A novel treatment approach combining chemoradiotherapy with tislelizumab-based immunochemotherapy has shown promising results in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). The Phase II NEXUS-1 trial, published in Clinical Cancer Research, demonstrated the safety and potential efficacy of this conversion therapy, offering a chance for durable cancer-free status through subsequent surgery.
The study, led by Dr. Yin Li from the Chinese Academy of Medical Sciences and Peking Union Medical College, addressed the challenge that fewer than half of ESCC patients have resectable disease at diagnosis. The rationale behind the study was that locally advanced esophageal cancer often precludes curative resection, leading to unfavorable prognoses, with only about 35.8% of patients receiving definitive chemoradiation surviving five years.
Study Design and Methodology
The NEXUS-1 trial enrolled patients aged 18-75 with histologically confirmed unresectable locally advanced thoracic ESCC, including T4 tumors or borderline resectable T3 tumors. Patients received radiotherapy (50 Gy over 25 fractions) combined with nab-paclitaxel (100 mg weekly) and cisplatin (25 mg/m2 weekly) for five weeks. This was followed by two 21-day cycles of tislelizumab (200 mg on Day 1) plus nab-paclitaxel (150 mg/m2) and cisplatin (75 mg/m2) on Day 2. Patients achieving resectability underwent surgery 2-4 weeks later.
The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included R0 resection rate, major pathologic response, pathologic complete response (pCR), postoperative complications, 2-year PFS rate, 1- or 2-year overall survival rate, locoregional recurrence-free survival, distant metastasis-free survival, and safety.
Key Findings
Of the 30 patients enrolled, 20 (66.7%) achieved resectability. Among those who underwent resection, 95.2% achieved R0 resection, and 65.0% experienced pathologic complete response. The 1-year progression-free survival and overall survival rates were 79.4% and 89.6%, respectively.
The R0 resection group exhibited significantly longer PFS (median, not reached vs. 8.4 months; HR=0.28; 95% CI: 0.08-0.84; P=0.02) and OS (median, not reached vs. 19.2 months; HR=0.18; 95% CI: 0.04-0.73; P<0.01) compared to the non-surgery group.
Safety Profile
The most common treatment-related adverse events (TRAEs) during chemoradiation included radiation esophagitis (93.3%), anemia (76.7%), and leukopenia (76.7%). Grade 3 or higher TRAEs occurred in 14 patients (46.7%). Among the 24 patients receiving immunochemotherapy, 20.8% developed immune-related pneumonitis.
Implications and Future Directions
Dr. Li noted that the trial demonstrated the effectiveness of combining chemoradiotherapy, chemoimmunotherapy, and surgery compared to non-surgical management alone. The remarkable pathologic complete response and strong survival outcomes exceeded initial expectations.
While the study's limitations include its single-arm Phase II design and small sample size, the results warrant further investigation in larger, multi-center trials. Dr. Li and colleagues mentioned that a three-arm trial comparing different sequences of treatment modalities (CRT followed by iCT and surgery vs. iCT followed by CRT and surgery vs. CRT followed by surgery) for unresectable ESCC is ongoing.
