A pilot study of hypoxia as a potential resistance mechanism to PD-1 checkpoint blockade therapy in neoadjuvant treatment of esophageal squamous cell carcinoma (HYPERION)

BackgroundImmune checkpoint inhibitors as neoadjuvant regimen showed promising efficacy among patients with esophageal squamous cell carcinoma (ESCC), whereas hypoxia, triggered by rapid oxygen consumption, could be a potential mechanism of resistance in immunotherapy.MethodsA phase II, prospective trial was conducted in Fudan University Shanghai Cancer Center. Before surgery, patients with locally advanced ESCC (T2-4aN0-3M0) were treated with pembrolizumab, paclitaxel and cisplatin. The primary outcome was efficacy (Pathological complete response [pCR]). Tumor samples of pre- and post-treatment were performed scRNA-seq, RNA-seq, IHC and multiplex IHC (mIHC). Hypoxia-induced factors were evaluated between responders (major pathological response [mPR]) and non-responders.ResultsBetween Feb 22nd and Nov 2nd in 2023, a total of 128 patients received neoadjuvant chemoimmunotherapy, of which 117 (91.4%) completed two cycles of treatments. By Jan 31st, 2024, majority of treatment-related adverse events were minor, and no immunotherapy related death was observed. Of the 111 patients who had surgery, 67 (60.4%) underwent Ivor Lewis and 44 (39.6%) underwent McKeown procedures. There were 98 (88.3%) patients had two-field lymphadenectomy. Postoperative mortality was 0.9% (1/111). There were 18 (16.2%) Tis/T0, 19 (17.1%) T1, 31 (27.9%) T2, 39 (35.1%) T3 and 4 (3.6%) T4 tumors, respectively. pCR was observed in 16 patients (14.4%), while MPR (≤10% residual tumor) in 42 (37.8%). Hypoxia associated immunotherapy resistance mechanism was investigated via multi-omics analysis of 128 baseline and 111 surgical samples with scRNAseq and bulk RNAseq combined with mIHC. In addition, preliminary translational analysis results indicated hypoxia as immunotherapy resistance mechanism.ConclusionsEsophagectomy after chemoimmunotherapy with pembrolizumab is effective with acceptable surgical risk and tumor response rates.Hypoxia could be a potential mechanism of resistance in immunotherapy.Clinical trial identificationNCT05281003.Legal entity responsible for the studyThe authors.FundingSupported in part by a research grant from Investigator-Initiated Studies Program of MSD.DisclosureAll authors have declared no conflicts of interest.