OBJECTIVES:Neoadjuvant chemoimmunotherapy has shown promising results for resectable, locoregionally advanced (LA) head and neck squamous cell carcinoma (L/A HNSCC). We published the first phase II trial of neoadjuvant camrelizumab combined with chemotherapy in resectable, L/A HNSCC, demonstrating it was safe and feasible with favorable pathological complete response (pCR). Here, we report the final analysis results for neoadjuvant chemoimmunotherapy in L/A HNSCC (minimum 2.0 years of follow-up). MATERIALS AND METHODS:Three cycles of chemoimmunotherapy were administered before surgery to patients with L/A HNSCC. Two-year disease-free survival (DFS), overall survival (OS) and quality of life (QOL) were reported. RESULTS:The overall two-year DFS and OS rates were 90 % and 100 %, respectively. With a median follow-up of 33.7 months, 9 of 10 (90 %) patients with pCR were alive and disease free. Patients with TNM stage (II/III) or < 20 % of residual viable tumor trended toward improved DFS; hazard ratio (HR), 0.44 [95 % confidence interval (CI), 0.04-5.28] and HR, 0.26 (95 % CI, 0.03-2.36), respectively. All QLQ-C30 functioning and symptom scales other than nausea and vomiting were resolved at 2 years after the completion of radiotherapy. CONCLUSION:Neoadjuvant camrelizumab in combination with chemotherapy provided encouraging clinical outcomes for patients with L/A HNSCC. Further studies with longer follow-up and larger samples are warranted. TRIAL REGISTRATION:Chictr.org.cn, ChiCTR1900025303. Registered Aug 22, 2019. https://www.chictr.org.cn/showproj.html?proj=41380.

Objectives:The study aims to evaluate the efficacy and safety of thoracic radiotherapy in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-treated patients with stage IV non-small-cell lung cancer (NSCLC). Methods:Patients with non-oligometastatic NSCLC harboring EGFR mutations were recruited. All patients received the first-generation TKI treatment with or without radiotherapy. The irradiated sites included primary and/or metastatic lesions. Of all the patients who underwent thoracic radiotherapy, some received radiotherapy before EGFR-TKI resistance, others received radiotherapy after progressive disease. Results:No statistically significant difference was observed in progression-free survival (PFS) (median 14.7 versus 11.2 months, p = 0.075) or overall survival (OS) (median 29.6 versus 40.6 months, p = 0.116) between patients treated with EGFR-TKIs alone and those with additional radiotherapy to any sites. However, EGFR inhibitors with thoracic radiation significantly improved OS (median 47.0 versus 31.0 months, p < 0.001) but not PFS (median 13.9 versus 11.9 months, p = 0.124). Moreover, longer PFS (median 18.3 versus 8.5 months, p < 0.001) was achieved in the preemptive thoracic radiation cohort than in the delayed thoracic radiation cohort. However, OS was similar between the two cohorts (median 40.6 versus 52.6 months, p = 0.124). The lower incidence rate of grade 1-2 pneumonitis occurred in preemptive radiation cohort (29.8% versus 75.8%, p < 0.001). Conclusion:Non-oligometastatic NSCLC patients with EGFR mutations benefited from thoracic radiotherapy while using EGFR inhibitors. Preemptive thoracic radiotherapy could be a competitive first-line therapeutic option due to superior PFS and favorable safety.

Background The failure rate after neoadjuvant chemoradiotherapy followed by surgery is approximately 34.6%–48% for resectable esophageal carcinoma. Pathologic complete response after neoadjuvant chemoradiotherapy is an important factor in predicting lower recurrence and better survival. Whether the sequential addition of immunotherapy to neoadjuvant chemoradiotherapy will be beneficial to improving the pathologic complete response rate is unknown. Methods Patients with pathologically confirmed thoracic esophageal squamous cell carcinoma and at clinical T1-2N1-3M0 or T3-4aN0-3M0 (stage II–IVA) according to the eighth edition of American Joint Committee on Cancer staging will be allocated to receive neoadjuvant radiotherapy (41.4 Gy with 23 fractions to planning target volume) with concurrent chemotherapy (albumin-bound paclitaxel, 100 mg/m 2 , once weekly for five weeks; carboplatin, area under the curve of 2 mg/mL/min, once weekly for five weeks) plus tislelizumab monotherapy sequentially (200 mg every three weeks for three cycles, beginning from the first to the 14th day after the end of radiotherapy). Then, subtotal esophagectomy with two-field lymphadenectomy, including the whole mediastinum and abdomen, will be performed. The primary endpoint for this study is the pathologic complete response rate after neoadjuvant chemoradiotherapy plus tislelizumab. Discussion The optimal timing of the combination of immunotherapy and neoadjuvant chemoradiotherapy in esophageal carcinoma is not determined. The results of this phase II trial will be helpful to clarify the safety and efficacy of the sequential addition of tislelizumab after neoadjuvant chemoradiotherapy for locally advanced resectable esophageal carcinoma. Trial registration This study was approved on January 26, 2021 and retrospectively registered with ClinicalTrials.gov ( NCT04776590 ) on March 1, 2021.

Supplementary Data from Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial

Abstract Purpose: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. Results: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). Conclusions: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

Background: A reliable model is needed to estimate the risk of postoperative recurrence and the benefits of postoperative radiotherapy (PORT) in patients with thoracic esophageal squamous cell cancer (TESCC). Methods: The study retrospectively reviewed 3652 TESCC patients in stage IB-IVA after radical esophagectomy, with or without PORT. In one institution as the training cohort ( n = 1620), independent risk factors associated with locoregional recurrence (LRR), identified by the competing-risks regression, were used to establish a predicting nomogram, which was validated in an external cohort ( n = 1048). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate discrimination. Risk stratification was conducted using a decision tree analysis based on the cumulative point score of the LRR nomogram. After balancing the baseline of characteristics between treatment groups by inverse probability of treatment weighting, the effect of PORT was evaluated in each risk group. Results: Sex, age, tumor location, tumor grade, and N category were identified as independent risk factors for LRR and added into the nomogram. The AUC values were 0.638 and 0.706 in the training and validation cohorts, respectively. Three risk groups were established. For patients in the intermediate- and high-risk groups, PORT significantly improved the 5-year overall survival by 10.2% and 9.4%, respectively ( p < 0.05). Although PORT was significantly associated with reduced LRR in the low-risk group, overall survival was not improved. Conclusion: The nomogram can effectively estimate the individual risk of LRR, and patients in the intermediate- and high-risk groups are highly recommended to undergo PORT.

BACKGROUNDThe role of postoperative radiotherapy in pathological T2-3N0M0 esophageal squamous cell carcinoma is unknown. We aimed to evaluate the efficacy and safety of postoperative radiotherapy in patients with pathological T2-3N0M0 thoracic esophageal squamous cell carcinoma.MATERIALS AND METHODSPatients aged 18-72 years with pathological stage T2-3N0M0 esophageal squamous cell carcinoma after radical surgery and without neoadjuvant therapy were eligible. Patients were randomly assigned to surgery alone or to receive postoperative radiotherapy of 50.4 Gy in supraclavicular field and 56 Gy in mediastinal field in 28 fractions over 6 weeks. The primary endpoint was disease-free survival. The secondary endpoints were local-regional recurrence rate, overall survival, and radiation-related toxicities.RESULTSFrom October 2012 to February 2018, 167 patients were enrolled in this study. We analyzed 157 patients whose follow-up time was more than 1 year or who had died. The median follow-up time was 45.6 months. The 3-year disease-free survival rates were 75.1% (95% confidence interval [CI] 65.9-85.5) in the postoperative radiotherapy group and 58.7% (95% CI 48.2-71.5) in the surgery group (hazard ratio 0.53, 95% CI 0.30-0.94, p = .030). Local-regional recurrence rate decreased significantly in the radiotherapy group (10.0% vs. 32.5% in the surgery group, p = .001). The overall survival and distant metastasis rates were not significantly different between two groups. Grade 3 toxicity rate related to radiotherapy was 12.5%.CONCLUSIONPostoperative radiotherapy significantly increased disease-free survival and decreased local regional recurrence rate in patients with pathological T2-3N0M0 thoracic esophageal squamous cell carcinoma with acceptable toxicities in this interim analysis. Further enrollment and follow-up are warranted to validate these findings in this ongoing trial.IMPLICATIONS FOR PRACTICEThe value of adjuvant radiotherapy for patients with node-negative esophageal cancer is not clear. The interim results of this phase III study indicated that postoperative radiotherapy significantly improved disease-free survival and decreased local-regional recurrence rate in patients with pathological T2-3N0M0 thoracic esophageal squamous cell carcinoma compared with surgery alone with acceptable toxicities. The distant metastasis rates and overall survival rates were not different between the two groups. Adjuvant radiotherapy should be considered for pathologic T2-3N0M0 thoracic esophageal squamous cell carcinoma. Prospective trials to identify high-risk subgroups are needed.

Background Information on the optimal salvage regimen for recurrent esophageal cancer is scarce. We aimed to assess the patterns of locoregional failure, and evaluate the therapeutic efficacy of salvage therapy along with the prognostic factors in recurrent thoracic esophageal squamous cell carcinoma (TESCC) after radical esophagectomy. Methods A total of 193 TESCC patients who were diagnosed with recurrence after radical surgery and received salvage treatment at our hospital were retrospectively reviewed from 2004 to 2014. The patterns of the first failure were assessed. The post-recurrence survival rate was determined using the Kaplan-Meier method and analyzed using the log-rank test. Multivariate prognostic analysis was performed using the Cox proportional hazard model. Results The median time of failure was 7.0 months. Among the 193 patients, 163 exhibited isolated locoregional lymph node (LN) recurrence and 30 experienced locoregional LN relapse with hematogenous metastasis. Among the 193 patients, LN recurrence was noted at 302 sites; the most common sites included the supraclavicular (25.8%; 78/302) and mediastinal LNs (44.4%; 134/302), particularly stations 1 to 6 for the mediastinal LNs (36.4%; 110/302). The median overall survival (OS) was 13.1 months after recurrence. In those treated with salvage chemoradiotherapy, with radiotherapy, and without radiotherapy, the 1-year OS rates were 68.5, 55.0, and 28.6%; the 3-year OS rates were 35.4, 23.8, and 2.9%; and the 5-year OS rates were 31.8, 17.2, 2.9%, respectively ( P < 0.001). Furthermore, patient survival in those who received salvage chemoradiotherapy was significantly better than those treated with salvage radiotherapy alone ( P = 0.044). Multivariate analysis showed that the pathological TNM stage and salvage treatment regimen were independent prognostic factors. Conclusions Supraclavicular and mediastinal LN failure were the most common types of recurrence after R0 surgery in TESCC patients. Salvage chemoradiotherapy or radiotherapy could significantly improve survival in esophageal cancer with locoregional LN recurrence.

Background: Targeted metabolomics was utilized in case studies of non-small cell lung cancer (NSCLC) to develop and test metabolite classifiers in serum as potential biomarkers for new lung cancer diagnostic strategies, cancer staging, and subtype determination in the Chinese population. Methods: A total of 77 samples, including 45 NSCLC patients from stage I to IV, and 32 healthy controls were included in this study. After serum extraction, metabolic assays based on a wide range of targeted metabolome technologies and the UPLC-MS-MS detection platform were performed to detect metabolites in them. Custom database and multivariate statistical analysis were utilized to evaluate the difference of metabolome between different arms. Results: A total of 296 metabolites were detected in all samples, of which 81 were found differentially expressed among lung cancer patients and controls. While the principal component analysis indicated that the metabolome analysis is clearly powerful in differentiating lung cancer patients from normal controls, no significant differences in the serum metabolites between different lung cancer stages or between adenocarcinoma and squamous cell carcinoma were observed. Conclusions: This study showed the power of the novel UPLC-MS/MS platform in serum metabolic profiling for the detection of NSCLC, which might provide new potential tumor biomarkers and can accelerate the development of new diagnostic strategies in NSCLC.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have significantly changed the landscape of cancer treatment, but the response rate of non-small-cell lung carcinoma (NSCLC) to ICIs is less than 30%. Tumor mutational burden (TMB) is the most promising predictive biomarker for NSCLC immunotherapies. However, some NSCLC patients with high-TMB have little response to ICIs. The neoantigen intratumor heterogeneity (ITH), which determined by the ratio of subclonal neoantigen in the tumor, has been verified to be a potential therapeutic biomarker for immunotherapies in some cancer types. Pulmonary pleomorphic carcinoma, a rare subtype of pulmonary sarcomatoid carcinoma, has been shown to respond remarkably to ICIs, but the biomarkers for ICIs in pulmonary pleomorphic carcinoma have not been fully proven. CASE PRESENTATION:A 57 years old female pulmonary pleomorphic carcinoma patient, who underwent surgery, chemotherapy, anti-angiogenic therapy, radiotherapy, and anti-PD1 therapy, with disease relapse at the last, was included in this study. Primary and relapse tumor samples were collected for gene sequencing by a target sequencing panel which covered 811 cancer genes, during ICIs treatment. Peripheral bloods were collected for ctDNA and T cell receptor sequencing every two months. The results showed that the TMB (>10 muts/Mb) was high, but the clonal neoantigen load (1.33 neos/Mb) was low. The neoantigen ITH was increased after chemotherapy and radiotherapy with a score at nearly 0% in the primary tumor but increased to 85.72% in relapse tissues. The clonal neoantigen ratio detected by ctDNA was increased ~0.8 fold, while the high-frequency clonotypes of TCR to neoantigens dropped during ICIs treatment. CONCLUSIONS:Our results indicated that cytotoxic chemotherapy and radiotherapy can induce the subclonal neoantigens production and increase the neoantigen ITH, thus might negatively regulating patients’ response to ICIs therapy. These results highlight that the neoantigen ITH might be an important auxiliary to TMB in predicting patient response to immune therapies. More studies and clinical trials are needed to further validate these results. Citation Format: Xiaohua Hong, Yuting Liu, Yiying Liu, Yue Hu, Qifan Yang, Di Wu, Kai Zhang, Yongchao Li, Jinsong Yang, Jiaqian Wang, Jun Liu, Li Liu. Radiation and chemotherapies result in increasing neoantigen intratumor heterogeneity and resistance to nivolumab in a patient with pleomorphic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3229.

Objectives: Immune checkpoint blockades, such as PD-1/PD-L1 inhibitors, has recently shown remarkable clinical benefit in many types of cancers. Recent studies have revealed that TMB is highly correlated with immunotherapy efficacy. In this study, a method for evaluating TMB using CGP was established.

RATIONALE:Although lung cancer is the leading cause of cancer-related death in the world, targeted therapy plays an essential role in improving the survival of lung cancer. Next-generation sequencing (NGS) technology can dynamically monitor the genomic profiles of tumors and assist cancer diagnosis and treatment.PATIENT CONCERNS:We reported on a 55-year-old man who presented with chest tightness and wheezing for 1 month.DIAGNOSES:The patient was diagnosed with stage cT4N2M1a non-small cell lung cancer (NSCLC) and was found to have wild-type EGFR by pleural effusion cytology.INTERVENTIONS:The patient received systemic treatments, including chemotherapy, targeted therapy, and radiotherapy. During the cancer development, sequential DNA sequencing data that used circulating cell-free tumor DNA, and NGS revealed EGFR L858R and T790M mutations, MYC amplification, and other gene variations.OUTCOMES:The patient died of brain and lung metastases, and had an overall survival as long as 37 months.LESSONS:The dynamic monitoring of tumor genomic profiles has important implications for NSCLC diagnosis, treatment, and prognosis.

8520 Background: Although PD-L1 positivity improves immunotherapy efficacy, PD-L1 testing alone is insufficient for patient selection in most malignancies. High tumor mutational burden (TMB) is an emerging positive biomarker of immunotherapy in a growing number of malignancies. In this study, a method for TMB by cancer-gene panel (CGP) was set up, by which TMB from Chinese lung adenocarcinoma samples was measured to analyze the association between TMB and genes alterations in the implications for immunotherapy. Methods: The accuracy of TMB detection by our CGP was confirmed from data of TCGA and whole exome sequencing (WES) in our clinical samples. TMB detection method by CGP was further validated from sequencing accuracy, coefficient of variation, and the limit of detection of tumor purity. The level of TMB in Chinese lung adenocarcinoma samples and its correlation with genes alterations were then analyzed. Results: In our study, TMB measured by CGP has a high correlation with that measured by WES in 31 clinical tumor samples (R2= 0.9111). Immunotherapy from the Rizvi cohort confirmed the accuracy of TMB detection by CGP. The mean level of TMB measured by CGP from 599 Chinese lung adenocarcinoma samples was similar with that from 389 TCGA lung adenocarcinoma samples (7.29 vs 7.6 mutations/Mb). We found that high level of TMB was significantly correlated with several genes alterations including TP53, KRAS and genes in DNA damage response pathway as BRCA1/2, ATR, CHEK2, POLE and MMR genes. However, low level of TMB was correlated with EGFR and ALK alteration obviously. Of note, we first discovered that the level of TMB was lower in the early stage lung adenocarcinoma compared with that in the late stage lung adenocarcinoma from Chinese clinical samples. Conclusions: TMB calculated by CGP and WES was highly correlated via analyzing data both from TCGA and our tumor samples. We found that the level of TMB was effected by several genes alterations in the analysis of our samples. We also found that the low level of TMB might imply a poor effect of mono-immunotherapy in the treatment of early stage lung adenocarcinoma. Of note, combining immunotherapy with DNA damaging agents could be a good way to improve efficacy.

Programmed death‐ligand 1 (PD‐L1) expression either indicates immune inhibitory status or concurrent immune response. Although the relationship between PD‐L1 and clinical outcomes has been studied widely in recent years, its role in prognosis of esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we assessed the significance of PD‐L1 in ESCC and its association with epidermal growth factor receptor (EGFR) and radiation response. We found that PD‐L1 was present both on the surface of tumor cells and tumor‐infiltrating immune cells. Patients with tumor‐infiltrating immune cell PD‐L1 expression had better survival. PD‐L1 expression on immune cells was an independent prognostic factor for patients with ESCC. PD‐L1 expression either on tumor‐infiltrating immune cells or tumor cells was negatively associated with EGFR expression. EGFR/PD‐L1 pairs could separate the survival between EGFR low/PD‐L1 positive and EGFR high/PD‐L1 negative groups. In ESCC cell lines with EGFR high expression, PD‐L1 expression was induced significantly when EGFR signaling was activated by radiation and was dramatically inhibited by an EGFR tyrosine kinase inhibitor. In conclusion, tumor‐infiltrating immune cell PD‐L1 expression is an independent prognostic factor for ESCC, and the association between EGFR and PD‐L1 is vital to determining survival. It is important to consider radiotherapy‐induced imbalance of pro‐tumor and anti‐tumor immune response. A combination of radiotherapy and PD‐L1‐targeted therapy could be a promising therapeutic strategy for ESCC patients.

Introduction: The role of conformal radiotherapy (cRT) in thoracic esophageal squamous cell carcinoma (TESCC) has not been addressed in adjuvant settings. The aim of this study was to investigate whether postoperative radiotherapy using cRT after an R0 resection improves outcomes in pT3N0M0 TESCC compared with resection alone.Methods: This study included 678 patients with pT3N0M0 TESCC who were treated at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2004 to December 2011. The patients were divided into two groups: a surgery plus cRT group (S+cRT group) comprising patients who underwent cRT after an R0 resection and a surgery group (S group), comprising a control group of patients who underwent an R0 resection alone. Propensity score matching was used to create patient groups that were balanced across several covariates (n = 83 in each group). Outcome measures included overall survival (OS), disease free survival (DFS), and recurrence.Results: In the overall study cohort, 5-year OS (75.2% versus 58.5%, p = 0.004) and DFS (71.8% versus 49.2%, p = 0.001) rates were significantly higher in the S+cRT group than in the S group. These data were confirmed in the matched samples (5-year OS, 75.7% versus 58.8% [p = 0.017]; DFS, 71.7% versus 50.3% [p = 0.009]). The overall (p = 0.001) and locoregional (p = 0.004) recurrence rates in the S+cRT group were significantly lower than in the S group. Multivariate Cox analyses in the matched samples revealed that surgery and postoperative cRT were independently associated with longer OS (hazard ratio = 0.505, 95% confidence interval: 0.291-0.876, p = 0.015) and longer DFS (hazard ratio = 0.513, 95% confidence interval: 0.309-0.854, p = 0.010) than resection alone.Conclusions: Postoperative radiotherapy using cRT is strongly associated with improved OS and DFS in patients with pT3N0M0 TESCC. A multicenter, randomized phase III clinical trial is warranted to confirm these findings. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.