As a Head and Neck medical Oncologist with a special interest in salivary cancers, it was uplifting to see so much ongoing work in salivary gland cancers, an orphan disease for which no standard therapies exist. Salivary cancers represent less than one percent of all malignancies and have notoriously been resistant to standard chemotherapeutics. In addition, there are greater than 20 subtypes of salivary cancer ranging from slow-growing to aggressive, making it challenging to design and conduct clinical trials in this space.
At the American Society of Clinical Oncology Meeting in Chicago, Illinois, targeted therapies for salivary cancers were presented in the Head and Neck cancer oral abstract session, poster session, and in the online electronic abstracts, representing an exciting array of ongoing work seeking to provide therapeutic options for patients with this rare group of cancers. In the oral abstract session on Friday, Dr. Bob Li from Memorial Sloan-Kettering Cancer Center in New York presented data from a phase II study of ado-trastuzumab emtansine in patients with HER2-amplified salivary gland cancers, showing an impressive preliminary response rate of 90% (J Clin Oncol 37, 2019 (suppl; abstr 6001). HER2 amplification occurs in a small number of salivary cancers overall (8%) and a larger proportion of the aggressive subtype salivary duct carcinoma (approximately 30%). Although the study reported on the results of only 10 patients, findings were notable for five (50 percent) patients achieving a complete response to therapy and for responses seen in heavily pre-treated patients including those who had received prior HER2-directed therapy.
In the poster session on Saturday, Dr. Renata Ferraroto from MD Anderson Cancer Center in Texas reported on an ongoing trial in adenoid cystic carcinoma targeting the NOTCH pathway based on preclinical and phase 1 data in solid tumor showing activity of the NOTCH inhibitor AL-101 (J Clin Oncol 37, 2019 (suppl; abstr TPS6098)). Notch activating mutations are found in a subset of patients with adenoid cystic carcinoma (11–22%), and early data on the use of AL-101 is promising. The trial of AL-101 in recurrent and metastatic adenoid cystic carcinoma is currently ongoing with an expansion phase underway. Two posters in the poster discussion session presented data on the use of targeted therapy for salivary cancer. One poster by Dr. Alan Ho from Memorial Sloan-Kettering Cancer Center presented the efficacy results of a cooperative group study of enzalutamide in patients with androgen receptor-positive salivary gland cancers (J Clin Oncol 37, 2019 (suppl; abstr 6020)).
Although the initial response rate was encouraging at 15%, many responses were not durable resulting in a confirmed response rate (lasting eight weeks or longer) of only 4%. Despite the somewhat disappointing overall results, the trial did show activity of enzalutamide in patients who had previously received hormone therapy, and more importantly, demonstrated the feasibility of conducting a multi-center, prospective, biomarker-driven trial in a distinct subset of an already rare cancer.
A second poster presented by Dr. Samuel Rack and colleagues from the United Kingdom reported on their PROSPERO study that looked at using a focused 24 gene targeted panel to assess 125 patients with recurrent or metastatic salivary gland cancer for actionable mutations that could lead to personalized therapeutic interventions (J Clin Oncol 37, 2019 (suppl; abstr 6086)).
The investigators identified 43 actionable alterations in 33 patients within the following genes: TP53 (21%), PIK3CA (8%), ERBB2 (6%), PTEN (3%), BRAF (2%), EGFR (T790M) (1%), and AKT1 (1%). Targeted therapy was selected based on genomic findings in 12 percent of these patients. In patients with adenoid cystic carcinoma, actionable alterations were seen in 25 percent compared with 55 percent of patients with non-adenoid cystic carcinoma subtypes (nine adenocarcinoma, five salivary duct carcinoma, three carcinoma ex pleomorphic adenoma, two mucoepidermoid carcinoma and one myoepithelial carcinoma).
Finally, two abstracts published online reported on the use of whole exome sequencing/RNA sequencing and next generation sequencing to identify therapeutic options for patients. A German group (first author Dr. Damian Rieke) found that whole exome sequencing/RNA sequencing led to the initiation of a targeted treatment in one-third of patients and clinical benefit was seen in 21% of patients treated (J Clin Oncol 37, 2019 (suppl; abstr e17577)).
Finally, investigators from Israel (first author Dr. Assaf Moore) found targetable mutations in 48% of tumors tested with next-generation sequencing with one-third of patients receiving treatment based on the results (J Clin Oncol 37, 2019 (suppl; abstr e17582)).
Given that the historical response rate for cytotoxic chemotherapy for unselected salivary cancer is 15%, the use of various commercially and institutionally-available sequencing panels to identify targeted therapy for patients with recurrent or metastatic salivary cancer is increasingly feasible, affordable, and promising, and should be incorporated into standard of care practices for evaluating patients with recurrent or metastatic salivary cancer. The landscape of salivary gland cancers is evolving similarly to that of non-small cell lung cancer with distinct subsets of cancers emerging with specific molecularly targeted therapies. It is exciting to see considerable momentum and collaboration in the field of salivary gland malignancies.
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