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Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma.

ABSTRACT:

Background

Immunotherapy is effective in treating unresectable esophageal squamous cell carcinoma (ESCC), but little is known about its role in the preoperative setting. The aim of this study was to evaluate the safety, feasibility and efficacy of neoadjuvant treatment with camrelizumab plus chemotherapy in locally advanced ESCC.

Methods

Patients diagnosed with locally advanced ESCC were retrospectively included if they had received neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy between November, 2019 and June, 2020 at Sun Yat-sen University Cancer Center. Primary endpoints were safety and feasibility. In addition, pathological response and the relationship between tumor immune microenvironment (TIME)/tumor mutational burden (TMB) and treatment response were also investigated.

Results

Twelve patients were included and they all received three courses of preoperative treatment with camrelizumab plus nab-paclitaxel/S1. No grade 3 or higher toxicities occurred. No surgical delay or perioperative death was reported. Nine patients (75%) responded to the treatment, four with a complete pathological response (pCR) and five with a major pathological response (MPR). Neither programmed death-ligand 1 (PD-L1) expression nor TMB was correlated with treatment response. TIME analysis revealed that a higher abundance of CD56dim natural killer cells was associated with better pathological response in the primary tumor, while lower density of M2-tumor-associated macrophages was associated with better pathological response in the lymph nodes (LNs).

Conclusions

Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective in locally advanced ESCC and is worth further investigation.

SUBMITTER: Yang G

PROVIDER: S-EPMC8421958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeoadjuvant therapy followed by esophagectomy has been recognized as an effective treatment for locally advanced esophageal cancer, though still has a dismal prognosis. Antibodies against programmed death 1 (PD-1) protein improve survival in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) compared with chemotherapy in second-line therapy. However, neoadjuvant PD-1 inhibitor combined with chemotherapy has not been tested in locally advanced ESCC. We conducted this study to evaluate the efficacy and safety of pd-1 inhibitor in neoadjuvant chemotherapy.MethodsIn this study, we administered 28 adults with untreated, surgically resectable locally advanced ESCC. PD-1 inhibitor with chemotherapy [albumin paclitaxel 100 mg/m2 on days 1 and 8 + carboplatin with an area under the curve (AUC) of 5 on day 1] were administered every 3 weeks intravenously, and surgery was performed approximately 3-5 weeks after the second dose. The primary purpose of the study was to evaluate the feasibility and safety of this regimen.ResultsIn all, 28 locally advanced ESCC patients were enrolled, 27 patients received surgery, 9 (33.3%) patients' postoperative pathological specimens suggested pCR, and 11 (40.7%) patients' primary tumor suggested complete response. Neoadjuvant PD-1 inhibitor with chemotherapy had an acceptable side-effect profile, 26 patients' tumors were completely resected (96.3% were R0). According to the RESIST v.1.1, the response in all 27 patients was evaluated by a computed tomography (CT) scan before surgery, showing 12 patients with complete response (CR), 12 with partial response (PR), and 3 with stable disease (SD). For surgical procedures, 15 (55.6%) patients underwent minimal invasive surgery, 4 (14.8%) underwent right transthoracic open esophagectomy, and 8 (29.6%) underwent hybrid approaches.ConclusionsThe novel treatment of PD-1 inhibitor with chemotherapy in the neoadjuvant setting for locally advanced ESCC produced satisfactory outcomes: an unprecedentedly high pCR rate for neoadjuvant chemotherapy, a high R0 resection rate, and a low-toxicity profile were achieved. The long-term efficiency of this novel treatment and the validity of the present findings should be confirmed with longer follow-up and prospective comparative trials.

Project description:Lessons learnedRadiotherapy plus anti-PD-1 antibody as first-line therapy is safe and feasible in locally advanced esophageal squamous cell carcinoma (ESCC). Tumor-infiltrating and peripheral lymphocytes were associated with patient survival. Further studies combining chemoradiotherapy with immunotherapy in locally advanced ESCC and exploration of predictive biomarkers are warranted.BackgroundWe conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD-1) monoclonal antibody camrelizumab as first-line treatment for locally advanced esophageal squamous cell carcinoma (ESCC).MethodsWe planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression-free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy.ResultsTwenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow-up time of 31.0 months (95% confidence interval [CI], 27.0-35.1), median OS and PFS times were 16.7 months (95% CI, 5.9-27.9) and 11.7 months (95% CI, 0-30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan-Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD-L1) expression, PD-1+ CD8+ , PD-1+ CD4+ T cells, and PD-L1+ CD4+ T cells; peripheral blood CD4+ , CD8+ , CD4+ regulatory T cells, and their subsets.ConclusionRadiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.

Project description:ImportanceThe prognosis of patients with locally advanced esophageal squamous cell carcinoma (ESCC) remains poor after surgery. Neoadjuvant chemoradiotherapy (NCRT) has been shown to potentially improve survival.ObjectiveTo compare the treatment efficacy of NCRT plus surgery with surgery alone for long-term survival among patients with locally advanced ESCC.Design, setting, and participantsThe Neoadjuvant Chemoradiotherapy for Esophageal Cancer 5010 study was a multicenter open-label randomized phase 3 clinical trial that enrolled patients between June 1, 2007, and December 31, 2014. Follow-up ended on December 31, 2019. The study was conducted at 8 centers in China. A total of 451 patients aged 18 to 70 years with thoracic ESCC stage T1-4N1M0/T4N0M0 were enrolled and randomized. Data were analyzed from December 1, 2019, to June 30, 2020.InterventionsPatients randomized to receive NCRT plus surgery (NCRT group) received preoperative chemotherapy (25 mg/m2 of vinorelbine on days 1 and 8 and 75 mg/m2 of cisplatin on day 1 or 25 mg/m2 of cisplatin on days 1 to 4) every 3 weeks for 2 cycles and concurrent radiotherapy (40.0 Gy, administered in 20 fractions of 2.0 Gy for 5 days per week) followed by surgery. Patients randomized to receive surgery alone (surgery group) underwent surgery after randomization.Main outcomes and measuresThe primary end point was overall survival in the intention-to-treat population. The secondary end point was disease-free survival.ResultsA total of 451 patients (mean [SD] age, 56.5 [7.0] years; 367 men [81.4%]) were randomized to the NCRT (n = 224) and surgery (n = 227) groups and were eligible for the intention-to-treat analysis. By December 31, 2019, 224 deaths had occurred. The median follow-up was 53.5 months (interquartile range, 18.2-87.4 months). Patients receiving NCRT plus surgery had prolonged overall survival compared with those receiving surgery alone (hazard ratio, 0.74; 95% CI, 0.57-0.97; P = .03), with a 5-year survival rate of 59.9% (95% CI, 52.9%-66.1%) vs 49.1% (95% CI, 42.3%-55.6%), respectively. Patients in the NCRT group compared with the surgery group also had prolonged disease-free survival (hazard ratio, 0.60; 95% CI, 0.45-0.80; P < .001), with a 5-year survival rate of 63.6% (95% CI, 56.0%-70.2%) vs 43.0% (95% CI, 36.0%-49.7%), respectively.Conclusions and relevanceIn this randomized clinical trial, treatment with NCRT plus surgery significantly improved long-term overall survival and disease-free survival and therefore may be considered a standard of care for patients with locally advanced ESCC.Trial registrationClinicalTrials.gov Identifier: NCT01216527.