Before 2019, a combination of 5-fluoropyrimidine and platinum-based chemotherapy was widely accepted worldwide as the first-line therapy for treating unresectable advanced and metastatic EC cases. Various chemotherapy strategies showed a median OS of ~ 10 months for advanced and metastatic EC [14, 15]. In the event of first-line therapy failure, the subsequent second-line treatment options are limited, further leading to a dismal
survival benefit. PD-1 and PD-L1 is a molecule pair that performs T cell inhibitory functions [16]. The PD-L1 expression was detected on tumor surface, and it binds with PD-1, which is expressed on the T cell surface. Immune checkpoint inhibitors (ICIs) based on the PD-1 pathway blockade have been proven to cause tumor cell regression [17]. Several clinical studies have demonstrated promising survival benefit and manageable safety profile of ICIs in several cancer types, including non-small cell carcinoma, head and neck cancer, and ESCC [18, 19]. The phase 3 KEYNOTE-181 was a randomized study of second-line pembrolizumab monotherapy versus investigator’s choice chemotherapy in EC patients with advanced/metastatic EC; in this study, compared with investigator’s choice chemotherapy, pembrolizumab showed a significantly increase in OS of patients with a PD-L1 combined positive score (CPS) of ≥ 10 (9.3 months vs. 6.7 months, P = 0.0074). Fewer patients had treatment-related AEs (any grade) in the pembrolizumab group than in the chemotherapy group [10]. The phase 3 ATTRACTION-3 was a randomized multicenter study of second-line nivolumab versus chemotherapy in patients with unresectable advanced or recurrent ESCC. Regardless of their PD-L1 status, 419 patients were enrolled. Nivolumab was superior to chemotherapy in terms of OS (10.9 months vs. 8.4 months, P = 0.019). Grade 3 or 4 treatment-related AEs were found in 18% patients in the nivolumab group versus 63% patients in the chemotherapy group [9]. Based on these results, nivolumab and pembrolizumab were approved by the United Stated Food and Drug Administration as second-line ICI treatments of ESCC. In 2021, KEYNOTE-590, a randomized, placebo-controlled, phase 3 study, revealed that pembrolizumab + chemotherapy was superior to placebo + chemotherapy in terms of the OS in all randomized patients regardless of their CPS (12.4 months vs. 9.8 months, P < 0.001) and in patients with ESCC (P = 0.0006), PD-L1CPS ≥ 10 (P < 0.0001), and ESCC PD-L1 ≥ 10 (P < 0.0001)[20]. Therefore, pembrolizumab was first approved for locally advanced or metastatic EC regardless of histology and PD-L1 CPS status. Several randomized phase 3 studies that followed, such as ESCORT and ESCORT-1st, also reported better safety and efficacy of ICIs in patients with EC. ESCORT and ESCORT-1st showed that camrelizumab monotherapy and camrelizumab combined with chemotherapy both significantly improved the OS as second- and first-line therapies in Chinese patients with advanced or metastatic ESCC, respectively. Therefore, Chinese National Medical Products Administration has approved camrelizumab monotherapy as the second-line treatment and camrelizumab in combination with chemotherapy as the first-line treatment for treating ESCC regardless of the PD-L1 CPS status. The RCTs mentioned above have proven the efficacy of ICIs, including camrelizumab, in locally advanced ESCC. However, data on the use and outcomes of camrelizumab on the real-world treatment methods in uncontrolled patients with ESCC are still lacking. In our real-world study, we used real-world data to analyze the efficacy and safety of monotherapy and combination therapy with camrelizumab in clinical practice in China. Receiving > 4 cycles of camrelizumab and having a good LIPI were independent predictors of better PFS and OS. Moreover, camrelizumab monotherapy and combination therapy showed satisfactory ORRs and manageable treatment-related AEs. Therefore, it could be considered a safe and efficient treatment method.
Several studies have demonstrated that systemic inflammatory response significantly boosts cancer cell growth, primary tumor invasion, distant metastasis, and immune tolerance [21–24]. Tumor cells obtain energy from aerobic glycolysis. Cancer cells promote the expression of aerobic glycolysis enzymes to maintain cancer cell growth. Lactate dehydrogenase (LDH) is a crucial glycolysis enzyme [25–27]. Inflammatoty-based prognostic factors, such as neutrophil-to-lymphocyte ratio (NLR) and serum LDH, are associated with a poor prognosis and have shown potential value to predict prognosis in patients with several cancer types [28–32]. However, whether pretreatment inflammatory marker and serum LDH levels can be treated as predictors of benefits from ICIs remains unclear. In 2018, Mezquita et al. studied 466 patients with advanced non-small cell lung cancer receiving PD-1/PD-L1 inhibitors and were the first to develop the lung immune prognostic index (LIPI) to investigate the relationship between poor outcomes of PD-1/PD-L1 inhibitors and the LIPI score. In that study, the LIPI score was defined on the basis of NLR greater than 3 and LDH greater than the upper limit of the normal value and divided into three groups (good, 0 factors; intermediate, 1 factor; and poor, 2 factors). The median OS was 3 months, 10 months, and 34 months for poor, intermediate, and good LIPI groups, respectively (P < 0.001). Moreover, the median PFS was 1 month, 3 months, and 6 months for poor, intermediate, and good LIPI groups, respectively (P = 0.001). LIPI can predict ICIs’ treatment outcomes and can be a useful indicator of NSCLC patients likely to benefit from ICIs [33]. In 2019, Sorich et al. studied 1489 NSCLC patients treated with ICIs and found that the median PFS ranged from 1.4 months for the poor LIPI group to 4.2 months for the good LIPI group. In addition, the median OS ranged from 4.5 months for the poor LIPI group to 18.4 months for the good LIPI group. Good LIPI was associated with significantly prolonged OS (P < 0.001) and PFS (P < 0.001) in NSCLC patients treated with ICIs. Moreover, in chemotherapy-treated NSCLC patients, pretreatment LIPI was also statistically significantly associated with OS and PFS (P < 0.001). LIPI can also be viewed as a potential prognostic indictor for survival of NSCLC patients treated with chemotherapy. Notably, LIPI has also been investigated in patients with extrapulmonary cancers [34]. Feng et al. studied 361 ESCC patients who underwent curative esophagectomy and found that the 5-year cancer-specific survival rates associated with LIPI 0, LIPI 1, and LIPI 2 were 40.9%, 19.0%, and 9.8%, respectively. Multivariate analysis also revealed that LIPI was an independent predictor of cancer-specific survival in patients with resected ESCC [35]. In the present study, we found that good LIPI was positively associated with prolonged PFS and OS in patients with ESCC who received camrelizumab. Consistently, multivariate analysis also demonstrated that good LIPI independently predicted better PFS and OS. Then, we further performed exploratory subgroup analyses and found that good LIPI group patients benefited from camrelizumab + RT combination in terms of their PFS (P = 0.008) and OS (P = 0.011). LIPI may be an efficient marker for predicting the efficacy of camrelizumab + RT combination therapy.
To our knowledge, this is the first multicenter real-world study of its kind to (i) evaluate the efficacy and safety of camrelizumab in patients with unresectable advanced, recurrent, or metastatic ESCC, (ii) assess the predictive value of LIPI to justify the addition of camrelizumab to radiotherapy, and (iii) identify high-risk patients who could benefit from camrelizumab monotherapy and combination treatment.
This study has some limitations. First, the study population was relatively small, and large-scale studies are warranted to validate these findings. Second, the enrolled patients treated with camrelizumab monotherapy and camrelizumab + RT increase bias in this study. In the real world, a large proportion of ESCC patients is the elderly with severe complications. These patients could not accept the standard concurrent camrelizumab + CT. Camrelizumab monotherapy and camrelizumab + RT were still used in clinical practice. Third, we only analyzed ESCC patients in this study. Whether the results can be applied to esophageal adenocarcinoma still needs further investigation. Fourth, we did not analyze the impact of the PD-L1 expression in most patients.