bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant camrelizumab combined with chemotherapy and apatinib for locally advanced thoracic esophageal squamous cell carcinoma (ESCC): A single-arm, open-label, phase Ib study.
Authors: Wang Zhen 
Published: June 2021

4047 Background: Neoadjuvant therapy with PD-1 blockade plus chemotherapy has been found to be effective in the first-line treatment of advanced esophageal cancer. However, evidence of PD-1 blockade combined with chemotherapy as neoadjuvant treatment is limited. This study was designed to investigate the safety and efficacy of camrelizumab, a PD-1 blockade combined with chemotherapy and apatinib as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: A regiment of 2–4 cycles of neoadjuvant camrelizumab (200 mg, intravenous, day 1), nab-paclitaxel (150 mg/m2, intravenous, day 1), nedaplatin (50 mg/m2, intravenous, day 1), and apatinib (250 mg, orally, day 2–4) was given to the treatment-naive patients with resectable locally advanced ESCC. The treatments were repeated every 14 days. In this study, six patients were planned to receive two cycles of neoadjuvant therapy as safety assessment, and then 24 patients received four cycles of neoadjuvant therapy, followed by esophagectomy after 4–8 weeks. The primary end points were safety and feasibility. The secondary end points were the rate of major pathologic response (MPR) and pathologic complete response rate (pCR). Results: A total of 30 patients were enrolled, among them, five patients received two planned cycles of neoadjuvant therapy, and one patient missed the second cycle of therapy due to grade 3 ALT elevations. Further, all other 24 patients received four planned cycles of neoadjuvant therapy. A total of 11 patients (11/30, 36.7%) experienced grade 3 neoadjuvant treatment-related adverse events (TRAEs). No grade 4 and grade 5 TRAEs were reported. The most frequent grade 3 TRAEs was neutropenia (7/30, 23.3%). Twenty-nine patients underwent minimally invasive esophagectomy (McKeown procedure) after neoadjuvant therapy. The reason for not undergoing surgery was due to bone metastasis. There were five treatment-related surgical delays that were caused by adverse reactions (hyperglycemia, arthritis, anemia, leukopenia, capillary endothelial proliferation in oral mucosa). Among the 29 patients undergoing esophagectomy, 15 patients (15/29, 51.7%) achieved MPR, including 7 patients with pCR (7/29, 24.1%). Among the 24 patients who received four cycles of neoadjuvant treatment, there were 7 patients with pCR (7/24, 29.2%), and 14 patients with MPR (14/24, 58.3%). No surgery related mortality was documented. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy plus apatinib is a safe and tolerable treatment for patients with locally advanced ESCC, and the MPR and pCR rate are promising. Clinical trial information: ChiCTR1900023880.
The sequence of chemotherapy and anti-PD-1 antibody influence the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell cancer: A phase II study.
Authors: Zhao Lingdi , Xing Wenqun , Yang Yonghao , Zhang Yong , Ma Baozhen , Fu Xiaomin , Liang Guanghui , Shang Yiman , WANG Zibing , Lin Hongwei , Gao Quanli 
Published: June 2021

4051 Background: PD-1 blockade may result in expansion of tumor-specific T cells. However, traditional immunochemotherapy regimens usually designed to use chemotherapy drugs and anti-PD-1 antibody on the same day, which may make chemotherapy drugs kill activated T cells. The purpose of this study was to investigate the rate of pCR of chemotherapy plus anti-PD-1 therapy and the influence of sequence of chemotherapy and anti-PD-1 therapy on pCR in patients with locally advanced esophageal squamous cell cancer. Methods: Thirty esophageal squamous cell cancer patients with T3, T4, or lymph node positive were assigned into experiment group (anti-PD-1 antibody was administrated two days after chemotherapy) and control group ( anti-PD-1 antibody and chemotherapy were administrated on the same day) according to the order of enrollment. There were fifteen patients in each group. The chemotherapeutic regimen was paclitaxel and cisplatin, paclitaxel was given at the dose of 150-175mg/m2 on day 1 and cisplatin was given at the dose of 70-75mg/m2 on day 1. The anti-PD-1 antibody was toripalimab at the fixed dose of 240mg on day 3 or day 1. Operation was performed four to six weeks after the second cycle of chemotherapy combined with toripalimab. Results: From July 2019 to September 2020, a total of 30 patients completed at least one cycle of immunochemotherapy. 11 in the experimental group received operation after two cycles of neoadjuvant chemotherapy plus toripalimab. Thirteen in control groupreceived operation aftertwo cycles of neoadjuvant chemotherapy plus toripalimab. Four patients in experimental group and one in control group got pCR, the rates of pCR in experimental group and control group were 36.4% and 7.7% individually. Although the difference was not significant in statistics, the experimental group had the trend of higher pCR rate(c2= 3.092, p = 0.079). PD-L1 CPS examination before treatment was performed in fourteen patients, it was found that except one patient with PD-L1 CPS was 10, the left thirteen with PD-L1 CPS were all below one. The patient with PD-L1 CPS 10 was in control group and pCR was got in this patient. Except one patient in the experimental group had grade 3 immune-related enteritis, one patient in the control group died from immune-related myocarditis after operation, there were no more immune-related events more than grade 3. Conclusions: Toripalimab was delayed on day 3 when toripalimab plus chemotherapy was taken as neoadjuvant therapy regimen in locally advanced esophageal squamous cell carcinoma might achieve a higher pathological complete response than toripalimab and chemotherapy used on the same day. Clinical trial information: NCT 03985670.
IMbrave150: Exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor).
Authors: Ducreux Michel , Zhu Andrew X. , Cheng Ann-Lii , Galle Peter R. , Ikeda Masafumi , Nicholas Alan , Verret Wendy , Li Lindong , Gaillard Vincent E. , Lencioni Riccardo , Finn Richard S. 
Published: June 2021

4071 Background: Based on IMbrave150 (NCT03434379) results, atezo + bev has been approved in > 60 countries for pts with unresectable HCC who have not received prior systemic therapy (Finn RS, NEJM 2020). OS and objective response rate (ORR) improvements with atezo + bev vs sor were maintained with an additional 12 mo of follow up since primary analysis. Updated median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (stratified HR, 0.66; 95% CI: 0.52, 0.85). Updated ORR was 30% with atezo + bev vs 11% with sor by independently-assessed (IRF) RECIST 1.1 (Finn RS, ASCO GI 2021). Here, we report an exploratory analysis examining the association of response by RECIST 1.1 with OS and independent predictors of survival. Methods: Pts in this Ph III study were systemic treatment–naive with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. ORR was determined by IRF RECIST 1.1. Kaplan-Meier analyses of OS by response status were conducted without landmark and with 4- and 6-mo landmarks. Multivariate analysis was conducted using Cox modeling with time-dependent covariate (responder [yes/no]) with backwards elimination. These analyses only included pts treated with atezo + bev. Results: IMbrave150 enrolled 501 pts, including 336 treated with atezo + bev. Median follow-up was 15.6 mo. OS was longer in pts with confirmed response per RECIST 1.1 (responders, CR + PR) vs non-responders by Kaplan-Meier analyses without landmark and with 4- and 6-mo landmarks (Table). By multivariate analysis, in addition to responder (yes/no), 5 of the 10 initially included predictors of OS remained in the final Cox model ( P< 0.10): ECOG PS (0/1), geographic region (Asia excluding Japan/rest of the world), etiology (hepatitis B/hepatitis C/non-viral), macrovascular invasion and/or extrahepatic spread (yes/no), and baseline alpha-fetoprotein ( < 400 ng/mL/≥400 ng/mL). Conclusions: Atezo + bev is the new standard of care for pts with previously untreated, unresectable HCC. Here we showed that in IMbrave150 pts treated with atezo + bev, response by RECIST 1.1 was associated with OS, suggesting that confirmed response is an independent predictor of OS in these pts. Clinical trial information: NCT03434379. [Table: see text]
T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).
Authors: McCoon Patricia , Lee Young S , Kelley Robin Kate , Guthrie Violeta Beleva , Wu Song , Bien Stephanie A , Negro Alejandra , He Philip , Kurland John , Barrett J Carl , Pilataxi Fernanda , Ching Steven , Abou-Alfa Ghassan K. 
Published: June 2021

4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]
Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.
Authors: Cousin Sophie , Bellera Carine A. , Guégan Jean Philippe , Mazard Thibault , Gomez-Roca Carlos A. , Metges Jean Philippe , Cantarel Coralie , Adenis Antoine , Korakis Iphigenie , Poureau Pierre-guillaume , spalato-Ceruso Mariella , Bourcier Kevin , Kind Michèle , Soubeyran Isabelle , Bessede Alban , Italiano Antoine 
Published: June 2021

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.
Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma.
Authors: Bai Li , Sun Meili , Xu Aibing , Bai Yuxian , Wu Jian , Shao Guoliang , Song Lijie , Jin Xiaoping , Song Weifeng , Li Baiyong , Xia Yu , Jiao Shunchang 
Published: June 2021

4101 Background: Anti–PD-(L)1 plus anti-CTLA-4 therapies (e.g. nivolumab/ipilimumab, tremelimumab/durvalumab) produce durable immune responses in patients (pts) with advanced hepatocellular carcinoma (HCC). More recent data suggests that the combination of immune checkpoint inhibitors (ICIs) with a multi-kinase inhibitor is efficacious against unresectable HCC (uHCC). AK104 is a humanized IgG1 bispecific antibody that simultaneously binds to PD-1 and CTLA-4. Early data suggests that AK104 possesses encouraging anti-tumor activity in selected tumour types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 antibodies. Lenvatinib is a multi-kinase inhibitor and approved for first-line treatment of uHCC. Here, we report results from a phase 2 study of AK104 plus lenvatinib in pts with uHCC. Methods: In this single-arm, multicenter phase II study (NCT04444167), pts with uHCC, BCLC stage B or C, Child-Pugh class A, who had not previously received systemic treatment received AK104 (6 mg/kg IV q2w or 15 mg/kg IV q3w) and lenvatinib (8 mg [bodyweight < 60 kg] or 12 mg [weight ≥ 60 kg] PO QD). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: As of February 1 2021, 30 pts (86.7% male, median age 52.5yrs [31-71], 30% was ECOG 1, 93.3% was HBV+) had received the combination therapy of (AK104 6 mg/kg q2w plus lenvatinib). Of 18 pts evaluable for antitumor activity (defined as pts with the opportunity to be followed for at least 2 scans [≥13 weeks]), ORR per RECIST v1.1 was 44.4% (8/18), DCR was 77.8% (8 PRs and 6 SDs including 2 pts who had 28.4% and 29.2% reduction in tumor size from baseline). Median PFS has not been reached. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3 TRAEs occurred in 26.7% [8/30], and no G4 TRAEs or TRAEs leading to death). Most common TRAEs (≥15%) were increased AST (36.7%) and ALT (36.7%), decreased platelet count (33.3%), decreased neutrophil count (30.0%), and increased blood bilirubin (26.7%), with the vast majority being grades 1 or 2. Conclusions: AK104 plus lenvatinib as first-line therapy for uHCC has showed promising antitumor activity and an acceptable safety profile. Toxicities were manageable, with no unexpected safety signals. Enrollment for AK104 15 mg/kg q3w plus lenvatinib is currently ongoing, and longer follow-up is needed to further evaluate the durability of response. Clinical trial information: NCT04444167.
Should all pancreatic neuroendocrine tumors (PNET) over 1 cm be resected?
Authors: Hsu Diana , Le Sidney , Chang Alex , Spitzer Austin , Kazantsev George , Peng Peter D , Chang CK , Truong Thach-Giao 
Published: June 2021

4108 Background: Pancreatic neuroendocrine tumors (PNET) are a heterogeneous group of tumors that represent 1-2% of all pancreatic neoplasms. Their biologic behaviors are unpredictable with high grade, nodal metastasis, or liver metastasis lending an unfavorable prognosis. Current guidelines recommend resection for functioning tumors and those 2 cm or larger but are less straightforward regarding tumors < 2 cm in size. Previous data show that observation for nonfunctioning tumors < 2 cm can be safe and feasible; however, a significant portion of these patients may have nodal involvement or metastatic disease. Methods: A retrospective review was undertaken to identify patients with pancreatic neuroendocrine tumors treated at Northern California Kaiser Permanente (KP-NCAL) between February 2010 and December 2018. Univariate and multivariate analyses were performed with the log-rank test and Cox regression. Chi-squared test of relevant clinicopathologic factors determined which factors were predictive for overall survival (OS). Results: Mean age was 61 years in our cohort of 354 patients, with 29% over the age of 70. Mean tumor size was 3.43 cm; 32% of tumors were 2 cm or smaller. 51% of the patients had localized disease; 32% of the patients presented with metastatic disease. The pancreatic tail was the most common tumor location (38%), followed by the head of the pancreas (24%). On multivariate survival analysis, stage, location of the tumor, and surgical resection were statistically significant in terms of overall survival ( p<.001). Mean OS for patients with localized and metastatic disease was 93 months versus 37 months ( p<.001). Surgery was utilized in 8.9% of patients with metastatic disease ( p<.001). All patients with PNET smaller than 1 cm in our study group had localized disease only. However, in patients with tumor size between 1 and 2 cm, 11% had nodal or metastatic spread. Conclusions: PNETs are indolent but have malignant potential at any size. In our retrospective study, all of the patients with tumor size < 1 cm had localized disease. For those with PNETs 1-2 cm in size, 11% had nodal or metastatic spread. Based on our findings, we suggest a more aggressive surgical resection size criteria of 1 cm.[Table: see text]
Predictive value of germline ATM mutations in the CCTG PA.7 trial: Gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D) and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Renouf Daniel John , Loree Jonathan M. , Knox Jennifer J. , Kavan Petr , Jonker Derek J. , Welch Stephen , Couture Felix , Lemay Frederic , Tehfe Mustapha , Harb Mohammed , Aucoin Nathalie , Ko Yoo-Joung , Tang Patricia A. , Topham James T. , Jia Shidong , Du Pan , Schaeffer David F. , Gill Sharlene , Tu Dongsheng , O'Callaghan Christopher J. 
Published: June 2021

4135 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318.