Introduction
Tumor biology
Molecular and immunohistochemistry
Next generation sequencing
Somatostatin receptor 2 by IHC
Programmed cell death protein 1 and tumor infiltrating lymphocytes by IHC
Treatment
Chemotherapy
Metastatic and recurrent disease
Trial/author | Regimens studied | n | EBV status | ORR (%) | PFS | OS |
---|---|---|---|---|---|---|
Combined chemotherapy | ||||||
Hong, et al., 2021 [47] | Gemcitabine-cisplatin vs 5FU-cisplatin | 362 | Optional: GP: 8 EBV-, 13 EBV+. FP:1 EBV-, 6 EBV +. | N/A | 7.6% vs 0% (5-year PFS) | 22.1 vs 18.6 months |
Zhang et al., 2016 [46] | Gemcitabine-cisplatin vs 5FU-cisplatin | 362 | Optional (not reported) | 64% vs 42% | 7.0 vs 5.6 months | 29.1 vs 20.9 months |
Chen et al., 2013 [45] | Cisplatin-paclitaxel-5FU | 95 | N/A | 78.9% | 8.6 months | 22.7 months |
Jin et al., 2012 [49] | Cisplatin-5FU vs paclitaxel-cisplatin vs gemcitabine-cisplatin vs paclitaxel-cisplatin-5FU vs bleomycin-cisplatin-5FU | 822 | EBV -: 212 EBV +: 576 | 60.2% vs 61.7% vs 71.1% vs 69.1% vs 74.0% | 5.0 vs 5.5 vs 6.6 vs 5.5 vs 6.0 months | 19.5 vs 21.0 vs 21.5 vs 19.0 vs 21.0 |
Tan et al., 1999 [52] | Paclitaxel-carboplatin | 32 | N/A | 75% | 7.0 months | 12.0 months |
Yeo et al., 1998 [51] | Paclitaxel-carboplatin | 27 | N/A | 59% | 5.9 months | 13.9 months |
Second line chemotherapy | ||||||
Chan et al., 2005 [54] | Carboplatin-cetuximab (second line) | 60 | N/A | 11.7% | 81 days | 233 days |
Chua et al., 2000 [61] | Ifosfamide-5FU-leucovorin (second line) | 18 | N/A | 56% | 6.5 months | 51% [1-year survival] |
Single-agent chemotherapy | ||||||
Ngeow et al., 2011 [58] | Docetaxel | 30 | N/A | 36.7% | 5.3 months | 12.8 months |
Ciuleanu et al., 2008 [56] | Capecitabine | 23 | N/A | 48% | 15 months | 62% [1-year survival] |
Poon et al., 2005 [57] | Irinotecan | 28 | N/A | 14% | 3.9 months | 11.4 months |
Chua et al.,2003 [55] | Capecitabine | 17 | N/A | 23.5% | 4.9 months | 7.6 months |
Foo et al., 2002 [60] | Gemcitabine: chemo-naïve vs previously treated | 52 | N/A | 28% vs 48% | 3.6 vs 5.1 months | 7.2 vs 10.5 months |
Au et al., 1998 [59] | Paclitaxel | 24 | N/A | 21.7% | 2.5 months | 12 months |
Maintenance Chemotherapy | ||||||
Liu et al., 2022 [53] | Maintenance capecitabine vs best supportive care | 104 | N/A | 25% vs 11.5% | 35.9 vs 8.2 months | N/A |
Oligometastatic disease
Targeted and immunotherapy
Immune checkpoint inhibitors
Molecular therapy
Therapies targeting Epstein-Barr virus
Trial | Disease setting | Therapy studied | n | ORR | PFS | OS |
---|---|---|---|---|---|---|
Immune therapies | ||||||
Immune checkpoint inhibitors combination | ||||||
RATIONALE-309 Zhang L, et al., 2022. [74] | 1st line treatment. | Tislelizumab + gemcitabine + cisplatin vs Placebo + gemcitabine + cisplatin | 263 | N/A | 9.4 months vs 7.4 months | Not reached vs 23.0 months |
CAPTAIN-1st Yang Y, et al., 2021. [73] | 1st line treatment. | Cambrelizumab + gemcitabine + cisplatin vs Placebo + gemcitabine + cisplatin | 263 | 87.3% vs 80.6% | 9.7 months vs 6.9 months | Not reached vs 22.6 months |
JUPITER-02 Mai HQ, et al., 2021. [72] | 1st line treatment. | Toripalimab + gemcitabine + cisplatin vs Placebo + gemcitabine + cisplatin | 289 | 77.4% vs 66.4% | 11.7 months vs 8.0 months | 1-year: 91.6% vs 87.1% 2-year: 77.8% vs 63.3% |
Fang W, et al., 2018. [80] | 1st line treatment. | Camrelizumab + gemcitabine | 23 | 91% | 6 months: 86.4% 12 months: 61.4% | N/A |
Immune checkpoint inhibitors monotherapy | ||||||
KEYNOTE-122 Chan ATC, et al., 2021. [76] | Chemotherapy resistant. | Pembrolizumab vs Oncologist´s choice chemotherapy | 233 | 21.4% vs 23.3% | 4.1 months vs 5.5 months | 17.2 months vs 15.3 months |
POLARIS-02 Wang FH, et al., 2021. [79] | Chemotherapy resistant. | Toripalimab | 190 | 20.5% | 1.9 months | 17.4 months |
CAPTAIN Yang Y, et al., 2021. [81] | Chemotherapy resistant. | Camrelizumab | 156 | 28.2% | 3.7 months | 17.4 months |
Even C, et al., 2021. (129) | Chemotherapy resistant. | Spartalizumab vs Oncologist´s choice chemotherapy | 122 | 17.1% vs 35.0% | 1.9 months vs 6.6 months | 25.2 months vs 15.5 months |
AK105-202 Chen X, et al., 2020. (130) | Chemotherapy resistant. | Penpulimab | 130 | 27.0% | 3.7 months | 18.6 months |
Lim D, et al., 2019. [82] | Chemotherapy resistant. | Spartalizumab vs Oncologist´s choice chemotherapy | 113 | 18.4% vs 32.4% | 1.9 months vs 6.6 months | N/A |
Wang S, et al., 2019. (131) | Chemotherapy resistant. | Tislelizumab | 21 | 43% | 4.0 months | 1-year: 60% |
NCI-9742 Ma BBY, et al., 2018. [77] | Chemotherapy resistant. | Nivolumab | 44 | 20.5% | 1-year: 19.3% | 1-year: 59% |
Fang W, et al., 2018. [80] | Chemotherapy resistant. | Camrelizumab | 93 | 34% | 5.6 months | N/A |
Shen L, et al., 2018. (132) | Chemotherapy resistant. | Atezolizumab | 20 | 10% | N/A | N/A |
KEYNOTE-028 Chiun Hsu, et al., 2017. [43] | Chemotherapy resistant with PD-L1 >1%. | Pembrolizumab | 27 | 25.9% | 6 months: 50% 12 months: 33.4% | 6 months: 85.2% 12 months: 63.0% |
CheckMate-358 Delord JP, et al., 2017. [78] | ≤ 2 prior systemic therapies. | Nivolumab | 24 | 20.8% | 2.4 months | Not reached |
CTLs and TILs | ||||||
VANCE Toh HC, et al., 2022. [109] | 1st line treatment EBV +. | Carboplatin-gemcitabine + Autologous EBV-specific CTLs vs carboplatin-gemcitabine | 330 | 61.0% vs 63.3% | 7.9 months vs 8.5 months | 25 months vs 24.9 months |
Walsh RJ, et al., 2020. [117] | Chemotherapy resistant. | Autologous CD137L-dendrtici cell with EBV (LMP1/LMP2) vaccine. (CD137L-DC-EBV-VAX) | 14 | 8.3% | 26 weeks | N/A |
Huang J, et al., 2017. [107] | Chemotherapy resistant EBV + | Autologous EBV-specific CTLs | 28 | 4.8% | 2.2 months | 16.7 months |
Chia WK, et al., 2013. [108] | 1st line treatment EBV +. | Cisplatin-gemcitabine + Autologous EBV-specific CTLs | 38 | 71.4% | 7.6 months | 29.9 months |
Secondino S, et al., 2012. (133) | Chemotherapy resistant EBV +. | Autologous EBV-specific CTLs | 11 | 18.18% | N/A | N/A |
Louis CU, et al., 2010. [106] | Chemotherapy resistant EBV+ | Autologous EBV-specific CTLs | 23 | 48.7% | 1-year: 65% 2-years: 52% | 1-year: 87% 2-years: 70% |
Straathof KCM, et al., 2005. [104] | Remission or chemotherapy resistant EBV+ | Autologous EBV-specific CTLs | 10 | 30% | N/A | N/A |
Comoli P, et al., 2005. [105] | Chemotherapy resistant EBV+ | Autologous EBV-specific CTLs | 10 | 20% | N/A | N/A |
Vaccines | ||||||
Chia WK, et al., 2012. [115] | Chemotherapy resistant. | Adenovirus vaccine (Ad-LMP1-LMP2) | 16 | 6.25% | 1.92 months | 6.0 months |
Lin CL, et al., 2002. [111] | Chemotherapy resistant. | Autologous dendritic cells vaccine with HLA epitopes LMP2 | 16 | 12.5% | N/A | N/A |
Oncolytic viruses | ||||||
Smith C, et al., 2017. (128) | Active R/M disease and minimal residual disease | Adenoviral vector (AdE1-LMPpoly)-based CTLs | 29 | 0% | 5.5 months | 38.1 months |
Xia ZJ, et al., 2004. [125] | Chemotherapy resistant. | Intratumoral adenovirus vaccine (H101) + cisplatin + 5FU or adriamycin + 5FU vs cisplatin + 5FU or adriamyacin + 5FU | 123 | 78.8% vs 39.6% | N/A | N/A |
Targeted therapy | ||||||
EGFR inhibitors | ||||||
You B, et al., 2012. [11] | Maintenance therapy postchemotherapy | Erlotinib maintenance postgemcitabine-platinum | 20 | 0% | 6.9 months | 12 months: 80% |
Chua DTT, et al., 2008. [91] | Chemotherapy resistant. | Gefitinib | 19 | 0% | 4 months | 16 months |
Ma B, et al., 2008. [92] | Chemotherapy resistant. | Gefitinib | 16 | 0% | 2.7 months (mean) | 12 months (mean) |
Chan ATC, et al., 2005. [54] | Chemotherapy resistant EGFR+. | Cetuximab + carboplatin | 60 | 11.7% | 81 days | 233 days |
VEGFR inhibitors | ||||||
Li L, et al., 2020. [102] | Chemotherapy resistant. | Apatinib | 51 | 31.37% | 9 months | 16 months |
Jiang W, et al., 2019. (134) | Chemotherapy resistant. | Apatinib | 33 | 36.3% | 5.0 months | 1-year: 83.1% |
Hui EP, et al., 2018. [101] | Chemotherapy resistant. | Axitinib | 40 | 2.7% (confirmed) 18.9% (unconfirmed) | 5.0 months | 10.4 months |
Jin T, et al., 2018. (135) | 1st line treatment. | Endostar + cisplatin + gemcitabine | 72 | 77.8% | 12 months | 19.5 months |
Huang Y, et al., 2013. (136) | Chemotherapy resistant. | Famitinib | 58 | 8.6% | 3.2 months | N/A |
Jin T, et al., 2013. (137) | 1st line treatment. | Endostar + cisplatin + gemcitabine | 30 | 85.7% | 19.2 months | 1-year: 90.2% |
Xue C, et al., 2012. [98] | 1st line treatment. | Sorafenib + cisplatin + 5FU | 54 | 77.8% | 7.2 months | 11.8 months |
Lim WT, et al., 2011. [99] | Chemotherapy resistant. | Pazopanib | 33 | 6.1% | 4.4 months | 10.8 months |
Hui EP, et al., 2011. [100] | Chemotherapy resistant. | Sunitinib | 13 | 7.1% | 3.5 months | 10.5 months |
Elser C, et al., 2007. [97] | ≤ 1 prior chemotherapy | Sorafenib | 27 | 3.7% | 1.8 months | 4.2 months |
Ongoing phase 2/3 clinical trials
NCT ID | Phase | Viral status | Purpose/primary objective | Targets | Primary outcome | |
---|---|---|---|---|---|---|
First-line treatment | ||||||
NCT03097939 (recruiting) | II | EBV positive | Evaluate the impact in overall response rate that nivolumab + ipilimumab has in EBV + NPC. | PD-1 CTLA-4 | Overall Response Rate | |
NCT04974398 (recruiting) | III | EBV positive | Evaluate the efficacy and safety of penpulimab + cisplatin + gemcitabine as first-line treatment. | PD-1 | Progression free survival. | |
NCT05162872 (recruiting) | II | Not specified | Efficacy and safety of niraparib + sintilimab in first-line or recurrent scenarios. | PARP PD-1 | Overall Response Rate | |
NCT04458909 (active not recruiting) | III | Not specified | Compare efficacy and safety of adding nivolumab to standard chemotherapy. | PD-1 | Overall survival | |
NCT05385926 (recruiting) | II | Not specified | Safety and efficacy of first-line cisplatin-gemcitabine + toripalimab combined with radiotherapy. | PD-1 | Progression free survival | |
Second or more lines of treatment | ||||||
NCT03422536 (completed awaiting results) | II | EBV negative | To assess the efficacy of ficlatuzumab, with or without concurrent cetuximab in cetuximab-resistant patients. | c-MET EGFR | Progression free survival | |
NCT03915678 (recruiting) | II | EBV positive | Assess the effects of atezolizumab + BDB001 + radiotherapy in multiple solid tumors, including viral associated tumors (e.g., NPC EBV +). | PD-L1 TLR-7 | Disease control rate. | |
NCT03357757 (recruiting) | II | EBV positive | Evaluate the feasibility and efficacy of valproic acid combined with avelumab for the treatment of virus associated cancers. | GABAr PD-L1 | Clinical response rate. | |
NCT04825990 (recruiting) | II | EBV positive | Evaluate the efficacy and safety of pembrolizumab + olaparib in platinum resistant scenarios. | PD-L1 PARP | Overall Response Rate | |
NCT05166577 (recruiting) | II | EBV positive | Evaluate the safety and efficacy of nanatinostat + valganciclovir with or without pembrolizumab. | HDAC DNA pol PD-L1 | Overall Response Rate | |
NCT04396886 (active not recruiting) | II | EBV positive | Evaluate the efficacy and safety of bintrafusp alfa in previously treated non-keratinizing NPC patients. | PD-L1/TGFβ | Objective tumor response | |
NCT04996758 (recruiting) | II | Not specified | Evaluate efficacy and safety of toripalimab + anlotinib in patients with recurrent or metastatic disease after failure of ≥ 1 platinum-based chemotherapy. | PD-1 TKI (VEGFR, FGFR, PDGFR) | Overall Response Rate and Disease Control Rate | |
NCT04978012 (recruiting) | II | Not specified | Evaluate the efficacy and safety of fluzoparib + camrelizumab. | PARP PD-1 | Overall Response Rate | |
NCT04872582 (active not recruiting) | II | Not specified | Evaluate the efficacy and safety of PD-1 inhibitors + bevacizumab after failure of first-line chemotherapy. | PD-1 VEGFR | Overall Response Rate | |
Other agents / combinations with future potential impact | ||||||
Drug | Target | |||||
Triprilimab | PD-1 | |||||
Camrelizumab | PD-1 | |||||
Surufatinib | VEGFR, FGFR1, CSF-1R | |||||
Apatinib | VEGFR | |||||
Bevacizumab + cetuximab | VEGFR EGFR | |||||
Camrelizumab + apatinib | PD-1, VEGFR | |||||
Triprilimab + surufatinib | VEGFR, FGFR1, CSF-1R |