bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]