Prospective exploration of a prognostic biomarker of nivolumab for head and neck cancer patients (BIONEXT)

BACKGROUND Nivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors. METHODS Pre-treatment plasmas ( N = 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples ( N = 20) were assayed to elucidate biological implications of the PEX mRNA signature. RESULTS A combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%; P = 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055; P = 0.0002348). In paired samples, PEX HLA-E mRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein ( P = 0.0191) and the dense population of tumor-infiltrating NK cells ( P = 0.024) in the corresponding tumor, suggesting the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade in patients with high PEX HLA-E mRNA. CONCLUSION The PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs. TRIAL REGISTRATION This study is registered to the UMIN Clinical Trial Registry: UMIN000037029. FUNDING This study is partly funded by JSPS KAKENHI (Grant number JP 21436707 to MM) and Sota memorial fund to MM. PEXmRNA analyses were conducted by Showa Denko America Materials. CReS Kyushu organized sample collection and transfer, and conducted clinical data management with funding provided by Ono and Bristol-Myers Squibb. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is partly funded by JSPS KAKENHI (Grant number JP 21436707 to MM) and Sota memorial fund to MM. PEXmRNA analyses were conducted by Showa Denko America Materials. CReS Kyushu organized sample collection and transfer, and conducted clinical data management with funding provided by Ono and Bristol-Myers Squibb. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of the National Kyushu Cancer Center (2019-024) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: pending:yes