This is the first prospective study on the efficacy and safety of comprehensive treatment, including chemotherapy, immunotherapy, anti-angiogenic therapy and chemoradiotherapy, in patients with local advanced NPC and high risk of distant metastasis. Current findings suggest that the combination of camrelizumab and apatinib with IC of nab-paclitaxel, cisplatin and capecitabine and CCRT has promising distant metastasis control with acceptable safety profile in patients with TanyN3M0 NPC.
In our study, the 2-year rate of DMFS among N3 patients was improved by 11.7% in comparison to our historical cohort treated with IC and CCRT 9. Of note, given about half of distant metastasis events occurred within 1 year, this new strategy would be a promising first-line option for patients with locally advanced NPC and high risk of distant metastasis. In addition, detectable EBV DNA after radical treatment indicated high risk of treatment failure 23,24. Historically, 50%-75% and 25%-30% of N2-3/N3 patients had detectable EBV DNA levels after IC and CRT, respectively, and subsequently they were the ones with the highest frequency experiencing distant failure eventually 23–25. In our study, 85% and 96% patients had undetectable EBV DNA levels after IC and CCRT, respectively, indicating this combination regimen did effectively eradicate micrometastatic lesions and imply satisfactory long-term distant control.
Patients achieving CR/PR after IC had significantly longer FFS compared to those with stable disease (SD) or progressive disease (PD) 25,26. The CR rate of 0–8% and SD rate of 10%-16% were observed in N3 patients in previous trials 7,9,25,26. Our combinatory induction therapy resulted in a CR rate of 26.5% and objective response rate of 100% for patients with N3 disease, indicating that at least 10% of N3 patients who would be SD or PD after treatment with traditional IC achieve CR or PR from this new combination regimen. In addition, a pathological CR is associated with a survival benefit 27,28. Indeed, a high pathological CR rate was observed in our study that 85% of biopsied primary tumor samples and 73% of biopsied lymph nodes after receiving 2–3 cycles of combination regimen had negative pathological finding. In the studies involved with traditional CRT, the FFS improvement is mainly derived from LRFS, rather than from DMFS for patients with satisfactory tumor response to IC 25. This indicates that traditional chemotherapy is not enough to eradicate micrometastatic dissemination in patients with N3 disease. In fact, the present combination regimen significantly improved both FFS and DMFS compared with traditional regimen used in our historical N3 cohort 9, but not LRFS, suggesting that the benefit of FFS in our study mainly originates from distant metastasis control.
In this trial, we used NAB-TPC as IC regimen rather than traditionally used gemcitabine/cisplatin (GC) or cisplatin/5-FU (PF). As we reported recently that TPC as IC regimen is more efficacious than PF for patients with stage IVA to IVB NPC 9, that leads to be a strong recommendation as Class IA evidence by the Chinese Society of Clinical Oncology (CSCO) guideline. However, none of the N3 patients who received TPC regimen achieved CR, and 2-year FFS rate was only 85% 9. Therefore, it is reasonable to assume that the addition of the 2 new biological drugs likely significantly improve the therapeutic efficacy of IC and CCRT.
Meanwhile, we used 2 rather than 3 cycles of cisplatin CRT with the consideration of the reduction of toxicities while maintaining comparable or even achieving improved efficacy with additional agents. Our group has shown that the 2 cycles of once-every-3-weeks concurrent cisplatin is preferred to once-a-week cisplatin in the locoregionally advanced NPC with the advantage of lower acute and late-onset auditory loss toxicities but comparable efficacy 29. Indeed, the additional two drugs to induction therapy and subsequent CCRT with reduced cisplatin dose reached exceptional efficacy while maintaining low toxicity profile.
With the abovementioned changes, the combination regimen did not result in any unexpected grade 3 or 4 TRAEs or irAEs in the trial. The cumulative TRAE rate of 65% is similar to other studies (ranging from 66–76%) [6, 7, 8]. Previous studies [6, 7] showed that the proportion of patients completing 3 cycles of IC and 2 cycles of CCRT ranges from 88–97% and 88–92%, respectively 30. In the present study, 100% (49/49) and 87% (41/47) patients received 3 cycles of induction chemotherapy and 2 cycles of CCRT, respectively. This suggests that the combination regimen is well tolerated. Interestingly, the incidence of RCCEP in our study is higher than that in the CAPTAIN-1st study using combination regimen of camrelizumab plus GC to treat R/M NPC (86% versus 58%) 16, probably because of the multiple-drug interactive effects and intensive toxicity monitoring in our study with limited sample size.
There are several limitations in this study. First, this trial is a single-arm phase II trial that the conclusions need to be validated in a large randomized, multicenter, controlled trial in the same NPC patient population. Second, this trial was not designed to compare the efficacy of this combination regimen to other treatment options. Although we compared the results to the one from our recent clinical trial cohort 9, but further head-to-head comparison is needed in a perspective randomized controlled phase III trial. Third, the question of whether all N3 patients require this combination therapy should be addressed in phase III trial with stratification of disease, e.g. T classification and plasma EBV DNA level 31,32.