PSMA radioligand therapy for solid tumors other than prostate cancer: background, opportunities, challenges, and first clinical reports.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

Case series of docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and ado-trastuzumab emtansine (T-DM1) as second line for recurrent or metastatic HER2-positive salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) overexpresses Human Epidermal growth factor Receptor 2 (HER2) in 29-46% of cases, favoring anti-HER2 therapy. Here, we present the results of patients with recurrent or metastatic HER2-positive SDC treated with docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and subsequently ado-trastuzumab emtansine (T-DM1) in second line. Furthermore, we searched for potential biomarkers. METHODS: Retrospective case series from a tertiary hospital. First line anti-HER2 treatment consisted of DTP, after progression T-DM1 was considered for patients with an adequate performance status. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed and related to mRNA-based PI3K and MAPK signaling pathway activity scores. RESULTS: Thirteen SDC HER2 + patients received DTP. In twelve evaluable patients, one complete response (CR) and six partial responses (PR) were observed (ORR 58%), with a median PFS of 6.9 months (95%-CI 5.3-8.5). Seven patients received subsequent T-DM1 in second line, resulting in four PR (ORR 57%), with a median PFS of 4.4 months (95%-CI 0-18.8). Median OS after start of DTP was 42.0 months (95%-CI 13.8-70.1). Grade ≥ 3 toxicity on DTP was seen in 39% of patients, and 14% on T-DM1. Highest combined PI3K and MAPK signaling was seen in the patient with CR and lowest in the patient with progressive disease on DTP. CONCLUSION: In R/M HER2-positive SDC patients DTP followed by T-DM1 upon progression are promising treatments, leading to responses in the majority (58%) of the patients at an acceptable toxicity profile.

Systemic therapy in the management of recurrent or metastatic salivary duct carcinoma: A systematic review.

BACKGROUND: Salivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer. Approximately half of SDC patients will develop recurrences or metastases. Therapeutic palliative therapy is therefore often needed. The majority of SDC tumors expresses the androgen receptor (AR) and one-third expresses human epidermal growth factor receptor 2 (HER2), both are potential therapeutic targets. The aim of this paper is to systematically review and summarize the evidence on systemic palliative therapy for SDC and to provide treatment recommendations. MATERIALS AND METHODS: Electronic libraries were systematically searched with a broad search strategy to identify studies where SDC patients received systemic therapy. Due to the rarity of SDC no restrictions were placed on study designs. RESULTS: The search resulted in 2014 articles of which 153 were full-text analyzed. Forty-five studies were included in the analysis, which included in total 256 SDC patients receiving systemic therapy. Two phase 2 trials primarily including SDC patients were identified. The majority of the studies were case series or case reports, resulting in an overall low quality of available evidence. Based on studies including ≥ 5 SDC patients, objective responses to HER2 targeting agents were observed in 60-70%, to AR pathway agents in 18-53% and to chemotherapy in 10-50%. CONCLUSION: For AR or HER2 positive SDC, agents targeting these pathways are the cornerstone for palliative treatment. Regarding chemotherapy, the combination of carboplatin combined with a taxane is best studied. Regarding other targeted agents and immunotherapy evidence is anecdotal, limiting formulation of treatment recommendations for these antineoplastic agents.