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Camrelizumab vs Placebo in Combination With Gemcitabine and Cisplatin as First-Line Treatment for Recurrent or Metastatic Nasopharyngeal Carcinoma
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial.
METHODS
In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing.
FINDINGS
Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death).
INTERPRETATION
Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion.
Additional Info
Disclosure statements are available on the authors' profiles:
Camrelizumab Versus Placebo in Combination With Gemcitabine and Cisplatin as First-Line Treatment for Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN-1st): A Multicentre, Randomised, Double-Blind, Phase 3 Trial
Lancet Oncol 2021 Jun 23;[EPub Ahead of Print], Y Yang, S Qu, J Li, C Hu, M Xu, W Li, T Zhou, L Shen, H Wu, J Lang, G Hu, Z Luo, Z Fu, S Qu, W Feng, X Chen, S Lin, W Zhang, X Li, Y Sun, Z Lin, Q Lin, F Lei, J Long, J Hong, X Huang, L Zeng, P Wang, X He, B Zhang, Q Yang, X Zhang, J Zou, W Fang, L ZhangFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
EBV-associated nasopharynx cancer is an endemic form of head and neck cancer often studied independently of other head and neck squamous cancers because of different constraints on local therapy and a higher likelihood of developing distant recurrence. Thus, although these cancers are frequently PD-L1–expressing and infiltrated by lymphocytes, they were excluded from the randomized trial that established pembrolizumab alone or in combination with chemotherapy as standard first-line therapy for metastatic head and neck squamous cell carcinoma. Activity for several PD-1 axis–directed antibodies has been demonstrated in EBV-related nasopharynx cancer, including for pembrolizumab, nivolumab, camrelizumab, and toripalimab. At ASCO 2021, the JUPITER-02 trial comparing gemcitabine/cisplatin combination with the same combination with the addition of the PD-1 inhibitor toripalimab concurrently and as maintenance was presented by Dr. Rui-Hua Xu. In this trial, the addition of toripalimab increased the response rate from 66.4% to 77.4%, improved PFS from 8 to 11.7 months, and, in preliminary survival analysis, showed a hazard for death of 0.60 with the addition of toripalimab. Yang et al conducted a very similar study with the PD-1 inhibitor camrelizumab, albeit in a population with slightly more patients with recurrent disease or ECOG PS of 1. This trial achieved very similar results to those of JUPITER-02. Here, the addition of camrelizumab improved the response rate from 80% to 87% and increased PFS from 6.9 to 10.8 months; although overall survival data were not mature, the hazard for death was 0.67 with the addition of camrelizumab. Camrelizumab has previously been associated with reactive capillary endothelial proliferation, and, although this was observed, the rate and severity of this toxicity were not increased by concomitant chemotherapy. Thus, this randomized trial of camrelizumab with gemcitabine/cisplatin chemotherapy adds to the evidence that incorporation of PD-L1 inhibition into front-line treatment of recurrent/metastatic nasopharyngeal cancer is warranted. As neither toripalimab nor camrelizumab is currently approved in the United States, oncologists should weigh with their patients the risks and benefits of moving forward with an available PD-1 inhibitor in combination with chemotherapy in this setting.