bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanoparticle albumin-bound (nab) paclitaxel in combination with nivolumab as treatment of recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC) that progressed on a PD-1 inhibitor: A single-arm, phase 2 trial.
Authors: Cohen Jared , Oppelt Peter John , Pennock Sarah , Liu Jingxia , Ley Jessica C. , Adkins Douglas
Published: June 2023

6023

Background: Drugs bound to albumin selectively target cancer cells with upregulated macropinocytosis, an endocytic nutrient-scavenging process driven by constitutive hyper-activation of the EGFR, RAS, PIK3CA and Syndecan1 signaling pathways that frequently occur in HNSCC. nab-paclitaxel is an active drug in HNSCC and has immunologic effects that can prime an immune response to PD-1 inhibitors, potentially reversing resistance to these agents. These effects include decreased TREGs, increased pro-inflammatory macrophages and differentiation of MDSC to dendritic cells, increased HLA class I expression and antigen presentation, and recruitment of CD8+ CTLs into tumor. Methods: In a single-arm phase 2 trial, patients with RM-HNSCC that progressed on a PD-1 inhibitor received 28-day cycles of nab-paclitaxel (125 mg/m2 IV days 1, 8, and 15) and nivolumab (480 mg IV day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed with RECIST1.1 by an independent radiologist. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with standard chemotherapy or cetuximab in similar patients. A Simon optimal two-stage design tested the null hypothesis (H0: ORR≤30%) versus the alternative hypothesis (H1: ORR=50%) at the type I error rate of 5% and power 0.80. In the first stage, 15 patients were to be accrued. If ≥6 responses occurred, 31 additional patients were to be accrued. The null hypothesis will be rejected if ≥19 responses are observed in these 46 patients. We report the results of the primary endpoint for the first stage of the trial. Results: 15 evaluable patients enrolled into the first stage of the trial. Key tumor characteristics and prior treatment history included HPV status (positive: 8; negative: 7), PD-L1 status (CPS 1-19: 7; ≥20: 8), # of lines of prior systemic treatment for RM disease (1-2: 12; ≥3: 3), interval (months) from prior PD-1 inhibitor (<6: 11; ≥6: 4), duration (months) on prior PD-1 inhibitor (median: 6, range: 1-16), and best response to prior PD-1 inhibitor (PR: 4; SD: 6; PD: 5). Tumor response to nab-paclitaxel and nivolumab occurred in 7 of 15 patients (ORR 47%). The best tumor response was PR (7), SD (5) and PD (3). Conclusions: Among patients with RM-HNSCC that progressed on a PD-1 inhibitor, the ORR with nab-paclitaxel and nivolumab was 47% during the first stage of the phase 2 trial. Enrollment to the second stage is ongoing. Clinical trial information: NCT04831320 .
Prognostic value of circulating Epstein-Barr virus DNA level post-induction chemotherapy for patients with nasopharyngeal carcinoma: A recursive partitioning risk stratification analysis.
Authors: Kong Fang-Fang , Pan Guang-Sen , Ni Meng-Shan , Du Cheng-Run , Zhang Zhen , Hu Chaosu , Ying Hong-Mei
Published: June 2023

6024

Background: To evaluate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level post-induction chemotherapy (IC) for patients with nasopharyngeal carcinoma (NPC). Methods: A total of 893 newly diagnosed NPC patients treated with IC were retrospectively reviewed. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. The receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off value of EBV DNA and compare the predictive validity. Results: Post-IC EBV DNA levels and overall stage were independent predictors for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). The RPA model base on post-IC EBV DNA and overall stage categorized the patients into three distinct risk groups: RPA I (low-risk: stage II-III and post-IC EBV DNA < 200 copies/mL), RPA II (median-risk: stage II-III and post-IC EBV DNA≥200 copies/mL, or stage IVa and post-IC EBV DNA < 200 copies/mL), and RPA III (high-risk: stage IVa and post-IC EBV DNA≥200 copies/mL), with 3-year PFS of 91.1%, 82.6%, and 60.2%, respectively (p < 0.001). The DMFS and OS rates in different RPA groups were also distinct. ROC analysis showed that the RPA model had superior predictive efficacy than the overall stage. Conclusions: Plasma EBV DNA level post-IC was a robust prognostic biomarker for NPC. We developed a risk stratification model that provides improved DMFS, OS, and PFS prediction over the 8th edition of the TNM staging system by integrating the post-IC EBV DNA level and the overall stage.
Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: An open-label phase II study.
Authors: Lu Nian , Jiang Yao-fei , Xia Weixiong , Huang Ying , Xie Chuan-miao , Xu Cheng , Ye Yan-Fang , Liu Guo-Ying , Bei Wei-Xin , Ke Liang-Ru , Li Wang-Zhong , Wang Xin , Xie Changqing , Liang Hu , Yanqun Xiang
Published: June 2023

6031

Background: There are limited treatment options for patients with metastatic nasopharyngeal carcinoma (mNPC) after failure of platinum-based chemotherapy. In this trial, we assessed the efficacy and safety of sintilimab plus bevacizumab in mNPC patients where platinum-based chemotherapy has failed. Methods: This was a single-center, open-label, single-arm, phase II trial for mNPC patients progressed after at least one line of systemic therapy. Patients were enrolled and received sintilimab (200 mg) plus bevacizumab (7.5mg/kg) intravenously every 3 weeks. The primary end point was objective response rate (ORR) assessed by investigators following the guidelines of RECIST 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This trial is registered with ClinicalTrials.gov (NCT04872582). Results: Thirty-three patients were enrolled. Median age was 46 years (range, 18-64 years), and 63.6% of patients had previously received two or more lines of chemotherapy for metastatic disease. Median follow-up was 7.6 months (range, 4.1-17.5 months). ORR was 54.5% (95% CI, 36.4- 71.9%) with 3 complete responses (9.1%) and 15 partial responses (45.5%). Median PFS was 6.8 months (95% CI, 5.2 months to not estimable). Median DOR was 7.2 months (95% CI, 4.4 months to not estimable). Median OS was not reached. The most common potential immune-related AE was grade 1-2 hypothyroidism (42.4%). Treatment-related grade 3 or 4 adverse events (AEs) occurred in 7 patients (21.2%), including nasal necrosis (9%), hypertension (3%), pruritus (3%), total bilirubin increased (3%) and anaphylactic shock (3%). No treatment-related deaths and severe epistaxis occurred. Conclusions: This phase II trial showed that sintilimab plus bevacizumab demonstrated promising antitumor activity and manageable toxicities in mNPC patients after failure of platinum-based chemotherapy. Clinical trial information: NCT04872582 .
To test, or not to test, that is the question: A real-world analysis of PD-L1 expression testing patterns in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Black Chris M. , Hair Gleicy , Zheng Dandan , Ai Lei , Wang Liya , Hanna Glenn J.
Published: June 2023

6033

Background: PD-L1 expression testing plays an important role in identifying patients who benefit from immunotherapy when treating R/M HNSCC. We aimed to understand how PD-L1 expression testing evaluated by Combined Positive Score (CPS) is used in clinical practice and how testing results impact treatment decision-making. Methods: A retrospective cohort study was conducted using the Flatiron Health Advanced Head and Neck database. We included adult R/M HNSCC patients who initiated first-line (1L) treatment between 07/01/19 and 12/31/21 with follow-up until 06/30/22. Patients were excluded if they received platinum therapy within 6 months prior to 1L treatment, had other primary cancers before advanced diagnosis, were treated on protocol, or were tested but did not have any record of date of specimen collected, received, or results returned. Multivariable logistic regression was conducted to assess factors associated with PD-L1 testing decisions before 1L therapy start and the association between testing results and choice of 1L treatment. Results: A total of 1,762 patients with R/M HNSCC were included, with 32.0% tested for PD-L1 prior to 1L therapy start, 25.6% tested after, and 42.4% never tested. Most patients were tested using the IHC 22C3 pharmDx assay, an FDA-approved companion diagnostic. Among patients tested before 1L treatment initiation, the most prescribed regimens were pembrolizumab or pembrolizumab + platinum + 5-FU for patients with PD-L1(+) (55.9%, 14.2%) and PD-L1(-) tumors (25.3%, 32.0%), respectively. Patients tested after 1L treatment initiation regardless of CPS and patients never tested were most often prescribed platinum monotherapy for 1L. In a multivariable model, patients who were older, treated in academic settings, HPV(+), or had an ECOG≥2 were more likely to get PD-L1 testing before 1L treatment initiation. Compared to CPS<1, CPS≥20 and 1≤CPS<20 were associated with a higher likelihood of receiving immunotherapy (OR=3.36, 95% CI, 1.69-6.75, p<0.001; OR=3.11, 95% CI, 1.59-6.14, p<0.001, respectively). Conclusions: As an important part of treatment decision-making, PD-L1 testing by CPS should guide 1L single-agent immunotherapy use, but there are many patients not tested before initiating 1L therapy. Age and fitness, clinical practice setting, and HPV status appear to impact testing patterns.[Table: see text]
NeoIRX trial: Immunologic induction with peri-lymphatic cytokines to enhance pembrolizumab (pembro) response in stage II/III triple-negative breast cancer (TNBC).
Authors: Page David B. , Su Alan , Moxon Nicole , Mellinger Staci L. , Kelly Tracy , Conlin Alison Katherine , Topp Zheng Zhu , Newell Pippa , Fredrich Nicole , Massimino Kristen P. , Wu Yaping , Redmond William L , Aliabadi Shaghayegh , Sun Zhaoyu , Imatani James , Stanton Sasha E.
Published: June 2023

604

Background: The addition of pembro to neoadjuvant chemotherapy (NACT) improves pathological complete response (pCR) rate and recurrence-free survival in stage II/III TNBC, albeit with substantial chemotherapy-attributed toxicity. We hypothesize that locoregional cytokine therapy could be combined with pembro to optimize immune response and clinical outcome. In a phase Ib early-stage breast cancer trial, we previously demonstrated that peri-lymphatic cytokine injection (IRX-2 regimen, comprised of physiologic doses of IL-2, IFNg, and other cytokines derived from activated donor lymphocytes, given with low-dose cyclophosphamide) is well tolerated and associated with increased intratumoral lymphocytes, T-cell activation, and PD-L1 expression. Here, we report preliminary outcomes of neoIRX, a phase II trial evaluating induction IRX-2 + pembro preceding NACT + pembro. Methods: Subjects with stage II/III TNBC were randomized to receive induction pembrolizumab (all subjects: 200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of NACT + pembro. The primary endpoint was pCR rate following NACT + pembro (n = 15 subjects/arm planned); secondary endpoints were safety and tolerability. We explored post-induction/pre-NACT radiographic (ultrasound) and histologic outcomes (TILs, tumor regression) as a biomarker strategy to predict pCR. Results: The trial terminated after n = 12 subjects due to withdrawal of drug support for IRX-2. The IRX-2 arm achieved 83% pCR (n = 5/6, CI 36-100%) compared to 33% pCR with pembro alone (n = 2/6, CI 4-78%). The regimen was well-tolerated with minimal IRX-2-attributed toxicities (67% grade I skin bruise). Toxicities during NACT + pembro were similar to Keynote-522. 67% (n = 4/6) of IRX-2 subjects experienced week 3 radiographic regression, with evidence of brisk lymphocyte infiltration on week 3 biopsy, and with 100% pCR rate (n = 4/4) following NACT + pembro. n = 2/6 subjects receiving pembro+IRX-2 experienced pCR on week 3 biopsy, versus n = 0/3 evaluable in control arm. Conclusions: Induction IRX-2 + pembro is well tolerated and is associated with encouraging outcomes, supporting further study of peri-lymphatic induction cytokine therapy in stage II/III TBNC. Post-induction radiographic and histologic outcomes may identify patients with immune-responsive tumors, for whom NACT de-escalation may be a promising therapeutic approach to mitigate toxicity. Clinical trial information: NCT04373031 .
Updated results from a phase 2 study of the oral vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor rivoceranib for recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC).
Authors: Kang Hyunseok , Ahn Myung-Ju , Keam Bhumsuk , Bowles Daniel W. , Wong Deborah J.L. , Ho Alan Loh , Kim Sung-Bae , Worden Francis P. , Yun Tak , Jang Seong , Meng Xianzhang , Hanna Glenn J.
Published: June 2023

6040

Background: ACC is a rare tumor that overexpresses VEGF, primarily affecting salivary glands. Often indolent, it can progress, with metastases common in the lungs, liver, and bone. There are no FDA-approved systemic treatments (tx) for R/M ACC. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR2. Methods: In this single-arm, open-label multicenter trial, patients (pts) with R/M ACC with evidence of ≥20% progression by RECIST v1.1 or new lesions within the preceding 6 months (mos) were eligible, with no limit on prior tx. Pts received rivoceranib 700 mg daily until disease progression or withdrawal with pre-planned dose reductions for toxicity. Primary endpoint was overall response rate (ORR) per RECIST v1.1 by investigator (INV) and by Independent Review Committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and safety exploratory analysis included disease control rate (DCR) and ORR using CHOI criteria by IRC. Results: As of 11/2022, 80 pts (72 evaluable) were enrolled in the US and Korea (53% male; median age, 54 yrs), and 6 pts remain on tx. Primary tumor sites: major (34%) and minor (59%) salivary glands and other (8%). 74 pts (93%) had metastatic disease. 61.3% had prior systemic tx (18% prior VEGFR TKI). INV and IRC-assessed efficacy data are listed in the table. ORR by CHOI was 52.5% (53.1% VEGFR TKI-naive and 50% VEGFR TKI treated). mOS was 25.3 mos (28.3 mos VEGFR TKI-naïve and 22.6 mos VEGFR treated). Common adverse events (AEs) were hypertension (66%), fatigue (64%), and nausea (54%). Grade ≥3 AEs that occurred in >5% of pts were hypertension (43%), stomatitis (8%), fatigue and anemia (6% each). There were 4 Grade 5 AEs (2 epistaxis [1 related], 1 acute respiratory failure, 1 respiratory failure). Conclusions: Updated results with additional 9-month follow-up data continue to demonstrate that Rivoceranib has clinical efficacy and a manageable safety profile in pts with R/M ACC. Clinical trial information: NCT04119453 . [Table: see text]
Personalized therapy for head and neck squamous carcinoma (HNSCC) utilizing tissue proteomics profiling.
Authors: Thyparambil Sheeno P. , Liao Wei-Li , Strasbaugh Amanda , Melkie Marya Abebe , Ghafourian Negin , Heaton Robert , Ling Xuefeng
Published: June 2023

6045

Background: Chemotherapy is widely used in the treatment of HNSCC, yet no biomarkers for chemotherapy is used for selection of the chemo agent in the treatment of HNSCC. We examined 143 HNSCC cancer using targeted proteomics for the protein expression levels of several chemo agents. These include markers of resistance to platinum agents (ERCC1), anti-tubulin inhibitors (TUBB3) and sensitivity markers for topoisomerase inhibitors (Topo1 – irinotecan, topotecan; Topo2A – doxorubicin, etoposide). We also measured markers for several antibody-drug conjugates (EGFR, Her2, Trop2, FR-alpha, Mesothelin). Methods: Tumor areas from Formalin-fixed, paraffin-embedded (FFPE) tumor tissues from clinical samples of HNSCC that were received at our CLIA certified laboratory were microdissected and a selected reaction monitoring mass spectrometry (SRM-MS) quantitative proteomic analysis of 72 protein biomarkers were conducted concurrently from 2-3 sections of FFPE tissue. Results: Platinum agents are widely agent in HNSCC cancer. ERCC1, a resistance marker for platinum agents was expressed in 44% of HNSCC. Similarly, TUBB3, a resistance marker for Paclitaxel, docetaxel was also expressed in ~45% of HNSCC. These indicate that ~45% of HNSCC could potentially be refractory to platinum and paclitaxel-based therapy. Additionally, ALDH1A1, a marker for resistance of cyclophosphamide, was expressed in 78% of HNSCC. Temozolomide, an alkylating agent used in other cancer type could be beneficial in 14% of HNSCC because of the lack of resistance marker MGMT. On the other hand, 88% of HNSCC expressed Topo1, which is a sensitivity marker for irinotecan or topotecan based therapy. Additionally, Top1 is also the target for the payload of several ADCs (e.g. trastuzumab deruxtecan and sacituzumab govitecan). Similarly, 55% of HNSCC expressed Topo2A, a target for etoposide and doxorubicin. Additionally, 57% of HNSCC expressed hENT1, a transporter of gemcitabine. HNSCC also expressed various targets for targeted and ADC agents. These include EGFR (86% detected with 37x range of distribution), Her3 (11%), IGF1R (16%), MET (13%), Folate receptor- alpha (18%), Mesothelin (13%), and Trop2 (89% with 134x range of distribution). Her2 was overexpressed ( > 750 amol/ug) in 11% of HNSCC, however, it was observed in 46% of HNSCC with a 53x range (276 – 14705 amol/ug), indicating that a significant population of HNSCC might be eligible for low Her2 clinical trials. Conclusions: Every cancer is unique, and the ability to analyze 72 protein biomarkers from 2-3 FFPE sections simultaneously at the same time provides a wealth of actionable information for clinical treatment or patient stratification for clinical trials.
Phase II study evaluating the efficacy of niraparib and dostarlimab (TSR-042) in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients.
Authors: Zamulko Olga , Karivedu Vidhya , Riaz Muhammad Kashif , Monroe Ilaina , Romano Audrey , Mulanda Rachel , Kurtzweil Nicky , Forsythe Allison , Allen Casey , Harun Nusrat , Wise-Draper Trisha M.
Published: June 2023

6046

Background: Patients with recurrent and/or metastatic (R/M) HNSCC have poor overall survival. Immune checkpoint inhibitors (ICIs), specifically programmed death-1 (PD-1) inhibitors, result in durable responses in R/M HNSCC but <20% benefit. Tumor mutational burden (TMB) correlates with ICI response. DNA pathway repair mutations have been reported in 17% of sporadic HNSCC and are associated with higher rates of TMB. Poly (ADP-ribose) polymerase (PARP) inhibition has demonstrated efficacy as a single agent in cancers with a DNA repair defect. We tested the combination of PARP inhibitor (niraparib) with the PD-1 inhibitor (dostarlimab) in R/M HNSCC patients (NCT04313504) with funding support from Tesaro/GSK. Methods: Patients with R/M HNSCC who failed at least one line of prior treatment including a PD-1 inhibitor and for whom no surgical or radiation curative options existed were eligible for the study. Patients received niraparib (200 mg daily) beginning one week prior to initiation of dostarlimab (500 mg q3wks x4 followed by 1000 mg q6wks). The primary endpoint was overall response rate (ORR) including complete response (CR), partial response (PR) and stable disease (SD) using RECIST v1.1. Fourteen patients were planned for the first stage and 10 additional patients for the second stage if ≥8 patients had a confirmed response. Safety was evaluated by CTCAE v5.0. Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS). TMB was considered high if ≥10Mut/Mb. Results: Ten of 24 planned patients were enrolled. Of the first 10 patients, 8 patients were evaluable by imaging and 1 patient clinically progressed on exam. Of the 9 evaluable patients, there were 0 CR, 1 PR, 1 SD, and 7 with progressive disease (PD). The trial was ended early for futility as it was not possible for at least 8 out of 14 patients to develop response. The patient with a PR remains on treatment past 24 months, was PD-L1 positive, had low TMB and no DDR deficiency. All patients had previously failed a PD-1 inhibitor. One patient had high TMB, 2 patients had a DDR, and 6 patients were PDL1 positive but 2 patients had insufficient tissue or indeterminate results for sequencing. Grade ≥ 3 adverse events occurred in 70% of patients with most common being hypertension (20%), hyponatremia (20%), and lung infection (20%). Conclusions: PARP-1 inhibition and PD-1 inhibition combined does not appear to enhance response over PD-1 inhibitor alone in R/M HNSCC who had previously failed PD-1 inhibitor treatment. However, a more focused population including those with DNA damage response (DDR) mutations and PD-1 treatment naïve may benefit. Clinical trial information: NCT04313504 .[Table: see text]
Moderate physical exercise and immune system modulation in patients with breast cancer treated with neoadjuvant chemotherapy.
Authors: Garrone Ornella , Paccagnella Matteo , Abbona Andrea , Ruatta Fiorella , Vanella Paola , Tomasello Gianluca , Croce Nicoletta , Barbin Francesca , Rossino Maria Grazia , Merlano Marco Carlo
Published: June 2023

605

Background: The link between physical activity (PA) and immune system is known. However, are not clearly understood which mechanisms are activated by PA. We investigated the effect of moderate PA (MPA), on a panel of circulating cytokines during neoadjuvant chemotherapy (CT) in patients (pts) with breast cancer. Methods: Pts received sequential epirubicin and cyclophosphamide for 4 cycles followed by weekly paclitaxel ± trastuzumab. MPA consisted of Nordic or fit walking, 3 workouts/week, 1 hour each, in the 9 weeks before Surgery (S). Blood samples were collected in pts underwent MPA (TR) and in a group of pts who declined MPA (UN) at baseline (T0), at day 1 of week 6 of paclitaxel (starting MPA) (T1) and before S (T2). At each time point the level of 22 cytokines (IL1b, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL15, IL17a, IL18, IL21, CCL2, CCL4, CXCL10, CCL22, IFNγ, TGFβ, TNFα, VEGF) was measured using Simple Plex Ella. Sample size was calculated using effect size method considering a Cohen’s d of 0.65 as observed for a candidate cytokine (IL-6) between two groups. Considering a desired statistical power of 0.8 and a probability level of 0.05 a minimum of 78 patients were required. The difference among the median value of cytokines was analysed using non parametric Mann Whitney U test. Comparisons between time points in the same group were analysed with Wilcoxon signed-rank test. Results: Accrual is completed. 61 pts were TR and 20 UN. Main patients’ characteristics are listed. At T0 IL4, IL17, IL18 and VEGF level was significantly higher in UN respect to TR pts. At T1 IL4, IL17 and IL18 level remained significantly higher in UN pts. At T2, UN pts showed significantly higher value of IL4, IL6, IL7, IL8, IL17, IL18 VEGF and TGFβ. IL21 was significantly higher in TR pts. Longitudinal analysis between T0 and T1 in TR and UN pts showed significantly lower level of CCL22 and significantly higher level of IL7, IL13 and CXCL10 in TR pts and significantly higher level of IL8 in UN pts. Longitudinal analysis between T1 and T2 showed significantly higher level of IL21, CXCL10, CCL22, TNFα and significantly lower level of IFNγ, IL6, IL8, CCL2, TGFβ in TR pts and significantly lower level of CXCL10 in UN pts. Conclusions: TR and UN pts differed modestly at baseline including acceptance of MPA. The longitudinal analysis T0-T1 showed that CT induced more evident changes in TR than in UN pts. Longitudinal analysis T1-T2 demonstrated major changes in Th1 and Th2 cytokines only in TR pts. Overall, CT induced weak changes in UN and greater changes in TR pts strengthened by the addition of MPA. These observations suggest a more efficient immune system in TR pts and a possible additional benefit derived from MPA. [Table: see text]
Phase I/II trial of durvalumab plus tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma: Final results.
Authors: Bahig Houda , Aubin Francine , Nguyen-Tan Phuc Felix , Soulieres Denis , Debenham Brock John , Charpentier Danielle , Palma David A. , Winquist Eric , Jamal Rahima , Sultanem Khalil , Ballivy Olivier , Filion Edith , Pittman Tyler , Maganti Manjula , Wong Philip
Published: June 2023

6050

Background: Anti-PD-1/PD-L1 is now part of first line therapy in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic radiotherapy (SBRT) to metastatic lesions can reduce tumor burden and could be immune-stimulatory. The combination of SBRT with dual-checkpoint blockade with Durvalumab (D, anti-PD-L1) and Tremelimumab (T, anti-CTLA-4) has not previously been tested in HNSCC. We report on the safety and efficacy of this triple treatment combination (TTC) consisting of SBRT sandwiched between cycles of D and T in oligometastatic HNSCC. Methods: This is a phase I/II single arm multi-institutional study powered for 35 patients with oligometatastatic HNSCC (2-10 lesions) (NCT03283605). D (1500 mg) and T (75 mg) were given for 4 monthly cycles, followed by monthly D for 8 monthly cycles. SBRT to 2-5 lesions was administered during cycle 2. The safety of the TTC was the primary endpoint of the phase I and was evaluated through assessment of Grade 3-5 TTC-related adverse events (AE), based on CTCAE (v 4.03). The primary endpoint of the phase II portion was 6-month progression free survival (PFS), with a predetermined 6-month PFS (6moPFS) rate greater than 27% considered as a positive signal to conduct further research on this combination. Results: A total of 33 evaluable patients were recruited (study accrual was interrupted by the COVID pandemic). The table describes patients’ characteristics. Patients had received 1, 2 and 3 prior systemic therapy lines in 48%, 21% and 9% of the cases, including 6 (18%) patients who had received prior anti-PD-1/L1 or anti-CTLA-4 therapies. The median prescribed and maximum SBRT doses were 45 Gy (range: 18-50) and 52.3 Gy (range: 28.1-69) in 3-5 fractions, respectively Fourteen patients (42%) had Grade ≥ 3 AE attributable to D and T. Only 1 patient developed Grade ≥ 3 AE attributable to SBRT. This patient, who had mucosal radionecrosis after re-irradiation and refused surgical debridement and flap reconstruction, specifically developed 2 Grade 3, 1 Grade 4 and 1 Grade 5 AE. Our primary efficacy endpoint, 6moPFS, was 69.7% (95% CI: 55.6-87.3). Median PFS was 11.9 months (6.94-14.5) and median OS was 25.1 months (17.9-28.4). Rates of complete response, partial response, stable disease and progressive disease were 9%, 21%, 33% and 12%, respectively, with 8 (24%) patients with no evaluable non-SBRT treated lesion. Conclusions: The addition of SBRT to dual-checkpoint inhibition led to 1 (3%) additional patient developing severe AE. Best response rates were encouraging. Our primary efficacy outcome, 6mo PFS was attained and was higher than what was expected in this patient population. Clinical trial information: NCT03283605 . [Table: see text]
A proteomic signature associated with prognosis in HPV-related locally advanced oropharyngeal squamous cell carcinoma (LA-OPSCC).
Authors: Liu Jia (Jenny) , Jackson Christopher , Anees Asim , Noor Zainab , Williams Steven , Porceddu Sandro , Liu Howard , Ladwa Rahul , Whitfield Joseph , Reddel Roger R , Zhong Qing , Panizza Benedict J , Robinson Phillip J
Published: June 2023

6055

Background: Although HPV-related LA-OPSCC is associated with better prognosis than HPV-negative disease, ~30% of cases relapse despite curative-intent chemoradiotherapy. New prognostic biomarkers are needed to rationalise curative-intent treatment without compromising efficacy. We aimed to develop a proteomic signature associated with risk of recurrence from diagnostic biopsies of patients with HPV-positive OPSCC. Methods: We analysed 139 formalin fixed paraffin embedded archival core biopsy specimens from 124 patients with HPV-related (p16 IHC positive) T1-4N0-3M0 LA-OPSCC tumours. All patients were treated with definitive chemoradiotherapy at the Princess Alexandra Hospital (Brisbane, Australia) between 2007-2019. The cohort included 50 patients with recurrence less than five years from diagnosis and 74 age/performance-status matched patients with no recurrence. Proteomic analysis was performed utilizing data-independent acquisition mass spectrometry (DIA-MS). A proteomic prognostic signature associated with recurrence free survival (RFS) at five years was the primary endpoint of interest. It was developed using a computational pipeline comprising an initial univariate Cox model step, followed by multiple runs of multivariate Cox models with Least Absolute Shrinkage and Selection Operator (LASSO) regularization, and then a final step of recursive feature selection. Results: A total of 7,597 proteins were quantified and 665 were differentially expressed proteins between tumour and normal adjacent tissues. There were 5,199 proteins remaining in the tumour samples after filtering. RFS was significantly (q-value < 0.05) associated with 252 proteins, whose functions are enriched in adaptive and innate immunity and MAPK6/MAPK4 signalling pathways. A 16-protein signature associated with RFS stratified patients into low, intermediate, or high-risk groups (C-index = 0.885, p < 0.0001). The 16-protein signature outperformed clinico-pathological covariates including age, stage, ECOG and smoking history with the highest area under the receiver operating characteristic curve (AUROC 0.95). Conclusions: DIA-MS-based proteomics on core biopsies can be used to risk stratify HPV-related OPSCC patients. A 16-protein signature associated with RFS was successfully identified as a basis for future studies. Validation of this proteomic prognostic signature in independent cohorts is required and may be used to inform future clinical trials to better tailor upfront therapy.
Spatial relationships and immune subsets in the tumor immune microenvironment of head and neck cancers.
Authors: Henry Leanne E. , Krishnan Santhoshi , Patil Siddhi , Bellile Emily , Perera Chamila D. , Li Shiting , Qin Tingting , Taylor Jeremy M.G. , Rao Arvind , Chinn Steven B. , Rozek Laura S. , Sartor Maureen A.
Published: June 2023

6061

Background: The tumor microenvironment provides important insights into cancer behavior and its response to treatment. In particular, the cellular composition and spatial arrangement of tumor immune infiltrates are associated with patient prognosis and survival. We optimized and employed a novel method using readily available hematoxylin and eosin (H&E) slide images, termed the G-cross score, which reflects immune cell infiltration levels and their proximity to tumor cells. The G-cross score is calculated by estimating the probability distribution of immune cells, of any type, within a certain distance from a tumor cell, with higher scores indicating greater immune cell infiltration. However, because G-cross scores are calculated from H&E slides, the method is unable to distinguish among immune cell types. Using head and neck squamous cell carcinoma (HNSCC) patients having both G-cross scores and bulk RNA-seq data, we determined which subset of tumor-infiltrating immune cell types best correlate with G-cross scores, and its predictive and prognostic value. Methods: G-cross scores were calculated for 425 HNSCC samples from University of Michigan, of which 64 had paired bulk RNA-seq data. We applied the cell-type deconvolution tool, CIBERSORTx, to identify immune cell type proportions based on RNA-seq data. G-cross scores were correlated against cell-type deconvolution results, immune cell activation expression signatures, and validated gene expression-based radiosensitivity index scores. Pearson's correlation coefficient and p-value using HPV status as a covariate in a linear model was calculated for each comparison. For survival and recurrence analysis, Cox proportional hazards multivariate regression was performed using the entire 425 sample cohort. Results: G-cross scores were significantly correlated with total T cells (R = 0.52, p = 4.63✕10-5), B cells (R = 0.33, p = 2.08✕10-2), and dendritic cells (R = 0.46, p = 7.71✕10-4), but not macrophages or mast cells. G-cross scores also had a positive correlation with T cell activation (R = 0.46, p = 2.17✕10-4) and B cell activation (R = 0.53, p = 1.24✕10-4) and were correlated with radiation sensitivity (R = -0.44, p = 6.67✕10-4). Survival analysis showed higher G-cross scores were associated with a longer time to recurrence and improved overall survival (p = 3.0✕10-4). Conclusions: G-cross scores are mainly driven by T cell and dendritic cell levels among tumor-infiltrating lymphocytes and are correlated with B and T cell activation. Importantly, G-cross scores also correlate with gene expression profiles associated with response to radiotherapy as well as time to recurrence and overall survival. G-cross scores may be an important biomarker of radiation response and indicative of protective immune subsets for HNSCC patients.
The impact of genetic predisposition to depression on quality of life in patients with head and neck cancer immediately post-treatment: A longitudinal study.
Authors: Henry Melissa , Chen Lawrence , Meaney Michael , Rosberger Zeev , Frenkiel Saul , Hier Michael , Zeitouni Anthony , Kost Karen , Mlynarek Alexander , Richardson Keith , Deamond Haley , Lang Jacob , Silver Jennifer , Ducharme Laurence , Mascarella Marco Antonio , Sadeghi Nader , Sultanem Khalil , Shenouda George , Cury Fabio , O'Donnell Kieran
Published: June 2023

6063

Background: The primary aim of this study was to investigate the contribution of genetic predisposition to depression, through polygenic risk scores (PRS), on quality of life levels in patients with head and neck cancer (HNC) immediately post-treatment period (i.e., 3 months post-diagnosis). Methods: Prospective longitudinal study of 223 consecutive adult patients with HNC (72% participation) newly diagnosed with a first occurrence of primary HNC, including saliva samples analyzed using the Illumina PsychChip, psychometric measures, Structured Clinical DSM Interviews, and medical chart reviews. Results: Level of quality of life at 3 months on the FACT-G+H&N was predicted by (r2 = 0.51, r2 adj. = 0.33, p = 0.001) the polygenic risk score for depression (standardized b = -0.28, p = 0.01) and a previous history of suicidal ideation (standardized b = -0.25, p = 0.04). Other variables were non-significant in the analyses: sociodemographic (i.e., age, sex, education, living alone), psychosocial (i.e., SCID current and past diagnoses (trend), past history of abuse), and medical variables (i.e., cancer stage and site, HPV status, functional status/ECOG, treatment). Conclusions: Our results outline the importance of attending to genetic predisposition and past history of suicidal ideation as markers for quality of life compromise immediately post-treatment in patients with head and neck cancers. Strategies are needed to address psychosocial vulnerability early-on as part of pre-habilitation in the treatment of patients with head and neck cancer.
One-year reductions in cisplatin-related chronic kidney disease (CKD) in patients with head and neck (HNC) cancer treated with avasopasem manganese: A prespecified analysis from the phase 3 ROMAN trial.
Authors: Allen Bryan G. , Spitz Douglas R. , Mapuskar Kranti A. , Zepeda-Orozco Diana , Beardsley Robert Alan , Kennedy Eugene Paul , Anderson Carryn M.
Published: June 2023

6066

Background: Cisplatin-induced acute kidney injury (AKI), acute kidney disease (AKD), and chronic kidney disease (CKD) are associated with increased production of reactive oxygen species, notably superoxide, in conjunction with alterations in mitochondrial electron transport chain complex activities in tubular epithelial cells (Mapuskar et al. Antioxidants 2021;10:1329). These pathologies can be targeted and thereby inhibited by increasing superoxide dismutase activity, which converts superoxide to hydrogen peroxide. The investigational new drug avasopasem manganese (AVA), a selective dismutase mimetic, ameliorated cisplatin-induced kidney injury in mice (Mapuskar et al. Redox Biol 2019;20:98). Preclinical results also demonstrate that AVA does not interfere with cisplatin anticancer activity (Mohanty et al. Cancer Res 2018;78[13_suppl]:Abstract 2929). Consistent with this, a retrospective analysis of 1- and 2-year kidney function of a limited subset of patients treated in a randomized, placebo (PBO)-controlled phase 2b trial of AVA to reduce severe oral mucositis (SOM) from radiotherapy and cisplatin (CRT) suggested that AVA prevented or reduced cisplatin-related CKD compared to PBO (Steinbach et al. J Clin Oncol 2020;38[15_suppl]:Abstract 12071). Methods: The ROMAN phase 3 trial (NCT03689712; ITT n = 407) of CRT in combination with AVA or PBO demonstrated improved incidence, duration, and onset of SOM by AVA (n = 241) vs PBO (n = 166) (Anderson et al. J Clin Oncol 2022;40[16_suppl]:Abstract 6005). In ROMAN, prospectively defined follow-up of serum creatinine (sCr) and estimated glomerular filtration rates (eGFR) were assessed every 3 months for 1 year following 7 weeks of CRT. Results: At 1-year follow-up, AVA was associated with significant improvements in preservation of eGFR ( P= 0.0008) and sCr ( P= 0.006) levels vs PBO. Grade 3+ CKD (eGFR < 60 mL/min) results through 12 months show 10% AVA vs 20% PBO (relative risk 0.55, P= 0.0043). Regarding cisplatin schedule, patients receiving Q3W therapy show grade 3+ CKD of 12% AVA vs 22% PBO; patients receiving QW therapy show AVA 9% vs PBO 19%. During treatment, nominal reduction of the incidence of AKI adverse events (0.8% AVA vs 3.6% PBO) was also observed. Conclusions: At 1-year follow-up, AVA appears to reduce cisplatin-related CKD in the study population and may also reduce cisplatin-related AKI during treatment. These results carry significance beyond CRT for HNC, potentially impacting platinum-containing regimens in other cancers. Clinical trial information: NCT03689712 .
Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin and radiotherapy in locoregionally advanced nasopharyngeal carcinoma: A single arm, open label, phase II clinical trial.
Authors: Fangzheng Chen , Deng Ying , Yang Fang , Wang Meng-Yao , Yin wen-Jing , Liu Jin-Quan , Chen Dong-Ping , Qi Bin
Published: June 2023

6067

Background: To evaluate the efficacy of induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin combined with radical radiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This is a prospective, single-arm, open-label, phase II trial. Patients with aged 18-65 years, newly diagnosed stage III-IVa (except T3-4N0) nasopharyngeal carcinoma were enrolled. Eligible patients received induction chemotherapy with docetaxel (60 mg/m² intravenously on days (D) 1, 22 and 43), Nedaplatin (60 mg/m² intravenously on D 1, 22 and 43) and fluorouracil (600 mg/m² per day as a continuous 120 hours (h) infusion on D 1-5, 22-26 and 43-47) every three weeks for three cycles, thereafter received intensity-modulated radiotherapy (IMRT) concurrently with nedaplatin (100mg/m2 intravenously on D 1, 22 and (or) 43) every three weeks for two or three cycles. The primary end point was objective response rate (ORR). The secondary end points included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and local recurrence-free survival (LRFS). Results: Between March 2020 and June 2021, a total of 32 patients with LA-NPC were enrolled. With a median follow-up duration of 14.0 months (IQR 11.7-16.3), 32 patients (100%) achieved ORR at three months after treatment. The 12-month PFS was 95.7% (95% CI 87.3% to 100%) and the 12-month OS was 100%. The most common grade 3 or 4 adverse events during induction chemotherapy were neutropenia (3 [9.4%]), diarrhea (3 [9.4%]) and hepatoxicity (3 [9.4%]), followed by leucopenia (2 [6.3%]) and fatigue (1 [3.1%]). The most common grade 3 or 4 adverse events during concurrent chemotherapy were mucositis (3 [9.4%]), leucopenia (1 [3.1%]), neutropenia (1 [3.1%]) and thrombocytopenia (1 [3.1%]). All of these adverse events were manageable. Conclusions: Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin combined with radical radiotherapy showed promising antitumor activity and manageable toxicities in patients with LA-NPC. Further phase III randomized controlled trials are warranted to validate our findings. Clinical trial information: NCT04834206 .
Induction chemotherapy with nanosomal docetaxel lipid suspension (NDLS), cisplatin, and fluorouracil in patients with locally advanced head and neck squamous cell carcinoma.
Authors: Biswas Ghanashyam , Ganta Ranga Raman , N Kharthik , Kantharia Rajesh , Bondarde Shailesh , Raghu Raman Ramaiyer , Mahajan Manoj , Ahmad Ateeq , Sheikh Saifuddin , Ali Shoukath M , Paithankar Mahesh , Patel Lav , Rajani Anil , Bunger Deepak , Chaturvedi Alok , Ahmad Imran
Published: June 2023

6074

Background: Nanosomal docetaxel lipid suspension (NDLS), a polysorbate-80 and ethanol free formulation, was developed to overcome the toxicity issues and to improve disease outcomes associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS based TPF (NDLS, cisplatin and 5-fluorouracil [FU]) induction chemotherapy in patients with inoperable/unresectable Locally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC). Methods: In this multicentric, single arm, open label, Phase IV clinical study, patients with inoperable/ unresectable LA HNSCC received induction chemotherapy with NDLS (75 mg/m2; Day 1), cisplatin (75 mg/m2; Day 1) and 5-FU (750 mg/m2/day for 5 days) based TPF regimen every 3 weeks (q3w) for 4 cycles followed by radiotherapy. The study outcomes were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Fifty patients were enrolled in this study. Most of the patients belonged to the age group of 35-64 years (86%) and had a WHO performance status of 1 (66%). In the modified intent-to-treat (mITT) population ( n = 40), the ORR after NDLS based TPF induction chemotherapy was 42.5%, which increased to 60.0% after loco-regional therapy. In the per-protocol (PP) population ( n = 14), the ORR was 64.3%, which increased to 80.0% after loco-regional therapy (Table). At 2 years, the PFS and OS rates were 82.5% and 97.5%, respectively, in the mITT population and 85.7% and 100% respectively, in the PP population. The most common grade 3/4 adverse effects reported were neutropenia (10%), leukopenia (6%), febrile neutropenia (4%), asthenia (2%), diarrhea (2%), and thrombocytopenia (2%) respectively. Grade 3/4 infusion-related reactions, hyperglycemia or neuropathy were not reported. Conclusions: NDLS based induction chemotherapy was effective and well-tolerated in the treatment of inoperable LA HNSCC and showed high response rates. Clinical trial information: CTRI/2017/12/010938 .[Table: see text]
Neoadjuvant pembrolizumab, GX-188E, and GX-I7 in patients with human papillomavirus-16- and/or 18-positive head and neck squamous cell carcinoma: Single-arm, phase 2 trial with single cell transcriptomic analysis and artificial intelligence-powered spatial analysis.
Authors: Kim Hye Ryun , Kim Chang Gon , Koh June-Young , Hong Min Hee , Hong Hyun Jun , Kim DaHee , Sim Nam Suk , Yoon Sun Och , Kim Gamin , Lee Jung Eun , Son Wonrak , Lee Chang , Kim Kyung Hwan , Lee Jeong Seok , Yoo Donggeun , Ock Chan-Young , Koh Yoon Woo
Published: June 2023

6075

Background: With the increasing prevalence of head and neck squamous cell carcinoma (HNSCC) associated with human papilloma virus (HPV) infection, effective treatment strategies for HPV-positive HNSCC are urgently needed. Here, we present the results of neoadjuvant checkpoint blockade of pembrolizumab, therapeutic HPV DNA vaccine of GX-188E, and long-acting interleukin-7 of GX-I7 for patients with resectable HPV-16 and/or 18-positive HNSCC. Methods: In this single-arm, phase 2 trial, patients with resectable HPV-16 and/or 18-positive HNSCC were enrolled. Patients were given pembrolizumab 200mg on day 1 and day 22; GX-188E 2mg on day 1, 8, and 22; and GX-I7 1200 ug/kg on day 8 before surgical resection. Major pathologic response (MPR; defined as residual viable tumor of less than or equal to 10%) was primary endpoint with null and alternative hypothesis of MPR rate ≤5% and ≥35%, respectively. Secondary objectives were safety, recurrence, and survival. Results: Of the 11 patients included, all underwent surgical resection after neoadjuvant treatment without delays in surgery or increased surgical complications. MPR was achieved in seven patients (63.6%) and pathologic complete response was achieved in four patients (36.3%), which met the primary endpoint. Single cell RNA sequencing of baseline and post-treatment paired specimens revealed that the proportion of follicular helper T cell cluster, featured with CXCR5 and BCL6 expression, was significantly increased among tumor-infiltrating immune cells, accompanied with the reinvigoration of CD8 T cell cluster toward less exhausted phenotypes, represented with the upregulation of TCF7 and CD28 expression. In addition, artificial intelligence-powered spatial analysis revealed that triple combination significantly increased the density of tumor-infiltrating lymphocytes, completely converting immune-desert and immune-excluded type of tumor to inflamed immune phenotype. Conclusions: Neoadjuvant pembrolizumab, GX-188E, and GX-I7 showed promising activity and manageable safety profile in patients with resectable HPV-16 and/or 18-positive HNSCC. Therapeutic induction of brisk immune responses significantly reshaped the tumor microenvironment and associated with pathologic regression, warranting further investigation of pembrolizumab, GX-188E, and GX-I7 for patients with HPV-positive HNSCC. Clinical trial information: NCT05286060 .