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Clinical trial data of Anti–PD-1/PD-L1 therapy for recurrent or metastatic nasopharyngeal Carcinoma: A review

  • Douglas R. Adkins
    Correspondence
    Corresponding author at: Director, Head and Neck and Thyroid Medical Oncology, Division of Medical Oncology, Washington University School of Medicine, 660 S. Euclid, Box 8056, St. Louis, MO 63110, USA.
    Affiliations
    Division of Medical Oncology and Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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  • Robert I. Haddad
    Affiliations
    Department of Medical Oncology, Center for Head & Neck Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Open AccessPublished:June 14, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102428

      Highlights

      • Anti–PD-1 monotherapy has clinical activity in previously-treated RM-NPC.
      • Anti–PD-1 therapy provides durable clinical response in RM-NPC.
      • Anti–PD-1 therapy added to chemotherapy improves PFS in RM-NPC.
      • Anti–PD-1 therapy added to chemotherapy appears to improve OS in RM-NPC.

      Abstract

      Importance

      Anti–programmed cell death receptor-1 (PD-1) therapy is standard of care for incurable recurrent or metastatic non-nasopharyngeal head and neck cancer. In contrast, there are no regulatory agency–approved anti–PD-1 agents indicated for the treatment of recurrent or metastatic nasopharyngeal carcinomas (RM-NPC) in the Western hemisphere, and no standard treatment option exists beyond first-line chemotherapy for RM-NPC. The pace of development of novel systemic therapy regimens for RM-NPC has been slow compared to many other advanced tumor types, leaving an unmet clinical need for these patients with a poor prognosis.

      Observations

      Recent clinical trials have documented the clinical activity of anti–PD-1 therapy in RM-NPC. In particular, randomized clinical trials in the first-line setting have demonstrated significant improvements in progression-free survival (PFS) with the addition of anti–PD-1 therapy to standard chemotherapy. Whether the observed PFS benefits require combination chemoimmunotherapy or can be achieved with chemotherapy followed by crossover to immunotherapy upon progression remains unknown. Ongoing clinical trials are exploring novel anti–PD-1 therapy–based combinations, which may further solidify a role for these agents in RM-NPC.

      Conclusions and Relevance

      Among patients with RM-NPC, anti–PD-1 therapy added to first-line standard-of-care gemcitabine plus cisplatin provides significantly better efficacy outcomes compared to chemotherapy alone, and anti–PD-1 monotherapy appears to have comparable clinical activity and better tolerability than chemotherapy in previously treated disease. Thus, anti–PD-1 therapy is poised to advance standard of care for the treatment of RM-NPC.

      Keywords

      Introduction

      Nasopharyngeal carcinoma is a distinct type of head and neck cancer

      Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that differs from other head and neck cancers in terms of etiology and treatment [
      • Cohen E.E.W.
      • Bell R.B.
      • Bifulco C.B.
      • Burtness B.
      • Gillison M.L.
      • Harrington K.J.
      • et al.
      The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).
      ,
      • Wang Y.
      • Zhang Y.
      • Ma S.
      Racial differences in nasopharyngeal carcinoma in the United States.
      ]. In fact, clinical trials leading to the approval of pembrolizumab (KEYNOTE-048) and nivolumab (CheckMate 141) for the treatment of squamous cell carcinoma of the head and neck specifically excluded patients with NPC [
      • Cohen E.E.W.
      • Bell R.B.
      • Bifulco C.B.
      • Burtness B.
      • Gillison M.L.
      • Harrington K.J.
      • et al.
      The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).
      ]. NPC is commonly classified by its major histological subtypes (keratinizing squamous cell carcinoma, nonkeratinizing differentiated cell carcinoma, nonkeratinizing undifferentiated carcinoma, or other) and disease stage [
      • Wang Y.
      • Zhang Y.
      • Ma S.
      Racial differences in nasopharyngeal carcinoma in the United States.
      ,
      • Argirion I.
      • Zarins K.R.
      • Ruterbusch J.J.
      • Vatanasapt P.
      • Sriplung H.
      • Seymour E.K.
      • et al.
      Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
      ]. Nonkeratinizing NPC predominates in endemic regions including China and Southeast Asia. Epstein-Barr virus (EBV) infection is generally accepted as the primary etiologic factor in nonkeratinizing NPC, which distinguishes it from other types of head and neck cancer that have a close association with human papillomavirus (HPV) infection such as squamous cell oropharyngeal cancer [
      • Argirion I.
      • Zarins K.R.
      • Ruterbusch J.J.
      • Vatanasapt P.
      • Sriplung H.
      • Seymour E.K.
      • et al.
      Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
      ,

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ]. The keratinizing subtype of NPC is more closely associated with cigarette smoking/alcohol consumption and is observed in a higher proportion of cases in nonendemic regions including the United States and Europe [
      • Wang Y.
      • Zhang Y.
      • Ma S.
      Racial differences in nasopharyngeal carcinoma in the United States.
      ,
      • Argirion I.
      • Zarins K.R.
      • Ruterbusch J.J.
      • Vatanasapt P.
      • Sriplung H.
      • Seymour E.K.
      • et al.
      Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
      ]. Despite differences in etiology and histology, current clinical management of NPC is consistent across the histologic subtypes, with disease stage being the primary driver of treatment selection [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ].

      Current treatment landscape and unmet need

      Standard of care for non-metastatic NPC includes radiotherapy with or without chemotherapy which is associated with good outcomes in the majority of cases, although among head and neck cancers, NPC is one of the most prone to development of distant metastases [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ,

      Ayodele O, Siu LL. New drugs for recurrent or metastatic nasopharyngeal cancer. In: Vermorken JB, Budach V, Leemans CR, Machiels JP, Nicolai P, O’Sullivan B, editors. Critical issues in head and neck oncology. 10.1007/978-3-030-63234-2_23.

      ]. Patients with NPC can present with distant metastases (synchronous metastatic NPC), or more commonly, develop distant metastases following initial chemoradiotherapy (metachronous metastatic NPC) [
      • Zhang L.-L.
      • Xu F.
      • He W.-T.
      • Huang M.-Y.
      • Song D.i.
      • Li Y.-Y.
      • et al.
      Development and validation of a prognostic nomogram for the pre-treatment prediction of early metachronous metastasis in endemic nasopharyngeal carcinoma: a big data intelligence platform-based analysis.
      ]. The majority of disease recurrences/treatment failures, including development of distant metastases, occur in the early period following initial treatment (within 1–2 years) which is associated with a poor prognosis, but recurrence/failure is also commonly observed years after treatment completion [
      • Liu X.u.
      • Tang L.-L.
      • Du X.-J.
      • Li W.-F.
      • Chen L.
      • Zhou G.-Q.
      • et al.
      Changes in disease failure risk of nasopharyngeal carcinoma over time: analysis of 749 patients with long-term follow-up.
      ]. Unlike patients with early stage and locoregionally advanced NPC, those with recurrent or metastatic NPC (RM-NPC) and no surgical or radiation therapy option have limited effective treatment options and a poor prognosis [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ,

      Ayodele O, Siu LL. New drugs for recurrent or metastatic nasopharyngeal cancer. In: Vermorken JB, Budach V, Leemans CR, Machiels JP, Nicolai P, O’Sullivan B, editors. Critical issues in head and neck oncology. 10.1007/978-3-030-63234-2_23.

      ]. Current NCCN Head and Neck Cancer Clinical Practice Guidelines® recommend gemcitabine plus cisplatin (category 1 recommendation) as the preferred first-line systemic therapy for RM-NPC [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ]. Although standard-of-care (SOC) gemcitabine plus cisplatin can provide clinical benefit in RM-NPC, it is not effective in many patients or only provides short-lived benefit (per the phase 3 GEM20110714 study: objective response rate [ORR], 64%; median progression-free survival [PFS], 7.0 months; and median overall survival [OS], 22.1 months) [
      • Zhang L.i.
      • Huang Y.
      • Hong S.
      • Yang Y.
      • Yu G.
      • Jia J.
      • et al.
      Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Hong S.
      • Zhang Y.
      • Yu G.
      • Peng P.
      • Peng J.
      • Jia J.
      • et al.
      Gemcitabine plus cisplatin versus fluorouracil plus cisplatin as first-line therapy for recurrent or metastatic nasopharyngeal carcinoma: final overall survival analysis of GEM20110714 phase III study.
      ]. Accordingly, novel treatment options are needed to improve outcomes for patients with RM-NPC.
      Despite recommendations for anti–programmed cell death receptor-1 (PD-1) therapy as the preferred first-line treatment of recurrent or metastatic non-nasopharyngeal head and neck cancer, NCCN Head and Neck Cancer Clinical Practice Guidelines have historically only included anti–PD-1 monoclonal antibodies (mAbs) as subsequent-line therapy in specific situations for RM-NPC. Specifically, pembrolizumab monotherapy has been and continues to be recommended for patients with previously treated, programmed death ligand-1 (PD-L1)–positive RM-NPC and considered useful for patients with previously treated tumor mutational burden–high tumors, while nivolumab has been and continues to be recommended for patients with previously treated, nonkeratinizing RM-NPC [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ]. Only in the most recent update to the NCCN Head and Neck Cancer Clinical Practice Guidelines have anti–PD-1 mAbs been added as a component of an “other recommended regimen” for first-line therapy combined with gemcitabine plus cisplatin in patients with RM-NPC not amenable to surgery or radiotherapy [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ]. In contrast to anti–PD-1 mAbs, NCCN Head and Neck Cancer Clinical Practice Guidelines do not include anti–PD-L1 mAbs as part of any recommended regimen for RM-NPC [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ].

      Rationale for Anti–PD-1/PD-L1 therapy in RM-NPC

      NPC is commonly associated with viral infection, specifically EBV, which is capable of inducing PD-L1 expression on NPC cells [

      Ayodele O, Siu LL. New drugs for recurrent or metastatic nasopharyngeal cancer. In: Vermorken JB, Budach V, Leemans CR, Machiels JP, Nicolai P, O’Sullivan B, editors. Critical issues in head and neck oncology. 10.1007/978-3-030-63234-2_23.

      ,
      • Fang W.
      • Zhang J.
      • Hong S.
      • Zhan J.
      • Chen N.
      • Qin T.
      • et al.
      EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy.
      ]. PD-L1 expression occurs in up to 95% of NPC tumors and high expression is significantly correlated with worse disease-free survival in patients treated with conventional chemoradiotherapy [
      • Fang W.
      • Zhang J.
      • Hong S.
      • Zhan J.
      • Chen N.
      • Qin T.
      • et al.
      EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy.
      ,
      • Zhang J.
      • Fang W.
      • Qin T.
      • Yang Y.
      • Hong S.
      • Liang W.
      • et al.
      Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma.
      ]. The frequent expression of PD-L1 and its association with a negative prognosis in NPC suggests that anti–PD-1/PD-L1 therapy may be an effective approach to treatment and means of improving patient outcomes. This article provides a comprehensive review of clinical trial data for anti–PD-1/PD-L1 mAbs alone or as a component of systemic therapy for RM-NPC, the most recent of which indicate that these agents will soon become an integral component of SOC. Although anti–PD-1/PD-L1 mAbs are also being investigated in combination with radiation therapy and/or surgery in RM-NPC, the data are preliminary and beyond the scope of this review.

      Methods

      Prospective clinical trials investigating anti–PD-1 and anti–PD-L1 mAbs in patients with RM-NPC not suitable for local/regional treatment were identified via a search of PubMed and the ASCO Meeting Library website. The PubMed search was performed using the search string “(nasopharyngeal OR NPC) AND (carcinoma OR cancer) AND (PD-1 OR PD-L1 OR pembrolizumab OR nivolumab OR dostarlimab OR atezolizumab OR avelumab OR durvalumab OR toripalimab OR tislelizumab OR camrelizumab OR cemiplimab OR spartalizumab OR sintilimab OR sugemalimab OR penpulimab).” The ASCO Meeting Library website search was performed using the same search string as the PubMed search. A search of the ClinicalTrials.gov website was performed to identify planned/ongoing clinical trials with anti-PD-1/PD-L1 mAbs in RM-NPC using the advanced search function with “recurrent metastatic NPC” entered as the “Condition or disease” terms, “PD-1 OR PD-L1 OR pembrolizumab OR nivolumab OR dostarlimab OR atezolizumab OR avelumab OR durvalumab OR toripalimab OR tislelizumab OR camrelizumab OR cemiplimab OR spartalizumab OR sintilimab OR sugemalimab or penpulimab” as the “Other terms” with results limited to “Interventional Studies (Clinical Trials)” with a recruitment status of “Not yet recruiting”, “Recruiting”, “Enrolling by invitation, or “Active, not recruiting”.
      Studies comprising patients with various solid tumors were included only if the data from the RM-NPC cohort were presented distinctly. Similarly, studies that mixed first-line (i.e. untreated) and second-line plus (i.e. previously treated) patients were only included if they reported the results for these two patient groups separately. As a final validation step, we compared the prospective clinical trials identified using our search approach to those listed in the most recent prior review of anti–PD-1/PD-L1 mAbs in RM-NPC. The most recent review [
      • Johnson D.
      • Ma B.B.Y.
      Targeting the PD-1/ PD-L1 interaction in nasopharyngeal carcinoma.
      ] was identified by performing a PubMed search using the string “(PD-1 OR PD-L1) AND recurrent metastatic NPC” with results restricted to reviews, systematic reviews, and meta-analyses.

      Results

      Our search results revealed three notable observations. First, all reports of clinical trial data in RM-NPC identified using our search criteria investigated anti–PD-1 rather than anti–PD-L1 mAbs. Second, the vast majority of identified clinical trials were conducted in Asia, likely due to the substantially higher rates of disease there compared to other regions of the world, making it a conducive location to enroll NPC clinical trials. Third, only a minority of identified studies selected patients based on EBV status or probed for differential treatment effects in EBV-positive versus -negative RM-NPC subgroups.

      Second-Line plus studies of Anti–PD-1/PD-L1 therapy for RM-NPC

      Several clinical trials were identified in the search process that investigated anti–PD-1 mAb monotherapy in previously treated patients with RM-NPC. Outside of our search results, we also identified RM-NPC clinical trial results from investigations of the anti–PD-L1 mAb atezolizumab, and separately, nivolumab plus ipilimumab [
      • Shen L.
      • Zhang L.
      • Hu X.
      • Pan H.
      • Liu T.
      • Bai Y.
      • et al.
      Atezolizumab monotherapy in Chinese patients with locally advanced or metastatic solid tumours.
      ,

      Kao HF, Ang MK, Ng QS, Tan DSW, Tan W, Rajasekaran T, et al. Combination ipilimumab and nivolumab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): updated efficacy and safety analysis of NCT03097939. In: Presented at: European Society for Medical Oncology (ESMO); Sep 19-21, 2020. Abstract 266O. 10.1016/j.annonc.2020.10.260.

      ]. Efficacy results from these clinical trials are summarized in Table 1.
      Table 1Second-Line Plus Clinical Trials of Anti–PD-1/PD-L1 mAbs in Patients With RM-NPC.
      StudyYearPhaseTreatmentNORR,

      %

      (95% CI)
      Median DoR, months

      (95% CI)
      Median PFS, months

      (95% CI)
      Median OS, months

      (95% CI)
      NCT028259401320181Atezolizumab2010NANANA
      NCT027215891520181Camrelizumab9134

      (24–44)
      NR



      (NR-NR)
      6

      (2–13)
      NA



      (NA)
      KEYNOTE-02816 (NCT02054806)20171/2Pembrolizumab2726

      (11–46)
      17



      (NA)
      7

      (4–13)
      17

      (10-NR)
      CheckMate 35817 (NCT02488759)20171/2Nivolumab1916



      (3–40)
      NANANA
      CheckMate 07718 (NCT02593786)20191/2Nivolumab3213

      (4–29)
      NA



      (NA)
      4

      (2–6)
      NR



      (NA)
      CTR201608721920201/2Tislelizumab2143

      (22–66)
      8



      (NA)
      10

      (4–11)
      NR



      (9-NR)
      NCT030979391420202Nivolumab + ipilimumab4030



      (17–47)
      6



      (4–9)
      5



      (3–6)
      18



      (13–30)
      CAPTAIN20 (NCT03558191)20202Camrelizumab15628

      (21–36)
      NR



      (7-NR)
      4

      (2–4)
      17



      (15-NR)
      NCI-974221 (NCT02339558)20182Nivolumab4421

      (10–35)
      9

      (4–13)
      3

      (2–7)
      17



      (11-NR)
      POLARIS-0222 (NCT02915432)20212Toripalimab19021

      (15–27)
      13

      (9-NR)
      2

      (2–4)
      17



      (12–23)
      NCT026059672320212Spartalizumab8217

      (10–27)
      10



      (7-NR)
      2

      (2–4)
      25



      (13-NR)
      ICC4035

      (21–52)
      6

      (4–7)
      7

      (4–9)
      16



      (8–21)
      KEYNOTE-12224 (NCT02611960)20213Pembrolizumab11721

      (14–30)
      12

      (NA)
      4

      (2–6)
      17

      (12–23)
      ICC11623

      (16–32)
      13

      (NA)
      6

      (4–8)
      15

      (11–18)
      Abbreviations: DoR, duration of response; ICC, investigator’s choice of chemotherapy; mAbs, monoclonal antibodies; NA, not available; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RM-NPC, recurrent or metastatic nasopharyngeal carcinoma.
      Most trials were nonrandomized, single-arm, phase 1 or 2 clinical trials except for NCT02605967 [
      • Even C.
      • Wang H.M.
      • Li S.H.
      • Ngan R.K.C.
      • Dechaphunkul A.
      • Zhang L.
      • et al.
      Phase II, randomized study of spartalizumab (PDR001), an anti-PD-1 antibody, versus chemotherapy in patients with recurrent/metastatic nasopharyngeal cancer.
      ], which was a randomized phase 2 trial of spartalizumab vs chemotherapy, and KEYNOTE-122 [

      Chan AT, Lee VHF, Hong RL, Ahn MJ, Chong WQ, Kim SB, et al. Results of KEYNOTE-122: a phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy for platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: European Society for Medical Oncology (ESMO); September 16-21, 2021. Abstract 858O. 10.1016/j.annonc.2021.08.1268.

      ], which was a randomized phase 3 trial of pembrolizumab vs chemotherapy. Anti–PD-1/PD-L1 mAbs assessed in these trials included pembrolizumab, nivolumab, camrelizumab, spartalizumab, tislelizumab, toripalimab, and atezolizumab. Most trials enrolled patients regardless of histology, PD-L1 expression level, or EBV status, and most patients were from Southeast Asia with platinum-pretreated, EBV-related nonkeratinizing RM-NPC. Overall, the single-arm trials established the clinical activity of anti–PD-1 mAb monotherapy in patients with previously treated RM-NPC, with ORRs that ranged from 13% to 43% (Table 1). Compared to the anti–PD-1 mAb monotherapy trials, the investigation of anti–PD-L1 mAb monotherapy with atezolizumab reported a lower ORR (10%) [
      • Shen L.
      • Zhang L.
      • Hu X.
      • Pan H.
      • Liu T.
      • Bai Y.
      • et al.
      Atezolizumab monotherapy in Chinese patients with locally advanced or metastatic solid tumours.
      ], while combined blockade of PD-1 and CTLA-4 with nivolumab plus ipilimumab reported a similar ORR (30%) [

      Kao HF, Ang MK, Ng QS, Tan DSW, Tan W, Rajasekaran T, et al. Combination ipilimumab and nivolumab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): updated efficacy and safety analysis of NCT03097939. In: Presented at: European Society for Medical Oncology (ESMO); Sep 19-21, 2020. Abstract 266O. 10.1016/j.annonc.2020.10.260.

      ]. Safety was generally manageable, as rates of grade ≥ 3 treatment-related adverse events (TRAEs) were < 35% and TRAE-related discontinuation < 20%. KEYNOTE-122, the only phase 3 trial, showed that pembrolizumab monotherapy had comparable, albeit not better, efficacy as compared to chemotherapy [

      Chan AT, Lee VHF, Hong RL, Ahn MJ, Chong WQ, Kim SB, et al. Results of KEYNOTE-122: a phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy for platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: European Society for Medical Oncology (ESMO); September 16-21, 2021. Abstract 858O. 10.1016/j.annonc.2021.08.1268.

      ].

      First-Line studies of Anti–PD-1 therapy for RM-NPC

      Five clinical trials were identified in the search process that reported results for anti–PD-1 mAb therapy in previously untreated patients with RM-NPC (Table 2). All but one trial combined an anti–PD-1 mAb with gemcitabine plus cisplatin chemotherapy, and all but two were randomized phase 3 trials.
      Table 2First-Line Clinical Trials of Anti–PD-1 mAbs in Patients With RM-NPC.
      StudyYearPhaseTreatmentNORR,

      %
      Median DoR, monthsMedian PFS,

      months (95% CI)
      Median OS,

      months (95% CI)
      JUPITER-0225,26 (NCT03581786)
      Results for JUPITER-02 are from the most recent data update (prespecified final PFS analysis) [26].
      2021/

      2022
      3Toripalimab + GC



      → Toripalimab
      1467918.021.4

      (11.7-NR)
      HR, 0.52

      (0.37–0.73)
      NR

      (NR-NR)
      HR, 0.59
      OS data not mature.


      (0.37–0.94)
      Placebo + GC

      → Placebo
      143676.08.2

      (7.0–9.8)
      NR

      (NR-NR)
      CAPTAIN-1st27 (NCT03707509)20213Camrelizumab + GC

      → Camrelizumab
      134878.510.8

      (8.5–13.6)
      HR, 0.51

      (0.37–0.69)
      NRHR, 0.67
      OS data not mature.


      (0.41–1.11)
      Placebo + GC

      → Placebo
      129815.66.9

      (5.9–7.9)
      22.6

      (19.2-NR)
      RATIONALE 30928,29 (NCT03924986)
      Results for RATIONALE 309 are from the most recent data update (updated PFS analysis) [29].
      2021/

      2022
      3Tislelizumab + GC

      → Tislelizumab
      131708.59.6

      (7.6–11.7)
      HR, 0.50

      (0.37–0.68)
      NR

      (23.7-NR)
      0.60
      OS data not mature.


      (0.35–1.01)
      Placebo + GC

      → Placebo
      132556.17.4

      (5.7–7.6)
      23.0

      (19.8-NR)

      NCT031217161520181Camrelizumab + GC → Camrelizumab2291NRNRNR
      CheckMate 35817 (NCT02488759)20171/2Nivolumab540NANANA
      Abbreviations: DoR, duration of response; GC, gemcitabine plus cisplatin; HR, hazard ratio; mAbs, monoclonal antibodies; NA, not available; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RM-NPC, recurrent or metastatic nasopharyngeal carcinoma.
      a Results for JUPITER-02 are from the most recent data update (prespecified final PFS analysis)

      Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

      .
      b Results for RATIONALE 309 are from the most recent data update (updated PFS analysis)
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      .
      c OS data not mature.
      The phase 1/2 CheckMate 358 trial included 24 patients with nonkeratinizing RM-NPC, among whom five had untreated disease [

      Delord JP, Hollebecque A, De Boer JP, De Greve J, Machiels JPH, Leidner RS, et al. An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). In: Presented at: American Society of Clinical Oncology (ASCO); June 1-5, 2017. Abstract 6025. 10.1200/JCO.2017.35.15_suppl.6025.

      ]. Neither EBV status nor PD-L1 expression were used to select patients, but 88% of the overall study population were from Europe and had EBV-positive disease. This single-arm study treated patients with nivolumab (240 mg) monotherapy every 2 weeks until progression or unacceptable toxicity. ORR and safety were the primary endpoints. The ORR with nivolumab was 40% (two patients achieved a partial response), with responses reportedly observed regardless of PD-L1 or EBV status in the entire study population. Safety results were only reported for the entire study population of untreated and pretreated patients, among whom 8% experienced a grade 3 or 4 TRAE.
      The phase 1 NCT03121716 trial included Chinese patients (N = 23) with nonkeratinizing RM-NPC [
      • Fang W.
      • Yang Y.
      • Ma Y.
      • Hong S.
      • Lin L.
      • He X.
      • et al.
      Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials.
      ]. Neither histologic subtype, EBV status, nor PD-L1 expression were used to select patients. Treatment consisted of camrelizumab (200 mg) in combination with gemcitabine and cisplatin for six cycles, followed by camrelizumab maintenance. Safety was the primary endpoint; 20 patients (87%) experienced a grade ≥ 3 TRAE and two patients (9%) experienced a serious TRAE with no treatment-related deaths. The ORR with camrelizumab plus gemcitabine and cisplatin was 91%.
      The double-blinded, phase 3 JUPITER-02 trial (NCT03581786) included patients with RM-NPC from mainland China, Taiwan, and Singapore (N = 289). Patients were randomized to toripalimab (240 mg) or placebo in combination with gemcitabine plus cisplatin for up to six cycles, followed by toripalimab or placebo maintenance [
      • Mai H.Q.
      • Chen Q.Y.
      • Chen D.
      • Hu C.
      • Yang K.
      • Wen J.
      • et al.
      Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.
      ]. Crossover was not permitted. Neither histologic subtype, EBV status, nor PD-L1 expression were used to select patients, but most had nonkeratinizing RM-NPC (99%) that was PD-L1 positive (75% [≥1% of tumor cells [TC] or immune cells [IC] expressing PD-L1 by JS311 immunohistochemistry [IHC] staining]) and had a baseline serum EBV copy number ≥ 2000 (63%). The primary endpoint was blinded independent review committee–assessed PFS. At the prespecified interim analysis, significant prolongation in PFS was observed in the toripalimab group versus the placebo group (median, 11.7 vs 8.0 months; HR, 0.52 [95% CI, 0.36–0.74]) [
      • Mai H.Q.
      • Chen Q.Y.
      • Chen D.
      • Hu C.
      • Yang K.
      • Wen J.
      • et al.
      Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.
      ]. Improvement in PFS with toripalimab versus placebo was observed across all relevant subgroups, including those patients with PD-L1–positive and –negative tumors (HR, 0.59 [95% CI, 0.39–0.89] and HR, 0.35 [95% CI, 0.15–0.81], respectively), and with baseline serum EBV copy number ≥ 2000 or < 2000 (HR, 0.46 [95% CI, 0.30–0.72] and HR, 0.59 [95% CI, 0.31–1.11]) [
      • Mai H.Q.
      • Chen Q.Y.
      • Chen D.
      • Hu C.
      • Yang K.
      • Wen J.
      • et al.
      Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.
      ]. At the final PFS analysis/interim OS analysis, the toripalimab arm had a significant longer median PFS (21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37–0.73], two-sided p < 0.0001), higher 1-year PFS rate (59.0% vs 32.9%), higher ORR (78.8% vs 67.1% [p = 0.022], and longer median DOR (18.0 vs 6.0 months; HR, 0.49 [95% CI, 0.33–0.72]) (Table 2) [

      Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

      ]. Median OS had not been reached in either arm, but a trend favoring toripalimab was reported (HR, 0.59 [95% CI, 0.37–0.94]; p = 0.024). The PFS improvement with toripalimab was observed across PD-L1 expression subgroups. Notably, a dynamic decrease of plasma EBV DNA copy number from baseline was associated with a favorable response. The incidence of grade ≥ 3 TEAEs (90% vs 90%) and fatal AEs (2.7% vs 2.8%) were similar in the toripalimab and placebo arms at the final PFS analysis [

      Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

      ].
      The double-blinded, phase 3 CAPTAIN-1st trial (NCT03707509) included patients from China with RM-NPC (N = 263) [
      • Yang Y.
      • Qu S.
      • Li J.
      • Hu C.
      • Xu M.
      • Li W.
      • et al.
      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.
      ]. Neither histologic subtype, EBV status, nor PD-L1 expression were used to select patients, but most had nonkeratinizing RM-NPC (98%) and positive plasma EBV DNA results (69%). Patients were randomized to camrelizumab (200 mg) or placebo plus gemcitabine and cisplatin for four to six cycles, followed by camrelizumab or placebo maintenance. Crossover was not permitted. The primary endpoint was PFS, assessed by a blinded independent review committee. With a median follow-up of 15.6 months, the median PFS significantly favored the camrelizumab group over the placebo group (median, 10.8 vs 6.9 months; HR, 0.51 [95% CI, 0.37–0.69]) (Table 2). Prolongation of PFS with camrelizumab plus chemotherapy was present in most subgroups analyzed, including those with plasma that was either positive or negative for EBV DNA at baseline (HR, 0.45 [95% CI, 0.32–0.64] and HR, 0.57 [0.31–1.05], respectively), although PFS benefit stratified by PD-L1 expression was not reported. Among patients in the camrelizumab group, early clearance of plasma EBV DNA (from baseline to cycle 4) was associated with longer PFS compared to those who had persistently measurable EBV DNA (HR, 0.37 [95% CI, 0.22–0.63]). OS data were immature, but median OS was not reached in the camrelizumab group compared to 22.6 months in the placebo group (HR, 0.67 [95% CI, 0.41–1.11]). The ORR was 87.3% versus 80.6% and DoR was 8.5 versus 5.6 months in the camrelizumab and placebo groups, respectively. TRAEs of grade ≥ 3 occurred in 93% of patients in the camrelizumab group versus 90% in the placebo group, whereas serious TRAE rates were 36% versus 29%; the rates of study treatment discontinuation due to a TRAE were 9% versus 5%, respectively.
      The randomized, double-blind phase 3 RATIONALE 309 trial (NCT03924986) evaluated tislelizumab (200 mg) or placebo plus gemcitabine and cisplatin for four to six cycles in Asian patients with RM-NPC (N = 263) [

      Yang Y, Pan J, Wang H, Qu S, Chen N, Chen X, et al. RATIONALE 309: a randomized, global, double-blind, Phase 3 trial of tislelizumab vs placebo, plus gemcitabine + cisplatin, as 1L treatment for recurrent/metastatic nasopharyngeal cancer. In: Presented at: European Society for Medical Oncology Immuno-Oncology (ESMO-IO); December 8-11, 2021. Abstract 1210. Available at: https://oncologypro.esmo.org/meeting-resources/esmo-immuno-oncology-congress/rationale-309-a-randomized-global-double-blind-phase-3-trial-of-tislelizumab-tis-vs-placebo-plus-gemcitabine-cisplatin-gp-as-1l-treatme. Accessed April 4, 2022.

      ,
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      ]. Crossover to tislelizumab monotherapy was permitted in patients randomized to placebo plus chemotherapy following disease progression (49.2% crossover rate). The primary endpoint was PFS, assessed by a blinded independent review committee. Most patients had nonkeratinizing disease (86%), EBV DNA level ≥ 500 IU/mL (76%), and tumor cell PD-L1 expression ≥ 10% (62%). With a median follow-up of 10.0 months at the planned interim analysis, the median PFS significantly favored the tislelizumab group over the placebo group (median, 9.2 vs 7.4 months; HR, 0.52 [95% CI, 0.38–0.73]). Prolongation of PFS with tislelizumab plus chemotherapy was present in most subgroups, including those with tumor PD-L1 ≥ 10 and < 10 (HR, 0.53 [95% CI, 0.35–0.79] and HR, 0.38 [95% CI, 0.20–0.72], respectively) and with baseline serum EBV copy number ≥ 500 or < 500 (HR, 0.52 [95% CI, 0.36–0.75] and HR, 0.45 [95% CI, 0.21–0.94], respectively). OS data were immature and not reported. The ORR was 69.5% versus 55.2% and DoR was 8.5 versus 6.1 months in the tislelizumab and placebo groups, respectively. At an updated analysis with an additional 5.5 months median follow-up (15.5 months total), PFS improvement with tislelizumab plus chemotherapy persisted (median, 9.6 vs 7.4 months; HR, 0.50 [95% CI, 0.37–0.68) (Table 2) [
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      ]. Median OS had not been reached in the tislelizumab arm but was 10.3 in the placebo arm (HR, 0.60 [95% CI, 0.35–1.01]). The PFS improvement with tislelizumab also persisted across PD-L1 expression subgroups. Notably, the PFS benefit with tislelizumab was greatest in the “hot” tumor microenvironment cluster defined as the subgroup with the highest expression of immune cells, including dendritic cells. TEAEs of grade ≥ 3 occurred in 81% of patients in the tislelizumab group versus 82% in the placebo group, whereas serious TEAE rates were 28% versus 33%; the rates of study treatment discontinuation due to a TEAE were 2% versus 2%, respectively [
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      ].

      Ongoing and planned trials of Anti–PD-1/PD-L1 therapy for RM-NPC

      A search for planned and ongoing trials registered on ClinicalTrials.gov identified a number of trials beyond those identified via PubMed or the ASCO Meeting Library and already discussed in this review (Table 3). Most of the studies are being conducted in Asia and enrolling patients with previously treated RM-NPC. The majority are open to enrollment regardless of histologic subtype, EBV status, or PD-L1 expression. The most common partner agents with anti–PD-1/PD-L1 therapy are antiangiogenic therapy, chemotherapy, or PARP inhibitors. ORR is the most common primary endpoint.
      Table 3Planned/Ongoing Clinical Trials Investigating Anti–PD-1/PD-L1 mAbs in Patients With RM-NPC.
      Anti-PD-1/PD-L1

      (NCT #)
      Partner agent

      (class)
      PhaseRegimensPrimary endpointLocationPrimary completion
      Previously untreated
      Nivolumab

      (NCT04458909)
      Gemcitabine, cisplatin, carboplatin

      (chemotherapy)
      3Nivolumab + gemcitabine + cisplatin or carboplatinOSUSA, Canada, ChinaMay 2028
      Gemcitabine + cisplatin or carboplatin
      Penpulimab (NCT04974398)Gemcitabine, cisplatin

      (chemotherapy)
      3Penpulimab + gemcitabine + cisplatinPFSUSA, ChinaJuly 2023
      Placebo + gemcitabine + cisplatin
      Previously treated
      Atezolizumab (NCT05063552)Bevacizumab

      (antiangiogenic)
      2/3Atezolizumab + bevacizumab



      (±docetaxel + cisplatin/carboplatin)
      PFS, OSUSADecember 2027
      Bevacizumab + docetaxel + cisplatin/carboplatin
      Cetuximab + docetaxel + cisplatin/carboplatin
      Avelumab

      (NCT04562441)
      Axitinib

      (antiangiogenic)
      2Avelumab + axitinibORRHong KongDecember 2026
      Camrelizumab (NCT05222035)G-CSF

      (growth factor)
      2Camrelizumab + G-CSFORRChinaDecember 2022
      Camrelizumab
      Camrelizumab

      (NCT04586088)
      Apatinib

      (antiangiogenic)
      2Camrelizumab + apatinibORRChinaJanuary 2022
      Camrelizumab

      (NCT04548271)
      October 2022
      Camrelizumab

      (NCT04547088)
      October 2022
      Camrelizumab (NCT04978012)Fluzoparib

      (PARP inhibitor)
      2Camrelizumab + fluzoparibORRChinaDecember 2024
      Pembrolizumab

      (NCT04825990)
      Olaparib

      (PARP inhibitor)
      2Pembrolizumab + olaparibORRItalySeptember 2024
      Pembrolizumab (NCT03813394)Bevacizumab

      (antiangiogenic)
      1/2Pembrolizumab + bevacizumabORRSingaporeMarch 2023
      Pembrolizumab
      Pembrolizumab (NCT05166577)Nanatinostat



      (HDAC inhibitor), valganciclovir (antiviral)
      1/2Pembrolizumab + nanatinostat + valganciclovirSafety, ORRUSA, Australia, Canada, AsiaMay 2024
      Nanatinostat + valganciclovir
      SHR-1701 (NCT05020925)Famitinib

      (antiangiogenic)
      1/2SHR-1701 + famitinibORRChinaMay 2022
      SHR-1701

      (NCT04282070)
      Gemcitabine, cisplatin,

      nab-paclitaxel

      (chemotherapy)
      1SHR-1701SafetyChinaApril 2022
      SHR-1701 +

      gemcitabine + cisplatin
      SHR-1701 + nab-paclitaxel
      Sintilimab

      (NCT04945421)
      IBI310

      (immunotherapy)
      1/2Sintilimab + IBI310ORRChinaAugust 2022
      Sintilimab

      (NCT04872582)
      Bevacizumab

      (antiangiogenic)
      2Sintilimab + bevacizumabORRChinaJuly 2022
      Sintilimab

      (NCT04917770)
      Radiotherapy2Sintilimab + multimodal radiotherapyORRChinaJune 2022
      Sintilimab

      (NCT05162872)
      Niraparib

      (PARP inhibitor)
      2Sintilimab + niraparibORRChinaJune 2023
      Toripalimab

      (NCT04996758)
      Anlotinib

      (antiangiogenic)
      2Toripalimab + anlotinibORR, DCRChinaAugust 2023
      Toripalimab

      (NCT04955886)
      Surufatinib

      (antiangiogenic/immunotherapy)
      2Toripalimab + surufatinibORRChinaAugust 2022
      TQB2858

      (NCT05198531)
      Anlotinib

      (antiangiogenic),

      gemcitabine, cisplatin (chemotherapy)
      1/2TQB2858 + anlotinibSafetyChinaOctober 2022
      TQB2858 + gemcitabine + cisplatin → TQB2858 + anlotinib
      TQB2858 + gemcitabine + cisplatin + anlotinib → TQB2858 + anlotinib
      Unspecified PD-1 (NCT04350190)Apatinib

      (antiangiogenic)
      2Anti − PD-1 + apatinibORRChinaMay 2021
      Abbreviations: G-CSF, granulocyte colony-stimulating factor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RM-NPC, recurrent or metastatic nasopharyngeal carcinoma; USA, United States of America.

      Discussion

      This comprehensive review of clinical trial data demonstrates that anti–PD-1 mAbs provide meaningful clinical benefit to patients with incurable RM-NPC and are poised to become an integral component of SOC first-line therapy. The recent double-blinded, placebo-controlled phase 3 trials conducted in the first-line setting demonstrated that the addition of an anti–PD-1 mAb (toripalimab, camrelizumab, or tislelizumab) to current SOC gemcitabine plus cisplatin provided a significant improvement in PFS and preliminary indications of an improvement in OS, although the OS data remain immature [
      • Mai H.Q.
      • Chen Q.Y.
      • Chen D.
      • Hu C.
      • Yang K.
      • Wen J.
      • et al.
      Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.
      ,

      Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

      ,
      • Yang Y.
      • Qu S.
      • Li J.
      • Hu C.
      • Xu M.
      • Li W.
      • et al.
      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.
      ,

      Yang Y, Pan J, Wang H, Qu S, Chen N, Chen X, et al. RATIONALE 309: a randomized, global, double-blind, Phase 3 trial of tislelizumab vs placebo, plus gemcitabine + cisplatin, as 1L treatment for recurrent/metastatic nasopharyngeal cancer. In: Presented at: European Society for Medical Oncology Immuno-Oncology (ESMO-IO); December 8-11, 2021. Abstract 1210. Available at: https://oncologypro.esmo.org/meeting-resources/esmo-immuno-oncology-congress/rationale-309-a-randomized-global-double-blind-phase-3-trial-of-tislelizumab-tis-vs-placebo-plus-gemcitabine-cisplatin-gp-as-1l-treatme. Accessed April 4, 2022.

      ,
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      ]. Whether the observed survival benefits require combination chemoimmunotherapy or can be achieved with chemotherapy followed by crossover to immunotherapy upon progression remains unknown and seems worthy of investigation. In the second- and subsequent-line settings, phase 1 and 2 trials showed efficacy of anti–PD-1 mAb monotherapy in patients who had disease progression during or after platinum-based chemotherapy, with ORRs of 13–43% and median DoRs > 8 months [
      • Shen L.
      • Zhang L.
      • Hu X.
      • Pan H.
      • Liu T.
      • Bai Y.
      • et al.
      Atezolizumab monotherapy in Chinese patients with locally advanced or metastatic solid tumours.
      ,

      Kao HF, Ang MK, Ng QS, Tan DSW, Tan W, Rajasekaran T, et al. Combination ipilimumab and nivolumab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): updated efficacy and safety analysis of NCT03097939. In: Presented at: European Society for Medical Oncology (ESMO); Sep 19-21, 2020. Abstract 266O. 10.1016/j.annonc.2020.10.260.

      ,
      • Fang W.
      • Yang Y.
      • Ma Y.
      • Hong S.
      • Lin L.
      • He X.
      • et al.
      Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials.
      ,
      • Hsu C.
      • Lee S.-H.
      • Ejadi S.
      • Even C.
      • Cohen R.B.
      • Le Tourneau C.
      • et al.
      Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028 study.
      ,

      Delord JP, Hollebecque A, De Boer JP, De Greve J, Machiels JPH, Leidner RS, et al. An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). In: Presented at: American Society of Clinical Oncology (ASCO); June 1-5, 2017. Abstract 6025. 10.1200/JCO.2017.35.15_suppl.6025.

      ,
      • Ma Y.
      • Fang W.
      • Zhang Y.
      • Yang Y.
      • Hong S.
      • Zhao Y.
      • et al.
      A phase I/II open-label study of nivolumab in previously treated advanced or recurrent nasopharyngeal carcinoma and other solid tumors.
      ,
      • Shen L.
      • Guo J.
      • Zhang Q.
      • Pan H.
      • Yuan Y.
      • Bai Y.
      • et al.
      Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study.
      ,
      • Zhang L.
      • Yang Y.
      • Chen X.
      • Li J.
      • Pan J.
      • He X.
      • et al.
      A single-arm, open-label, multicenter phase II study of camrelizumab in patients with recurrent or metastatic nasopharyngeal carcinoma who had progressed on ≥2 lines of chemotherapy: CAPTAIN study.
      ,
      • Ma B.B.Y.
      • Lim W.T.
      • Goh B.C.
      • Hui E.P.
      • Lo K.W.
      • Pettinger A.
      • et al.
      Antitumor activity of nivolumab in recurrent and metastatic nasopharyngeal carcinoma: an international, multicenter study of the Mayo Clinic Phase 2 Consortium (NCI-9742).
      ,
      • Wang F.-H.
      • Wei X.-L.
      • Feng J.
      • Li Q.i.
      • Xu N.
      • Hu X.-C.
      • et al.
      Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02).
      ,
      • Even C.
      • Wang H.M.
      • Li S.H.
      • Ngan R.K.C.
      • Dechaphunkul A.
      • Zhang L.
      • et al.
      Phase II, randomized study of spartalizumab (PDR001), an anti-PD-1 antibody, versus chemotherapy in patients with recurrent/metastatic nasopharyngeal cancer.
      ,

      Chan AT, Lee VHF, Hong RL, Ahn MJ, Chong WQ, Kim SB, et al. Results of KEYNOTE-122: a phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy for platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: European Society for Medical Oncology (ESMO); September 16-21, 2021. Abstract 858O. 10.1016/j.annonc.2021.08.1268.

      ]. Two randomized trials (NCT02605967 [
      • Even C.
      • Wang H.M.
      • Li S.H.
      • Ngan R.K.C.
      • Dechaphunkul A.
      • Zhang L.
      • et al.
      Phase II, randomized study of spartalizumab (PDR001), an anti-PD-1 antibody, versus chemotherapy in patients with recurrent/metastatic nasopharyngeal cancer.
      ] and KEYNOTE-122 [

      Chan AT, Lee VHF, Hong RL, Ahn MJ, Chong WQ, Kim SB, et al. Results of KEYNOTE-122: a phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy for platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: European Society for Medical Oncology (ESMO); September 16-21, 2021. Abstract 858O. 10.1016/j.annonc.2021.08.1268.

      ]) conducted in patients previously treated with platinum-based chemotherapy reported similar but not better efficacy (assessed by ORR, DoR, PFS, or OS) with anti–PD-1 mAb monotherapy versus chemotherapy. However, anti–PD-1 mAb may have better tolerability, as both trials reported lower rates of grade ≥ 3 AEs and discontinuation due to AEs with anti–PD-1 mAb compared to chemotherapy.

      Applicability of data from Asia to North America and Europe

      Most patients included in the clinical trials described within this review were from Asia where the nonkeratinizing subtypes of RM-NPC related to EBV predominate. In contrast, the keratinizing subtype related to alcohol/smoking and nonkeratinizing subtypes related to EBV display a more balanced prevalence in North America and Europe [
      • Wang Y.
      • Zhang Y.
      • Ma S.
      Racial differences in nasopharyngeal carcinoma in the United States.
      ,
      • Argirion I.
      • Zarins K.R.
      • Ruterbusch J.J.
      • Vatanasapt P.
      • Sriplung H.
      • Seymour E.K.
      • et al.
      Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
      ]. In the absence of comparable clinical trials conducted in patients from North America and Europe, it is unclear how applicable the RM-NPC data described in this review from mostly endemic regions are to these nonendemic Western regions. We anticipate that the results from clinical trials conducted in Asia are applicable to non-endemic regions of the world, including the Western hemisphere, for several reasons. First, nearly half of NPC cases from North America occur in patients of Asian/Pacific Islander descent, among whom most have the nonkeratinizing subtypes [
      • Wang Y.
      • Zhang Y.
      • Ma S.
      Racial differences in nasopharyngeal carcinoma in the United States.
      ,
      • Argirion I.
      • Zarins K.R.
      • Ruterbusch J.J.
      • Vatanasapt P.
      • Sriplung H.
      • Seymour E.K.
      • et al.
      Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
      ], and similarly, findings of nonkeratinizing carcinoma being the predominant histology have been reported among white populations living in Europe [
      • Svajdler Jr, M.
      • Kaspirkova J.
      • Mezencev R.
      • Laco J.
      • Torday T.
      • Dubinsky P.
      • et al.
      Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non-endemic Eastern European population.
      ,
      • Ruuskanen M.
      • Irjala H.
      • Minn H.
      • Vahlberg T.
      • Randen-Brady R.
      • Hagström J.
      • et al.
      Epstein-Barr virus and human papillomaviruses as favorable prognostic factors in nasopharyngeal carcinoma: a nationwide study in Finland.
      ,
      • Slevin F.
      • Pan S.
      • Mistry H.
      • Sen M.
      • Foran B.
      • Slevin N.
      • et al.
      A multicentre UK study of outcomes of nasopharyngeal carcinoma treated with intensity-modulated radiotherapy ± chemotherapy.
      ]. Second, incidence of the nonkeratinizing subtype is increasing in North America [
      • Argirion I.
      • Zarins K.R.
      • Ruterbusch J.J.
      • Vatanasapt P.
      • Sriplung H.
      • Seymour E.K.
      • et al.
      Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
      ]. Third, the available efficacy data from Asia for anti–PD-1 therapy stratified by histology demonstrated their effectiveness in both nonkeratinizing and keratinizing subtypes of RM-NPC, although the number of patients with the keratinizing subtype was low [
      • Wang F.-H.
      • Wei X.-L.
      • Feng J.
      • Li Q.i.
      • Xu N.
      • Hu X.-C.
      • et al.
      Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02).
      ]. Fourth, retrospectively analyzed real-world data collected from multiple institutions in the USA reported that anti-PD-1 mAb therapy in patients with RM-NPC provided a similar degree of activity compared with that reported in prior trials conducted in Asia [

      Park JC, Wirth LJ, Clark JR, Durbeck J, Ho WJ, Boudadi K, et al. Immune checkpoint inhibitor in nasopharyngeal carcinoma: multi-institution experience. In: Presented at: American Society of Clinical Oncology (ASCO); May 29-31, 2020. Abstract 6538. 10.1200/JCO.2020.38.15_suppl.6538.

      ]. Finally, current NCCN and ESMO Practice Guideline recommendations for the treatment of RM-NPC do not differ between histologic subtypes, with the lone exception being the NCCN category 2B recommendation for nivolumab in previously treated patients with nonkeratinizing RM-NPC [

      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      ,
      • Bossi P.
      • Chan A.T.
      • Licitra L.
      • Trama A.
      • Orlandi E.
      • Hui E.P.
      • et al.
      Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ].

      Efficacy across PD-L1 expression subgroups

      Whether or not the efficacy of anti–PD-1 mAb therapy in RM-NPC varies by tumor PD-L1 expression status is an important issue to address, as it may guide treatment decisions. A 2018 meta-analysis of eight randomized trials in 4174 patients with advanced or metastatic non-NPC cancers reported a significantly prolonged OS with anti–PD-1/PD-L1 mAb monotherapy versus conventional therapy in both PD-L1–positive (HR, 0.66 [95% CI, 0.59–0.74]) and PD-L1–negative (HR, 0.80 [95% CI, 0.71–0.90]) subgroups [
      • Shen X.
      • Zhao B.
      Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.
      ]; however, the benefit was greater in patients with PD-L1–positive cancer (p = 0.02). This relationship was observed despite the use of different PD-L1 antibodies (28–8, 22C3, and SP142), IHC platforms (Dako [Carpinteria, CA], Merck & Co. Inc., [Kenilworth, NJ], Ventana Medical Systems, Inc. [Tucson, AZ]), and scoring methods (tumor cells vs tumor and immune cells).
      In RM-NPC, second- and subsequent-line trials demonstrated higher ORRs with anti–PD-1 mAb monotherapy among patients with higher tumor PD-L1 expression, including the POLARIS-02 trial of toripalimab monotherapy (ORR 27% vs 19% in PD-L1 > 1% vs ≤ 1 subsets, and 38% vs 19% in PD-L1 > 25% vs ≤ 25% subsets) [
      • Wang F.-H.
      • Wei X.-L.
      • Feng J.
      • Li Q.i.
      • Xu N.
      • Hu X.-C.
      • et al.
      Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02).
      ]. Similarly, the CTR20160872, CAPTAIN, and NCI-9742 trials of tislelizumab, camrelizumab, and nivolumab monotherapy also reported higher ORRs in patients with higher tumor PD-L1 expression (ORRs in subgroups with tumor cell PD-L1 ≥ 10% vs < 10% [tislelizumab: 50% vs 25%; camrelizumab: 35% vs 19%; nivolumab: 33% vs 17%) [
      • Shen L.
      • Guo J.
      • Zhang Q.
      • Pan H.
      • Yuan Y.
      • Bai Y.
      • et al.
      Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study.
      ,
      • Zhang L.
      • Yang Y.
      • Chen X.
      • Li J.
      • Pan J.
      • He X.
      • et al.
      A single-arm, open-label, multicenter phase II study of camrelizumab in patients with recurrent or metastatic nasopharyngeal carcinoma who had progressed on ≥2 lines of chemotherapy: CAPTAIN study.
      ,
      • Ma B.B.Y.
      • Lim W.T.
      • Goh B.C.
      • Hui E.P.
      • Lo K.W.
      • Pettinger A.
      • et al.
      Antitumor activity of nivolumab in recurrent and metastatic nasopharyngeal carcinoma: an international, multicenter study of the Mayo Clinic Phase 2 Consortium (NCI-9742).
      ]. Among the first-line phase 3 trials, the JUPITER-02 trial of toripalimab in combination with chemotherapy versus chemotherapy alone demonstrated that the prolongation of PFS with addition of toripalimab to chemotherapy occurred in both PD-L1–positive/high (TC or IC ≥ 1%: HR, 0.59 [95% CI, 0.41–0.86]; TC or IC ≥ 5: HR, 0.65 [95% CI, 0.44–0.95]) and PD-L1–negative/low subgroups (TC and IC < 1%: HR, 0.37 [95% CI, 0.17–0.80; TC and IC < 5: HR, 0.27 [95% CI, 0.13–0.58]] [

      Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

      ]. Similar findings were demonstrated in RATIONALE 309, in which prolongation of PFS with tislelizumab plus chemotherapy was observed regardless of tumor PD-L1 expression (tumor PD-L1 ≥ 1 vs < 1 and ≥ 10 and < 10) [
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      ].
      Collectively, the available data in RM-NPC suggest that anti–PD-1 therapy may provide benefit regardless of PD-L1 expression status, and PD-L1 expression status may be useful in predicting the benefit of anti–PD-1 monotherapy but not when used in combination with chemotherapy. These observations are consistent with findings from a recent meta-analysis of 15 randomized controlled trials (N = 10,074) evaluating PD-1/PD-L1 inhibitors in advanced non–small cell lung cancer; the meta-analysis concluded that PD-L1 expression may be predictive for efficacy of anti–PD-1/PD-L1 monotherapy, but was not predictive when anti–PD-1/PD-L1 therapy was used in combination with chemotherapy in the first-line setting [
      • Xu Y.
      • Wan B.
      • Chen X.i.
      • Zhan P.
      • Zhao Y.
      • Zhang T.
      • et al.
      The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials.
      ].

      Impact on current treatment landscape

      The JUPITER-02 [
      • Mai H.Q.
      • Chen Q.Y.
      • Chen D.
      • Hu C.
      • Yang K.
      • Wen J.
      • et al.
      Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.
      ,

      Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

      ], CAPTAIN-1st [
      • Yang Y.
      • Qu S.
      • Li J.
      • Hu C.
      • Xu M.
      • Li W.
      • et al.
      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.
      ], and RATIONALE 309 [

      Yang Y, Pan J, Wang H, Qu S, Chen N, Chen X, et al. RATIONALE 309: a randomized, global, double-blind, Phase 3 trial of tislelizumab vs placebo, plus gemcitabine + cisplatin, as 1L treatment for recurrent/metastatic nasopharyngeal cancer. In: Presented at: European Society for Medical Oncology Immuno-Oncology (ESMO-IO); December 8-11, 2021. Abstract 1210. Available at: https://oncologypro.esmo.org/meeting-resources/esmo-immuno-oncology-congress/rationale-309-a-randomized-global-double-blind-phase-3-trial-of-tislelizumab-tis-vs-placebo-plus-gemcitabine-cisplatin-gp-as-1l-treatme. Accessed April 4, 2022.

      ,
      • Zhang L.i.
      • Yang Y.
      • Pan J.-j.
      • Chen X.
      • Sun Y.
      • Wang H.
      • et al.
      RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
      ] phase 3 clinical trials in the first-line setting support the use of anti–PD-1 mAbs in combination with standard gemcitabine plus cisplatin chemotherapy for the clinical management of incurable RM-NPC. In the second-line setting, the phase 3 KEYNOTE-122 trial did not show an OS benefit with pembrolizumab monotherapy compared to chemotherapy [

      Chan AT, Lee VHF, Hong RL, Ahn MJ, Chong WQ, Kim SB, et al. Results of KEYNOTE-122: a phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy for platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: European Society for Medical Oncology (ESMO); September 16-21, 2021. Abstract 858O. 10.1016/j.annonc.2021.08.1268.

      ]; however, the ORR, DoR, and PFS were similar between treatment arms, with better tolerability in the pembrolizumab arm. On this basis, treatment of second-line RM-NPC with anti–PD-1 monotherapy is reasonable.

      Limitations

      There are several limitations to the current analysis. Many of the studies described in this review did not provide a comprehensive description of certain baseline population characteristics (e.g. PD-L1 expression levels, EBV status, the number of lines and types of prior therapy) and/or report efficacy results by PD-L1 expression level or EBV status. In addition, the PD-L1 assays and cutoff values differed across trials, which convolutes indirect comparison of results across trials. In the first-line setting of RM-NPC, the completed phase 3 trials continued anti–PD-1 therapy for up to 2 years after completion of chemotherapy. Maintenance chemotherapy lacks established benefit in this setting; however, future trials comparing maintenance anti–PD-1 mAb monotherapy to maintenance chemotherapy or combined maintenance with an anti–PD-1 mAb plus chemotherapy are worthy of pursuit. Furthermore, the available OS data from these phase 3 trials of first-line anti–PD-1 mAb plus chemotherapy were immature, and longer follow-up is required to confirm the effect of anti–PD-1 mAbs on OS. In the second- and subsequent-line setting of RM-NPC, the benefit of combining an anti–PD-1 mAb with chemotherapy remains unknown and is also worthy of pursuit.

      Conclusion

      As first-line therapy for incurable RM-NPC, anti–PD-1 therapy significantly improved efficacy outcomes when added to SOC gemcitabine plus cisplatin chemotherapy. Whether these benefits require combination chemoimmunotherapy or can be achieved with chemotherapy followed by crossover to immunotherapy upon progression remains unknown. In previously treated RM-NPC, anti–PD-1 monotherapy appears to yield efficacy comparable to chemotherapy with greater tolerability. Thus, anti–PD-1 mAbs are poised to advance the SOC for RM-NPC. In 2021, both toripalimab and camrelizumab were approved by the National Medical Products Administration in China as first- and third-line treatment of RM-NPC [

      Junshi Biosciences. Junshi Biosciences announces approval of supplemental new drug application by NMPA for toripalimab in combination with cisplatin and gemcitabine as first-line treatment for patients with locally recurrent or metastatic nasopharyngeal carcinoma [press release]. Published November 29, 2021. Available at: https://www.globenewswire.com/news-release/2021/11/30/2342602/0/en/Junshi-Biosciences-Announces-Approval-of-Supplemental-New-Drug-Application-by-NMPA-for-Toripalimab-in-Combination-with-Cisplatin-and-Gemcitabine-as-First-Line-Treatment-for-Patient.html. Accessed April 4, 2022.

      ,

      Hengrui. NMPA approves a new indication of camrelizumab: combined with chemotherapy as 1L treatment for NPC [press release]. Published June 17, 2021. Available at: https://www.hengrui.com/en/media/detail-27.html. Accessed April 4, 2022.

      ]. At this time, no anti–PD-1 mAb has a regulatory agency–approved indication for RM-NPC in the Western hemisphere; however, we anticipate that anti–PD-1 mAbs will become a mainstay in the management of these patients.

      CRediT authorship contribution statement

      Douglas R. Adkins: Conceptualization, Writing – original draft, Writing – review & editing. Robert I. Haddad: Writing – original draft, Writing – review & editing.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [D. R. Adkins has received research support from Pfizer, Lilly, Merck, Celgene/Bristol Myers Squibb, Novartis, AstraZeneca, Blueprint, Celldex, Enzychem, Exelixis, Innate Pharma, Sensei Biotherapeutics, Cue Biopharma, Kura, and Oncolys; and consulting fees from Coherus BioSciences, Lilly, Merck, Blueprint, Cue Biopharma, Kura, twoXAR, Vaccinex, Oncolys, and Xilio. R. I. Haddad has received grant support and personal fees from Merck, Bristol Myers Squibb, Pfizer, GlaxoSmithKline, Merck Serono, Eisai, Bayer, AstraZeneca, Kura, NCCN, Nanobiotix, ISA Therapeutics, and Mirati; and consulting fees from Coherus BioSciences.].

      Acknowledgement

      Medical writing and editorial support were provided by Joshua R. Rodman, PhD, and Brittany B. Carson, PhD, of MEDiSTRAVA Consulting and funded by Coherus Biosciences, Inc.

      Funding

      This work was supported by Coherus BioSciences, Inc.

      Role of the Funder

      The funder of this work was responsible for its conception and provided critical revision of the initial draft.

      References

        • Cohen E.E.W.
        • Bell R.B.
        • Bifulco C.B.
        • Burtness B.
        • Gillison M.L.
        • Harrington K.J.
        • et al.
        The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).
        J Immunother Cancer. 2019; 7https://doi.org/10.1186/s40425-019-0662-5
        • Wang Y.
        • Zhang Y.
        • Ma S.
        Racial differences in nasopharyngeal carcinoma in the United States.
        Cancer Epidemiol. 2013; 37: 793-802https://doi.org/10.1016/j.canep.2013.08.008
        • Argirion I.
        • Zarins K.R.
        • Ruterbusch J.J.
        • Vatanasapt P.
        • Sriplung H.
        • Seymour E.K.
        • et al.
        Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.
        Cancer. 2020; 126: 121-130
      1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and Neck Cancers Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437. Accessed April 4, 2022.

      2. Ayodele O, Siu LL. New drugs for recurrent or metastatic nasopharyngeal cancer. In: Vermorken JB, Budach V, Leemans CR, Machiels JP, Nicolai P, O’Sullivan B, editors. Critical issues in head and neck oncology. 10.1007/978-3-030-63234-2_23.

        • Zhang L.-L.
        • Xu F.
        • He W.-T.
        • Huang M.-Y.
        • Song D.i.
        • Li Y.-Y.
        • et al.
        Development and validation of a prognostic nomogram for the pre-treatment prediction of early metachronous metastasis in endemic nasopharyngeal carcinoma: a big data intelligence platform-based analysis.
        Ther Adv Med Oncol. 2020; 12https://doi.org/10.1177/1758835920978132
        • Liu X.u.
        • Tang L.-L.
        • Du X.-J.
        • Li W.-F.
        • Chen L.
        • Zhou G.-Q.
        • et al.
        Changes in disease failure risk of nasopharyngeal carcinoma over time: analysis of 749 patients with long-term follow-up.
        J Cancer. 2017; 8: 455-459
        • Zhang L.i.
        • Huang Y.
        • Hong S.
        • Yang Y.
        • Yu G.
        • Jia J.
        • et al.
        Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.
        Lancet. 2016; 388: 1883-1892
        • Hong S.
        • Zhang Y.
        • Yu G.
        • Peng P.
        • Peng J.
        • Jia J.
        • et al.
        Gemcitabine plus cisplatin versus fluorouracil plus cisplatin as first-line therapy for recurrent or metastatic nasopharyngeal carcinoma: final overall survival analysis of GEM20110714 phase III study.
        J Clin Oncol. 2021; 39: 3273-3282
        • Fang W.
        • Zhang J.
        • Hong S.
        • Zhan J.
        • Chen N.
        • Qin T.
        • et al.
        EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy.
        Oncotarget. 2014; 5: 12189-12202
        • Zhang J.
        • Fang W.
        • Qin T.
        • Yang Y.
        • Hong S.
        • Liang W.
        • et al.
        Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma.
        Med Oncol. 2015; 32https://doi.org/10.1007/s12032-015-0501-6
        • Johnson D.
        • Ma B.B.Y.
        Targeting the PD-1/ PD-L1 interaction in nasopharyngeal carcinoma.
        Oral Oncol. 2021; 113105127https://doi.org/10.1016/j.oraloncology.2020.105127
        • Shen L.
        • Zhang L.
        • Hu X.
        • Pan H.
        • Liu T.
        • Bai Y.
        • et al.
        Atezolizumab monotherapy in Chinese patients with locally advanced or metastatic solid tumours.
        Ann Oncol. 2018; 29
      3. Kao HF, Ang MK, Ng QS, Tan DSW, Tan W, Rajasekaran T, et al. Combination ipilimumab and nivolumab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): updated efficacy and safety analysis of NCT03097939. In: Presented at: European Society for Medical Oncology (ESMO); Sep 19-21, 2020. Abstract 266O. 10.1016/j.annonc.2020.10.260.

        • Fang W.
        • Yang Y.
        • Ma Y.
        • Hong S.
        • Lin L.
        • He X.
        • et al.
        Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials.
        Lancet Oncol. 2018; 19: 1338-1350
        • Hsu C.
        • Lee S.-H.
        • Ejadi S.
        • Even C.
        • Cohen R.B.
        • Le Tourneau C.
        • et al.
        Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028 study.
        J Clin Oncol. 2017; 35: 4050-4056
      4. Delord JP, Hollebecque A, De Boer JP, De Greve J, Machiels JPH, Leidner RS, et al. An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). In: Presented at: American Society of Clinical Oncology (ASCO); June 1-5, 2017. Abstract 6025. 10.1200/JCO.2017.35.15_suppl.6025.

        • Ma Y.
        • Fang W.
        • Zhang Y.
        • Yang Y.
        • Hong S.
        • Zhao Y.
        • et al.
        A phase I/II open-label study of nivolumab in previously treated advanced or recurrent nasopharyngeal carcinoma and other solid tumors.
        Oncologist. 2019; 24: 891-e431
        • Shen L.
        • Guo J.
        • Zhang Q.
        • Pan H.
        • Yuan Y.
        • Bai Y.
        • et al.
        Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study.
        J Immunother Cancer. 2020; 8https://doi.org/10.1136/jitc-2019-000437
        • Zhang L.
        • Yang Y.
        • Chen X.
        • Li J.
        • Pan J.
        • He X.
        • et al.
        A single-arm, open-label, multicenter phase II study of camrelizumab in patients with recurrent or metastatic nasopharyngeal carcinoma who had progressed on ≥2 lines of chemotherapy: CAPTAIN study.
        Ann Oncol. 2020; 31 (Abstract 912): S599-S628https://doi.org/10.1016/j.annonc.2020.08.1027
        • Ma B.B.Y.
        • Lim W.T.
        • Goh B.C.
        • Hui E.P.
        • Lo K.W.
        • Pettinger A.
        • et al.
        Antitumor activity of nivolumab in recurrent and metastatic nasopharyngeal carcinoma: an international, multicenter study of the Mayo Clinic Phase 2 Consortium (NCI-9742).
        J Clin Oncol. 2018; 36: 1412-1418https://doi.org/10.1200/JCO.2017.77.0388
        • Wang F.-H.
        • Wei X.-L.
        • Feng J.
        • Li Q.i.
        • Xu N.
        • Hu X.-C.
        • et al.
        Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02).
        J Clin Oncol. 2021; 39: 704-712
        • Even C.
        • Wang H.M.
        • Li S.H.
        • Ngan R.K.C.
        • Dechaphunkul A.
        • Zhang L.
        • et al.
        Phase II, randomized study of spartalizumab (PDR001), an anti-PD-1 antibody, versus chemotherapy in patients with recurrent/metastatic nasopharyngeal cancer.
        Clin Cancer Res. 2021; 27: 6413-6423https://doi.org/10.1158/1078-0432.CCR-21-0822
      5. Chan AT, Lee VHF, Hong RL, Ahn MJ, Chong WQ, Kim SB, et al. Results of KEYNOTE-122: a phase III study of pembrolizumab (pembro) monotherapy vs chemotherapy for platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: European Society for Medical Oncology (ESMO); September 16-21, 2021. Abstract 858O. 10.1016/j.annonc.2021.08.1268.

        • Mai H.Q.
        • Chen Q.Y.
        • Chen D.
        • Hu C.
        • Yang K.
        • Wen J.
        • et al.
        Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.
        Nat Med. 2021; 27: 1536-1543https://doi.org/10.1038/s41591-021-01444-0
      6. Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. In: Presented at: American Association for Cancer Research (AACR); April 8-13, 2022. Abstract 7448. Available at: https://www.abstractsonline.com/pp8/#!/10517/presentation/20289. Accessed April 4, 2022.

        • Yang Y.
        • Qu S.
        • Li J.
        • Hu C.
        • Xu M.
        • Li W.
        • et al.
        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; 22: 1162-1174
      7. Yang Y, Pan J, Wang H, Qu S, Chen N, Chen X, et al. RATIONALE 309: a randomized, global, double-blind, Phase 3 trial of tislelizumab vs placebo, plus gemcitabine + cisplatin, as 1L treatment for recurrent/metastatic nasopharyngeal cancer. In: Presented at: European Society for Medical Oncology Immuno-Oncology (ESMO-IO); December 8-11, 2021. Abstract 1210. Available at: https://oncologypro.esmo.org/meeting-resources/esmo-immuno-oncology-congress/rationale-309-a-randomized-global-double-blind-phase-3-trial-of-tislelizumab-tis-vs-placebo-plus-gemcitabine-cisplatin-gp-as-1l-treatme. Accessed April 4, 2022.

        • Zhang L.i.
        • Yang Y.
        • Pan J.-j.
        • Chen X.
        • Sun Y.
        • Wang H.
        • et al.
        RATIONALE-309: Updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/metastatic nasopharyngeal cancer.
        JCO. 2022; 40
        • Svajdler Jr, M.
        • Kaspirkova J.
        • Mezencev R.
        • Laco J.
        • Torday T.
        • Dubinsky P.
        • et al.
        Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non-endemic Eastern European population.
        Neoplasma. 2016; 63: 107-114https://doi.org/10.4149/neo_2016_013
        • Ruuskanen M.
        • Irjala H.
        • Minn H.
        • Vahlberg T.
        • Randen-Brady R.
        • Hagström J.
        • et al.
        Epstein-Barr virus and human papillomaviruses as favorable prognostic factors in nasopharyngeal carcinoma: a nationwide study in Finland.
        Head Neck. 2019; 41: 349-357https://doi.org/10.1002/hed.25450
        • Slevin F.
        • Pan S.
        • Mistry H.
        • Sen M.
        • Foran B.
        • Slevin N.
        • et al.
        A multicentre UK study of outcomes of nasopharyngeal carcinoma treated with intensity-modulated radiotherapy ± chemotherapy.
        Clin Oncol (R Coll Radiol). 2020; 32: 238-249
      8. Park JC, Wirth LJ, Clark JR, Durbeck J, Ho WJ, Boudadi K, et al. Immune checkpoint inhibitor in nasopharyngeal carcinoma: multi-institution experience. In: Presented at: American Society of Clinical Oncology (ASCO); May 29-31, 2020. Abstract 6538. 10.1200/JCO.2020.38.15_suppl.6538.

        • Bossi P.
        • Chan A.T.
        • Licitra L.
        • Trama A.
        • Orlandi E.
        • Hui E.P.
        • et al.
        Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2021; 32: 452-465
        • Shen X.
        • Zhao B.
        Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.
        BMJ. 2018; 362k3529https://doi.org/10.1136/bmj.k3529
        • Xu Y.
        • Wan B.
        • Chen X.i.
        • Zhan P.
        • Zhao Y.
        • Zhang T.
        • et al.
        The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials.
        Transl Lung Cancer Res. 2019; 8: 413-428
      9. Junshi Biosciences. Junshi Biosciences announces approval of supplemental new drug application by NMPA for toripalimab in combination with cisplatin and gemcitabine as first-line treatment for patients with locally recurrent or metastatic nasopharyngeal carcinoma [press release]. Published November 29, 2021. Available at: https://www.globenewswire.com/news-release/2021/11/30/2342602/0/en/Junshi-Biosciences-Announces-Approval-of-Supplemental-New-Drug-Application-by-NMPA-for-Toripalimab-in-Combination-with-Cisplatin-and-Gemcitabine-as-First-Line-Treatment-for-Patient.html. Accessed April 4, 2022.

      10. Hengrui. NMPA approves a new indication of camrelizumab: combined with chemotherapy as 1L treatment for NPC [press release]. Published June 17, 2021. Available at: https://www.hengrui.com/en/media/detail-27.html. Accessed April 4, 2022.