Discussion

This is the first report that compares the safety and efficacy of different anti-PD-1 drugs with/without chemotherapy in RM-NPC, which provides preliminary evidence and integrative insights into the future design and implementation of immune clinical trials in NPC. The general safety of nivolumab and pembrolizumab ranked high, while the incidences of grade 3–5 AEs were relatively low in camrelizumab and nivolumab. Integrating with the specific toxicity spectra of each drug, we postulate that camrelizumab has the least toxicity profile; the high incidence of all-grade AEs may be attributed to reactive capillary hemangiomas, which is generally unthreatening and self-resolved [8]. In general, anti-PD-1 therapy was safer than standard chemotherapy; however, once it was combined with chemotherapy, the incidence of grade 3–5 AEs and AE-related discontinue rate doubled over chemotherapy alone, which suggests potentially synergized toxicity. This is in accordance with the safety profiles in the KEYNOTE-048 trial investigating anti-PD-1 + chemotherapy versus chemotherapy alone in non-nasopharynx head and neck cancer [11].

The response rate with anti-PD-1 monotherapy for pretreated RM-NPC approximated 20–30%, whereas ORR increased to 40% in treatment-naive patients. Additionally, the incidences of AEs with anti-PD-1 regimen were generally lower than those with chemotherapy. Though the sample size in first-line anti-PD-1 group is limited, it provides preliminary evidences that comparing first-line anti-PD-1 monotherapy versus standard chemotherapy is a “trial-worthy” approach.

Interestingly, we observed similar CR rates between GP chemotherapy and anti-PD-1 + chemotherapy. Considering that anti-PD-1 monotherapy only achieved limited CR rate (~ 0–2%), it might suggest that the addition of anti-PD-1 agents may not be adequate enough to increase complete elimination of tumor cells (CR rate), though this combination therapy can still substantially improve tumor killing efficacy (PR rate). Likewise, a phase 2 trial by Chia and colleagues [12] reported a similar CR rate (8.6%) and a relatively higher PR rate (62.9%) in treatment-naive RM-NPC receiving chemotherapy followed by EBV-specific cytotoxic T lymphocytes (CTLs), compared to that of GP chemotherapy (Table 2). These results implicate that the combination of immunotherapy agents (either anti-PD-1 or EBV-CTLs) with chemotherapy may not achieve synergic effects (similar CR rates) in NPC patients; however, the substantially increased PR rate may still translate into patient survival benefits. Our findings need to be verified in ongoing/future prospective randomized trials evaluating the combination of immunotherapy and chemotherapy versus chemotherapy alone.

One major challenge of immunotherapy remains that it only benefits small subsets of patients. Prior trial data [6, 9] showed a numerically higher ORR in patients with PD-L1–positive RM-NPC than in those with PD-L1–negative tumors; and high-PD-L1 expression was associated with better survival outcomes in both NPC and other head and neck cancer [13, 14]. We further performed pooled analysis to increase statistical power. Unfortunately, a significant margin was still not reached; the possible reason would be limited sample size. Moreover, PD-L1 expression alone may not be the only determinant of treatment benefits; it might be contingent on other factors in the tumor microenvironment that are yet to be identified. Future studies are warranted to identify reliable biomarkers for tailoring anti-PD-1 therapies. Improvement in treatment efficacy can also be achieved by breakthroughs in combination therapy. It is shown that camrelizumab+GP combination approach achieved a remarkable ORR in first-line treatment. Additionally, previous exposure to ipilimumab significantly improved antitumor activity of camrelizumab [8]. Going forward, these preliminary findings construct a road-map for the design of future trials to assess the efficacy of immuno-oncology cocktail and/or dual inhibition of immune checkpoints approaches in NPC. Results from relevant ongoing trials (e.g. NCT03581786, NCT03707509, NCT03097939) are eagerly awaited.

One major limitation of this study is that all trials were in phase 1/2, therefore long-term survival data are still lacking and the sample sizes were limited, especially for first-line nivolumab (n = 5) and the combination therapy group (n = 23). Our findings need to be verified in future large-scale, head-to-head, phase 3 trials. Secondly, the results of subgroup analyses regarding PD-L1 expression level should be interpreted with cautions, in view of the different immunohistochemical assays used [5, 6, 9].