Adjuvant Sintilimab Plus Capecitabine Fails to Improve PFS Over Capecitabine Alone in Suboptimal-Response Locoregionally Advanced NPC

Intensifying adjuvant therapy with the addition of sintilimab (Tyvyt) to capecitabine did not significantly improve 2-year progression-free survival (PFS) outcomes compared with adjuvant capecitabine alone in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) who had a suboptimal response to cisplatin-based induction chemotherapy, according to results from a phase 2 trial (NCT05201859) presented at the 2026 ASCO Annual Meeting.¹

In the intention-to-treat population, at a median follow-up of 41 months (IQR, 35.3-44), the primary end point of 2-year PFS rate was not met. The 2-year PFS rate was 88.2% (90% CI, 80.4%-93.0%) with sintilimab plus capecitabine (n = 78) vs 87.8% (90% CI, 79.9%-92.8%) with capecitabine alone (n = 74; stratified HR, 0.87; 90% CI, 0.44-1.72; log-rank P = .77). No improvements were observed in 2-year overall survival rate (stratified HR, 1.28; 90% CI, 0.34-4.79; log-rank P = .72), 2-year locoregional relapse–free survival rate (stratified HR, 1.39; 90% CI, 0.56-3.47; log-rank P = .46), or 2-year distant metastasis–free survival rate (stratified HR, 0.60; 90% CI, 0.20-1.83; log-rank P = .38) with the addition of sintilimab. Patterns of treatment failure were similar between the 2 arms. Progression occurred in 14.5% of patients who received sintilimab/capecitabine vs 16.2% of those who received capecitabine alone, with comparable respective rates of distant failure (5.3% vs 9.5%) and locoregional failure (7.9% vs 5.4%).

What was the rationale for adding sintilimab to adjuvant capecitabine in patients with NPC after suboptimal response to induction chemotherapy?

“NPC is endemic in Southeast Asia and Southern China, and induction chemotherapy followed by concurrent chemoradiotherapy [CCRT] is standard of care for locoregionally advanced NPC,” Lin-Quan Tang, MD, PhD, of the Department of Nasopharyngeal Carcinoma at Sun Yat-sen University Cancer Center in Guangzhou, China, stated in a presentation of the data. “But, even [in] patients who have received gemcitabine/cisplatin and CCRT, about 20% experience treatment failure.”

Tang added that patients who have a suboptimal response to induction chemotherapy—defined in this trial as detectable plasma Epstein-Barr virus (EBV) DNA or radiologically stable disease (SD) or progressive disease (PD) after 2 cycles of cisplatin-based induction chemotherapy—face an elevated risk of treatment failure. Data from a phase 3 trial showed that among patients with locoregionally advanced NPC, those who received induction chemotherapy with gemcitabine/cisplatin followed by CCRT achieved a 5-year FFS rate of 81.3% vs 67.3% with standard therapy (n = 238; HR, 0,51; 95% CI, 0.36-0.73; P < .001).² Additionally, analyses of the observational EP-SEASON study (NCT03855020) have shown that detectable EBV DNA and SD/PD post-induction chemotherapy characterize patients who are relatively insensitive to induction therapy.³

Given these data, the current phase 2 trial investigators tested whether adding the PD-1 inhibitor sintilimab to adjuvant capecitabine could further reduce the risk of recurrence in this higher-risk patient subgroup.¹

What was the design of the phase 2 trial of adjuvant sintilimab plus capecitabine in NPC following suboptimal response to induction chemotherapy?

The open-label, randomized phase 2 trial enrolled patients 18 to 70 years of age with histologically confirmed World Health Organization (WHO) grade II or III NPC and stage II to IVa disease (excluding T2N0 disease). Patients were eligible to enroll after suboptimal induction chemotherapy response following 2 cycles of cisplatin-based induction chemotherapy, and subsequently completing 3 cycles of cisplatin-based CCRT. A total of 521 patients were screened, and 150 patients were randomly assigned 1:1 to receive adjuvant sintilimab plus capecitabine or capecitabine alone, stratified by disease stage (II vs III vs IVa) and type of induction regimen (doublet vs triplet). Patients in the experimental arm received 10 cycles of sintilimab and 8 cycles of capecitabine; those in the control arm received 8 cycles of capecitabine.

The investigators noted that the baseline characteristics were well balanced. The median age was 46 years in both arms. Most patients had WHO grade III histology (99%; 97%), stage III or IVa disease (99%; 99%), and an ECOG performance status of 1 (57% vs 58%). Approximately one-third of patients in each arm had detectable EBV DNA at baseline (≥ 1500 copies/mL, 34% vs 31%), and approximately two-thirds of patients in each arm had SD as their induction chemotherapy response pattern (67% vs 64%). Treatment compliance was high; 85.5% of patients in the sintilimab/capecitabine arm completed all 10 planned cycles of sintilimab, and the median number of capecitabine cycles was 8 (IQR, 8-8) in both arms.

What were the additional efficacy and safety findings with adjuvant sintilimab plus capecitabine in patients with NPC who had suboptimal response to induction chemotherapy?

A subgroup analysis by PD-L1 tumor proportion score (TPS) found that, among patients who received sintilimab/capecitabine, those with a TPS of less than 50% had a trend toward worse PFS outcomes compared with those with a TPS of at least 50% (unstratified HR, 0.32; 95% CI, 0.06-1.67; P = .15).

The safety profile of sintilimab-capecitabine was consistent with the known toxicities of each agent. There were no significant differences in grade 3 or higher acute adverse effects (AEs) between arms. Neutropenia was the most common grade 3 or higher toxicity in the sintilimab/capecitabine group, seen at a rate of 12.2% vs 5.6% with capecitabine alone. However, grade 3 or higher hand-foot syndrome was more frequently observed in the capecitabine-alone group, at a rate of 9.9% vs 8.1% in the sintilimab arm. Grade 3 or higher immune-related AEs—including hypothyroidism (2.7%), myocarditis (2.7%), and rash (1.4%)—were observed exclusively in the sintilimab/capecitabine arm. The rates of late AEs—including dry mouth, auditory or hearing loss, and peripheral neuropathy—were distributed similarly between the 2 groups, with no significant differences in the incidence of these AEs at grade 3 or higher.

Disclosures: Tang declared no conflicts of interest.

References

1. Liu L, Mai H, Chen Q, et al. Adjuvant sintilimab-capecitabine versus capecitabine alone in locoregionally advanced nasopharyngeal carcinoma with suboptimal response to induction chemotherapy: an open-label, randomized, controlled, phase 2 trial. J Clin Oncol. 2026;44(suppl 17):LBA6005. doi:10.1200/JCO.2026.44.17_suppl.LBA6005
2. Zhang Y, Chen L, Hu GQ, et al. Final overall survival analysis of gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma: a multicenter, randomized phase III trial. J Clin Oncol. 2022;40(22):2420-2425. doi:10.1200/JCO.22.00327
3. Lv J, Xu LX, Li ZX, et al. Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: the EP-SEASON study. Cancer Cell. 2024;42(8):1401-1414.e4. doi:10.1016/j.ccell.2024.07.001