Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma

Abstract

Background: Camrelizumab and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the safety and efficacy of camrelizumab plus neoadjuvant chemotherapy, using pathologically complete response (pCR) as primary endpoint, in the treatment for locally advanced ESCC.

Methods: Patients with locally advanced but resectable thoracic ESCC, staged as T1b-4a, N2-3 (≥3 stations), and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes) were enrolled. Eligible patients received intravenous camrelizumab (200 mg, day 1) plus nab-paclitaxel (100 mg/m², day 1, 8, 15) and carboplatin (area under curve of 5 mg/mL/min, day 1) of each 21-days cycle, for two cycles before surgery. The primary endpoint is pCR rate in the per-protocol population. Safety was assessed in the modified intention-to-treat population that was treated with at least one dose of camrelizumab.

Results: From November 20, 2019 to December 22, 2020, 60 patients were enrolled. 55 (91.7%) patients completed the full two-cycle treatment successfully. 51 patients underwent surgery and R0 resection was achieved in 50 (98.0%) patients. pCR (ypT0N0) was identified in 20 (39.2%) patients and 5 (9.8%) patients had complete response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). 58 patients (96.7%) had any-grade treatment-related adverse events (TRAEs), with the most common being leukocytopenia (86.7%). 34 patients (56.7%) had adverse events of grade 3 or worse, and one patient (1.7%) occurred a grade 5 adverse event. There was no in-hospital and postoperative 30-day as well as 90-day mortality.

Conclusions: The robust antitumor activity of camrelizumab and chemotherapy was confirmed and demonstrated without unexpected safety signals. Our findings established camrelizumab and chemotherapy as a promising neoadjuvant treatment for locally advanced ESCC.

Trial registration number: ChiCTR1900026240.

Keywords: Clinical Trials, Phase II as Topic; Combined Modality Therapy; Immunotherapy.

Figure 1

Waterfall plot of pathological tumor regression in the per-protocol population (n=51). Each bar represents one patient. The upper column shows clinical characteristics and radiological responses. CPS, Combined Positive Score; LLD, lesion longest diameter; LN, lymph node; SDL, short diameter of the largest; TPS, Tumor Proportion Score.

Figure 2

Correlation of radiological response and pathological tumor regression. (A) Pathological regression was marginally correlated with radiological response by RECIST assessment (p=0.046). (B) LLD reduction was positively correlated with SUVmax reduction of primary tumor (p=0.005). (C) LLD reduction was not correlated with SDL reduction (p=0.750). (D) LLD reduction was positively correlated with pathological tumor regression (p<0.001). (E) SDL reduction was not correlated with pathological tumor regression (p=0.842). (F) SUVmax reduction of primary tumor was positively correlated with pathological tumor regression (p<0.001). LLD, lesion longest diameter; PCR, pathologically complete response; SDL, short diameter of the largest.

Figure 3

Case of radiological responses after neoadjuvant camrelizumab and chemotherapy. CT and PET-CT images before (upper row) and after (lower row) neoadjuvant treatment of patient 57 were compared. This shows the radiological images of a 67-year-old man with a stage III ESCC before neoadjuvant treatment. CT and PET-CT shows significant shrinkage and SUVmax reduction for the primary tumor and suspected lymph nodes, respectively. This patient achieved pathological regression of 95% for esophageal lesion with no residual lymph node metastasis according to surgical specimen. ESCC, esophageal squamous cell carcinoma; RLN, recurrent laryngeal nerve.

Figure 4

Association between biomarkers and pathological regression. (A–D) PD-L1 scores and relationship to pathological regression. (E) Comparison of TMB between the PCR and non-pCR groups. (F) Distribution of TMB and the percentage of residual viable tumor cells. The dashed black line indicates the linear regression line. CPS, Combined Positive Score; PCR, pathologically complete response; TMB, tumor mutational burden; TPS, Tumor Proportion Score; TRG, tumor regression grade.