NISCAHN: a phase II trial of nivolumab in patients with salivary gland carcinoma (Unicancer ORL-08)

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.

Materials and methods

Results

Efficacy

Efficacy data are summarised in table 2 and Consolidated Standards of Reporting Trials flow diagram is presented in online supplemental figure 1.

Table 2

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Efficacy data summary

Three patients were not evaluable for NPR_6m (one ACC without 6-month RECIST evaluation and two non-ACC, one consent withdrawal and one death of intercurrent disease before 6-month evaluation). In the ACC cohort, the primary endpoint was met with 15/45 (33.3%) patients alive without progression at 6 months (one-sided 95% CI 21.8% to -). In the non-ACC cohort, nivolumab demonstrated low level of efficacy with only 7/50 non progressive patients at 6 months, for a NPR_6m of 14% (one-sided 95% CI 6.8 to –).

ORR were estimated at 8.7% (95% CI 2.4% to 20.8%) and 3.8% (95% CI 0.5% to 13.2%) in the ACC and non-ACC cohorts, respectively, with only 6/98 objective responses (ACC: 4 PR; non-ACC: 2 PR). Median PFS was 5.3 months (95% CI 3.2 to 5.6) for patients with ACC and 1.8 months (95% CI 1.7 to 3.5) for patients with non-ACC (figure 1). Median OS was longer in the ACC cohort with 17.2 months (95% CI 12.5 to NE) and 11.5 months (95% CI 7.5 to 14.8) (online supplemental figure 2). Tumour growth rate was not decreased after the start of nivolumab (data not shown). Swimmer plots are available in online supplemental figure 3. They describe patient by patient the duration of treatment and clinical endpoints.

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Figure 1

Progression-free survival in the (A) adenoid cystic carcinoma (ACC) and (B) non-ACC cohorts. Consolidated Standards of Reporting Trials flow diagram.

Health-related quality of life

Compliance to QLQ-C30 and QLQ-H&N35 questionnaires was 86% (84/98 patients) at cycle 1, 86% (60/70 treated patients) at cycle 3, 77% (36/47) at cycle 5 and 54% (53/98 patients) at the end of treatment. In the ACC cohort, there was no great variation in term of HRQoL during the start of treatment and cycles 3 and 5 (online supplemental tables 6, 7, 9 and 10). Then, a slight decrease was registered at the end of the treatment when the majority of patient had stopped the treatment due to progression. This HRQoL seemed poorer at the end of treatment on the items of both QLQ-C30 (figure 2A) and QLQ-H&N35 (figure 2B) questionnaires. Similar data were observed in the non-ACC cohort (online supplemental tables 6, 8, 9 and 11).

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Figure 2

Evolution of the reported health-related quality of life scores at baseline, cycles 1, 3, 5 and end of treatment in patients with adenoid cystic carcinoma according to the European Organization for Research and Treatment of Cancer QLQ-C30 (A) and H&N35 (B) questionnaires. The symptom scales were reversed: the better the quality of life, the larger is the circle. The graphics represent the evolution of the cohort as a whole and not the evolution of each individual. AP, appetite loss; CF, cognitive functioning; CO, constipation; DI, ciarrhoea; DY, dyspnoea; EF, emotional functioning; FA, fatigue; FI, financial difficulties; HNCO, coughing; HNDR, dry mouth; HNFE, feeding tube; HNFI, felt ill; HNNU, nutritional supplements; HNOM, opening mouth; HNPA, pain; HNPK, pain killers; HNSC, trouble with social contact; HNSE, senses problems; HNSO, trouble with social eating; HNSP, speech problems; HNSS, sticky saliva; HNSW, swallowing; HNSX, less sexuality; HNTE, teeth; HNWG, weight gain; HNWL, weight loss; NV, nausea and vomiting; PA, pain; PF, physical functioning; QL, global health status; RF, role functioning; SF, social functioning; SL, insomnia.

Discussion

The NISCAHN phase II study aimed to identify nivolumab activity on SGC cancers. Because of their natural history, SGC tumours were classified into two groups: ACC and non-ACC. Therefore, the two cohorts were analysed separately in the NISCAHN trial, and differential responses were observed. In the non-ACC cohort, the primary endpoint was not met with only seven non-progressive patients at 6 months and a lower bound of the one-sided 95% CI 6.8 to -, much lower than the 20% expected. In the ACC cohort, the primary endpoint was met but the response was not robust with only 15/45 non progressive patients showing an one-sided 95% of 21.8% which (>20% threshold) and a target efficacy of 40% included in the CI. If the null hypothesis could not be rejected, the 40% target was not reached. Moreover, median PFS and response rate were low in this cohort with 5.3 months and 8.7% (4/46), respectively. ACC is a heterogeneous group that comprises slow to relatively fast growing tumours. To minimise the heterogeneity of the disease, the NISCAHN cohort was limited to patients with confirmed disease progression within a 6-month period. However, despite this criterion, with no comparator arm, we cannot rule out that the 33.3% (one-sided 95% CI: 21.8 to -) of no progression at 6 months was not a reflect of the natural history of the indolent malignancy.

In the NISCAHN study, the relationship between the efficacy and the expression of biomarkers such as PD-L1 was also investigated. Indeed, high PD-L1 expression, which could result in sensitivity to anti-PD-1 blockage, was previously reported in high-grade SGC subtypes,21 and the expression of PD-L1 and PD-L2 was correlated with nivolumab efficacy in other head and neck cancers like Head and Neck Squamous Cell Carcinomas.28 29 Noteworthy, non-ACC tumours previously showed relatively higher PD-L1 protein expression than ACCs, which could result in a greater sensitivity to anti-PD-1 blockade.21 22 30–34 Moreover, in the KEYNOTE-028 phase I study, pembrolizumab, another anti-PD-1 monoclonal antibody, demonstrated antitumor activity in patients with SGC, mostly non-ACC (92%).35 In this basket trial, pembrolizumab was tested on 26 prescreened PD-L1 positive patients and demonstrated a NPR_6m of 23% (95% CI 9% to 44%).35 In the NISCAHN non-ACC cohort, we observed a lower NPR_6m of 14% (one-sided 95% CI 7 to -), and PD-L1 expression observed in 13 out of the 27 tested patients was not correlated with efficacy since only 1/4 patient was both NPR_6m and CPS≥1. Another phase 2 prospective clinical study also evaluated the use of immunotherapy in combination with radiation therapy for the treatment of metastatic ACC.36 The trial failed to demonstrate the efficacy of the combination over radiation alone but the authors hinted that patients with PD-L1 expression greater than 1% in tumour cells tended to achieve SD more frequently than patients with no PD-L1 expression. However, the difference was not significant due to the limited number of patients included in the trial. As expected, in the NISCAHN ACC cohort, PD-L1 expression was lower than in the non-ACC cohort. Indeed, a few ACC tumours expressed PD-L1 at a very low level (5/20 had a CPS≥1 among which none≥20), and only one out of the seven non-progressive patients at 6 months with available PD-L1 analyse had a CPS≥1. Despite the lack of PD-L1 expression, our data, based on a large cohort, suggest that patients with ACC still benefit from PD-1 inhibitor therapy.

The resistance to PD-1 blockage could be explained by the absence of mutations in SGC. Indeed, tumours with high mutational burden and increased neoantigens expression are generally more responsive to immunocheckpoint blockage therapy, and SGC often harbour no or few mutations.37 Nevertheless, it was interesting to test the effect of an immune checkpoint inhibitor as cancers such as renal cell carcinoma (RCC),38 which have lower mutational rates than other tumours, appear to be sensitive to nivolumab therapy, even though RCC being predominantly frameshift, low mutational burden could also result from high neoantigen levels. Moreover, the rate of progression (ROP), defined as the increase in the tumour burden per unit of time, and used to define slow and rapid tumour progression, has recently been correlated with survival prior to starting PD-1 inhibitors. In this study, PFS and OS were shorter in rapid ROP.39 However, in the NISCAHN trial, the slow disease did not allow efficacy of anti-PD-1 checkpoint inhibitor. Taking together, these results highlight the importance of identifying factors able to predict standardised and reproductive responsiveness to anti-PD-1 treatment. The importance of a targeted therapy based on tumour molecular characteristics have already been demonstrated by the efficacy of anti-HER2 treatments for HER-2-amplified tumours10 11 or specific NTKR inhibitors in case of NTRK-rearrangement.12 Inclusion of patients with SGC in clinical trials proposing large molecular analysis such as the SPECTA programme of the EORTC could allow the identification of relevant genomic alterations that could be used as prognostic and predictive factors to validate appropriate treatments for these orphan group of diseases.

As only few patients benefit from immune checkpoints treatments, research currently focus on identifying the possible mechanisms leading to immunotherapy resistance and developing novel combination strategies to improve their effectiveness. In the NISCAHN study, the good tolerability of nivolumab was confirmed and was consistent with BMS-nivolumab investigator brochure and previously published data. No new signal of toxicity was reported and patients’ HRQoL was not impaired or decreased during and after the treatment, outside of the degradation due to disease progression. Therefore, combination of nivolumab with other agents could be tested to improve its efficacy in ACC. For this test, two major classes of agents should be considered.

First, chemotherapy that can increase the release of tumour antigens by cell destruction and then increase inflammation. In lung cancers or in head and neck cancers, the combination of chemotherapy with immunotherapy increase its efficacy, mostly in tumour with lower response to anti-PD-1/PD-L1 monotherapy.40 Moreover, reported early data showed that the combination of chemotherapy with nivolumab was feasible with promising early outcomes.40 41

Then, TKIs and mostly anti-VEGF(R) agents that can modulate immune microenvironment and potentiate anti-PD-1/PD-L1 treatments.42 Of late, a phase II single-arm study previous studies have demonstrated a median PFS of 19.8 months, an ORR of 46.2% and a manageable toxicity in patients with recurrent or metastatic ACC treated with apatinib.43

This study presents with some limitations. For instance, no interim analysis was planned. The individual data were not revealed during the study and before the database lock in order to avoid bias of the results such as an overselection of the patients included. The availability of the FFPE blocks of the tumours samples was also an issue when PD-L1 expression and TILs score were analysed in only half of the samples. The data were missing completely at random due to end of stock, and storage difficulties that did not allow their staining and analyse.

To summarise, the NISCHAN study demonstrated limited clinical benefit of nivolumab monotherapy in patients with recurrent and/or metastatic SGC who have progressed during the 6-months period before entering the study. Currently, studies combining nivolumab with other agents to improve its efficacy are currently underway. Given the rarity of these tumours, this study showed the possibility to conduct an extensive trial on a rare group of tumours with the inclusion of 98 patients in 12 different centres in 1 year. This study also underlined the importance of molecular characterisation and profiling in the determination of treatment in SGC.