Introduction
Salivary gland carcinomas (SGC) are rare cancers accounting for less than 5% of head and neck cancers. At the histological level, a very diverse range of 22 SGC subtypes were listed in the 2017 classification of the WHO,1 2 the three major being mucoepidermoid carcinoma, adenocarcinoma not otherwise specified and adenoid cystic carcinoma (ACC). SGC can then be classified into two groups: ACC, which represents 60% of the malignant histotypes, and non-ACC. ACC are aggressive tumours characterised by frequent local recurrences and distant metastases and more than half of patients with ACC present locally advanced or metastatic disease.3 Growth is slow but relentless, and progression poses a challenge to clinicians. Unlike ACC, non-ACC SGC are a heterogeneous group with distinct histologies and variable biological behaviour.
Possible therapies are scarce for patients who suffers from SCG. Surgery followed by radiotherapy is the curative treatment of choice, and for inoperable recurrent or metastatic disease, treatments are only systemic and palliative. Prognosis is poor with an overall response rate (ORR)<10% under chemotherapy.4 Due to the rarity of these tumours, it is very difficult to obtain clear data on SGC. However, overall survival (OS) was estimated at 32.3 months after apparition of lung metastases and 20.6 months for metastases elsewhere. The median doubling time of pulmonary metastasis of ACC was estimated at 393 days.1 2 Patients with recurrent or metastatic non-ACC SGC may achieve ORR ranging from 15% to 50% with conventional cytotoxic chemotherapy but duration of response is typically limited to 6–9 months.1 2 5
When the NISCAHN study was designed, no randomised study were realised and only small trials were published. Most efficient drugs were cisplatin, fluorouracil, anthracyclines, taxanes or vinorelbine, but only disappointing results were obtained.1 2 6 7 Molecular dismemberment made it possible to better classify SGC and highlighted targetable molecular abnormalities8 9 such as HER2 amplification that allowed the use of HER2 inhibitors alone or in combination with taxanes,10 11 or fusion ETV6-NTRK3 in secretory carcinoma treated with larotrectinib.12 Several targeted therapies like EGFR or KIT inhibitors2 13 14 were also tested but only treatments using multitarget tyrosine kinase inhibitors (TKIs), in particular VEGFR inhibitors, seemed promising.15–18 In that regard, a non-blinded randomised phase II trial comparing axitinib to placebo recently demonstrated a 6-month progression-free survival (PFS) rate of 73.2% vs 23.2% (p<0.001) and a median PFS of 10.8 months versus 2.8 months.19
As they have proven to play a pivotal role in the outcome of various types of cancers, the immune checkpoint programmed death-1 (PD-1) receptor and its corresponding ligands (PD-L1 and PD-L2) offer a scientific interest for the treatment of SGC. Indeed, if the effectiveness of anti-PD-1 antibodies is correlated with the tumour mutation burden and SGC often harbour no or few mutations,20 the usual slow disease progression could allow efficacy of checkpoint inhibitors. Moreover, high PD-L1 expression was reported in high-grade SGC subtypes previously shown to be associated with aggressive behaviour (eg, salivary duct carcinoma and squamous cell carcinoma) and linked to an inferior disease-free survival,21 and both cytoplasmic and membranous PD-L2 expression were observed in ACC tumour cells.22 23
In the multicentre phase II NISCAHN trial, we assessed the efficacy of nivolumab, an anti-PD-1 monoclonal antibody, in patients with SGC. As response rate was probably not a relevant objective to evaluate a new drug in the ACC cohort, non-progression rate at 6 months became the primary objective of this study. Interestingly, this primary endpoint was also presumably more adapted to test immune checkpoint inhibitors.24 Furthermore, since ACC progression is generally slow, a proof of progression according to Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 criteria in the 6 months period prior to entering the study, was mandatory to confidently evaluate NISCAHN main objective. Finally, in the NISCAHN study, ACC and non-ACC cohorts were conducted and analysed in parallel as their natural history is quite different.