Esophageal cancer (EC) is one of the most common malignant tumors in the world, and China is a high-incidence area for EC. The morbidity and mortality ranked sixth and fourth among all malignant tumors, respectively. Multiple phase III clinical studies, such as Keynote-181 (1), Attraction-3 (2), Escort (3), and Rationale302 (4), have suggested that, compared with chemotherapy alone, immunotherapy improved overall survival (OS) (from 6.2 months to 10.9 months) and progression-free survival (PFS) (from 1.6 months to 3.4 months) in the second-line treatment of EC. Following, multiple phase III clinical studies, including Keynote-590 (5), Checkmate-648 (6), Escort-1 (7), Orient-15 (8) and Jupoiter-06 (9) have suggested that, compared with chemotherapy alone, the combination of chemotherapy and immunotherapy improved OS (from 9.8 months to 17.2 months) and PFS (from 5.3 months to 7.3 months) in the first-line treatment of EC. Previous studies have shown that the efficacy of immune checkpoint inhibitors is increased in earlier lines of therapy across multiple tumor types compared with in later lines of therapy (10–14). However, it is rarely reported in the real world whether the first-line application of immunotherapy in locally advanced or metastatic EC can bring longer survival benefits. In this study, we retrospectively analyzed the survival of patients with locally advanced or metastatic esophageal squamous cell cancer (ESCC) treated with immunotherapy as the first-or second-line treatment, exploring the value of early application of immunotherapy. This real-world study focused on EC, which has rarely been reported previously, and conducted a subgroup analysis, indicating the population that can benefit from early immunotherapy, which has more guiding significance for clinical medication.

Treatment outcomes are poor for patients with advanced disease. The median OS rates are ~10 months and ~6 months for first-line and second-line chemotherapy, respectively, with objective response rates of ~30% and ~10%, respectively (15). With the advent of the immune era, immunotherapy has gradually become the standard treatment for advanced EC. Keynote-181 (1) confirmed the efficacy of pembrolizumab in PD-L1 cps ≥ 10 in patients with locally advanced EC; there was a two-fold improvement in survival at 12 months (43% vs. 20%) compared with chemotherapy alone (fluorouracil combined with platinum). Therefore, in 2019, it became the first immune drug approved for second-line treatment of advanced EC in the United States. Attraction-3 (2) confirmed that at a minimum follow-up time (i.e., time from random assignment of the last patient to data cutoff) of 17.6 months, OS was significantly improved in the nivolumab group compared with the chemotherapy group (10.9 months vs. 8.4 months, HR = 0.77, p = 0.019).

With the overall success of immune drugs in second-line therapy, their use is gradually advancing to first-line therapy. Keynote590 (5) reported that first-line palivizumab + chemotherapy (fluorouracil + platinum-based) vs. first-line chemotherapy in locally advanced or metastatic EC, regardless of the expression status of PD-L1 CPS, showed that the first-line immunized group improved OS (12.4 months vs. 9.8 months; 0.73 [0.62–0.86]; p < 0.0001) and progression-free survival (6.3 months vs. 5.8 months; 0.65 [0.55–0.76]; p < 0.0001), demonstrating a significant benefit. The escort-1 (7) trial confirmed that first-line immunization + chemotherapy (paclitaxel + cisplatin) was better than chemotherapy alone (paclitaxel + cisplatin) in terms of both OS and progression-free survival in the Chinese population, which were 15.3 vs. 12.0 months, respectively (HR = 0.7) and 6.9 vs. 5.6 months (HR = 0.56). The Orient-15 (8) trial also demonstrated a survival benefit for Sintilimab in first-line chemotherapy (paclitaxel + cisplatin/fluorouracil + cisplatin). Overall survival (median 16.7 vs. 12.5 months, HR = 0.63, 95%CI 0.51–0.78, p < 0.001) and progression-free survival (7.2 vs. 5.7 months, HR = 0.56, 95%CI 0.46–0.68, p < 0.001).

Our retrospective data show that after PSM, the OS of 15.7 months with first-line immunotherapy + chemotherapy in locally advanced or metastatic ESCC is consistent with the OS reported with camrelizumab (15.3 months) and sintilizumab (16.7 months), which is higher than the OS reported with pembrolizumab. One possible explanation for this discrepancy may be that a smaller proportion of patients in the control arm of the Keynote-590 study had been exposed to second-line immunotherapy. In terms of PFS, our data showed that the median PFS1 of the two groups was 8.7 months and 7.6 months, respectively (p = 0.032, HR = 0.72), which was similar to the HR values of the above three reports (0.65, 0.56, 0.56). The median PFS2 of the two groups was 12.97 months in the EIT group and 12.93 months in the LIT group, with a statistically significant difference (p = 0.045, HR = 0.73).

Previous reports showed that in non-small cell lung cancer, patients previously treated with fewer lines of therapy (i.e., in the first-line setting) might have less refractory and immunosuppressive tumor microenvironments than patients who have progressed on therapy (16). Pembrolizumab + chemotherapy in the Keynote-189 study reduced the risk of death by 44% in metastatic non-squamous NSCLC (17). Nivolumab as a second-line treatment reduced the risk of death by 27% in metastatic non-squamous NSCLC (18). The keynote-059 (14) trial showed that pembrolizumab monotherapy was effective, safe, and well tolerated in locally advanced gastric or gastroesophageal junction cancer with at least two previous lines of therapy, regardless of PD-L1 expression.

So, whether the early application of immunotherapy is more effective is still controversial. It is also rarely reported whether first-line immunotherapy has a greater survival benefit than second-line immunotherapy in treating locally advanced or metastatic EC. Our retrospective real-world study showed no significant difference in OS between the use of first-line immunotherapy + chemotherapy and chemotherapy alone in patients with locally advanced or metastatic EC, but a benefit in progression-free survival was observed with the addition of immunotherapy to the first-line regimen.

Our study showed that there was no significant difference in OS between the two groups, which we believe is mainly because twice as many patients in the LIT group compared to the EIT group received third-line therapy by the date of follow-up (15.5% vs. 30%), which resulted in significantly longer OS in the LIT group. However, there were statistically significant differences in PFS1 and PFS2 between the two groups, further indicating the benefit of immune drugs in treatment; the benefit was more significant in the early application.

In EIT groups, our subgroup analysis showed that male patients with middle thoracic EC, younger than 65 years old, with only one site of metastasis, only lymph node progression, no combined radiotherapy after progression, and TP (paclitaxel + platinum) regimen chemotherapy had better progression-free survival. In clinical practice, for young patients with lymph node metastasis or single organ metastasis, or when local radiotherapy cannot be added in time, immunotherapy should be given to patients in a timely manner.

Fluorouracil combined with cisplatin is commonly used in combination chemotherapy in Western countries, while paclitaxel combined with platinum is preferred in China (19, 20). Our retrospective data also showed that more patients chose the paclitaxel + platinum regimen. Previous retrospective reports (21) showed no significant difference in the efficacy of the two regimens in EC. However, our subgroup analysis suggests that the TP (paclitaxel + platinum) regimen is preferred as the chemotherapy regimen when combined with immunotherapy.

Li et al. (22) reported for the first time the difference in survival between first-line immunotherapy + chemotherapy and chemotherapy alone in locally recurrent or advanced metastatic esophageal squamous cell carcinoma. In their retrospective study, there was no significant difference in OS (13.5 vs. 13.1 months, p = 0.7) between immunotherapy + chemotherapy and chemotherapy alone, while PFS1 was significantly different (7.1 vs. 4.1 months, p = 0.001, HR = 0.53). Our retrospective data showed that the OS of first-line immunotherapy combined with chemotherapy and chemotherapy alone was 15.7 months and 17.7 months, respectively (p = 0.185, HR = 1.25). PFS1 was 8.7 months and 7.6 months, respectively (p = 0.032, HR = 0.72), consistent with the above conclusions. However, compared with this retrospective study, the number of patients in our article is larger, the follow-up time is longer, and the previous treatment history of the enrolled patients is more detailed, complex, and closer to the actual clinical treatment. Furthermore, we conducted subgroup analyses to inform our practice of which patients would be more inclined to be treated with immunotherapy in the first-line treatment.

For patients with locally advanced and metastatic EC, early application of immunotherapy has a progression-free survival benefit. In clinical practice, patients with middle thoracic EC, younger than 65 years old, with only one site of metastasis, only lymph node progression, no combined radiotherapy after progression, and TP (paclitaxel + platinum) regimen chemotherapy are inclined to be treated with immunotherapy in the first-line treatment.