Nasopharyngeal · NPC

First phase 3 demonstration that adding concurrent cisplatin plus adjuvant PF to RT roughly doubles PFS and OS in locally advanced NPC. Trial stopped early at interim for efficacy. Recalibrated NCCN NPC standard-of-care from RT-alone to CCRT worldwide. The predominantly keratinizing North American population limited direct extrapolation to endemic Asian non-keratinizing NPC, motivating the subsequent Hong Kong and Singaporean confirmation trials.

Population: Stage III-IV (non-metastatic) NPC, North American centres (WHO any histology)

Confirmed INT-0099 findings in an endemic-area East Asian population with predominantly WHO type II/III histology. Five-year OS advantage of 18% for CCRT over RT alone established the generalisability of CCRT outside North America. Use of a lower-intensity concurrent regimen (split-course cisplatin/5-FU) rather than q3w cisplatin demonstrated that the CCRT benefit is robust to schedule variation.

Population: Stage III-IV (M0) NPC, Taiwanese population (predominantly non-keratinizing/undifferentiated WHO type II/III)

Hong Kong confirmation of INT-0099 in the largest single Asian CCRT RCT at the time (N=348). Demonstrated significant failure-free and locoregional control improvement, though overall survival at 3 years was paradoxically identical (78% both arms) — attributed to salvage effectiveness and short follow-up. The nodal-advanced eligibility criterion (N2-3) specifically targeted the highest-risk subset in endemic NPC. Follow-up data later showed OS benefit at 5 and 10 years.

Population: T1-4N2-3M0 non-keratinizing/undifferentiated NPC (advanced nodal disease), Hong Kong centres

Third regional confirmation of CCRT benefit in endemic-area NPC, demonstrating that chemoradiotherapy reduces distant metastasis risk (cumulative incidence difference 17% at 2 years, p=0.0029) in addition to improving locoregional control. Provided the strongest signal for CCRT's impact on distant control among the Asian confirmation trials, reinforcing its inclusion as the backbone for all subsequent induction-chemo addition strategies.

Population: Locally advanced NPC (all stages), National Cancer Centre Singapore; predominantly ethnic Chinese, non-keratinizing histology

Factorial design tested whether adding concurrent chemo, accelerating fractionation, or both improved outcomes in T3-4N0-1 NPC. The interaction of CRT and AF was strongly synergistic (interaction p=0.006), with the AF+C arm achieving 94% 3-year FFS. Neither AF alone nor CCRT alone significantly outperformed RT alone in this T3-4N0-1 specific population, reflecting that the CCRT benefit seen in N2-3 disease (NPC-9901) may not extrapolate directly to node-limited disease. Trial terminated early due to slow accrual.

Population: T3-4N0-1M0 NPC (locoregional advanced, node-limited disease), Hong Kong multicentre

First large-scale IMRT-era Chinese multicentre phase 3 RCT demonstrating that adding TPF induction chemotherapy to CCRT significantly improves failure-free survival in locoregionally advanced NPC. Led entirely by Sun Yat-sen University Cancer Center (PI: Ma J / Sun Y team), this trial repositioned TPF induction as a viable strategy in IMRT-based practice. Driven mainly by better distant metastasis control, consistent with the micrometastasis hypothesis. The 3-year OS result numerically favoured induction but was not powered for this endpoint.

Population: Locoregionally advanced NPC (stage III-IVB, M0) confirmed by IMRT era staging, multicentre mainland China

Established nedaplatin as a non-inferior alternative to cisplatin as the concurrent sensitiser in CCRT for NPC. Nedaplatin significantly reduced grade 3-4 nausea (2% vs 9%), vomiting (6% vs 18%), anorexia (13% vs 27%), and late auditory toxicity compared with cisplatin. This provides an evidence-based option for patients with cisplatin-related renal or auditory risk. The trial was conducted entirely at SYSU — a single-centre registration trial validating a domestic platinum compound.

Population: Stage II-IVB NPC (M0), Sun Yat-sen University Cancer Center, IMRT era

Published in NEJM, this trial demonstrated that gemcitabine-cisplatin (GP) induction chemotherapy, compared with TPF, offers a more tolerable profile (lower myelosuppression from omitting docetaxel) while achieving superior recurrence-free survival and, uniquely among NPC induction trials, a statistically significant overall survival benefit at 3 years. The GP doublet also achieved 96.7% completion rate for three induction cycles, significantly higher than historical TPF completion rates. This paper rebalanced global expert opinion toward GP as the preferred induction backbone.

Population: Locoregionally advanced NPC (stage III-IVB, M0), IMRT-era, multicentre China

The largest head-to-head RCT of cisplatin scheduling in NPC CCRT. Demonstrated that q3w high-dose cisplatin is non-inferior to weekly cisplatin for tumour control while causing significantly less acute haematological toxicity (leukopenia 16% vs 27%) and substantially less late-onset grade 3-4 hearing loss (6% vs 13%). This solidified q3w cisplatin as the dominant concurrent regimen in IMRT-era CCRT, enabling simpler outpatient delivery.

Population: Locoregionally advanced NPC (LANPC), three mainland China hospitals, 2011-2016, IMRT era

Tested whether adding the adjuvant PF component from INT-0099 to CCRT (the component often dropped in practice) provided additional benefit over CCRT alone. The answer was no — adjuvant PF did not significantly improve failure-free survival after CCRT. This was the first large Chinese RCT to formally de-escalate adjuvant chemotherapy in NPC, challenging the INT-0099 triphasic paradigm and supporting CCRT-only as an adequate locoregional treatment. The negative result catalysed the field's pivot toward alternative adjuvant strategies (metronomic, maintenance, EBV-guided).

Population: Locoregionally advanced NPC, post-CCRT, stage III-IVB M0, multicentre China (SYSU-led)

Tested the conceptually attractive hypothesis that post-RT plasma EBV DNA can identify high-risk patients for adjuvant chemotherapy. Although the EBV-DNA screening rate was high (27.4% detectable post-RT, indicating micrometastatic burden), adjuvant GC did not improve relapse-free survival in this molecularly-selected group. The trial was underpowered (only 104 randomised from 789 screened) and the choice of GC doublet as adjuvant may have been suboptimal. The negative result dampened enthusiasm for EBV-guided adjuvant escalation strategies but confirmed that post-RT EBV DNA level independently predicts all failure types.

Population: NPC stage IIB-IVB with detectable plasma EBV DNA at 6-8 weeks post-radiotherapy (high-risk residual molecular disease), Hong Kong multicentre

The ONE positive modern adjuvant trial in locoregional NPC. After a decade of negative adjuvant results (including Chen L 2012, Chan 2018), metronomic low-dose continuous capecitabine for one year significantly improved 3-year failure-free survival by ~10 percentage points and halved the risk of recurrence or death (HR 0.50). The mechanism — sustained anti-angiogenic and immunomodulatory effects of metronomic dosing rather than cytotoxic killing — differs fundamentally from conventional adjuvant PF. Grade 3 toxicity was modest (17% vs 6%), with hand-foot syndrome as the main dose-limiting event and no treatment-related deaths.

Population: High-risk locoregionally advanced NPC (stage III-IVB, excluding T3-4N0 and T3N1), post-CCRT, no progression, multicentre mainland China

Gemcitabine-cisplatin (GP) demonstrated superior PFS over the historical fluorouracil-cisplatin (PF) regimen. This established GP as the global standard first-line chemotherapy backbone for recurrent/metastatic NPC, superseding PF. All subsequent PD-1 combination trials used GP as the control arm, making this trial the foundational reference for the Chinese chemo-IO breakthrough era.

Population: Recurrent or metastatic NPC (treatment-naive for RM disease), no prior platinum-based chemotherapy for RM setting; enrolled at 22 Chinese centers

Camrelizumab (Hengrui 恒瑞 domestic Chinese anti-PD-1) plus GP significantly improved PFS over GP alone in treatment-naive RM NPC. The HR of 0.54 was consistent with the parallel JUPITER-02 trial (HR 0.52), confirming that the PD-1 + GP strategy is robust across different domestic Chinese antibodies. This is the second trial of the Chinese phase 3 triad.

Population: Treatment-naive recurrent or metastatic NPC; ECOG PS 0–1; enrolled at 29 sites in China

JUPITER-02 was the first positive phase 3 trial of chemo-IO combination versus chemo-alone in first-line recurrent/metastatic NPC worldwide. Toripalimab (Shanghai Junshi domestic Chinese anti-PD-1) plus GP produced both PFS and OS benefit. The trial led to FDA and NMPA approval of toripalimab + GP. Interim data were published in Nat Med 2021 (PMID: 34341578); final OS data in JAMA 2023 (PMID: 38015220).

Population: Treatment-naive recurrent or metastatic NPC (95% of patients enrolled from Chinese mainland, Hong Kong, Taiwan, and Singapore); ECOG PS 0–1

Tislelizumab (BeiGene 百济神州 domestic Chinese anti-PD-1) plus GP produced a near-identical PFS HR (0.52) to JUPITER-02 and CAPTAIN-1st, completing the extraordinary Chinese phase 3 triad. Three different domestic PD-1 antibodies, each added to GP, each hitting HR ~0.52 PFS improvement in the same RM NPC population. Gene expression profiling identified an activated dendritic cell signature associated with benefit.

Population: Treatment-naive recurrent or metastatic NPC (R/M NPC); ECOG PS 0–1; enrolled at multiple Chinese centers

KEYNOTE-028 established early proof-of-concept that PD-1 blockade with pembrolizumab has single-agent activity in heavily pretreated RM NPC. The 25.9% ORR in PD-L1-selected patients was promising enough to motivate the subsequent randomized KEYNOTE-122 trial. However, KEYNOTE-028 was a small, single-arm, PD-L1-selected cohort and does not constitute a definitive efficacy readout.

Population: PD-L1-positive (≥1%) recurrent or metastatic NPC previously treated with at least one prior line; 92.6% had received prior therapy for RM-NPC; 70.4% had ≥3 prior therapies

The Fang 2018 phase 1 study provided the critical early evidence for camrelizumab's activity in NPC, generating the hypothesis for CAPTAIN-1st. The 34% ORR for monotherapy in heavily pretreated patients and near-complete 91% ORR for the treatment-naive combination cohort were landmark signals from Hengrui's domestic Chinese PD-1. Camrelizumab is the specific drug — not toripalimab or tislelizumab.

Population: Two separate NPC cohorts: (1) 93 patients with recurrent/metastatic NPC receiving camrelizumab monotherapy across dose-escalation and expansion; (2) 23 treatment-naive patients receiving camrelizumab + GP combination

This Western-led NCI study demonstrated nivolumab has single-agent antitumor activity in recurrent/metastatic NPC, with a 20.5% ORR and a 1-year OS of 59% that compared favorably with historical chemotherapy data. The study noted no correlation with PD-L1 expression, but HLA class I loss was associated with better PFS — a unique biomarker finding in NPC. This trial, alongside KEYNOTE-028, defines the early Western ICI monotherapy signal in NPC.

Population: Recurrent or metastatic NPC with at least one prior line of therapy; international multicenter including Asian centers; unselected for PD-L1

POLARIS-02 was the pivotal single-arm phase 2 study that supported the NMPA approval of toripalimab in chemorefractory RM NPC. With 190 patients — the largest single-arm 2L NPC immunotherapy study — it demonstrated durable responses (median DOR 12.8 months) despite a modest ORR of 20.5%. EBV DNA ≥50% decrease at day 28 was strongly predictive of response (ORR 48.3% vs 5.7%). Toripalimab is the drug — not camrelizumab or tislelizumab.

Population: Chemorefractory recurrent or metastatic NPC; all patients had failed prior chemotherapy; 92 of 190 had failed at least two prior lines; enrolled at Chinese centers

KEYNOTE-122 was a negative phase 3 trial: pembrolizumab monotherapy did not significantly improve OS versus chemotherapy in platinum-pretreated RM NPC, despite promising earlier signals from KEYNOTE-028. The HR of 0.90 showed no meaningful difference. Grade ≥3 toxicity was substantially lower with pembrolizumab (10.3% vs 43.8%), but the primary OS endpoint was missed. This negative result is clinically crucial: it established that PD-1 monotherapy as a substitute for chemotherapy in 2L RM NPC does not work, which is why the 1L chemo-IO combination strategy was the correct approach.

Population: Platinum-pretreated recurrent or metastatic NPC; PD-L1 positive (CPS ≥1); prior platinum-based chemotherapy (most from Asian centers)

KL-A167 (Kelun-Biotech domestic Chinese anti-PD-L1 antibody) demonstrated a 26.5% ORR in platinum-pretreated RM NPC, with durable responses (median DOR 12.4 months). Baseline low EBV DNA was consistently associated with better efficacy across DCR, PFS, and OS endpoints. No treatment-related deaths occurred. These results are similar to POLARIS-02 (toripalimab, 20.5% ORR), suggesting a class effect for ICI monotherapy in 2L NPC.

Population: Previously treated recurrent or metastatic NPC; platinum-pretreated; enrolled at multiple Chinese centers; evaluated for EBV DNA biomarker correlation

The dual PD-1/CTLA-4 blockade strategy (nivolumab + ipilimumab) produced a 38% BOR in platinum-pretreated EBV-positive RM NPC — numerically higher than nivolumab monotherapy (NCI-9742: 20.5%) or pembrolizumab (KEYNOTE-028: 25.9%), though the trial did not meet its pre-planned BOR threshold. No correlation was found with PD-L1 or TMB; low baseline EBV DNA (<7800 IU/ml) trended to better outcomes. Deep immunophenotyping identified CTLA-4/PD-1 co-expressing CD8 subpopulations as potential predictive biomarkers.

Population: Recurrent or metastatic EBV-positive NPC who failed prior platinum-based chemotherapy; enrolled at Singapore center (NCCS); unselected for PD-L1 or TMB