bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of tislelizumab plus cetuximab and irinotecan in patients with previously treated RAS wild-type advanced colorectal cancer: A phase II, single-arm study.
Authors: Xu Xiaojing , Yu Yiyi , Wang Yan , Cui Yuehong , Li Wei , Liang Li , Li Qian , Yu Shan , Feng Yi , Liu Qing , Zhang Pengfei , Lv Minzhi , Liu Tianshu
Published: January 2023

125

Background: For adequately treated patients (pts) with advanced colorectal cancer, the current third-line treatment standard of TKIs or TAS-102 administration has a low clinical objective response rate and its effectiveness seems to be limited. Preclinical studies have suggested that EGFR pathway blockage and immune checkpoint inhibition have synergistic therapeutic effects in these pts. The purpose of this study was to examine the efficacy and safety of tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan in pts with previously treated RAS wild-type advanced colorectal cancer. Methods: This is an open-label, single-arm, phase II study. RAS wild-type advanced colorectal cancer pts with at least two previous lines of therapy were included in this study and administered with tislelizumab plus cetuximab and irinotecan until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) (RESCIT 1.1). Secondary endpoints included DCR, PFS, OS and safety. Results: In total, 35 eligible RAS wild-type advanced colorectal cancer pts were enrolled from March 2021 to September 2021. The median age was 58 years. All 35 pts were identified as BRAF/RAS wild-type, and 33 (94%) had left-sided colon cancer. The percentages of pts with second-line, third-line and ≥fourth-line previous treatments were 37%, 49%, and 14%, respectively. Thirty-four pts (97%) had received targeted therapies previously, including 29 (83%) with anti-EGFR therapy. By Aug 17th, 2022, 2 pts had withdrawn from the study for personal reasons, and the remaining 33 pts were evaluated for efficacy. Twelve of the 33 (36.4%) pts achieved clinical partial remission and 14 (42.4%) achieved stable disease; disease progression occurred in 6 pts and 1 patient died. The unconfirmed ORR was 36.4% and the DCR was 78.8%. The confirmed ORR was 33.3%. Until Aug 17th, 2022, 1 pts continued treatments. The median PFS was 6.83 months. Among the 33 treated pts, 32 (97.0%) had treatment-related adverse events (AEs). Common AEs included rash (n=32), fatigue (n=30), decreased appetite (n=30), nausea (n=28), diarrhea (n=16), vomiting (n=14), liver dysfunction (n=13), leukopenia (n=12) anemia(n=10), neutropenia (n=9), paronychia (n=8), oral mucositis (n=4), and thrombocytopenia (n=4). Three (9.1%) of the 33 pts reported grade ≥3 AEs, including rash (n=1), neutropenia (n=2). Conclusions: Tislelizumab plus cetuximab and irinotecan showed an encouraging clinical efficacy and tolerable safety in previously treated pts with RAS wild-type advanced colorectal cancer. Clinical trial information: NCT05143099 .
Efficacy and safety of neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in microsatellite stable (MSS)/mismatch repair proficient (pMMR) locally advanced rectal cancer.
Authors: Dai Sheng , Wang Fei , Shen Yanbin , Shi Liming , Xu Lingna , Lai Chuanxi , Zhang Feixiang , Zhang Kangke , Xu Dengyong , Shan Lina , Cao Gaoyang , Wang Da , Lao Weifeng , Sun Xiaonan , Huang Xuefeng
Published: January 2023

134

Background: Chemoradiation is the standard neoadjuvant treatment for locally advanced rectal cancer. Microsatellite stable (MSS)/ mismatch repair proficient (pMMR) rectal cancer rarely responds to immune checkpoint inhibitor monotherapy, but combination with chemoradiation may improve sensitivity of MSS/pMMR tumors by inducing immune-stimulatory effects. Therefore, we aimed to investigate the efficacy and safety of patients treated with neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX for MSS/pMMR locally advanced rectal cancer. Methods: This is an open-label, single-center, phase ¢ò study. Patients (pts) with locally advanced rectal adenocarcinoma with MSS/pMMR were eligible. MMR protein expression was tested by immunohistochemistry (IHC) £¬and MSI status was confirmed by NGS (next generation sequencing). All pts included in this study underwent neoadjuvant short-course radiation (total dose of 5¡Á5Gy) in the first week after enrollment, then followed by 6 cycles of envafolimab (anti-PD-L1 inhibitor,150mg, d1, subcutaneous injection, QW) plus 2 cycles of CAPEOX in the next six weeks, and subsequently underwent total mesorectal excision (TME) in the ninth week. The primary endpoint is pathological complete response rate. Secondary endpoints include tumor regression grade (TRG), 3 year disease free survival, overall survival, toxicity, and quality of life (QoL). Results: This study intends to recruit 32 pts, and a total of 21 pts were enrolled from January 2022 to September 2022. Overall median age was 67 (42-79) years. 12 pts completed study designed treatment protocol (envafolimab plus CAPOX) followed with TME procedures, and 9 pts are still undergoing neoadjuvant treatment. All 12 pts achieved major partial response (MPR) evaluated by diffusion-weighted magnetic resonance imaging (DW-MRI), and 8 pts (8/12,76.6%) achieved pCR. During neoadjuvant treatment period, 20 pts (20/21, 95.2%) presented with treatment-related AEs (TRAEs) of any grade, 18 pts (18/21, 85.7%) had grade 1-2 and one each pts had grade 3 and 4 thrombocytopenia (2/21, 9.5%). The most common TRAEs were sensation of rectal tenesmus. Conclusions: Neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in MSS/pMMR locally advanced rectal cancer achieved a promising pathologic response. Meanwhile, this combination neoadjuvant therapy is safe and worthy of application to clinical practice. (Funded by Sir Run Run Shaw Hospital Zhejiang University School of Medicine.) Clinical trial information: NCT05216653 .
Fruquintinib combined with tislelizumab and SBRT as a later-line therapy in microsatellite stability (MSS) metastatic colorectal cancer (mCRC): Results from the FRUIT trial.
Authors: Yuan Xianglin , Zhang Mingsheng , Hou Huiying
Published: January 2023

150

Background: MSS patients (pts) account for the majority of all CRC pts and show poor response to immunotherapy. While fruquintinib plus PD-1 inhibitors is an effective option for MSS CRC pts in China who are refractory to multiple lines of therapy. In addition, immunomodulatory effects of stereotatic body radiotherapy (SBRT) have demonstrated in previous studies. Here, we report FRUIT trial of fruquintinib combined with tislelizumab and SBRT as a later-line therapy in MSS mCRC pts. Methods: In this single-arm, open-label, single-center, phase II trial (NCT04924179), we included mCRC pts who have failed with at least second-line therapy. Eligible pts undergo the following regimens on a 21-days cycle: fruquinitib (5mg, QD, PO, d1-14) plus tislelizumab (200mg, d1, I.V.) and SBRT (8-10Gy×5F, QOD). The primary endpoint is progression-free survival (PFS), and secondary endpoints are disease-control rate (DCR), objective response rate (ORR), overall survival (OS), and safety. The responses are evaluated according to RECIST Version 1.1 and adverse events are evaluated by CTCAE v5.0. Results: AS of August 31, 2022, 24 pts were included in the trial and 23 (11 male; media age 60 years; all pts with MSS; 7 had received 3 prior lines of therapy) in the efficacy analysis. 87%, 9% and 17% pts had received bevacizumab, regorafenib and cetuximab in previous therapy, respectively. Among 23 pts, median follow-up was 7.8 mo (95%CI: 4.31, 11.29). The median PFS was 5.1mo (95%CI: 0.57-9.63), with 9 pts still on treatment at data cutoff. 6pts achieved partial response (PR), 13 stable disease (SD), illustrating an ORR of 26% and a DCR of 83%. Adverse events (AEs) occurred in 22 (96%) pts which were mostly grade 1/2. 17% pts experienced a grade 3/4 AEs, including hypertension (9%), hand foot skin reaction (4%) and thrombocytopenia (4%). The combination regimen was well tolerate. Conclusions: Fruquintinib plus tislelizumab and SBRT as a later-line therapy in refractory MSS mCRC pts shows a promising clinical benefit, with a manageable safety profile, which suggests a potential new paradigm for therapy in MSS mCRC pts. Clinical trial information: NCT04924179 .
Synergistic effects of alpelisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor) combination in preclinical colorectal cancer models.
Authors: Aslam Razia , Hennessy Bryan T , Toomey Sinead , Richards Catherine
Published: January 2023

167

Background: Multiple activating genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways have been implicated in the development of resistance to anti-cancer therapies. Ribociclib has limited activity as a single agent in CRC. However, combining Ribociclib with targeted therapies of the MAPK and PI3K pathways may be a promising treatment strategy for CRC. Methods: We explored the in vitro efficacy of drug combinations Ribociclib (R) and Alpelisib (A) in four CRC cell lines with different mutational status; CACO2 ( PIK3CA/KRAS wild-type), LS1034 ( KRAS mutated), SNUC4 ( PIK3CA mutated) and DLD1 ( PIK3CA/KRAS mutated). Drug combination index (CI) was calculated using Calcusyn Biosoft software. We used a western immunoblotting method for protein analysis. The Chick Chorio-Allantoic Membrane (CAM) assay was used for in-vivo analysis of the effect of the drug combination. Results: IC50s for R and A were calculated for all four cell lines. CACO2 and DLD1 cells were resistant to Ribociclib (IC50 > 15µM). The cell lines had varying sensitivity to both drugs. Drug combination analysis showed that the combination of R and A has a synergistic anti-proliferative effect in all CRC cell lines tested. The combination of R and A is highly synergistic in LS1034 cells which harbour a KRAS mutation (CI = 0.16). Relative expression of the proteins Cyclin D1, E2F-1, p-BCL-2, p-AKT, p-Rb and p-S6 was determined by measuring the density of each band from the western blot experiments and normalizing to β-actin. Combined inhibition of CDK4/6 and PI3Kα caused a simultaneous reduction of p-RB, p-AKT and p-S6 and a more complete inhibition of the PI3K/AKT/mTOR pathway in all four cell lines tested. There was also an increase in the expression of the apoptotic marker pBCL2 in cells treated with the combination of R and A compared to vehicle control(VC). We observed a macroscopic reduction of visible tumour in all cell lines treated with the R and A combination in vivo as compared to VC. Microscopic examination also showed less Ki67 staining and negative cytokeratin staining in combination treated groups. Conclusions: We see a synergistic response to treatment with the combination of R and A in all cell lines and this combination may be a rational treatment strategy in colorectal cancer.
Plasma phosphocreatine (PC) as a predictive biomarker for immune checkpoint inhibition in patients with refractory metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.
Authors: Ma Lucy Xiaolu , Loree Jonathan M. , Jonker Derek J. , Kennecke Hagen Fritz , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aucoin Nathalie , Aubin Francine , Koski Sheryl L. , Tu Dongsheng , O'Callaghan Christopher J. , Chen Eric Xueyu
Published: January 2023

183

Background: In response to energetic stress, colorectal cancer cells secrete creatine kinase brain-type (CKB). CKB converts creatine and ATP from the extracellular matrix to PC, which is imported intracellularly to sustain survival and metastatic spread. In addition, PC modulates immune cell functions and may play a role in mediating responses to immune checkpoint inhibition. CO.26 was a phase II trial (NCT02870920) that randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). In an exploratory, post-hoc analysis, we investigated the role of plasma PC as a predictive biomarker for response to D+T. Methods: PC concentrations were determined from pre-treatment blood samples with HPLC-tandem mass spectrometer. A minimum p-value approach was used to select an optimum cut-off value which dichotomized patients into low (< 95.6 ng/ml) versus high (≥ 95.6 ng/ml) groups predictive for benefit. Cox proportional hazard models were used to analyze predictive impacts of PC on progression free survival (PFS) and overall survival (OS). Results: Of 180 pts enrolled, pre-treatment blood samples were available for 162 pts (N =115 for D+T; 47 BSC). Pre-treatment PC was low in 15% (N=24) and high in 85% (N=138). There were no differences in baseline characteristics between pts included in this analysis and the total study pts, or PC low and high pts. D+T improved OS significantly in PC low pts (median OS 4.7 months vs 2.3 months; Hazard Ratio (HR) 0.32, 95% confidence interval (CI): 0.11 – 0.95, p = 0.03). There was no improvement in PC high pts with D+T (median OS 6.8 vs 5.2 months; HR 0.80, 95% CI: 0.55 – 1.17, p = 0.24. Interaction p < 0.0001). Plasma PC values had no impact on PFS and rates of disease control. Conclusions: Pts with low plasma PC derived more benefit from immune checkpoint inhibition with D+T in pts with refractory mCRC. Further prospective validation studies are needed. Predictive analysis for OS with pre-treatment PC levels dichotomized by minimum p approach. [Table: see text]
The association between KRAS mutational status, clinicopathological factors including the preoperative systemic inflammatory response and outcomes in TNM stage I-III colon cancer.
Authors: Golder Allan Matthew , Pennel Kathryn AF , Mansouri David , Horgan Paul G. , Roxburgh Campbell SD , Biankin Andrew V , Edwards Joanne , McMillan Donald C. ,   GPOL Group
Published: January 2023

193

Background: TNM Stage is the most significant prognostic indicator in colon cancer however other tumour and host factors (eg the systemic inflammatory response (SIR)) are associated with long-term outcomes. The relationship between the tumour and the host SIR remains poorly understood. KRAS mutations are associated with adverse outcomes in metastatic disease and have been reported to have an inflammatory phenotype however this has not been widely studied in non-metastatic disease. The present study investigates the association between KRAS mutations, clinicopathological factors including the SIR and outcomes in TNM I-III colon cancer. Methods: Two cohorts of patients (single centre–2000-2008 and regional-2011-2014) undergoing curative surgery for TNM I-III colon cancer in the West of Scotland were shown to be well-matched and combined. Mutational status was analysed retrospectively. The SIR was stratified using Systemic Inflammatory Grade (SIG). 3-year overall and cancer specific survival (OS and CSS) were measured from date of surgery until date of death. Results: 267 patients were identified, 45% with KRAS mutations. KRAS mutations were associated with: right sided (p=0.013), well differentiated (p=0.011), BRAF-wt (p<0.001), PIK3CA-wt (p=0.027) and P53-wt (p=0.002) tumours. A trend was seen between KRAS mutations and female sex (p=0.074) and increased SIG (p=0.072). No association was seen with age, deprivation, smoking, ASA Grade, TNM Stage or EMVI. KRAS mutant status was associated with adverse 3-year CSS (74% versus 82%, p=0.006) and OS (69% versus 78%, p=0.070). For CSS, TNM Stage (HR 2.92, p<0.001), KRAS mutant status (HR 1.64, p=0.050) and Systemic Inflammatory Grade (HR 1.34, p=0.004) were independently prognostic. For OS: age (HR 1.39, p=0.022), TNM Stage (HR 1.50, p=0.016) and SIG (HR 1.25, p=0.005) were independently prognostic. A trend was seen between KRAS mutant status and adverse OS (HR 1.47, p=0.079). Conclusions: The present results show an association between KRAS mutational status and SIG. Furthermore, both of these factors were associated with adverse oncological outcomes. Further investigation into the association between KRAS-mutant status and the local/systemic inflammatory response in TNM I-III colon cancer is warranted. While comprehensive genomic profiling is likely to become increasingly common place, staging the host (SIR) should also be routinely undertaken.
Assessment of immunoscore and MRI tumor regression grade to predict complete pathologic response in patients with locally advanced rectal cancer: Data from phase II Averectal study.
Authors: Shamseddine Ali , Machmouchi Ahmad , Natout Mustafa , Turfa Rim , Kattan Joseph Gergi , Temraz Sally Naji , Tawil Ayman , Elkhaldi Mousa , Jaber Omar , Amarin Rula , Awabdeh Tala , Charafeddine Maya , Al Darazi Monita , Hussain Hero
Published: January 2023

212

Background: In patients with locally advanced rectal cancer (LARC), magnetic resonance imaging is the most accurate non-invasive staging tool, enabling response assessment to total neoadjuvant therapy. Wang et al had reported that 46.6% of patients with Magnetic Resonance Tumor Regression Grade 1 (mrTRG=1; complete radiologic response) achieved pathologic complete response (pCR; no residual tumor cells). We reported previously in a Phase II Averectal study the correlation between pre-treatment biopsy Immunoscore (IS) and pCR probability (68% ± 22 SD in patients with a high IS as opposed to 52% ± 22 SD in patients with a low IS; P=0.036). This study explores the value of combining IS and mrTRG to predict pCR among LARC patients. Methods: This is an open-label, single-arm multicenter stage-2 phase II study investigating the efficacy and safety of 5 fractions of short course radiotherapy, followed by 6 cycles of mFOLFOX-6 plus avelumab, followed by Total Mesorectal Excision (TME), in patients with LARC. Mean density percentiles of CD3 and CD8 positive T cells infiltrating the tumor and the invasive margin in baseline tissue samples were used to calculate IS (62% is considered the cutoff between high and low IS). Baseline and post treatment MRI were reviewed by two independent radiologists to measure mrTRG and other variables. Results: Between July 2018 and October 2020, 44 patients were accrued, out of which 40 (90%) completed at least 1 cycle of mFOLFOX/Avelumab and underwent TME. Of the 40, 36 (90%) had baseline IS, mrTRG (pre-post treatment) and pTRG (pathologic Tumor Regression Grade) assessed. Out of 36, 15 (41.6%) achieved pCR, 24 (66.7%) had mrTRG=1 and 22 (61%) had high IS. Of the high IS (n=22) patients, 10 (45.45%) achieved pCR. Also, out of 24 patients with mrTRG=1, 11 (45.8%) attained pCR. Most importantly, of the patients with combined high IS and mrTRG=1 (n=14), 11 (78.6%) achieved pCR. In patients with both mrTRG=1 and high IS, pCR rate was 78.6% (11/14). This result is significantly different from pCR rate for patients with either high IS (10/22, 45.45%) or mrTRG=1 (11/24, 45.8%) with P=0.0247 and P=0.0243 respectively. Conclusions: Combining both IS and mrTRG achieved a promising predictive value for pCR in LARC and therefore upon further validation may be potentially used for patient selection in non-operative management strategies. Clinical trial information: NCT03503630 .
Utility of tumor marker levels in predicting survival of patients with appendiceal adenocarcinoma.
Authors: Yousef Abdelrahman M.G. , More Aditya , Zeineddine Mohammad A. , Chowdhury Saikat , Gu Yue , Dansby Julia , Naini Zahra Alavi , Uppal Abhineet , Raghav Kanwal Pratap Singh , Overman Michael J. , Fournier Keith F. , Shen John Paul Y.C.
Published: January 2023

221

Background: Due to the rarity of appendiceal adenocarcinomas (AA), systematic study of these tumors has been limited. Thus, guidelines for the diagnosis and treatment of AA are often based on other related tumor types such as colorectal cancer. However, given that AA has been shown to be molecularly and functionally distinct, there is a need for focused clinical data to guide disease management. In AA, tumor marker levels are used by some practitioners to monitor response to treatment and aid in diagnosis. This study evaluates the association of elevated tumor marker levels with survival outcomes. Methods: The MDACC database was queried to identify patients with AA between 1997 to 2022. Patients with reported values for the tumor markers CA-125 (n=1076), CA 19-9 (n=1060), and CEA (n=1249) were then selected for analysis. Elevation of tumor markers was defined as above the laboratory upper limit of normal (CA-125 > 37 U/mL, CA 19-9 > 37 U/mL, and CEA > 3 ng/mL and survival outcomes were compared with a log-rank (Mantel-Cox) test. This analysis was repeated while controlling for tumor grade, which was defined by low-grade: well, well to moderately differentiated and high-grade: moderate, moderate to poor, and poorly differentiated. Results: Elevated CA-125 was predictive of overall survival in all patients with median survival not-yet-reached for those with normal CA-125 vs. 87.4 months for those with elevated CA-125 (HR: 5.8, p < 0.0001). Similarly, elevated CA 19-9 and CEA were also predictive of overall survival (HR: 2.8, 4.6, respectively, p < 0.0001 for each). Given that tumor grade is the primary driver of prognosis in AA, survival analysis was repeated while controlling for tumor grade. While elevated levels of all tumor markers were predictive of overall survival for both low-grade and high-grade tumors, elevated CA-125 was an especially strong predictor of survival in patients with high-grade tumors (OS: 69.8 months vs. not-yet-reached, HR: 14.3, p < 0.0001). Moreover, high-grade patients with elevated CA-125 had a reduced 5-year survival rate of 56% vs. 91%. Elevated CA-125 also stratified 5-year survival rate in low-grade patients (83% vs. 99%). Elevated levels of CA 19-9 and CEA were strongly predictive of overall survival for patients with low-grade tumors (HR: 10.6, 26.8, respectively, p < 0.0001 for each). Notably, patients with low-grade tumors expressing normal levels of CA 19-9 or CEA had excellent 5-year survival rates of 99% and 100%, respectively. Conclusions: These results highlight the utility of using tumor marker levels in conjunction with tumor grade to more accurately predict prognosis in AA. CA 19-9 and CEA were particularly useful indicators of outcome in patients with low-grade AA, while CA-125 had greatest prognostic value in high-grade tumors.
Effect of immunotherapy on the survival outcomes in tumor mutational burden-high (TMB-H) microsatellite stable (MSS) metastatic colorectal cancer (mCRC): A single-institution experience.
Authors: Gaber Ola , Karan Canan , Walko Christine Marie , Knepper Todd C , Kim Richard D. , Sahin Ibrahim Halil
Published: January 2023

239

Background: The benefit of immunotherapy for patients with mCRC with high tumor mutational burden (TMB-H) has been widely debated. In 2020, the FDA approved the use of pembrolizumab for the treatment of patients with TMB-H unresectable or metastatic solid tumors, with TMB-H defined as ≥10 mutations/Mb on a commercial tissue-based assay, based on KEYNOTE 158 results. However, the clinical value of applying this universal cut off to mCRC needs further investigation. Methods: We queried Moffitt Cancer Center (MCC) databases for patients with MSS mCRC, harboring TMB-H (tested with tissue and/or liquid biopsies) who received immunotherapy between January 2018 and December 2021. Patients with incomplete records were excluded. Clinical data were extracted by trained staff from electronic medical records. Objective response rate was measured by using clinical assessment from chart review. Results: We identified 40 patients with TMB-H MSS mCRC 13 of whom received immune checkpoint inhibitor therapy. Female patients represented 31% (n=4) of the 13 treated patients. Median age for the patients was 60 years (range 34-71. Thirty-eight percent (n=5) of the primary tumors originated in the right side. Thirty-one percent (n=4) presented with stage 4 CRC at diagnosis. Histopathology was adenocarcinoma in 92% (n=12) and one had neuroendocrine differentiation. Tumors were well-differentiated 8% (n=1), moderately differentiated 46% (n=6), or poorly differentiated 23% (n=3). Four patients (31%) had POLE/ POLD-1 mutations. The objective response rate (ORR) was 31% (4/13) with responses limited to tumors only with POLE/ POLD-1 mutations (100%, 4/4). The median progression free survival (mPFS) was 3.8 months for the overall cohort and 28.5 months for patients with POLE/POLD-1 mutated tumors. Agent specific analysis showed mPFS for patients treated with pembrolizumab was 3.5 months (mean 5.2; range 0.6-15.7), and 3.4 months (mean 12.1; range 0.5-12.1) for patients treated with nivolumab. Five patients received immunotherapy in combination with regorafenib. The mPFS for these patients was 3.4 months (mean 3.8; range 0.5-8.0). Of five patients with TMB>30 (38%), 4 (80%) had POLE/POLD-1 mutated tumors. One case without POLE/POLD-1 mutations, but with a TMB>30 did not experience any response. Conclusions: Although TMB-H demonstrated therapeutic significance in the KEYNOTE 158 study, the utility of 10 mutations/MB as a universal cutoff warrants additional evaluation. Here we report that a TMB-H cutoff value of ≥ 10 for patients with MSS CRC was not associated with clinically meaningful response to immunotherapy, but patients with MSS CRC with POLE/ POLD-1 mutations may be more likely to benefit from immunotherapy.
Safety of ramucirumab in patients with advanced gastric cancer in Europe and North America: A prospective observational registry.
Authors: Silvestro Lucrezia , De Vita Ferdinando , Vogel Arndt , Ettrich Thomas Jens , Van Cutsem Eric , Di Bartolomeo Maria , D'yachkova Yulia , Liepa Astra M. , Smolyakova Natalia , Lukanowski Mariusz , Huang Yu-Jing
Published: January 2023

341

Background: The objective was to describe the safety of ramucirumab (Ram) for previously treated advanced gastric cancer under real-world conditions in Europe and North America. Methods: This was a non-interventional, descriptive study of adult patients with advanced gastric or gastroesophageal junction adenocarcinoma whose disease had progressed after first-line chemotherapy (I4T-MC-JVDD). Data collection began in December 2015 and was completed in August 2021. Patients were followed up to 12 months after initiation of Ram. Safety outcomes included adverse events (AEs)/serious AEs (SAEs), and AEs leading to dose adjustment or death. Subgroups of interest were elderly, patients with cardiac comorbidities, hepatic, or renal impairment. Results: 606 patients were classified in 3 cohorts: Ram monotherapy (Ram Mono, N=51); Ram plus paclitaxel (Ram+PTX, N=547); or Ram plus other anti-cancer agents (N=8). Most patients were male (70%), white (97%) and aged ≥65 (55%); 22% of the population was ≥75 years old. Metastatic cancer was reported in 552 patients (96%); primary tumor location was gastric in 417 patients (69%) and in the gastroesophageal junction in 189 patients (31%). Patients were previously treated mainly with platinum (97%) and fluoropyrimidine (96%). Hypertension was the most frequently reported historical medical condition (25%). At baseline, 23% patients had documented cardiac comorbidities, 11% hepatic impairment and 6% renal impairment. The median duration of Ram was 8 weeks (IQR=4.0-10.6) in Ram Mono and 15 weeks (IQR=8.4-26.7) in Ram+PTX. Regardless of causality, 98% of patients experienced ≥1 AE; most commonly fatigue (31%) and abdominal pain (20%) in Ram Mono cohort; and fatigue (46%) and neuropathy (31%) in Ram+PTX cohort. In total, 40% experienced ≥1 AE of special interest; most commonly bleeding/hemorrhage (21% [mainly epistaxis]) and hypertension (11%). In total, 33 patients (5%) died due to AEs that occurred on, or within 90 days of last dose of Ram, 9 (2%) were related to Ram treatment as per physician’s assessment. Conclusions: The observed safety profile of Ram in the real-world setting was manageable and consistent with the established safety profile of Ram identified from clinical trials. No new safety concerns or notable findings were observed overall or in the subgroups of interest. Clinical trial information: ENCEPP/SDPP/9400 . [Table: see text]
First-line of camrelizumab plus pyrotinib and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: A dose escalation and expansion phase I study.
Authors: Zhu Liangjun , Li Sheng , Bao Jun , Li Xiaoyou , Yang Quanliang , Xu Junying , Chen Surong , Feng Ge , Gao Chao , Feng Lin , Lu Bin , Miao Min , Ni Xinchu , Wang Guofang , Yang Lei
Published: January 2023

356

Background: The combination of PD-1 and HER2 blockades showed potential benefit for patients with HER2-positive gastric cancer. This study aimed to investigate the safety and efficacy of camrelizumab plus pyrotinib and chemotherapy in the first-line setting for HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: This phase I, open-label, clinical trial (ChiCTR2000029717) included dose-escalation and dose-expansion cohorts. Patients aged 18 or older with HER2-positive G/GEJ cancer were enrolled. In dose-escalation phase, patients were administrated with three-week cycle of oral pyrotinib 240mg, 320mg or 400mg daily, intravenous camrelizumab 200mg and oxaliplatin 130mg/m2 on day 1, and oral capecitabine 1000mg/m2 twice a day for two weeks followed by one week off until unacceptable toxicities, progressive disease or death. Additional patients were enrolled in a dose-expansion phase and received maximum tolerated dose determined in the dose-escalation cohort. The primary endpoints were the safety and objective response rate (Response Evaluation Criteria in Solid Tumors version 1.1). Results: Between June, 2020 and June, 2022, a total of 31 patients were enrolled, with 9 patients in the dose-escalation phase (three patients received pyrotinib 240mg, 320mg or 400mg each) and 22 in the dose-expansion phase. During dose-escalation, five patients experienced six dose-limiting toxicity, including diarrhea (n=4), vomiting (n=1) and decreased appetite (n=1). The maximum tolerated dose of pyrotinib was 320 mg, which was chosen for dose-expansion. For 25 patients received pyrotinib 320 mg, 13 (52.0%) developed grade 3 or higher adverse events (AEs), and 6 (24.0%) discontinued treatment due to AE. The most common AE of any grade was diarrhea (96.0%), followed by vomiting (60.0%), decreased appetite (56.0%) and anemia (56.0%). The objective response rate and disease control rate were 96.0% and 100%, respectively. The 12-month progression-free survival rate and overall survival rate were 77.1% and 89.3%, respectively. Conclusions: Camrelizumab plus pyrotinib and chemotherapy showed promising efficacy in the first-line treatment of HER2-positive G/GEJ cancer, with acceptable safety profiles. The study is ongoing. Clinical trial information: ChiCTR2000029717 .[Table: see text]
Camrelizumab plus apatinib for immunochemotherapy-treated advanced esophageal squamous cell carcinoma: Preliminary results of cohort 2 in CAP 02 study.
Authors: Wang Feng , Wang Junsheng , Meng Xiangrui , Luo Zhiquan , Xia Jin , Hong Yong-Gui , Lu Ping , Ji Yinghua , Shan Zheng-Zheng , Fan Qingxia
Published: January 2023

384

Background: CAP 02 study (NCT03736863) is a single-arm phase 2 study to evaluate the efficacy and safety of camrelizumab plus apatinib (a VEGFR2 inhibitor) as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). Cohort 1 has been published recently, which enrolled patients who progressed after or were intolerant to first-line chemotherapy. The results showed an encouraging median overall survival (OS) of 15.8 months. Here, we reported the preliminary results of cohort 2. Methods: Cohort 2 enrolled unresectable locally advanced, locally recurrent, or metastatic ESCC patients aged 18-75 years with ECOG performance status of 0-1 who had progression on or were intolerant to first-line immunochemotherapy. The disease should be controlled without progression for at least three months during the first-line treatment. Patients received camrelizumab (200 mg Q2W) and apatinib (250 mg QD) until disease progression, intolerable toxicity, or withdrawal for other reasons. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate, progression-free survival (PFS), duration of response, time to response, OS, 3/6-month PFS rates, 6/9/12-month OS rates, and safety. Results: At the data cutoff (Sep 21, 2022), 33 of the planned 40 patients with an average of 68 years old had been enrolled, including 24 (73%) males and 24 (73%) patients with an ECOG PS score of 1. Twenty-one patients (64%) were previously treated with camrelizumab combined chemotherapy and 12 with other immunochemotherapy. Among the 17 evaluable patients, seven had the best overall response of partial response and nine with stable disease; the ORR was 41%. A total of 22 patients (67%) had treatment-related adverse events (TRAEs), with 12 patients (36%) with grade≥3. The most common TRAEs included white blood cell count decreased (11 patients, 33%), hypokalaemia (9, 27%), and alanine aminotransferase increased (8, 24%). Conclusions: Current results suggested the preliminary efficacy of second-line camrelizumab plus apatinib in patients with immunochemotherapy-treated advanced ESCC, with an acceptable safety profile. The study enrollment is ongoing, and further survival and safety data will be reported in the future. Clinical trial information: NCT03736863 .
Real-world survival of patients (pts) with colorectal adenocarcinoma liver metastases (CRLM) treated with transarterial radioembolization (TARE).
Authors: Mahmood Sharmeen , Hagopian Garo Greg , Sadeghi Ben , Kuo Jeffrey V , Imagawa David , Fernando Dayantha , Abi-Jaoudeh Nadine , Dayyani Farshid
Published: January 2023

40

Background: While TARE with yttrium-90 (Y90) microspheres can induce tumor responses and improve progression-free survival (PFS) in pts with CRLM, randomized trials have not shown an overall survival (OS) benefit. It is unclear whether this is due to suboptimal pt selection and/or trial design vs. possibly a radiation-induced delayed liver damage which compromises OS. The objective was to describe real world OS with TARE for pts evaluated at an academic center (University of California Irvine) with a dedicated multidisciplinary liver tumor board (MTB). Methods: Retrospective study of consecutive pts with CRLM undergoing TARE between 01/2016-07/2020. We performed descriptive analyses for relevant pt and tumor characteristics, Wilcoxon Signed-Rank Test for comparison of continuous variables, and Kaplan-Meier estimates for survival. Results: N=55 pts were included. Follow-up time was at least 24 mo. Median age was 60 yrs (range 36-84), 61.8% were female, Caucasian/Hispanic/Asian/Other= 54.4%/16.4%16.4%/12.7%, ECOG 0/1/2= 32.7%/58.2%/9.1%, tumor sidedness: left/right/unknown 72.7%/23.6%/3.6%, number or prior lines of systemic treatment 1/2/3+= 38.2%/26.4%/21.8%. MSI-High= 3.6% and RAS/RAF mutations were present/absent/unknown in 34.5%/49.1%/16.4%. Baseline and post-TARE liver function tests are shown in the table. Median time from diagnosis to first TARE was 16.4 mo (1.7-95.6) and 36.4% were treated within the first 12 mo of diagnosis. Median OS from diagnosis and first TARE were 43.2 mo (29.5-68.7) and 16.7 mo (9.9-35.2), respectively. Conclusions: The observed OS of pts with CRLM treated with TARE with a mature follow-up of at least 2 years exceeds 40 mo, despite early integration of TARE in a third of the pts within the first 12 mo of diagnosis. Evaluation of pts with CRLM for TARE at experienced centers with dedicated MTB might lead to improved outcomes. [Table: see text]
A phase 2 study of durvalumab plus DOS (docetaxel, oxaliplatin, S-1) neoadjuvant chemotherapy followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable locally advanced gastric cancer: An interim efficacy report.
Authors: Kim Hyung-Don , Ryu Min-Hee , Park Young Soo , Lee Jong Seok , Kang Yoon-Koo
Published: January 2023

408

Background: The phase 3 PRODIGY study showed that neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, was effective and tolerable in Asian patients with resectable locally advanced gastric cancer (LAGC). The current study aimed to evaluate the efficacy and safety of neoadjuvant durvalumab plus DOS, which was followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable LAGC. Methods: In this single-center, open-label, phase II study, patients with locally advanced gastric or gastroesophageal junction cancer (i.e., cT2/3N+ or cT4Nany) were enrolled. In patients with proficient mismatch repair protein (pMMR) tumors (main arm), 3 cycles of neoadjuvant durvalumab plus DOS were administered every 3 weeks, which was followed by surgery and adjuvant S-1 plus durvalumab administered every 6 weeks for 12 months. The primary endpoints were the rate of pathologic complete regression (pCR) and the safety. For an exploratory purpose, patients with deficient mismatch repair protein tumors (exploratory arm) were treated with 3 cycles of neoadjuvant durvalumab and tremelimumab every 4 weeks followed by surgery and adjuvant durvalumab administered every 4 weeks for 12 months. At this interim analysis, we report the results of patients with pMMR. Results: As of SEP 2022, 40 subjects with pMMR were enrolled and received ≥ 1 dose of neoadjuvant treatment. Thirty-five subjects completed 3 cycles of neoadjuvant treatment, and 31 received surgery as of the data cut-off. Among 31 patients who received surgery, a pCR was confirmed in 9 (29.0%), meeting the primary efficacy endpoint (8 pCR out of 40) early. Among those who received 3 cycles of neoadjuvant treatment, 3 (8.6%) experienced the predefined unacceptable severe toxicities during the neoadjuvant treatment: febrile neutropenia (n=2) and G4 neutropenia persisted for ≥ 7 days (n=1). Conclusions: The current study met its primary efficacy endpoint and is expected to meet the primary safety endpoint (<20%). Neoadjuvant durvalumab plus DOS followed by surgery and adjuvant durvalumab plus S-1 chemotherapy deserves to be investigated in a phase 3 trial in Asian patients with LAGC. Clinical trial information: 04221555 .
Investigation of predictive biomarkers in patients treated with atezolizumab monotherapy following definitive chemoradiotherapy for unresectable locally advanced esophageal squamous cell carcinoma (EPOC1802).
Authors: Bando Hideaki , Kumagai Shogo , Kotani Daisuke , Mishima Saori , Habu Takumi , Tsushima Takahiro , Hara Hiroki , Kadowaki Shigenori , Kato Ken , Chin Keisho , Yamaguchi Kensei , Kageyama Shun-ichiro , Hojo Hidehiro , Nakamura Masaki , Hidenobu Tachibana , Wakabayashi Masashi , Fukui Makoto , Fuse Nozomu , Nishikawa Hiroyoshi , Kojima Takashi
Published: January 2023

416

Background: Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients (pts) with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), invading the aorta, vertebral body, or trachea. However, complete response (CR) rates are low (11–25%), with a median overall survival (OS) of 9–10 months. We previously reported atezolizumab following dCRT indicated promising 42.1% of confirmed CR (cCR) rate and 65.8% of 12-months OS (Bando H, et al., ESMO Congress 2022 ). Methods: We investigated predictive biomarkers for cCR in this multicenter phase II study. PD-L1 tumor proportion score (TPS) was examined with VENTANA PD-L1. Immunological phenotypes of tumor microenvironments were assessed with multiplex immunohistochemistry (mIHC) and multi-color flow cytometry (FCM). Cancer gene aberrations and gene expression were investigated with whole exome and whole transcriptome sequencing (WES/WTS), respectively. Results: In 35 pts with an evaluable PD-L1 TPS, the cCR rates of <1% and ≥1% were 44.4% and 41.2%, respectively. In mIHC analysis of 28 pts, the number of CD3+CD8+PD-1+ T cells and CD3+CD8-FOXP3+ T cells prior to CRT in tumor tissue were significantly correlated with cCR and non-cCR, respectively (both are P<0.05). In FCM analysis of 19 pts, tumor-infiltrating PD-1+CD8+ T cells prior to CRT, after CRT, and after atezolizumab were significantly correlated with cCR (P<0.05). On the other hand, CTLA-4+FOXP3highCD45RA-CD4+ regulatory T cells (Treg cells) after CRT were significantly correlated with non-cCR (P<0.05). In WES of 27 pts, MYC amplification, EGFR mutation, PIK3CA mutation, PTEN mutation, and KEAP1 mutation were detected in pts with non-cCR. In WTS of 27 pts, gene expression signatures of IFN-γ response and inflammatory response were enhanced after CRT. Gene expression signatures of epithelial mesenchymal transition (EMT) and TGF-β signalings prior to CRT were significantly enriched in pts with cCR. Conclusions: Our biomarker analysis suggests that tumor-infiltrating PD-1+CD8+ T cells prior to CRT may be a predictive biomarker for cCR of CRT followed by atezolizumab, and that several driver gene abnormalities, cancer intrinsic signatures and tumor-infiltrating Treg cells are associated with treatment resistance. These findings could enable subsequent biomarker-selected clinical trials and lead to the development of novel cancer immunotherapeutic strategies. Clinical trial information: UMIN000034373 .
CA125 kinetics as a potential biomarker for ascites progression during taxane plus ramucirumab therapy in patients with advanced gastric cancer.
Authors: Ueda Akira , Yuki Satoshi , Ando Takayuki , Motoo Iori , Ito Ken , Kito Yosuke , Sakumura Miho , Ueda Yuko , Kajiura Shinya , Nakada Naokatsu , Nakajima Koji , Hosokawa Ayumu , Harada Kazuaki , Kawamoto Yasuyuki , Komatsu Yoshito , Yasuda Ichiro
Published: January 2023

437

Background: Ascites and peritoneal metastases are major interruptive factors in sequential chemotherapy for advanced gastric cancer (AGC), although there are no established markers that predict ascites burden during treatment. Therefore, we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with taxane plus ramucirumab (TAX/RAM). Methods: This multicenter retrospective study comprised AGC patients who received TAX/RAM in second or third line setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before TAX/RAM (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 73 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=31) than those in non-elevated group. The median value of CA125 before TAX/RAM was elevated according to ascites burden (none, 37.5 U/ml; mild, 57.9 U/ml; moderate/severe, 134.8 U/ml; p<0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 8.2 vs. 14.6 months, p=0.0004). Baseline CA125 elevation and peritoneal metastasis were independent prognostic factors in multivariate analysis. After TAX/RAM, first-time measure of CA125 was performed in a median of day 28. The median change of CA125 was correlated with ascites response (CR/PR, -1.86%/day; SD, 0.28%/day; PD, 2.33 %/day, p<0.001). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 0.0067%/day (specificity 74%, sensitivity 100%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 2.5 vs 6.1 months, p=0.0008). Conclusions: The serum CA125 before TAX/RAM was associated with ascites burden. Further, early change of CA125 after TAX/RAM was associated with prognosis in AGC patients with peritoneal dissemination. CA125 monitoring may be biomarker in determining timing of treatment change.
Impact of high-dose dexamethasone and prolonged infusion time to prevent hypersensitivity reaction related to oxaliplatin in patients with colorectal cancer.
Authors: Yoshino Koichiro , Osumi Hiroki , Ooki Akira , Fukuda Koshiro , Fukuoka Shota , Nakayama Izuma , Wakatsuki Takeru , Ogura Mariko , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei , Shinozaki Eiji
Published: January 2023

49

Background: Oxaliplatin (OXA) is one of the major cytotoxic agents for the treatment of gastrointestinal tumors. Hypersensitivity reaction (HSR) is one of major reasons of not continuing OXA-based chemotherapy, similar to chemotherapy-induced peripheral neuropathy (CIPN). We developed prevention of the HSR protocol and evaluated its clinical application. Methods: We have retrospectively evaluated and characterized HSR reaction in metastatic colorectal cancer patients exposed to an OXA-containing regimen between 2005 and 2019. We also evaluated the clinical utility of a prevention of the HSR protocol for mCRC patients occurred in grade 1, grade 2 or grade 3 HSR after administration of OXA-based chemotherapy. The prevention of HSR protocol is based on increasing the dose of dexamethasone to 16.5 mg/body, chlorpheniramine to 5 mg, famotidine to 20mg, and the administration time of OXA is extended to 4 hours. Results: A total of 209 patients (median age 61 years, range: 27 to 80) were experienced grade 1 (106 patients, 50.7%), grade 2 (98 patients, 46.0%), or grade 3 HSR (5 patients, 3.3%). Most of the patients had been treated with the FOLFOX4 or modified FOLFOX6 regimen (86.6%). The median number of cycles of OXA administration until the initial onset of HSR was 11 (range: 2 to 48). 111 patients (53.1%) succeeded in OXA re-administration under the prevention of HSR protocol. The median OXA free interval was 23 days (range: 13 to 890). The median progression-free survival after OXA re-administration was 7.0 months (95%CI: 5.3 to 10.4). The reason for the prevention of HSR protocoldiscontinuation was HSR in 98 patients (46.9%), disease progression in 77 patients (36.9%) and CIPN in 17 patients (8.1%), respectively. Forty-eight patients (49.0%) had HSR during the first cycle of OXA re-administration and the median time to HSR after OXA re-administration was 14 days (95%CI 0-19). Grade 3 HSR after OXA re-administrationwere observed in only 6 patients (6.1%) and no one experienced Grade 4 or 5 HSR. Conclusions: Hi-dose dexamethasone and an increased infusion time may allow for OXA re-administration. The prevention of the HSR protocol may provide an alternative to permanent discontinuation of OXA.