuzumab plus docetaxel with CAB.29

The rate of grade 3 or 4 (and in particular hematologic) AEs in this study was greater than that reported in patients with metastatic breast cancer treated with docetaxel 75 mg/m2 or 100 mg/m2.17,18 This may be a result of the greater toxicity of docetaxel observed in Asian populations compared with white populations.30 Cardiotoxicity is an infrequent AE linked to HER2-directed agents.17-19 In the present trial, no dose-limiting cardiotoxicities, including grade 3 LVEF decline or symptomatic congestive heart failure, were recorded.

In conclusion, our results provide evidence that clinical benefit is achievable with trastuzumab plus docetaxel therapy in patients with HER2-positive SDC, with an acceptable toxicity profile. These encouraging results deserve additional investigation to determine their effect on OS. As in breast cancer, newly developed anti-HER2 agents such as pertuzumab,23,31 trastuzumab emtansine,31-33 and DS-8201a34 represent the next step toward improving the clinical outcomes of patients with HER2-positive SGC. Our findings support the preliminary data from the basket trials in HER2-positive solid tumors, which demonstrated the concept of tissue- or site-agnostic drug approval on the basis of molecular profiling.23,32-34

© 2018 by American Society of Clinical Oncology

Presented at the 54th Annual Meeting of American Society of Clinical Oncology, Chicago, IL, June 1-5, 2018; the 9th International Conference on Head and Neck Cancer, Seattle, WA, July 16-20, 2016; the 4th Conference of the Asian Society of Head and Neck Oncology, Kobe, Japan, June 3-6, 2015; the 12th Annual Meeting of the Japanese Society of Medical Oncology, Fukuoka, Japan, July 17-19, 2014; and the 37th Annual Meeting of the Japan Society for Head and Neck Cancer, Tokyo, Japan, June 13-14, 2013.

Supported by Grants No. 18K09386, 17K18006, 17K08705, and 16K12400 from the Japan Society for the Promotion of Science and the International University of Health and Welfare.

The views expressed in this article are our own and not an official position of the institutions or funder.

Conception and design: Hideaki Takahashi, Yuichiro Tada, Takashi Saotome, Robert Y. Osamura, Shuhei Yamada, Toshitaka Nagao

Provision of study material or patients: Hideaki Takahashi, Yuichiro Tada, Robert Y. Osamura, Toshitaka Nagao

Collection and assembly of data: Hideaki Takahashi, Yuichiro Tada, Hiroya Ojiri, Chihiro Fushimi, Tatsuo Masubuchi, Takashi Matsuki, Hideaki Hirai, Kouki Miura, Shin-etsu Kamata, Toshitaka Nagao

Data analysis and interpretation: Hideaki Takahashi, Yuichiro Tada, Kohei Akazawa, Kaori Tani, Daisuke Kawakita, Toshitaka Nagao

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Phase II Trial of Trastuzumab and Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Salivary Duct Carcinoma

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

No potential conflicts of interest were reported.

ACKNOWLEDGMENT

We thank all patients and their families and caregivers. Moreover, we thank the medical teams at our institution and the physicians who participated in this collaborative study on salivary duct carcinoma for their dedicated efforts. We thank Moran Amit, MD, for his suggestions to improve and clarify this article.

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ARTICLE CITATION

DOI: 10.1200/JCO.18.00545 Journal of Clinical Oncology 37, no. 2 (January 10, 2019) 125-134.

Published online November 19, 2018.

PMID: 30452336

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