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Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma.This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863.Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred.Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing.Jiangsu Hengrui Pharmaceuticals.

310 Background: Compared to standard chemotherapy, immune checkpoint inhibitors monotherapy and combined with chemotherapy regimens have been shown significant benefits for patients with advanced or metastatic esophageal cancer in both second-line and first-line treatment, respectively. Anlotinib was an effective second-line monotherapy for esophageal squamous cell carcinoma in China and the combination of anlotinib and immunotherapy might be a promising strategy. The study aimed to investigate the efficacy and safety of anlotinib plus PD-1 inhibitors during the treatment of esophageal cancer in the real world setting. Methods: This is a multicenter real-world study in patients with unresectable locally advanced, recurrent or metastatic esophageal cancer, who would benefit from anlotinib plus a PD-1 inhibitor under the doctor's evaluation. The enrolled patients received treatment according to physicians. The primary endpoint was PFS, and secondary endpoints included ORR, DCR and OS. The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: Between May 2020 and Sep 2022, 207 pts were enrolled. 109 comprised the evaluable population. In the full analysis set, 203 patients were squamous cell and 4 were adenocarcinoma histology. 137 of 207 (66.2%) pts were male. 44(21.3%) had an ECOG performance status of 0, 136 (65.7%) status of 1 and 27 (13.0%) status of ≥2. 47 pts had previously used anti-PD-1/PD-L1 antibody or vascular targeting drugs, of which 8 cases had combined anti-PD-1/PD-L1 antibody and vascular targeting drugs. Among the 109 evaluable pts, 17 (15.6%) pts received first-line therapy, 64 (58.7%) second-line and 28(25.7%) third & above line. Of which, 5 patients achieved complete response (CR), 32 pts partial response (PR), 62 pts stable disease (SD), illustrating an ORR of 34.0% (95%CI 25.1-43.6) and a DCR of 90.8%(95%CI 83.8-95.5). In the first line therapy, ORR was 47.1% and DCR was 88.2%. In the second line therapy, ORR was 32.8% and DCR was 96.9%. In the third & above line, ORR with 28.6% and DCR with 78.6% were observed. Median PFS was not reached, 6m-PFS rate was 87.9%. Treatment related adverse events (TRAEs) were reported in 55 pts (50.5%). 6 patients had grade 3 or more TRAEs. Conclusions: Anlotinib plus PD-1 inhibitors for advanced or metastatic esophageal cancer demonstrated a promising clinical benefit and a manageable safety profile. Further investigation in larger cohorts and even randomized controlled studies is warranted. Clinical trial information: NCT04966611 .

Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

e16052 Background: Immunotherapy, particularly with anti-PD-1/PD-L1 antibodies, has shown therapeutic efficacy in various malignancies. Compared with chemotherapy, anti-PD-1 antibody monotherapy improved the median overall survival in advanced or metastatic esophageal cancer. The combination of an anti-PD-1/PD-L1 antibody with an angiogenesis inhibitor has shown efficacy in many cancers which including esophageal cancer. The purpose of this study is to investigate the efficacy and safety of anlotinib plus PD-1 inhibitors as chemo-free therapy during the treatment of esophageal cancer in the real world setting. Methods: This prospective, multicenter real-world study (NCT04966611) evaluated the efficacy and safety of anlotinib plus PD-1 inhibitors in the chemo-free therapy setting for advanced or metastatic esophageal cancer patients (pts). Primary endpoint was evaluation of PFS (progression-free survival), and secondary endpoints included ORR (objective response rate), DCR (disease control rate) and OS (overall survival). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: Between May 2020 and Dec 2021, 50 pts were enrolled. 45 comprised the evaluable population. In the full analysis set, 44 had squamous cell and 1 patient had adenocarcinoma histology. 29 (64.4%) of 45 pts were male. 10 (22.2%) had an ECOG performance status of 0, 32 (71.1%) status of 1 and 3 (6.7%) status of 2. Twenty (44.4%) pts had distant metastases and 29(64.4%) pts had comorbidities. 15 pts had previously used anti-PD-1/PD-L1 antibody or vascular targeting drugs, of which 5 cases had combined the two drugs. Among all evaluable pts, 5(11.1%) pts received first-line, 27(60.0%) second-line and 13(28.9%) third & above line therapy. Among all pts, 1 patient achieved complete response (CR), 16 pts partial response (PR), 25 pts stable disease (SD), illustrating an ORR of 37.8% and a DCR of 93.3%. In the first line therapy, ORR was 60.0%, DCR was 100%.In the second line therapy, ORR was 37.0%, DCR was 96.3%. In the third & above line, ORR with 30.8%, DCR with 84.6% was observed. Median PFS was not reached. Treatment related adverse events (trAEs) were reported in 24 pts(53.3%). No patient had grade 3 or more trAEs. Conclusions: Anlotinib plus PD-1 inhibitors in chemo-free therapy for advanced or metastatic esophageal cancer was active and showed excellent tumor response and was generally well tolerated. Further investigation is required in a larger real-world cohort to validate the benefit of anlotinib plus PD-1 inhibitor in esophageal cancer. Clinical trial information: NCT04966611.

320 Background: Anti-PD-1 mAb treatment has been shown to be effective in the treatment of esophageal cancer. Anlotinib has been approved in China as a second-line treatment for advanced esophageal cancer because of its good tolerance and efficacy. In the treatment of esophageal cancer, antiangiogenic target therapy combined with immunotherapy has been preliminarily recognized internationally. The purpose of this study is to investigate the efficacy and safety of anlotinib in combination with PD-1 inhibitors in second-line or later therapy during the treatment of esophageal cancer in the real world setting.(A LOT-EC3, NCT04966611). Methods: This is a prospective, multicenter real-world study. The esophageal cancer patients who received anlotinib in combination with PD-1 inhibitors in second-line or later therapy were enrolled. The primary endpoint was PFS (progression-free survival), and secondary endpoints were ORR (objective response rate), DCR (disease control rate) and OS (overall survival). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: From Jul 2020 to Sep 2021, 40 patients with a median age of 65.5 (range: 48̃81) were enrolled, in which the metastasis of more than 1 organ occurred in 62.5% of the 40 patients; the metastasis of more than 2 organs occurred in 37.5% (15 patients). 26 (65.0%) and 14 (35.0%) patients received anlotinib combined with PD-1 inhibitors as second line and third & above line therapy, respectively. Among all patients, 1 patient achieved complete response (CR), 11 patients partial response (PR), 23 patients stable disease (SD), illustrating an ORR of 30.0% and a DCR of 87.5%. In the second line therapy, ORR was 30.8 %, DCR was 92.3%. In the third & above line, ORR with 28.6%, DCR with 78.6% was observed. Median PFS was not reached. For all the 40 patients, 27 of which were treated with Camrelizumab, 10 were treated with Sintilimab, other 3 patients were treated with other kinds of PD-1 inhibitors. There was no significant difference in DCR between different PD-1 inhibitors. Treatment related adverse events (trAEs) occurred in 22 (55%) patients. 4 patients had grade 3 or more trAEs. No patient died due to trAE. Conclusions: Anlotinib combined with PD-1 inhibitors is found to be a reasonable option in second-line or later therapy for the treatment of advanced esophageal cancer. To our best knowledge, this is the first summarized real-world study on anlotinib combined with PD-1 inhibitors in advanced esophageal cancer. The treatment effects are similar to the outcomes in comparable clinical trials, which support the further recommendation of anlotinib combined with PD-1 inhibitors in the treatment of esophageal cancer. Clinical trial information: NCT04966611.

e16013 Background: Paclitaxel combined with cisplatin regimen has been the standard first-line therapy in advanced Esophageal Squamous Cell Carcinoma (ESCC) for almost two decades. However, the 5-year survival rate was only 4.8% in advanced ESCC. Therefore, more effective therapeutic treatments were needed to prolong the survival urgently. Anlotinib was demonstrated to be an effective second-line monotherapy for patients with advanced or recurrent ESCC in China. And the preliminary results of our trial had been reported in 2020 ESMO (Abs 1448) and 2021 ASCO-GI Symposium (Abs 181). Consequently, this study was to investigate the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC and report the update results regularly. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. For those who did not have disease progression, maintenance treatment was treated with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 criteria using computed tomography scans every two cycles. The predefined sample size was 47. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. Results: From Oct 2019 to Dec 2020, a total of 45 patients were enrolled. Among 34 pts who were available for efficacy and safety evaluation. there were 1 confirmed CR (2.9%), 26 confirmed PR (76.5%), 2 unconfirmed PR (5.9%) and 5 SD (14.7%). Consequently, ORR was 79.4% (95%CI: 62.1̃91.3) and DCR was 100.0% (95%CI: 89.7̃100.0). At the data cut-off date, 11 patients discontinued treatment due to PD, the preliminary prognostic result indicated that the median PFS of the 34 patients was 9.76 months (95%CI: 8.44-13.08). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia, hepatotoxicity and hemoptysis. And the common grade ≥3 adverse events were myelosuppression (20.6%), hypertension (8.8%), nausea and vomit (5.9%), fatigue (5.9%) and hypokalemia (5.9%). Conclusions: The update results suggested that the regimen of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT04063683.

215 Background: Esophageal squamous cell carcinoma (ESCC) is a lethal cancer with a high unmet medical need. Camrelizumab, an anti-PD-1 monoclonal antibody, significantly improved overall survival (OS) and objective response rate (ORR) in Chinese patients (pts) with advanced ESCC compared with chemotherapy, with a manageable safety profile in phase III randomized trial (ESCORT). However, the absolute long-term survival benefiting from PD-1 inhibitors is limited, and new effective treatments are needed. Here, our study aimed to assess the efficacy and safety of combination with camrelizumab and apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC. Methods: This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg intravenous camrelizumab every two weeks plus 250 mg oral apatinib daily in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results: At data cutoff (Sept 11, 2020), 36 pts were enrolled, 7 females and 29 males, and 25 pts had lymph node metastases. Twelve pts received radiotherapy and 25 underwent surgery. Twenty-five pts were included in the efficacy analysis with median follow-up time of 5.0 months and 36 pts in the safety analysis with median follow-up time of 4.6 months. The primary endpoint ORR without confirmation was 40 % with complete response in two pts (8%) and partial response in eight pts (32%). Thirteen pts (52%) had stable disease, and the DCR was 92%. The median PFS and OS were not reached. A total of 72.2% of pts had AEs, and 30.6% of pts experienced grade 3 AEs. The most common AEs (all grade, grade≥3) were elevated aspartate aminotransferase (30.6%, 19.4%), elevated alanine aminotransferase (30.6%, 13.9%), hypertension (25%, 2.8%),neutrophil (25%, 5.6%), thrombocytopenia (25%, 0%), leukopenia (22.2%, 2.8%), anemia (11.1%, 0%), proteinuria (11.1%, 0%), hematochezia (8.3%, 0%), reactive cutaneous capillary endothelial proliferation (5.6%, 2.8%), pruritus (5.6%, 0%), esophageal fistula (5.6%, 0%), fatigue (2.8%, 0%) and hypothyroidism (2.8%, 0%). Conclusions: This is the first study to explore the combination of PD-1 inhibitor and anti-angiogenesis inhibitor as a second-line treatment for advanced ESCC. Camrelizumab plus apatinib demonstrated encouraging clinical efficacy and acceptable safety as second-line treatment, and might be a favorable option for pts with advanced ESCC. Further phase III randomized trials are warranted. Clinical trial information: NCT03736863.

181 Background: The prognosis of pts with advanced ESCC remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. As a novel multitarget tyrosine kinase inhibitor mainly targeting antiangiogenic single pathway, anlotinib was demonstrated to be an effective second-line monotherapy for pts with advanced or recurrent ESCC in China. Consequently, the aim of this study was to investigate the efficacy and toxicity of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible subjects were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with anlotinib monotherapy (10mg, po, d1~14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans every two cycles. And the calculated sample size of this study was 47. The primary endpoint was PFS, secondary endpoints were safety, objective response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: From Oct 2019 to Aug 2020, 27 pts were available for efficacy and safety evaluation. In best overall response assessment, there were 7.4% CR (2/27), 66.7% PR (18/27) and 25.9% SD (7/27). ORR was 74.1% (95%CI: 53.7. ~ 88.9), and DCR was 100.0% (95%CI: 87.2~100.0). The median PFS of the 27 pts was not yet available. The safety profile indicated that the most common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia and hepatotoxicity. The common grade 3-4 treatment-related adverse events were myelosuppression (18.5%), hypertension (7.4%). Conclusions: The current results indicated that paclitaxel and cisplatin combined with anlotinib as first line therapy for advanced ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04063683. [Table: see text]