tbuckley/cabot-search huggingface dataset:
Efficacy and safety of camrelizumab combined with apatinib in previously treated recurrent or metastatic nasopharyngeal carcinoma: A phase II clinical trial.
Authors: Lin-Quan Tang, Guo-Dong Jia, xiao-Fei Lv, Siyi Xie, Yu Chen, Ji-Bin Li, Xiao Yun Li, Manyi Zhu, Sai Lan Liu, LiTing Liu, Xue-Song Sun, Shanshan Guo, Dong-Hua Luo, Qiu-Yan Chen, Hai-Qiang Mai
Journal: Journal of Clinical Oncology (2022)

6042 Background: The synergistic antitumour effect immune checkpoint inhibitors combined with antiangiogenic targeted therapy in refractory RM-NPC patients remains unknown. This phase 2 trial assessed the efficacy and safety of camrelizumab (an anti-programmed death 1 [PD-1] inhibitor) plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) after at least first-line therapy in refractory RM-NPC patients. Methods: We did a phase 2 single-armed study to evaluate the activity of camrelizumab plus apatinib in platinum-resistant (cohort 1) and PD-1 inhibitor resistant (cohort 2) NPC. Eligibility required measurable disease (RECIST 1·1), Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, age of 18-75 years, and disease progression on platinum but PD-1 inhibitor-naive (cohort 1) or disease progression on PD-1 inhibitor (cohort 2) after at least first-line therapy. Patients in cohort 1 received 200 mg intravenous camrelizumab every 3 weeks plus 250 mg oral apatinib daily. Patients in cohort 2 received apatinib monotherapy in the first two weeks to modify the immune-resistant microenvironment, and were then administered camrelizumab plus apatinib until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). This study was registered with ClinicalTrials.gov (NCT04547088, NCT04548271). Results: From August 20, 2020 to September 6, 2021, 72 patients were enrolled into the trial: 40 patients were enrolled in cohort 1 and 32 in cohort 2. Median follow-up was 13.1 months (IQR 10.0-15.2 months) for cohort 1 and 9.0 (5.9-10.7) months for cohort 2. Among the 40 evaluable patients in cohort 1, an objective response was achieved by 26 (65%; 95% CI, 49.6-80.4). A total of 16 (40%) patients had tumor progression, and the median PFS was not reached. Among the 32 evaluable patients in cohort 2, an objective response was achieved by 11 (34.4%; 95% CI, 17.0-51.8). A total of 22 (69%) patients had tumor progression, and the median PFS was 6.0 months (95% CI, 4.4 to 7.6). Grade ≥ 3 treatment-related adverse events (TRAE) were reported in 34 (47.2%) of 72 patients, with the most common TRAE being hypertension (18.1%), an increase of serum transaminase (13.9%) and hand and foot syndrome (12.5%). No treatment-related deaths occurred. Conclusions: In patients with platinum-resistant or PD-1 inhibitor resistant RM-NPC, camrelizumab plus apatinib achieved promising outcomes. Further studies of the camrelizumab plus apatinib treatment regimen are warranted in a phase 3 trial. Clinical trial information: NCT04547088, NCT04548271.
Imaging biomarkers of collagen architecture on baseline biopsies in association with response in patients with head and neck squamous cell carcinoma treated with immunotherapy.
Authors: Reetoja Nag, Haojia Li, Germán Corredor, Paula Toro, Vidya Sankar Viswanathan, Pingfu Fu, James Lewis, Jay Wasman, Theodoros Nicholas Teknos, Monaliben Patel, Quintin Pan, Anant Madabhushi
Journal: Journal of Clinical Oncology (2022)

6047 Background: Though immunotherapy (IO) has robust clinical efficacy, only a subset of head and neck squamous cell carcinoma (HNSCC) patients have shown to benefit from it. Collagen, a major component of the Tumor Microenvironment (TME), is involved in cancer fibrosis and collagen fiber organization has been shown to be associated with patient outcome for different cancers. In this work, we evaluated whether computationally extracted collagen fiber orientation disorder (CFOD) features from tumor related stroma regions (TS) in digitized H&amp;E-stained slides can help in distinguishing between responders and non-responders to immunotherapy in HNSCC patients. Methods: Whole slide images (WSIs) from 43 HNSCC patients treated with immunotherapy (23 non-responders and 20 responders) were obtained from University Hospitals, Cleveland; response was defined as per RECIST v1.1. A derivative-of-Gaussian model was used to identify collagen fiber orientations in TS of the digitized WSIs. Different statistics (e.g. mean, standard deviation, skewness) of the various disorder descriptors (e.g., contrast and entropy) were calculated across all the neighborhood windows in the tumor region to generate the final CFOD feature set. Minimum Redundance Maximum Relevance algorithm was employed to identify the top 3 features, which were combined with a Naive Bayes classifier to differentiate between responders and non-responders. Cross-validation was used to validate the classifier over 100 iterations via the area under the receiver operating characteristics curve (AUC). Multivariable analysis was done using a logistic regression method to see how different parameters (gender, age, smoking status) will affect IO response. Results: WSIs of responders to immunotherapy showed more disorganized collagen fiber structure as compared to non-responders WSIs. The selected top 3 features were related to the contrast feature descriptor from the orientation co-occurrence matrix. The average AUC for the model based on CFOD was 0.77±0.24. The results for multivariable analysis are shown in Table 1. Conclusions: We demonstrated an association between the architectural organization of collagen fiber from baseline biopsies of HNSCC patients with response to immunotherapy. Furthermore, we demonstrate a classifier based on computationally derived CFOD features able to derive detailed assessments of collagen orientation. None of the parameters analyzed were significantly associated with change in IO response (p&lt;0.05). Further validation on a larger independent cohort is warranted. Multivariable analysis for IO response. Parameter p value Gender (Male/Female) p=0.14 Age (&lt;60 years/≥60years) p=0.19 Smoking status (Yes/No) p=0.54
Infections and their impact on patients on pembrolizumab-based therapies for head and neck cancer.
Authors: Yuqi Zhang, Jiaqiong Xu, Ibrahim Muhsen, Ethan Burns, Shivan M Shah, Godsfavour Umoru, Charisma Mylavarapu, Kai Sun, Aubrey Crenshaw, Abdullah Esmail, Ryan Blair Kieser, Carlo Guerrero, Zimu Gong, Kelly Gee, Kirk Heyne, Monisha Singh, Jun Zhang, Maen Abdelrahim
Journal: Journal of Clinical Oncology (2022)

6035 Background: Immune checkpoint inhibitors (ICIs) stimulate the antitumor activity of the adaptive immune response and are used in combination with chemotherapy or as a monotherapy in metastatic head and neck squamous cell carcinoma (mHNSCC). Infections are known to impact outcomes in patients receiving chemotherapy, but the incidence and impact in patients receiving ICI is poorly defined. This analysis aims to identify the infectious burden and associated impact on clinical outcome in patients receiving pembrolizumab for mHNSCC. Methods: This is a retrospective study across 7 hospitals analyzing patients who received pembrolizumab from 1/1/2017-8/1/2021 and followed until 12/1/2021. Patients with mHNSCC that received pembrolizumab were dichotomized into infected and uninfected cohorts. Comparative covariates included gender, race, ECOG, comorbidities, anti-infectives use at ICI initiation, chronic infections, line of therapy (first or 1L, second or 2L, or &gt; 2L). Risk factors for infections were assessed by univariable and multivariable analysis with reported odds ratio (OR) and 95% confidence intervals (CI). Morbidity and mortality was assessed by all-cause emergency department (ED), inpatient, and intensive care unit (ICU) admissions, median cycles of ICI-based therapy, and overall survival (OS). OS was assessed via Kaplan-Meier analysis. P-value &lt; 0.05 was considered statistically significant. Results: Of the 45 evaluable patients with mHNSCC, 22 (48.9%) had at least one infection. Baseline characteristics and comorbidities were similar across cohorts. Risk factors for developing infection included anti-infective use at ICI initiation (OR 13.27, 95% CI: 1.13-156.53, p = 0.04). Fewer infections were observed with ICI as &gt; 2L compared to 1L (OR 0.1, 95% CI: 0.01-0.91, p = 0.041). Infection was the primary cause of death in 2 (9.5%) patients. Compared to the uninfected, infected patients received fewer cycles of therapy (4 vs 7, p = 0.026), and were more frequently admitted to the hospital [20 (90.9%) vs. 8 (34.8%), p &lt; 0.001)] and ICU [5 (11%) vs. 0, p = 0.022]. Number of ED visits were similar at 8 (36.4%) in the infected vs. 5 (21.7%) in the uninfected (p = 0.28). At median follow-up of 8 months, 13 (59.1%) in the infected cohort and 8 (34.8%) in the uninfected had died (p = 0.1). Median OS was significantly lower in the infected (9.2; 95% CI 4.9-12.8 months) compared to the uninfected (28.1; 95% CI 14.3-unreached months) (p = 0.009). Conclusions: For mHNSCC patients on pembrolizumab, infections are more common in the 1L setting and is associated with fewer treatment cycles, more hospitalizations, and significantly shorter OS. Risk factors for infection include anti-infective use at ICI initiation.
Comprehensive immune landscape and molecular characteristics of clinical responses to chemotherapy, antiangiogenic agents, and PD-1 inhibitors in recurrent or metastatic nasopharyngeal carcinoma.
Authors: Mingyuan Chen, You Rui, Xiong Zou, Zhang Meng-Xia, Weijing Zhang, Xi Ding, Xiao Wang
Journal: Journal of Clinical Oncology (2022)

6028 Background: The role of a triple combination of gemcitabine (chemotherapy) plus apatinib (anti-VEGF) and toripalimab (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma is unclear. Methods: Between August 2019 and April 2020, 54 patients with recurrent or metastatic NPC were screened, of whom 41 eligible patients were enrolled and received study treatment. Patients were treated with gemcitabine (1000 mg/m 2 ) on days 1 and 8 once every 3 weeks for a maximum of 6 cycles plus toripalimab (240 mg) on day 1 once every 3 weeks and apatinib (orally administered at 250 mg) once a day until disease progression, death, dose-limiting toxicities, or at the patient’s request to stop. The primary endpoint was the safety. The secondary endpoints included the objective response rate (ORR) and progression-free survival (PFS). Results: By the data cutoff date, the median follow-up time was 13.4 months. G3-4 hematologic, gastrointestinal and kidney toxicities were observed in no more than 3 (3/41, 7.3%) patients, while G3-4 nasopharyngeal wall necrosis was observed in 9 (9/41, 21.9%) patients. High-risk factors for nasopharyngeal necrosis, included repeated radiotherapy and an interval of less than 12 months from the last radiotherapy. Among all 41 patients, the ORR was 90.2% (95% CI: 76.9%-97.2%). The median PFS was 13.93 months (95% CI: NR-NR), and the 12-month PFS rate was 72.0% (95% CI: 57.1%-86.9%). A substantial increase of CD28+ and ICOS+ CD4+/CD8+ T cells and a decrease of PD1+ CD4+/CD8+ T cells were observed in the peripheral blood after the GAT treatment. 11q13.3 amplification and MRGPRF high expression in tumors correlated with poor PFS from the triple combination therapy. NPCs with 11q13.3 amplification was characterized by high epithelial mesenchymal transition (EMT) and immune suppressive transcriptional signatures. Furthermore, serial circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to combination therapy. Conclusions: The triple combination of GAT exhibits a promising antitumor activity and manageable toxicities in patients with recurrent/metastatic NPC. Patients with repeated radiotherapy and an interval of less than 12 months from the last radiotherapy should be carefully selected for antiangiogenic therapies. An integrated genomic and transcriptional analyses may aid to identify the beneficial patient populations in response to this novel combination therapy. Clinical trial information: NCT04073784.
Predictors of the survival for platinum-refractory head and neck squamous cell carcinoma by using contrast-enhanced magnetic resonance imaging.
Authors: Hsueh-Ju Lu, Chao-Yu Shen, Yu-Wei Chiu, Chih-Yu Peng, Hsien-Chun Tseng, Chung-Han Hsin, Chun-Yi Chuang, Chun-Chia Chen, Ming-Fang Wu, Wei-Shiou Huang, Wei-Chih Shen
Journal: Journal of Clinical Oncology (2022)

6038 Background: Platinum-refractory head and neck squamous cell carcinoma (HNSCC) was a poor prognosis. Under the treatment of immune checkpoint therapy, overall survival (OS) was still only 7.7 months. Moreover, the prognostic factors were unclear. Methods: For enrolled platinum-refractory HNSCC patients, the presented images of the axial, coronal, and sagittal planes from T1-Weighted Contrast-Enhanced Magnetic Resonance Imaging (T1 CE MRI) were independently reviewed by two physicians. First, the most representative characteristics of the recurrent tumor on the three planes were manually identified, and the intersection coordinate was calculated as a circle center by computerized methods. Then, the center delineated a region of interest (ROI) with a radius of 25 pixels on each representative slice and excluded the air areas. Descriptive features and four groups of texture features (Gray Level Co-occurrence Matrix [GLCM], Gray Level Run Length Matrix [GLRLM], Gray Level Size Zone Matrix [GLSZM], and Neighbouring Gray Tone Difference Matrix [NGTDM]) were derived from the ROI to depict MRI intensities' distribution and heterogeneity. Results: A total of 30 patients were retrospectively enrolled, including immune checkpoint therapy (N = 19) and cetuximab-based chemotherapy (N = 11) as front-line therapy. Median OS was 7.0 months with 17 death events during follow-up. The area size of ROI was not significantly associated with the death events. However, High Gray-level Run Emphasis (HGRE) and Short-Run High Gray-level Emphasis (SRHGE) of GLRLM as well as High Gray-level Zone Emphasis (HGZE) and Short-Zone High Gray-level Emphasis (SZHGE) of GLSZM were significant to predict the event of death. The area under the curve (AUC) of HGRE, SRHGE, HGZE, and SZHGE were 0.747 (P = 0.023), 0.842 (P = 0.002), 0.819 (P = 0.003), and 0.833 (P = 0.002) at discretization levels of 16, respectively. These features also significantly differed OS of platinum-refractory HNSCC (Table). Conclusions: Four texture features of GLRLM and GLSZM depicted the fragmentation of extracellular volume of the recurrent tumor on T1 CE MRI and significantly correlated with the outcomes of platinum-refractory HNSCC. However, future warranted studies were needed. 1-year survival Hazard ratio (95% CI) High Gray-level Run Emphasis (HGRE) 54.5% vs. 9.7% 2.218(0.629-7.826) Short-Run High Gray-level Emphasis (SHRGE) 65.9% vs. 0.0% 4.254(1.213-14.915) High Gray-level Zone Emphasis (HGZE) 75.0% vs. 0.0% 8.741(1.134-67.397) Short-Zone High Gray-level Emphasis (SZHGE) 100.0% vs. 0.0% 45.726(0.714-2927.085)
PDS0101, a novel type I interferon and CD8 T-cell activating immunotherapy, in combination with pembrolizumab in subjects with recurrent/metastatic HPV16-positive head and neck squamous cell carcinoma (HNSCC).
Authors: Jared Weiss, Ashish V. Chintakuntlawar, Katharine Andress Rowe Price, John M. Kaczmar, Nathalie Riebel, Frank K Bedu-Addo, Marya F. Chaney, Lauren V Wood
Journal: Journal of Clinical Oncology (2022)

6041 Background: Human papillomavirus (HPV) E6/E7 oncoproteins mediate immune evasion by down-regulating Type 1 interferons, TLR9, MHC Class I/II as well as other mechanisms, resulting in persistent infection and initiation of ̃5% of all cancers globally. Similarly, established cancers evade immune surveillance utilizing parallel mechanisms including the expression of checkpoint proteins. PDS0101 is a molecularly targeted immunotherapeutic based on an enantiospecific cationic lipid nanoparticle platform containing HPV16 neoantigens that exhibits anti-tumor activity with checkpoint inhibitors (CPIs) by upregulating Type I interferons and promoting antigen processing and cross presentation. This allows generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in treatment of CPI naïve and refractory patients with recurrent or metastatic HPV16-related HNSCC. Herein, we report preliminary safety and efficacy data for CPI naïve patients at a prespecified interim analysis. Methods: Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of Cycles1-4 and Cycle12; pembrolizumab continues up until 35 cycles, disease progression or intolerance to therapy. Results: Eighteen CPI naïve subjects with confirmed HPV16 tumors and a CPS score &gt; = 1, median age 62 yrs (range 46-71), all male, 17 (94%) of whom were White and 16 (88.9%) not Hispanic or Latino, received at least one cycle of combination therapy. At the time of analysis, 17 (94%) subjects had received &gt; = 4 doses of PDS0101 (median 4, range 1-5) and pembrolizumab (median 7, range 1-14). There were no Grade 3 or greater treatment-related toxicities and no drug discontinuation related to toxicity or immune-related AEs. Clinical activity (CR+PR+SD) was seen in 13 (72.2%) of 18 subjects, with best overall reponse per RECIST1.1 documenting: OR in 7 (38.9%; 2 CR, 5PR); stable disease (SD) in 6 (33.3%) and progressive disease in 3 (16.7%); 2 subjects had missing data. Tumor reduction was seen in 4 of 6 (67%) subjects with SD. Nine-month PFS and OS rates (95% CI) were 52% (22.5, 74.7) and 81% (37.8, 95.5) respectively; median PFS and OS have not been reached. Conclusions: The combination of PDS0101 and pembrolizumab demonstrates an excellent safety profile with preliminary evidence of clinical activity in the majority of CPI naïve patients with HPV-related HNSCC. Clinical trial information: NCT04260126.
Outcomes and adverse events of low-dose nivolumab in platinum refractory head and neck cancers.
Authors: Hemanth Kumar, Jatin Choudhary, Madala Ravikrishna, Nandini Sharrel Menon, Vijay Maruti Patil, Vanita Noronha, Kumar Prabhash, Amit Joshi
Journal: Journal of Clinical Oncology (2022)

6048 Background: Nivolumab is one of the recommended regimens for platinum refractory and second line treatment in head and neck cancers as per NCCN guidelines. However, accessibility of nivolumab in low- and middle-income countries is less than 1-3%. There is data suggesting that low doses of nivolumab can also be effective. Hence in this analysis we explore the outcomes and adverse events with low doses of nivolumab. Methods: The head and neck medical oncology unit of Tata memorial hospital maintains a prospective database of all patients undergoing immunotherapy. A query was raised in this database to identify head and neck cancer patients who were treated with low doses of nivolumab. We identified 42 patients. The baseline characteristics, compliance to nivolumab, the reason for administration of low dose and the outcomes (progression free survival, date of progression, date of death) were recorded. The dose of nivolumab used in this study was 40mg flat dose every 2 weeks. Descriptive statistics were performed. Kaplan Meier estimates were used to see overall survival (OS) and progression free survival (PFS). Results: The median age of the patients was 48.8 (IQR: 43 - 56.4) Male to female ratio was 13:1. The site of the disease was oral cavity in 29 (69%) patients, oropharynx in 3 (7%) patients, larynx in 4 (9.5%) patients, and others in 7(17%) patients. All patients were platinum refractory and had progressive disease within last 6 months of last dose of platinum. The ECOG performance status was 1 in 37 (88.1%) patients and 2 in 5 (11.9%) patients. All patients received low dose nivolumab in view of financial constraints to access full dose. The response was recorded in 32 patients. Out of them 6 had a partial response (14.3%). The median PFS was 4.9 months (95% Confidence interval: 3.4 - 6.4) and OS was 8 months (95% confidence interval: 5.9-10.1). The details regarding PD L-1 expression and effectiveness of nivolumab will be presented at the conference. Conclusions: Low doses of nivolumab can be an option which is efficacious in patients who do not have access to standard dose nivolumab. There is need for testing this regimen in large randomized studies as full dose of nivolumab is not accessible in low- and middle-income countries.
Efficacy and safety of chemotherapy plus subsequent locoregional radiotherapy and toripalimab in de novo metastatic nasopharyngeal carcinoma.
Authors: Si-Yuan Chen, Mingyuan Chen, You Rui, Yijun Hua, Xiong Zou, Zhi-Qiang Wang
Journal: Journal of Clinical Oncology (2022)

6025 Background: Approximately 50% of primary metastatic nasopharyngeal carcinoma (mNPC) patients who received sequential chemoradiotherapy experience disease progression within one year. Improvements in therapy are greatly needed. This phase II study aimed to investigate the efficacy and safety of programmed cell death protein-1 (PD-1) inhibitor combined with sequential chemoradiotherapy in de novo mNPC. Methods: Patients who demonstrated complete or partial response following 3 cycles of cisplatin and fluorouracil (PF) were enrolled. Eligible patients received 3 more cycles of PF and subsequent radiotherapy plus toripalimab every three weeks at a fixed dose of 240 mg. The primary end point was objective response rate (ORR) at three months after radiotherapy, and the secondary end points were progression-free survival (PFS), disease control rate (DCR) and safety profiles. Exploratory study included biomarker analysis and efficacy comparation based on a historical cohort. A Simon’s two-stage optimal design with one-sided type I error rate of 5% and power of 80% was utilized to compare a null hypothesis ORR of 54% against an alternative of 80%. Target accrual was a minimum of 22 patients (stage 1 and 2 combined). Results: Of the 22 enrolled patients (7 women and 15 men; median age of 54.5 years [IQR 40.5-57.5 years]), the ORR at three months after radiotherapy was 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the DCR was 81.8%. The median PFS was 19.4 months (95% CI 10.8-NR). Grade 3-4 adverse events occurred in 15 (68.2%) patients; two patients (9.1%) had grade 2 or 3 immune-related adverse events and discontinued toripalimab. This trial met its primary objective of demonstrating a significant ORR versus historical controls (81.8% vs. 54%, P = 0.024). Elevation of plasma EBV DNA post radiation was associated with worse median PFS (10.5 vs. 19.4 months; hazard ratio = 4.23, 95% CI 1.0-17.9; P = 0.033). Conclusions: The addition of toripalimab to sequential chemoradiotherapy displayed promising tumor response and manageable safety profile in primary mNPC. These results support a potential role of PD-1 inhibition as consolidation therapy in the first-line treatment of primary mNPC. Clinical trial information: NCT04398056.