Advanced Salivary Gland Carcinoma Research Articles

Evaluation of pembrolizumab monotherapy in patients with previously treated advanced salivary gland carcinoma in the phase 2 KEYNOTE-158 study

AimWe evaluated pembrolizumab monotherapy in patients with advanced salivary gland carcinoma on the phase 2 KEYNOTE-158 study (NCT02628067). MethodsEligible patients had histologically/cytologically confirmed advanced salivary gland carcinoma with prior failure or intolerance to standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1., and ECOG performance status 0–1. Patients were enrolled irrespective of tumour PD-L1 expression. Patients received pembrolizumab 200 mg Q3W for up to 35 cycles (∼2 years). Radiographic imaging occurred every 9 weeks through month 12, then every 12 weeks. PD-L1 positivity was defined as combined positive score ≥1 (evaluated using PD-L1 IHC 22C3 pharmDx). The primary endpoint was objective response rate per RECIST v1.1. ResultsIn total, 109 patients were enrolled (PD-L1–positive, 25.7%). At the data cutoff (October 5, 2020), median follow-up was 53.3 (range, 50.8–56.3) months. Objective response rate was 4.6% (95% CI, 1.5–10.4%) among all patients (complete response, n = 1; partial response, n = 4) and was 10.7% (95% CI, 2.3–28.2%) in patients with PD-L1–positive disease and 2.6% (95% CI, 0.3–9.1%) in patients with PD-L1–negative disease. Duration of response was ≥24 months for all 5 responders; median duration of response was not reached (range, 25.1–49.8+ months). Median progression-free survival and overall survival were 4.0 (95% CI, 2.6–4.2) and 21.1 (95% CI, 15.9–25.5) months, respectively. Treatment-related adverse events occurred in 75.2% (grade 3–4, 15.6%; grade 5, 0%) of patients. Immune-mediated adverse events occurred in 22.0% of patients (grade 3, 5.5%; grade 4–5, 0). ConclusionsA small subset of patients with advanced salivary gland carcinoma treated with pembrolizumab had a response; all had response duration ≥2 years. The safety profile of pembrolizumab was manageable.

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study

Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab+ trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab+ trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab+ trastuzumab, n= 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n= 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n= 1/1, PFS 18.5 months), and high TMB (atezolizumab, n= 1/1, PFS 5.5+ months). No unexpected toxicity occurred. Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

1166P - Combined androgen blockade in patients with advanced androgen receptor-positive salivary gland carcinoma: Exploratory biomarker analyses

BackgroundA phase II trial of combined androgen blockade (CAB) in patients with advanced androgen receptor (AR)–positive salivary gland carcinoma (SGC) showed 40% of the overall response rate. However, biomarkers which predict survival in this population remain unknown. MethodsA total of 99 patients with AR–positive SGC treated with leuprorelin acetate plus bicalutamide were included. Age, sex, ECOG performance status (PS), previous treatment with trastuzumab plus docetaxel, modified Glasgow Prognosis Score (mGPS), neutrocyte-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), serum C-reactive protein (CRP) and testosterone level, HER2 status (according to ASCO/CAP Guidelines), mutational status of BRAF, PIK3CA, HRAS, AKT1 and TP53, immunohistochemistry (IHC) score of AR, Ki-67, CK5/6, p53, HER3, Akt, PI3K, FOXA1, adipophilin, mTOR and PTEN were assessed and correlated with progression-free survival (PFS) and overall survival (OS). ResultsFemale sex, mGPS (1 or 2 vs. 0), NLR (≥4.48), PLR (≥234.27), and Ki-67 labeling index (≥ 40%) were significantly associated with shorter PFS (hazard ratio [HR], 3.57, 2.01, 1.76, 1.62, and 2.16, respectively) and OS (HR, 4.91, 4.98, 3.10, 2.95, and 1.78, respectively). IHC scores of PTEN (3+) and adipophilin (≥5%) were related with favorable PFS (HR, 0.57 and 0.49, respectively) and OS (HR, 0.48 and 0.42, respectively). Age, ECOG PS, CRP, testosterone, AR positive ratio (≥70% or<70%), HER2 status, previous treatment with trastuzumab plus docetaxel, FOXA1 immunopositivity, and mutational status of BRAF, PIK3CA, HRAS, and TP53 did not have significant association with survival. ConclusionsRather than age and PS, sex and higher inflammation-based prognostic scores can serve as predictive biomarkers in patients with advanced SGC treated with CAB. IHC assessment of Ki-67, PTEN, and adipophilin may predict survival of this population. Biological validation of such markers is warranted. Clinical trial identificationUMIN000009437, Released on 03/12/2012. Legal entity responsible for the studyThe authors. FundingMEXT/JSPS. DisclosureAll authors have declared no conflicts of interest.

Texture analysis of pretreatment [18F]FDG PET/CT for the prognostic prediction of locally advanced salivary gland carcinoma treated with interstitial brachytherapy

BackgroundThe aim of this study was to evaluate the prognostic value of positron emission tomography (PET) parameters and the PET texture features of fluorine 18-fluorodeoxyglucose ([18F]FDG) uptake on pretreatment PET/computed tomography (CT) in patients with locally advanced salivary gland carcinoma treated with interstitial brachytherapy.MethodsForty-three patients with locally advanced salivary gland carcinoma of the head and neck were treated with 125I interstitial brachytherapy as the sole modality and underwent [18F]FDG PET/CT scanning before treatment. Tumor segmentation and texture analysis were performed using the 3D slicer software. In total, 54 features were extracted and categorized as first-order statistics, morphology and shape, gray-level co-occurrence matrix, and gray-level run length matrix. Up to November 2018, the follow-up time ranged from 6 to 120 months (median 18 months). Cumulative survival was calculated by the Kaplan-Meier method. Factors between groups were compared by the log-rank test. Multivariate Cox regression analysis with a backward conditional method was used to predict progression-free survival (PFS).ResultsThe 3- and 5-year locoregional control (LC) rates were 55.4% and 37.0%, respectively. The 3- and 5-year PFS rates were 51.2% and 34.1%, respectively. The 3- and 5-year overall survival (OS) rates were 77.0% and 77.0%, respectively. Univariate analysis revealed that minimum intensity, mean intensity, median intensity, root mean square, and long run emphasis (LRE) were significant predictors of PFS, whereas clinicopathological factors, conventional PET parameters, and PET texture features failed to show significance. Multivariate Cox regression analysis showed that minimum intensity and LRE were significant predictors of PFS.ConclusionsThe texture analysis of pretreatment [18F]FDG PET/CT provided more information than conventional PET parameters for predicting patient prognosis of locally advanced salivary gland carcinoma treated with interstitial brachytherapy. The minimum intensity was a risk factor for PFS, and LRE was a favorable factor in prognostic prediction according to the primary results.

Salivary gland carcinoma (SGC) with perineural spread and/or positive resection margin \u2013 high locoregional control rates after photon (chemo) radiotherapy - experience from a monocentric analysis

BackgroundThe aim was to evaluate the outcome, especially locoregional control of patients with locally advanced salivary gland carcinoma (SGC) with perineural spread (Pn1) and/or positive resection margins (R1/2) after postoperative photon (chemo) radiotherapy in a single centre.MethodsWe retrospectively reviewed data of 65 patients with newly diagnosed locally advanced SGC without distant metastases who underwent radio (chemo) therapy in the department of radiation oncology of the university hospital of Erlangen from January 2000 until April 2017.Kaplan Meier method was used to calculate survival and recurrence rates. In univariate analysis the log-rank test was used to correlate patient−/tumor- and treatment-related parameters to survival and recurrence rates.ResultsMedian follow-up was 45 months (range: 6; 215).After 1, 3, 5 years cumulative incidence of local and locoregional failure was 3.1, 7.0, 7.0% and 3.1, 9.7, 12.9%, whereas cumulative incidence of distant metastases (DM) was 15.6, 36.0, 44.0%. After 1,3, 5 years cumulative Overall (OS) and Disease-free survival (DFS) was 90.5, 74.9, 63.9% and 83.0, 54.8, 49.4%.The only significant predictor for decreased local and locoregional control was a macroscopic resection margin(R2) (p = 0.002 and p = 0.04). High-grade histology (p = 0.006), lymph node metastases with extracapsular spread (p = 0.044) and an advanced T-stage (p = 0.031) were associated with an increased rate of DM. High-grade histology was the only factor predicting for a decreased DFS (p = 0.014).ConclusionPhoton radiotherapy leads to high local and locoregional control rates in a high-risk patient population with SGC with microscopically positive resection margins and/or perineural spread. The most common site of disease recurrence was distant metastases. Therefore the real challenge for the future should be to prevent distant metastases.

The Role of 18F-FDG PET/CT in Staging and Prognostic Prediction of Locally Advanced Salivary Gland Carcinoma Treated with Interstitial Brachytherapy

The treatment of locally advanced salivary gland carcinoma is challenging and controversial. Surgery is the mainstay treatment for salivary gland carcinoma. Radiotherapy is commonly recommended as an adjunctive therapy for patients at high risk of local recurrence. As an alternative, 125I interstitial brachytherapy had the advantage of being highly conformal, which resulted in a high local control in salivary gland carcinoma. The aim of this study was the relationship of fluorine-18-fluorodeoxyglucose (18F-FDG) uptake of primary tumor on PET/CT with survival in patients with locally advanced salivary gland carcinoma of head and neck.

A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma

BackgroundThere is no standard first-line chemotherapy for recurrent/metastatic (RM) or unresectable locally advanced (LA) salivary gland carcinoma (SGC). Patients and methodsWe conducted a single institution, open-label, single arm, phase II trial of combined androgen blockade (CAB) for androgen receptor (AR)-positive SGC. Leuprorelin acetate was administered subcutaneously at a dose of 3.75mg every 4weeks. Bicalutamide was administered orally at a daily dose of 80mg. Patients were treated until progressive disease or unacceptable toxicities. ResultsThirty-six eligible patients were enrolled. Thirty-three patients had RM disease and three patients had LA disease. The pathological diagnoses were salivary duct carcinoma (34 patients, 94%) and adenocarcinoma, NOS (two patients, 6%). The best overall response rate was 41.7% [n=15, 95% confidence interval (CI), 25.5%–59.2%], the clinical benefit rate was 75.0% (n=27, 95% CI, 57.8%–87.9%). The median progression-free survival was 8.8months (95% CI, 6.3–12.3months) and the median overall survival was 30.5months (95% CI, 16.8months to not reached). Additional analyses between treatment outcomes and clinicopathological factors or biomarkers including AR positivity, human epidermal growth factor receptor 2 status, and its complex downstream signaling pathway gene mutations showed no statistically significant differences. Elevated grade 3 liver transaminases and increased serum creatinine were reported in two patients, respectively. Discontinuation of leuprorelin acetate or bicalutamide due to adverse event occurred in one patient. ConclusionThis study suggests that CAB has equivalent efficacy and less toxicity for patients with AR-positive RM or unresectable LA SGC compared with conventional chemotherapy, which warrants further study. Clinical Trial RegistrationUMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703

Preliminary results for the advanced salivary gland carcinoma cohort of the phase 1b KEYNOTE-028 study of pembrolizumab.

6017Background: Patients (pts) with treatment-refractory salivary gland cancer have limited treatment options. The PD-1 pathway is upregulated in many tumors leading to immune response suppression....

Adjuvant chemo-radiotherapy (CRT) versus radiotherapy (RT) alone for locally advanced salivary gland carcinoma among older population: SEER-Medicare analysis.

6028 Background: Salivary gland carcinoma is an uncommon malignancy. For locally advanced or high risk disease, current standard of care consists of surgery followed by adjuvant RT. Limited data on...

Boron neutron capture therapy for advanced salivary gland carcinoma in head and neck

Boron neutron capture therapy (BNCT) is among the radiation treatments known to have a selective lethal effect on tumor cells. This study summarizes the tumor responses and the acute and late adverse effects of BNCT in the treatment of patients with both recurrent and newly diagnosed T4 salivary gland carcinoma. Two patients with recurrent cancer and 3 with newly diagnosed T4 advanced malignancy were registered between October 2003 and September 2007, with the approval of the medical ethics committees of Kawasaki Medical School and Kyoto University. BNCT was performed, in a single fraction using an epithermal beam, at Japan Research Reactor 4. All patients achieved a complete response within 6months of treatment. The median duration of the complete response was 24.0months; the median overall survival time was 32.0months. Three of the 5 patients are still alive; the other 2 died of distant metastatic disease. Open biopsy of the parotid gland after BNCT was performed in 1 patient and revealed no residual viable cancer cells and no serious damage to the normal glandular system. Although mild alopecia, xerostomia, and fatigue occurred in all patients, there were no severe adverse effects of grade 3 or greater. Our preliminary results demonstrate that BNCT is a potential curative therapy for patients with salivary gland carcinoma. The treatment does not cause any serious adverse effects, and may be used regardless of whether the primary tumor has been previously treated.

BNCT for Advanced Salivary Gland Carcinoma

Norimasa Morita MD, PhD Department of Otolaryngology Kawasaki Medical School Email: nori.morita@gmail.com Phone: +81-86-462-1111 Objectives: Boron neutron capture therapy (BNCT) is one of the radiation therapies known to have a selective lethal effect on tumor cells. This study summarizes the tumor responses and acute and rate phase reactions of the normal tissue with BNCT in the treatment of patients with recurrent T4 and newly diagnosed T4 salivary gland carcinomas. Methods: Two patients with recurrent cancers and 3 with newly diagnosed T4 advanced cancer were registered from October 2003 to September 2007 with the approval of the Medical Ethics Committees of Kawasaki Medical School and Kyoto University. BNCT was performed at the Japan Research Reactor 4 (JRR-4) in a single fraction using an epithermal beam. Results: All patients achieved a complete response within 6 months after BNCT. The median duration of the complete response was 24.0 months. The median overall survival time was 32.0 months. Three of 5 patients are still alive and remaining patients died of distant metastasis. Open biopsy of the parotid gland was performed in one patient at the selective neck dissection. The pathological examination revealed no residual viable cancer cells in the parotid gland without any serious damage of normal glandular system after BNCT. Although mild alopecia, xerostmia and fatigue were occurred in all patients, no severe adverse effects, Grade 3 and more, were observed in any patients. Conclusions: Our preliminary results demonstrate that BNCT is the potential curative therapy for patients with salivary gland carcinomas without causing any serious adverse effects, irrespective of whether the primary site of cancer has already been treated. BNCT for Advanced Salivary Gland Carcinoma Norimasa Morita1, Teruhito Aihara1, Masako Uno1, Koji Ono2, and Tamotsu Harada1 Department of Otolaryngology, Kawasaki Medical School, Kurashiki, Japan1 Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Osaka, Japan2

Concurrent chemoradiotherapy with cyclophosphamide, pirarubicin, and cisplatin for patients with locally advanced salivary gland carcinoma

Conclusion. This concurrent chemoradiotherapy with CPA, THP, and CDDP showed major antitumor activity with manageable toxicity as treatment of advanced salivary gland carcinoma patients. The high response rate (RR) justifies further evaluation of this chemoradiotherapy combination. Objectives. The aim of this study was to evaluate the efficacy and toxicity of a concurrent chemoradiotherapy using cyclophosphamide (CPA), pirarubicin (THP), and cisplatin (CDDP) in patients with locally advanced salivary gland carcinoma. Patients and methods. Seventeen patients with previously untreated stage III–IV salivary gland carcinoma were entered in this trial between January 2000 and September 2005. Chemotherapy consisted of CPA 400 mg/m2 on day 1, THP 40 mg/m2 by 6-h infusion on day 1, and CDDP 60 mg/m2 by 2-h infusion on day 1. Radiotherapy (2.0 Gy/fraction/day, mean total dose: 67.2 Gy (64.0–72.0 Gy)) administered 5 days per week, was targeted to begin on day 1. Results. The RR was 76% (13/17) and the pathological complete response (CR) was 24% (4/17). The primary site CR was 29% (5/17) and metastatic lymph node CR was 33% (4/12). The 5-year survival rate was 70%. Neutropenia, leukocytopenia and mucositis were common adverse effects, but all 17 patients were assessable for toxicity.

Cisplatin in advanced salivary gland carcinoma. A phase II study of 25 patients

A prospective Phase II study was carried out to test cisplatin (CDDP) as a single agent in salivary gland carcinomas. CDDP was administered (100 mg/m2) every 3 weeks to 25 consecutive patients with either recurrent or locally advanced salivary gland carcinoma. Six patients had received prior chemotherapy, and the other patients had had only surgery or radiation therapy or no treatment at all. The response rate was 18% (95% confidence interval [CI], 6% to 41%). Response duration was between 5 and 9 months. Median overall survival time was 14 months. CDDP is a moderately active drug in salivary gland carcinomas. It should be included in multidrug regimens to be tested in prospective studies, which are difficult to carry out due to the rarity of these tumors.