Androgen deprivation therapy (ADT) is first‐line palliative treatment in androgen receptor‐positive (AR+) salivary duct carcinoma (SDC), and response rates are 17.6–50.0%. We investigated potential primary ADT resistance mechanisms for their predictive value of clinical benefit from ADT in a cohort of recurrent/metastatic SDC patients receiving palliative ADT (n = 30). We examined mRNA expression of androgen receptor (AR), AR splice variant‐7, intratumoral androgen synthesis enzyme‐encoding genes AKR1C3, CYP17A1, SRD5A1 and SRD5A2, AR protein expression, ERBB2 (HER2) gene amplification and DNA mutations in driver genes. Furthermore, functional AR pathway activity was determined using a previously reported Bayesian model which infers pathway activity from AR target gene expression levels. SRD5A1 expression levels and AR pathway activity scores were significantly higher in patients with clinical benefit from ADT compared to those without benefit. Survival analysis showed a trend toward a longer median progression‐free survival for patients with high SRD5A1 expression levels and high AR pathway activity scores. The AR pathway activity analysis, and not SRD5A1 expression, also showed a trend toward better disease‐free survival in an independent cohort of locally advanced SDC patients receiving adjuvant ADT (n = 14) after surgical tumor resection, and in most cases a neck dissection (13/14 patients) and postoperative radiotherapy (13/14 patients). In conclusion, we are the first to describe that AR pathway activity may predict clinical benefit from ADT in SDC patients, but validation in a prospective study is needed.
6529 A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients. Background: Because c-MET and VEGFR are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in recurrent/metastatic (R/M) SGC pts. Methods: A single center, single arm, phase II study was conducted. Immunohistochemical c-MET positive (H-score ≥10) R/M SGC pts were included in 3 cohorts: adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and other SGCs. Objective growth or complaints due to the disease were required before inclusion in the ACC and other SGC cohort. No prior systemic treatments were required. Pts started 60 mg cabozantinib tablets OD. Primary endpoint was the objective response rate (ORR). A Simon two-stage design was used. In case of ≥1 objective response in the first 9 pts/cohort, 8 additional pts would be included in the cohort. Results: In total 25 pts were included from Sep. 2018 until premature closure due to severe toxicity in Nov. 2019. Median age was 56 years (range 49-72), prior treatments included: primary tumor resection ( n=19), radiotherapy ≥50Gy ( n=24), systemic therapy ( n=10; adjuvant in 2 pts, palliative in 8 pts). Six pts had grade 3 ( n=4), grade 4 ( n=1), or grade 5 ( n=1) wound/fistula complications, occurring at a median of 7.2 mths on cabozantinib (range 2.1-12.8). This resulted in a severe wound complication rate of 32% in 19 pts on treatment for ≥2 mths. Remarkably, 4 out of 6 pts developed this complication in the area exposed to high-dose Rx; 2/4 had a pre-existing fistula in this area. Median interval between Rx and start of cabozantinib was 71.3 mths (range 10.6-94.7). Other grade ≥3 adverse events in >1 pt were: hypertension (5 pts), diarrhoea (2 pts) and dehydration (2 pts). Current median follow-up is 6.8 mths. The ORR was 6% (1/17 pts) in the ACC cohort, 20% (1/5 pts) in the SDC cohort, and 0% (0/3 pts) in other SGC pts; median PFS is 12.6 mths (95% CI 6.8 – 18.4 mths), 9.0 mths (insufficient events for 95% CI), and 6.9 mths (95% CI 0 – 15.2 mths), respectively. Median OS is not reached in any cohort. Conclusions: This phase II study on cabozantinib in R/M SGC pts demonstrated severe wound and fistula complications in 32% of pts on treatment for ≥2 mths, mostly (4/6 pts) within the radiotherapy field. Because of this toxicity the study was closed prematurely. Furthermore, cabozantinib showed minimal clinical activity in SGC pts. Research funding: Ipsen Pharmaceuticals Clinical trial information: NCT03729297 .
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