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Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study.

ABSTRACT: Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m²] plus docetaxel [25 mg/m²] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9-24.5), OS and PFS time ranged from 8.2-28.5 and 4.0-28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c⁺ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.

SUBMITTER: Zhang W

PROVIDER: S-EPMC8489938 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:BackgroundThe gut microbiome is associated with the response to immunotherapy in a variety of advanced cancers. However, the influence of the gut microbiome on locally advanced esophageal squamous cell carcinoma (ESCC) during programmed cell death protein 1 (PD-1) antibody immunotherapy plus chemotherapy is not clearly demonstrated. To explore the crosstalk between the gut microbiome and clinical response in locally advanced thoracic ESCC during neoadjuvant camrelizumab and chemotherapy.MethodsPatients who were diagnosed with locally advanced thoracic ESCC and had not received treatment were enrolled. The treatment regimen was two cycles of camrelizumab combined with carboplatin and albumin paclitaxel before surgery. The research endpoints were pathological complete response (pCR) and major pathological response (MPR). Fecal samples were collected at three time points: before neoadjuvant therapy, after two cycles of neoadjuvant therapy, and after surgery. We performed 16S ribosomal ribonucleic acid (rRNA) V3-V4 sequencing of the gene amplicons of fecal samples, as well as bacterial diversity and differential abundance analyses.ResultsA total of 46 patients were recruited, and 44, 42, and 35 fecal samples were collected at the three time points, respectively. Statistically significant differences were observed in the amplicon sequence variant (ASV)-level alpha diversity indices, including Chao1, Shannon, and Good's coverage, between the three time points. The non-pCR-enriched gut microbiota included Proteobacteria, Dialister, Aeromonadales, Pseudomonadales, Thermi, Deinococci, Moraxellaceae, Rhodocyclales, Rhodocyclaceae, and Acinetobacter. The non-MPR-enriched gut microbiota included Pseudomonadales and the mitochondria family. The MPR-enriched gut microbiota included the Barnesiellaceae, Pyramidobacter, Dethiosulfovibrionaceae, Odoribacteraceae, Butyricimonas, Prevotella, Barnesiella, and Odoribacter. Patients with ≥3 grade adverse events (AEs) exhibited enrichment in the Succiniclasticum, Nakamurella, Rhizobium, Granulicella, Phyllobacteriaceae, Pelagibacteraceae, Actinosynnemataceae, Aquirestis, Flavisolibacter, Chelativorans, Coxiellaceae Acidicapsa, Acidobacteriaceae, Lentzea, Staphylococcus, Plesiomonas, Dysgonomonas, Pseudonocardia, and Ellin6075.ConclusionsWe found that the diversity of the gut microbiome declined after neoadjuvant PD-1 antibody immunotherapy plus chemotherapy and surgery. Patients with pCR had different types and proportions of gut microbiota before treatment compared to those without pCR. We also observed the difference between patients with or without ≥ grade 3 AEs. The taxonomic features of the gut microbiome are potential biomarkers that could predict the pathological response and AEs.

Project description:Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age <or=75 years, and adequate organ function were eligible. Both docetaxel and cisplatin were given on days 1, 8, 29, and 36. Doses of docetaxel/cisplatin (mg m(-2)) in the phase I study portion were escalated as follows: 20/30, 25/30, 30/30, 30/35, 30/40, 35/40, 40/40, and 45/40. Beginning on day 1 of chemotherapy, thoracic radiotherapy was given at a total dose of 60 Gy with 2 Gy per fraction over 6 weeks. In the phase I portion, the maximum tolerated doses (MTD) among 33 patients were docetaxel 45 mg m(-2) and cisplatin 40 mg m(-2). The major dose-limiting toxicity (DLT) was radiation oesophagitis. The recommended doses (RDs) for the phase II study were docetaxel 40 mg m(-2) and cisplatin 40 mg m(-2). A total of 42 patients were entered in the phase II portion. Common toxicities were leukopenia, granulocytopenia, anaemia, and radiation oesophagitis, with frequencies of grade >or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.

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Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study.

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