Locally advanced (stage III) lung cancer is often defined as a large tumor (≥5 cm in diameter) that invades vital organs such as the pericardium, heart, great vessels, esophagus, and augmentation, or is accompanied by regional lymph node metastases such as mediastinal lymph node (N2) and supraclavicular lymph node (N3) metastases, but not distant organs. For unresectable locally advanced (stage III) non-small cell lung cancer, the current platinum-based treatment options are synchronous chemotherapy and sequential radiotherapy. A meta-analysis including the NPC-95-01 study and the RTOG9410 study found that synchronous radiotherapy was superior to sequential radiotherapy, with an absolute improvement in OS of approximately 3 months. a meta-analysis of 1205 patients in 6 studies published in JCO in 2010 found that synchronous radiotherapy was superior to sequential radiotherapy, with absolute benefit rates of 5.7% at 3 years and 4.5% at 3 and 5 years, respectively. This benefit was mainly due to the reduced risk of future local loss of control and progression with concurrent radiotherapy (HR=0.77, P=0.01), with no significant effect on distant metastases (HR=1.04, P=0.69). This establishes the status of simultaneous radiotherapy as the standard of care for a considerable period of time in the future. In the NCCN, ASCO, CSCO and other major guidelines, platinum-based concurrent radiotherapy regimens are recommended for patients in good general health. Synchronized radiotherapy improves the efficacy, and although the acute pulmonary toxicity is similar, synchronized radiotherapy significantly increases the risk of acute esophageal toxicity, with the incidence of 3rd degree and higher esophageal toxicity increasing from 4% to 18%. Therefore, although synchronous radiotherapy is the standard of care, the use of sequential radiotherapy remains common in the real world, considering its safety and tolerability. Only 60%-70% of patients in Europe and the United States are able to receive simultaneous radiotherapy. In China, more than 70% of hospitals still use sequential radiotherapy as the main modality for inoperable locally advanced non-small cell lung cancer. Now that we have entered the era of immunotherapy, it is unknown whether the advantages of synchronized radiotherapy still exist compared to sequential radiotherapy or whether the combination of synchronized radiotherapy and chemotherapy will lead to more apoptosis of tumor cells, thus further enhancing the efficacy of immunotherapy. PACIFIC is a placebo-controlled, multicenter, randomized, double-blind phase III clinical study. Patients enrolled in the study were inoperable, stage III NSCLC patients with stable disease after radical concurrent radiotherapy, comprising a total of 713 patients from 235 hospitals in 26 countries, grouped in a 2:1 ratio. The experimental group received dulvalizumab, 10 mg/kg, once every 2 weeks for up to 1 year. The control group received placebo treatment. Progression-free survival (PFS) was significantly better in the dulvalizumab consolidation treatment group after synchronous radiotherapy than in the placebo group (median PFS 16.9 months vs. 5.6 months, HR=0.55, P<0.001), with a 5-year PFS rate of 33.1%. Median survival (OS) was 47.5 months, compared with 29.1 months in the placebo group, extending 18.4 months and reducing the risk of death by 29% (HR=0.71; 95% CI: 0.57-0.88). 1-year survival rates were 83.1% vs. 66.3%, 2-year survival rates were 75.3% vs. 55.6%, and 3-year survival rates were were 57% vs. 43.5%, 4-year survival rates were 49.6% vs. 36.3%, and 5-year survival rates were 42.9% vs. 33.4%, respectively. PACIFIC-6 is a phase II clinical study of sequential radiotherapy followed by consolidation with dulvalizumab in patients with inoperable stage III NSCLC, with the dulvalizumab consolidation regimen adjusted to one treatment cycle every 4 weeks. The primary endpoint was a safety/tolerability assessment, defined as grade 3/4 potentially treatment-related adverse reactions (PRAEs) occurring within 6 months. There were 22 patients (18.8%) with grade 3/4 AEs in the entire group, but 5 patients (4.3%) with grade 3/4 PRAEs, and all 5 patients with grade 3/4 PRAEs occurred within 6 months of starting dulvalizumab. The events that occurred were pneumonia (2 cases), hypothyroidism (1 case), adrenal insufficiency (1 case), and leukopenia (1 case). The objective remission rate for the whole group of patients was 17.1%, and the median progression-free survival (PFS) was 10.9 months, with a 12-month PFS rate of 49.6%. the median progression-free survival (PFS) for patients with PS score (0/1) was 13.1 months, with a 12-month PFS rate of 50.1%. Median overall survival (OS) was 25.0 months, with a 12-month OS rate of 84.1%. GEMSTONE-301 is a randomized, double-blind, placebo-controlled, phase III study designed to evaluate the efficacy and safety of sugilizumab as consolidation therapy in patients with unresectable stage III NSCLC who have not experienced disease progression after synchronous or sequential radiotherapy. A total of 381 patients from 50 centers were enrolled in the study, of whom 33.3% received prior sequential radiotherapy, 69.6% had an ECOG stamina status score of 1, 69.0% had squamous cell carcinoma, and 28%/55%/16% had stage IIIA/IIIB/IIIC, respectively. Patients were randomized 2:1 to receive consolidation therapy with sugilizumab or placebo. A pre-planned interim analysis performed at a median follow-up of 14 months showed that median progression-free survival (PFS) was 9.0 and 5.8 months in the sugilizumab and placebo groups, respectively, as assessed by a blinded independent central review committee (BICR), with sugilizumab significantly reducing the risk of disease progression or death by 36% (HR 0.64, 95% CI 0.48-0.85, P = 0.0026); the 12-month PFS rate was 45% vs. 26% and the 18-month PFS rate was 39% vs. 23% in the sugilizumab and placebo groups. Patients following either synchronous or sequential radiotherapy showed clinical benefit. The median PFS was 10.5 months vs. 6.4 months (HR=0.66) in the sugilizumab and placebo groups for patients who received synchronous radiotherapy before the trial and 8.1 months vs. 4.1 months (HR=0.59) in both groups for patients who received sequential radiotherapy before the trial. Median OS data are not yet mature, but the sugilizumab group has shown a clear trend toward benefit (not reached vs. 24.1 months, HR=0.44, 95% CI 0.27-0.73); 12-month OS rates were 89% vs. 76% and 18-month OS rates were 82% vs. 60% in the sugilizumab and placebo groups. Although, it is clear to oncologists that synchronous radiotherapy is superior to sequential radiotherapy, it is unclear whether synchronous radiotherapy can provide much of an advantage in the era of immunotherapy. Although, compared to the median survival of 25 months with sequential radiotherapy PACIFIC-6, the median survival with synchronous radiotherapy PACIFIC reached 47.5 months. However, after all, the PACIFIC-6 study was based on more patients who were older and had comorbidities. Perhaps the results of the final survival analysis of GEMSTONE-301 will tell us the answer. In any case, the results of the PACIFIC study tell us that the data that one-third of patients with locally advanced (stage III) inoperable non-small cell lung cancer treated with simultaneous radiotherapy followed by dulvalizumab consolidation will not experience disease progression for five years is stunning enough. Therefore, for patients with locally advanced (stage III) non-small cell lung cancer in good general condition, the concurrent radiotherapy regimen must be the preferred choice!