PD-1 blockade with sintilimab plus induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) versus IC-CCRT in locoregionally-advanced nasopharyngeal carcinoma (LANPC): A multicenter, phase 3, randomized controlled trial (CONTINUUM).

Abstract

LBA6002 Background: Despite the success of PD-1 blockade plus chemotherapy in recurrent/metastatic NPC, its role in LANPC is unproven. This trial evaluated the efficacy and safety of adding sintilimab (a PD-1 inhibitor) to IC-CCRT in LANPC. Methods: Patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0/T3N1) were enrolled at 9 centers in China, and randomized (1:1; stratified by center and stage with block size four) to the Standard Arm (gemcitabine and cisplatin IC plus cisplatin CCRT), or Sintilimab Arm (sintilimab plus IC-CCRT). Sintilimab 200mg was given intravenously once every 3 weeks for up to 12 cycles (3 induction, 3 concurrent, and 6 adjuvant). The primary endpoint was event-free survival (EFS) (i.e. freedom from local/regional/distant failure or death). It is estimated that approximately 417 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a two-sided type 1 error of 0.05. Quality of life (QoL) was assessed by EORTC-C30. Biomarkers including tertiary lymphoid structure (TLS), PD-L1, and gene expression were also analyzed. Results: Between December 2018, and March 2020, 425 patients were randomized to the Sintilimab Arm (n = 210) and Standard Arm (n = 215). After a median follow-up of 42 months (94% alive patients ≥36 months), the intention-to-treat analysis showed that 3-year EFS was 86.1% in the Sintilimab Arm and 76.0% in the Standard Arm (stratified HR, 0.59; 95% confidence interval [CI], 0.38-0.92; stratified log-rank p = 0.019). Grade 3-4 adverse events (AEs) occurred in 155 (74.2%) and 140 (65.4%) patients, including immune-related AEs in 20 (9.6%) and 2 (0.9%) patients and grade 5 AEs in 2 (0.95%) and 1 (0.5%) patients in the Sintilimab and Standard Arm, respectively (Table). No minimum clinically important differences in QoL were observed. The benefit of the addition of sintilimab was observed in patients with TLS (HR 0.18; 95% CI, 0.04-0.81; p = 0.011) but not in patients without TLS (HR 0.94; 95% CI, 0.50-1.76; p = 0.85). Conclusions: The addition of sintilimab to standard IC-CCRT results in significant improvement of EFS, manageable safety profile, and comparable QoL in high-risk LANPC. TLS appears to be a predictive biomarker for benefit of sintilimab. Clinical trial information: NCT03700476 . [Table: see text]

Additional PD-1 inhibitor improves complete response to induction chemotherapy in locally advanced nasopharyngeal carcinoma

“…Therefore, initiating PD-1 inhibitor treatment before radiotherapy may better activate the immune system and enhance the efficacy of immunotherapy. For LANPC patients, initial findings from the CONTINUUM study suggested that the use of Sintilimab (PD-1 inhibitor) in combination with IC, CCRT, and adjuvant therapy significantly improves the 3-year event-free survival rate compared to those treated with IC plus CCRT (86.1% vs. 76.0%) ( 22 ). In our study, we found short-term survival was excellent by using IC and PD-1 inhibitor with a median follow-up time of 17.0 months.…”

Embracing Personalized Strategies in Radiotherapy for Nasopharyngeal Carcinoma: Beyond the Conventional Bounds of Fields and Borders

“…Phase II single-arm trials for pembrolizumab [127] and tislelizumab [128] (both PD-1 inhibitors) have studied the efficacy of integrating PD-1 inhibitors with IC and CCRT, followed by maintenance therapy, with results presented in abstract form. The phase III CONTINUUM [129] study recruited patients with stage III-IVA NPC (except T3/T4N0 or T3N1). The experimental arm received up to 12 cycles of induction, concurrent and maintenance sintilimab (a PD-1 inhibitor), and it demonstrated improved 3-year event-free survival compared to the control arm treated with IC +CCRT (86.1% vs. 76%; stratified HR 0.59).…”

“…The CONTINUUM [129] study proposed that the clinical benefit of sintilimab was observed only in patients with tertiary lymphoid structure (TLS), the ectopic lymphoid tissues that can be found in the tumor or neighboring peripheral tissue [132]. Genomic studies on the tumor microenvironment may offer further insights [124,133].…”

Enhancing efficacy and reducing toxicity: Therapeutic optimization in locoregionally advanced nasopharyngeal carcinoma

“… 125 , 126 , 127 , 128 The only large-scale, phase III trial with published data thus far investigating PD-1 blockade in treating locoregionally advanced NPC demonstrated that adding sintilimab during GP IC, CCRT, and as adjuvant therapy significantly lowered recurrence or mortality risk by 41% in high-risk patients—with the 3-year event-free survival rate increasing by 10% (86.1% vs. 76.0%; HR 0.59, 95% CI 0.38–0.92; p = 0.019; Table S1 ). 129 Moreover, the sintilimab group demonstrated significant reductions in distant metastasis and locoregional recurrence risks (3-year DMFS rate, 90.3% vs. 82.8%, HR 0.57 [95% CI 0.33–0.98], p = 0.039; 3-year LR-FFS rate, 93.4% vs. 86.8%, HR 0.52 [95% CI 0.27–0.97], p = 0.038). Notably, no significant difference was observed in the quality of life between the groups.…”