bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors.
Authors: Gong Jifang , Shen Lin , Zang Aimin , Zhou Huan , Tang Jie , Liu Dan , Jia Youchao , Wang Beibei
Published: June 2024

2652

Background: LTC004, a novel IL-2Rβ/γ cytokine agonist, designed to minimize toxicity with improved potency. It has selective affinity for the receptor IL-2Rβγ subunits, preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. LTC004 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and murine models respectively. Methods: This is a first-in-human, multicenter, open-label, dose-escalation and dose-expansion phase I study of LTC004 in advanced solid tumors. Dose escalation part assessed safety and tolerability of intravenous LTC004 with doses ranging from 3.0 to 360 µg/kg. The dose escalation schedule utilized an accelerated titration and Bayesian Optimal Interval (BOIN) design. Eligible pts with advanced solid tumor were required to have received prior standard therapy. LTC004 is administrated intravenously once every 3 weeks. Results: The study completed dose-escalation part (3.0 to 360 µg/kg) as of cutoff date (Jan 10, 2024). 17 pts of multiple tumor types (including non-small cell lung, cervical, colorectal, sarcoma, melanoma, parotid adenocarcinoma, thymic adenocarcinoma, gastric and ovarian cancers) were enrolled and received ≥1 dose of LTC004. At baseline, 12 pts (70.6%) had received ≥2 prior lines therapy, 11 pts (64.7%) had received prior targeted therapy, 10 pts (58.8%) had received prior immune checkpoint inhibitor (ICI) therapy. LTC004 generally well tolerated and no dose-limiting toxicities (DLTs) up to and including 360 µg/kg was observed. The most common TEAEs overall in ≥30% of pts were fever, white blood cell decreased, anemia, AST/ALT increased, neutrophil count decreased, GGT increased, nausea and hypotension. Most of the reported AEs were G1 and G2, all drug related events reversible and responsive to supportive care therapy. Fever can be resolved with standard anti-pyretic treatment or steroids, transient hypotension can be preventable with prophylactic fluid infusion. Of 17 pts enrolled evaluable for efficacy per RECIST v1.1, the ORR were 5.9% (1/17), DCR were 58.8% (10/17). A confirmed PR was achieved in a pMMR/MSS CRC patient with prior therapies including fluoropyrimidines, irinotecan, oxaliplatin, targeted therapy and TKI. The starting dose was 45µg/kg, titration to 90µg/kg after 4 consecutive doses at 45µg/kg Q3W. As of cutoff date, the patient sustained PR for 4.8 months with follow-up ongoing. Conclusions: LTC004 demonstrated encouraging anti-tumor efficacy including cold tumor, and well tolerated in patients with advanced or metastatic solid tumors. The further dose expansion in selected tumor types is ongoing, and evaluations in combination with other agents are being planned. Clinical trial information: NCT05666635 .
A multi-centre, single arm, phase 2 trial of pembrolizumab in treatment-naïve patients with carcinoma of unknown primary site.
Authors: Monzon Jose Gerard , Karachiwala Hatim , Walker John WT , Goel Rakesh , Wheatley-Price Paul , Asmis Timothy R. , Navani Vishal , Tang Patricia A. , Vickers Michael M.
Published: June 2024

2659

Background: Cancer of unknown primary (CUP) represents a heterogeneous group of cancers that present with metastatic epithelial disease with no identifiable primary lesion at the time of diagnosis. Patients with poor prognostic features have limited effective systemic therapy options. Researchers hypothesize that these primary lesions are occult, in part, due to anti-cancer immune surveillance. We hypothesize, pembrolizumab will have activity in this setting. Methods: This single arm phase 2 study evaluated the use of pembrolizumab in treatment naïve patients with poor prognosis CUP. Patients ≥18 years of age with ECOG PS 0-1 and histologically proven, measurable metastatic carcinoma with no primary site identified were eligible. Pembrolizumab was administered at 200 mg intravenously every 3-weeks for up to 24 months. The primary endpoint was safety and objective response rate (ORR) per RECIST 1.1. Secondary objectives included progression free survival (PFS) and overall survival (OS). The study used a Simon’s two stage design based on a one-sided test with a type 1 error rate of 0.1, null hypothesis for ORR ≤ 20% yielding a power of 0.8 with an alternate hypothesis of ≥40%. The null hypothesis will be rejected if 8 or more responses are observed in 25 patients. Mismatch repair (MMR) and microsatellite instability (MSI) testing was not mandatory for patients. Results: There were 27 evaluable and 6 unevaluable (no response assessment, included in adverse event analysis) patients. The median age was 64 (range 21-80) and the majority were male (57.6%) and ECOG 1 (84.8%). Four patients experienced grade 3 treatment related adverse events (pain, anorexia, fatigue, confusion, and anemia). There were no treatment related deaths or new signals of toxicity. Of the evaluable patients, the ORR was 18.5% (4 partial responses and 1 complete response), disease control rate was 51.9% (9 stable disease) and thus the null hypothesis could not be rejected. For evaluable patients, the median PFS and OS were 2.56 (95% CI 2.10 – 7.46) and 9.79 (95% CI 3.84 – 16.03) months respectively. The one patient who developed a CR had MMR deficiency and has completed 2 years of therapy. Of the 4 patients with a partial response, one had an MMR proficient tumour, while the remaining 3 had unknown MMR status. Conclusions: Although not meeting the primary endpoint, pembrolizumab has some activity in CUP patients. Patients with CUP should be screened for MMR or MSI. Future studies should evaluate combination therapies with the addition of pembrolizumab. Clinical trial information: NCT03391973 .
A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation.
Authors: Heumann Thatcher Ross , Stockton Shannon , Cecchini Michael , Aljumaily Raid , Shyr Cathy , Whisenant Jennifer , Starr Jason S. , Dayyani Farshid , Baranda Joaquina Celebre , Trikalinos Nikolaos , Ivy S. Percy , LoRusso Patricia , Das Satya , Gore Steven , Beumer Jan Hendrik , Berlin Jordan
Published: June 2024

3077

Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]
Diversity in B7-H3/CD276 expression across cancer types: Exploring a dynamic novel immune checkpoint.
Authors: Larkin Brigid , Nishizaki Daisuke , Miyashita Hirotaka , Lee Suzanna , Nikanjam Mina , Nesline Mary K , Pabla Sarabjot , Conroy Jeffrey M , DePietro Paul , Sicklick Jason K. , Kurzrock Razelle , Kato Shumei
Published: June 2024

3133

Background: The resistance encountered in immune checkpoint blockade has persistently impaired the achievement of robust, durable antitumor immune responses in most cancer patients, prompting the search for additional immune targets. B7 homolog 3 (B7-H3)/CD276 is an emerging immune biomarker whose contrasting immune functions challenge conventional immune marker classifications, making it a compelling target. The present study aimed to characterize the expression of B7-H3/CD276 in a pan-cancer setting, analyze its co-expression patterns with potentially co-targetable immune checkpoints, and discuss implications for ongoing clinical trials. Methods: We conducted a focused analysis of B7-H3/CD276 expression in 514 cancer patients with diverse tumor histologies evaluated under the PREDICT protocol at the University of California San Diego. RNA sequencing of tissue specimens was performed, and results were used to characterize the RNA expression levels of B7-H3/CD276 and its correlation with key cancer immunity markers including PD-1, PD-L1, PD-L2, CTLA4, LAG3, BTLA, TIM3, VISTA, ADORA2A and IDO1. Results: Elevated expression levels of B7-H3/CD276 were observed in 41.6% [214/514] of the 514 tumor samples analyzed. When stratified by cancer type, the highest rates of elevated expression were found in sarcomas (58.30%, 14/24), followed by pancreatic (58.20%, 32/55) and liver and bile duct cancers (52.60%, 10/19). The independent association with pancreatic cancers was statistically significant on multivariate analysis (odds ratio 2.20, 95% confidence interval 1.09 – 4.45, p = 0.027). Ninety-three unique patterns of immune co-expression were observed among the 214 patients with high B7-H3/CD276 expression levels. Among them, the most commonly observed pattern was high expression of B7-H3/CD276 alone (26.2%, 56/214) followed by co-expression with high VISTA (7.0%, [15/214]) and high ADORA2A (5.6%, [12/214]). Of note, there was significant heterogeneity observed in the patterns of co-expression in cancer immunity markers, with 72.04% (67/93) in the cohort being unique to one patient. Conclusions: We have observed immunomic diversity in our analysis of B7-H3/CD276 expression levels across varied tumor types as well as in its co-expression patterns with other immune markers. Our findings suggest that leveraging immune profiling to build customized therapeutic regimens may be pertinent to optimizing response rates and minimizing toxicity to B7-H3/CD276 targeting therapies.
Comprehensive molecular profiling of newly diagnosed advanced, high-grade ovarian cancer: Unveiling BRCA1/2 mutations and genomic instability scores to advocate for public insurance coverage of genetic testing—Insights from the Hellenic Society of Medical Oncology (HeSMO) national program.
Authors: Saloustros Emmanouil S. , Liontos Michael , Timotheadou Eleni , Andreadis Charalampos , Skafida Efthymia , Syrios John , Kalykaki Antonia , Koutsoukos Konstantinos , Kesisis Georgios , Boukovinas Ioannis , Boutis Anastasios L. , Papakotoulas Pavlos , Ziogas Dimitrios C. , Karageorgopoulou Sofia , Giassas Stylianos , Lianos Evangelos , Chatzifoti Natalia , Papageorgiou Fotini , Saridaki Zacharenia (Zenia)
Published: June 2024

3146

Background: Homologous recombination deficiency (HRD) in ovarian cancer, indicative of impaired DNA repair, contributes to genomic instability (GIS). Beyond mutations in BRCA1/2 genes, GIS is particularly significant for identifying patients who may benefit from PARP inhibitors. Equivalence between Myriad Genetics' myChoice CDx and the standard diagnostic tests OncoScan and Amoy Diagnostics has been published, prompting HeSMO to launch a national program addressing GIS and BRCA 1/2 mutations in newly diagnosed advanced high grade ovarian cancer patients, with the utilization of these more economically advantageous tests, in order to guide effective therapeutic strategies, since official reimbursement is not yet applicable in our country. Methods: Patients with locally advanced or metastatic high-grade stage III/IV ovarian cancer were eligible for the HeSMO program, submitting an FFPE tissue tumor sample. The evaluation focused on HRD detection (positive or negative) and GIS assessment (high or low), combining results from OncoScan and Amoy Diagnostics. Results: Between August 2022 and December 2023, 511 patients from Greece underwent testing. 48.14% (n=246) tested HRD positive, 46.58% (n=238) HRD negative. High GIS score was observed in 44.81% (n=229), low GIS in 49.71% (n=254). Potential pathogenic mutations in BRCA1/2 genes were found in 19.96% (n=102). BRCA1 mutations (13.70%, n=70) included key mutations: c.190T>C p.(Cys64Arg), c.3700_3704delGTAAA p.(Val1234GlnfsTer8), c.4065_4068del p.(Asn1355LysfsTer10). BRCA2 mutations (6.26%, n=32) comprised of c.1129G>T p.(Glu377Ter), c.3650_3659del p.(Arg1217IlefsTer8), c.7150C>T p.(Gln2384Ter). In 27 samples (5.28%) no result was produced. Conclusions: HRD and GIS are vital genomic instability biomarkers in high-grade ovarian cancer. These metrics provide valuable insights into tumor aggressiveness, guiding therapeutic decisions, including the use of PARP inhibitors. In this study of 511 patients from 50 centers across Greece, 48.14% tested positive for HRD, emphasizing PARP inhibitors' significance and suggesting hereditary implications. Our commitment to enhance patient access to reliable diagnostic biomarker testing in Greece is unquestionable. Furthermore, we believe, our results will strengthen our efforts towards official state reimbursement, paving the way for local HRD testing solutions. [Table: see text]
The role of metastasectomy in patients with early onset metastatic colorectal cancer.
Authors: Pretta Andrea , Ziranu Pina , Perissinotto Eleonora , Scalia Raimondo , Marmorino Federica , De Grandis Maria Caterina , Ciracì Paolo , Russo Alessandra , Cerma Krisida , Cavalli Chiara , Chiaramonte Anna , Taravella Ada , Giampieri Riccardo , Berardi Rossana , Lonardi Sara , Bergamo Francesca , Pietrantonio Filippo , Cremolini Chiara , Scartozzi Mario
Published: June 2024

3541

Background: According to the literature, metastasectomies in colorectal cancer patients can lead to a significant increase in outcomes. However, the behavior of early-onset CRC (EO-CRC), which refers to cancer occurring in adults between 18 and 49 years, when subjected to metastasectomy, remains unclear. Clinical and prognostic data on this setting are limited and conflicting. Our study aimed to evaluate clinical, prognostic, and molecular differences in early-onset colorectal cancer (EO-CRC) patients undergoing metastasectomy to identify potentially relevant differences compared to a control group of late-onset CRC (LO-CRC). Methods: We retrospectively collected data from 1123 metastatic colorectal cancer patients from 5 different Italian Institutions. 673 (59.9%) EO-CRC and 450 (40.1%) LO-CRC as a control group. All patients had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment for metastatic disease. The main objective of the study was to evaluate clinical outcomes for the EO-CRC patients undergoing metastasectomy in comparison to patients included in the control group according to molecular profile. Results: In the EO-CRC group, the median age was 44.1 (20.0-50.9), while in the control group, it was 64.4 (51.0-86.2). Among EO-CRCs patients, 388 out of 673 (57.6%) underwent metastasectomy, whereas, in LO-CRCs patients, only 181 out of 450 (40.2%) had the procedure. In the general population, patients who underwent metastasectomy demonstrated a higher median overall survival (mOS) compared to those who did not undergo the procedure. However, within the metastasectomy group, EO-CRCs patients exhibited a lower mOS compared to LO-CRCs patients (46.0 versus 60.0 months, p < 0.0001). Similar results were obtained when evaluating subgroups of RAS-BRAF wild type patients (53.0 months versus 81.0 months, p < 0.0001) and RAS-BRAF mutated patients (42.0 months versus 45.0 months, p < 0.0001). Conclusions: Although EO-CRC patients seem more likely to undergo surgical resection for metastatic disease, our findings suggest a worse overall prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly, this seems to occur regardless of the molecular status. These observations could have a considerable impact on clinical practice and research. Further investigations will be necessary to better understand the specific clinical and molecular characteristics of this growing group of patients to better define the most appropriate therapeutic strategy.
Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Primary outcome of a multicenter randomized controlled trial.
Authors: Xu Jianmin , Yuan Weitang , Li Taiyuan , Tang Bo , Jia Baoqing , Zhou Yanbing , Zhang Wei , Zhao Ren , Zhang Cheng , Cheng Longwei , Zhang Xiaoqiao , Liang Fei , He Guodong , Wei Ye , Feng Qingyang
Published: June 2024

3617

Background: Robotic surgery for rectal cancer is gaining popularity, but persuasive evidence on long-term oncological outcomes is lacking. This multicenter randomized controlled trial compared robotic and conventional laparoscopic surgery regarding surgical quality and long-term oncological outcomes among patients with middle and low rectal cancer. Previously the short-term outcomes of this trial had been reported that robotic surgery had significantly lower circumferential resection margin positivity rate, lower postoperative complication rate, and better postoperative recovery. Now the long-term oncological outcomes were reported. Methods: This superiority trial was undertaken at 11 hospitals in 8 Chinese provinces. Patients with middle (> 5–10 cm from anal verge) or low (0–5 cm from anal verge) rectal adenocarcinoma, cT1–T3 N0–1 or ycT1–T3 Nx after preoperative radio-/chemoradiotherapy, and no evidence of distant metastasis were enrolled and randomly assigned in a 1:1 ratio to receive robotic or conventional laparoscopic surgery. The 3-year locoregional recurrence rate was the primary outcome and was compared using modified intention-to-treat (mITT) analysis. Secondary outcomes included disease-free survival and overall survival. All time-to-event outcomes were calculated using Kaplan-Meier method with log-rank test. This trial was registered with ClinicalTrials.gov (NCT02817126). Results: Between July 2016 and December 2020, 1240 patients were enrolled, and 1171 were included in the mITT analysis (586 in robotic and 585 in laparoscopic group). The pathological TNM stage of the mITT population was 73 (6.2%) patients with complete response, 346 (29.5%) with stage I, 368 (31.4%) with stage II, 384 (32.8%) with stage III. And the median follow-up time was 43.0 months (interquartile range = 36.7 to 60.0), with 34 (2.9%) patients lost to follow-up. The 3-year locoregional recurrence rate in robotic group (1.5%) was significantly lower than in laparoscopic group (4.0%, log-rank p=0.025, hazard ratio = 0.451, 95% confidence interval = 0.221 to 0.921). Robotic group also had significantly higher 3-year disease-free survival rate (87.3% vs. 83.6%, log-rank p=0.035). No significant difference was observed in 3-year overall survival rate (94.8% vs. 93.1%, log-rank p=0.155). Conclusions: Robotic surgery for middle and low rectal cancer significantly reduced locoregional recurrence and improved disease-free survival, compared with conventional laparoscopic surgery. Clinical trial information: NCT02817126 .
Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC).
Authors: Zhang Qi , Fu Qihan , Cao Wanyue , Wang Hongkan , Xu Xingyuan , Huang Jiaqi , Zou Andy , Zhu Judy , Wan Hui , Yao Yihong , Tu Eric , Stone John , Bondanza Attilio , Farsaci Benedetto , Liang Tingbo
Published: June 2024

4019

Background: GPC3 is a surface antigen overexpressed in HCC and virtually absent on healthy tissues. Chimeric antigen receptor (CAR) T cells targeting GPC3 offer a promising option for advanced unresectable HCC treatment. C-CAR031 is an autologous GPC3-directed CAR-T armored with dominant negative TGF-b receptor II. Here we report the safety and preliminary efficacy of C-CAR031 in advanced HCC patients (pts). Methods: The first-in-human, open-label dose-escalation trial employs an accelerated titration plus i3+3 design. GPC3+ advanced HCC pts who failed ≥ 1 line systemic treatments received a single i.v. infusion of C-CAR031 post standard lymphodepletion. Primary endpoints are safety and tolerability, others include pharmacokinetics and preliminary efficacy. Adverse events (AEs) were graded by CTCAE 5.0, and cytokine release syndrome (CRS) / immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed per ASTCT 2019 criteria. Objective response was assessed by investigator per RECIST 1.1. Results: As of Jan 5th, 2024, a total of 24 pts received C-CAR031 infusion at 4 dose levels (DLs). All pts had BCLC stage C HCC, 83.3% (20/24) had extrahepatic metastasis. The median number of prior lines of therapy was 3.5 (range 1-6), 23 (95.8%) pts received ICIs (immune checkpoint inhibitors) and TKIs (tyrosine kinase inhibitors). All pts were evaluable for safety. No dose-limiting toxicity and ICANS was observed. CRS was observed in 22 (91.7%) pts with only 1 (4.2%) grade (G) 3 CRS. The most common ≥G3 AEs were lymphocytopenia (100%), neutropenia (70.8%), thrombocytopenia (37.5%) and transaminase elevation (16.7%). One pt (4.2%) had G4 myelosuppression and 1 pt (4.2%) had G3 interstitial pneumonitis at DL4 caused by G3 CRS. All AEs were reversible. 22 pts were evaluable for efficacy. Tumor reductions were observed in 90.9% pts, not only in intrahepatic lesions but also extrahepatic ones with a median reduction of 44.0% (range, 3.4%-94.4%). The disease control rate was 90.9% and the objective response rate (ORR) was 50.0% for pts of all DLs. In DL4, the ORR was 57.1%. Conclusions: The study showed a manageable safety profile and encouraging anti-tumor activity of C-CAR031 in heavily treated advanced HCC patients. Clinical trial information: NCT05155189 . [Table: see text]
Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
Authors: Shitara Kohei , Van Cutsem Eric , Lordick Florian , Enzinger Peter C. , Ilson David H. , Shah Manish A. , Xu Rui-Hua , Lonardi Sara , Yamaguchi Kensei , Hung Yi-Ping , Kukielka-Budny Bozena , Bhattacharya Pranob P. , Matsangou Maria , Li Ran , Moran Diarmuid Martin , Ranganath Radhika , Pophale Rupesh , Ajani Jaffer A.
Published: June 2024

4036

Background: The phase 3 SPOTLIGHT study showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with 1L zolbetuximab + modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma at prespecified interim and later updated analyses. We present the prespecified final OS analysis. Methods: Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, D15, D29) for four 42-day cycles or to PBO + mFOLFOX6; pts without PD continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. The primary endpoint was PFS per RECIST v1.1 by IRC. OS was a key secondary endpoint; additional secondary endpoints were objective response rate (ORR) and safety. Ad hoc analyses examined PFS and OS in per-protocol set population (PPS; pts adherent to protocol) and time to progression (TTP) by best overall response (BOR). Results: At data cutoff (September 8, 2023), 565 pts were assigned to zolbetuximab arm (n = 283) or PBO arm (n = 282). In zolbetuximab vs PBO arms, median follow-up was 18.04 vs 17.91 mo for PFS and 33.28 vs 31.38 mo for OS, respectively. Efficacy results are summarized in Table. Median PFS and OS were significantly longer in zolbetuximab vs PBO arms. Separation of PFS and OS curves occurred earlier in the PPS population analysis (excluded majority of early withdrawals) compared with the ITT population. ORR was similar between treatment arms in ITT and pts with measurable lesions – despite this, TTP for patients with BOR of CR/PR was numerically longer in zolbetuximab vs PBO arms. Safety and tolerability were maintained with no new findings. Conclusions: Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a new standard of care option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma. Clinical trial information: NCT03504397 . [Table: see text]
Real-world data in Japan for the variants in homologous recombination gene on the etiology of gastric cancer in younger and older patients.
Authors: Kono Yoshiyasu , Ozato Toshiki , Horiguchi Shigeru , Tsutsumi Koichiro , Yamamoto Hideki , Hirasawa Akira , Ennishi Daisuke , Tomida Shuta , Toyooka Shinichi , Otsuka Motoyuki
Published: June 2024

4053

Background: A recent study has reported the roles of Helicobacter pylori infection and germline variants in homologous-recombination (HR) gene as early onset of gastric cancer. However, the prognostic factors and genetic characteristics, especially about the variants in HR gene on the etiology of gastric cancer in younger and older patients, have not been clarified. Methods: We retrospectively analyzed the data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) utilization portal following its policy. Between June 2019 and August 2023, gastric cancer patients who conducted comprehensive cancer profile tests (Foundation One CDx, Foundation One Liquid, and OncoGuide NCC Oncopanel) were divided into patients aged ≤ 40 years (YGC) group and patients aged ≥ 70 years (EGC) group. The frequency of variants in HR gene ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, RAD51, ATRX, ARID1A, BAP1, CDK12, MRE11, NBN, PTEN, FANCA, and FANCC), the incidence of microsatellite instability-high (MSI-H), the value of tumor mutation burden (TMB), and prognosis were compared between the two groups. Results: There were 81 patients in YGC group and 394 patients in EGC group. The proportion of female patients (63% vs. 25%, P< 0.01) and undifferentiated type cancer (60% vs. 27%, P< 0.01) were significantly higher in YGC group compared with those in EGC group. The frequency of variants in HR gene was higher in EGC group compared with that in YGC group (68% vs. 52%, P< 0.01). The incidence of MSI-H in YGC group was lower than that in EGC group (0% vs. 4.8%, P= 0.055), and the mean value of TMB in YGC group was significantly lower than that in EGC group as well (2.4mut/Mb vs. 7.0mut/Mb, P< 0.01). The median overall survival (OS) in YGC group was significantly shorter than that in EGC group (943 days vs. 1597 days, P < 0.01). Among EGC group, the median OS of patients with positivity of variants in HR gene was significantly longer than that of those without (1728 days vs. 1281 days, P < 0.05). On the other hand, the median OS was not significantly different between patients with positivity of variants in HR gene and those without in YGC group. Conclusions: In the present study, the YGC group had lower incidence of variants in HR gene and MSI-H, and lower value of TMB, compared with those in the EGC group. We estimate that the incidence of MSI-H and the value of TMB caused by the HR-deficiency, which may be linked with prognosis, differs according to the frequencies of the variants in HR gene or according to other factors, such as aging and lifestyle.
Neoadjuvant therapy using PD-1 inhibitor plus chemotherapy with different intervals between chemotherapy cycles for locally advanced gastric or gastroesophageal junction cancer: A randomized phase 2 study.
Authors: Gao Quanli , Zhao Lingdi , Zhao Weijie , Wang Zibing , Qin Peng , Jiang Zhiqiang , Huang Jinxi , Zhang Bin , Li Zhimeng , Fu Qiang , Zhao Yuzhou , Ren Yingkun , Shang Chuang , Wan Xiangbin , Gao Yang , Xu Yongchao , Yuan Long , Lu Chaomin , Li Zhi
Published: June 2024

4064

Background: To explore the influence of reducing dose-intensity of chemotherapeutic agents by prolonging the interval of chemotherapeutic cycles on clinical efficacy, especially when combined with immune checkpoint inhibitors, we conducted a single-center, prospective, randomized, phase II exploratory study in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Methods: Patients were randomly assigned to receive either toripalimab plus FLOT regimen for four biweekly cycles or three triweekly cycles before the operation. The primary endpoint was pathological complete response (pCR) rate, the secondary endpoints were major pathological response (MPR) rate, event-free survival (EFS), and safety. Results: 70 patients were enrolled; of these, 69 were eligible for inclusion. The overall pCR rate was 26.1% and the MPR rate was 55.1%. There were no statistical differences in pCR rates and MPR rates between the two groups. Although no statistical differences were found among the subgroups, the pCR rate for patients with PD-L1 CPS ≥1 was 42.1% (8/19) while 6.7% (1/15) for PD-L1 CPS<1 in the triweekly group ( P=0.047). Analysis of lymphocyte subsets in peripheral blood showed that CD3+CD8+PD-1+Ki-67+ T lymphocyte absolute counts were elevated in triweekly group and reduced in biweekly group before the second and third cycle of therapy. The incidence rates of pyrexia and myelosuppression in the biweekly group were higher than those in the triweekly group. Conclusions: These data support the idea that the efficacy of toripalimab plus FLOT, given triweekly for three cycles, was not inferior to its administration biweekly for four cycles in locally advanced G/GEJ cancer. The finding is particularly significant for those with PD-L1 CPS ≥1 and warrants further validation. Clinical trial information: NCT04891016 .
Safety and feasibility of esophagectomy following neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Analysis of two phase 2 clinical trials.
Authors: shen dijian , Chen Runzhe , Ji Yongling , Chen Qixun , Chen Ming
Published: June 2024

4070

Background: Despite the survival benefit of preoperative chemotherapy (CT) or chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC), the prognosis remains dismal. With the potential benefit of combining immune checkpoint inhibitors (ICIs) neoadjuvantly, we initiated two phase II single-armed clinical trials to explore the efficacy, feasibility, and safety of esophagectomy following the combination of preoperative PD-1 inhibitor with CT or CRT in ESCC. Methods: A total of 55 patients with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase 2, single-arm trials underwent neoadjuvant ICIs combined with chemotherapy (nICT) (n=38) (NCT04506138) or chemoradiotherapy (nICRT) (n=17) (NCT03940001) between May 2019 and June 2022 were enrolled. Patients received 2 doses of intravenous PD-1 inhibitor every 3 weeks, combined with 2 cycles of CT or CRT. Data on the pathological complete response (pCR) rates, operative time, blood loss volume, 30-day complications, hospital stay, and 30-day mortality were collected and assessed between these two groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. The primary endpoints of the studies were the safety and feasibility of esophagectomy after the combination of preoperative CT or CRT and PD-1 inhibitor. We also evaluated pCR, primary tumor pCR, operation time, postoperative stay, and 30-day mortality. Results: All the included patients successfully completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group, respectively (p=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group, respectively (p=0.19). Minimally invasive surgery was performed in 89.2% (33/37) of the nICT group and 94.1% (16/17) of the nICRT group. The risk of developing pulmonary, anastomotic, or other complications was similar in the two groups. Conclusions: Esophagectomy was safe after the addition of PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and exploratory endpoints, including biomarker analyses are ongoing. Clinical trial information: NCT03940001 ; NCT04506138 .
Whole transcriptome analysis to reveal epithelial-mesenchymal transition after neoadjuvant therapy with or without additional anti-EGFR treatment: Subgroup analysis of esophageal squamous cell carcinomas of the SAKK 75/08 and the EORTC AIO POWER study.
Authors: Siebenhuener Alexander Rheinhard , Ruhstaller Thomas , Planas-Paz Lara , Mühlberger Katharina , Hayoz Stefanie , Vassella Erik , Van Laarhoven Hanneke W.M. , Thuss-Patience Peter C. , Stahl Michael , Maderer Annett , Moehler Markus H. , Langer Rupert
Published: June 2024

4071

Background: In localized disease of esophageal squamous cell cancer (ESCC), a trend in higher pathological response rates and longer time to treatment failure was seen by addition of anti-EGFR treatment to radio-chemotherapy (RCTX) compared to RCTX alone (SAKK 75/08 trial and others). On the contrary, the effect of anti-EGFR treatment to chemotherapy (CTX) remains unclear as no survival benefit was detected within advanced patients (EORTC-AIO-POWER study). Since perfect discrimination and selection of subgroups with highest benefit for anti-EGFR treatment (AB) is missing, we investigated the predictive values of whole transcriptomic gene expression analysis (WTGE) applied on biopsy tissue. Methods: 50 pretherapeutic formalin fixed paraffin embedded specimens of ESCC patients from SAKK 75/08 study were analyzed for the effect of RCTX with and without anti-EGFR AB. As well as 26 historic controls of primary resected tumor stage equally distributed ESCC were analyzed. For the advanced setting, we analyzed 28 additional pretherapeutic biopsies and compared groups from CTX to CTX plus AB. The HTG EdgeSeq method was used for NGS-based WTGE. Response to treatment was assessed by histopathological tumor regression in localized disease and clinical courses. Response to treatment in the advanced tumor setting was assessed to the clinical course of stable disease and partial response versus non-responders. Results: Firstly, NGS-based WTGE failed to show significant differences in expression patterns between responding and non-responding ESCC patients, irrespective of treatment protocols and EGFR AB in the localized as well in advanced disease setting. Secondly however, comparison between pre-treatment biopsies and posttreatment residual tumor tissues detected 781 genes that were upregulated and 623 that were downregulated with gene sets associated with muscle processes and epithelial-mesenchymal transition (EMT) in the localized disease. EMT genes were also enriched in residual tumors after neoadjuvant RCTX compared to primary resection in an independent control cohort. Additionally performed immunohistochemical studies showed lower numbers of ZEB-1 positive ESCC in an independent collection of tumors treated by neoadjuvant RCTX compared to primary resection. Conclusions: Our Whole transcriptomic gene expression analyses suggest that EMT is involved in responses to neoadjuvant protocols including EGFR targeting therapies. Targeting EMT may be a molecular pathway to increase complete responses after neoadjuvant RCTX in ESCC.
Multi-region exome sequencing to determine the origin of esophageal spindle-cell squamous cell carcinoma.
Authors: Wang Yulu , Han Li , Li Boyi , Han Yuchen
Published: June 2024

4072

Background: Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of carcinomatous and sarcomatous components. However, the genomic origin and gene signature of ESS remain unclear. Methods: A total of 24 patients diagnosed with ESS were enrolled from Shanghai Chest Hospital and underwent either radical resection (23/24) or endoscopic submucosal dissection (1/24). Laser-capture microdissection was employed to isolate cancerous and sarcomatous components from tumor and lymph node metastatic tissues. The cancerous components were subsequently microdissected based on morphology. Whole exome sequencing (WES) was conducted on both tumor tissues and paired white cell samples to analyze genomic profiles. Results: The tumor tissue samples of carcinomatous and sarcomatous components showed high mutational commonality. With the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden, paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. It showed a significant association of CDC27, LRP2, APC, and SNAPC4 mutations with poor prognosis in ESS patients. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. Conclusions: In conclusion, our results regarding to the mutation characteristics of microdissected samples substantiate the monoclonal origin of both the carcinomatous and sarcomatous components of ESS.
Somatic mismatch repair deficiency in pancreas cancer (PC): Immune checkpoint blockade (ICB) outcomes and exploratory genomic analyses.
Authors: O'Connor Catherine A , Harrold Emily , Lin Yun-Te , Walch Henry S. , Gazzo Andrea , Kane Sarah R. , Keane Fergus , Schoenfeld Joshua David , Moss Drew , Suehnholz Sarah Phillips , Chakravarty Debyani , Balogun Fiyinfolu , Varghese Anna M. , Yu Kenneth H. , Kelsen David Paul , Latham Alicia , Weigelt Britta , Park Wungki , Stadler Zsofia Kinga , O'Reilly Eileen M.
Published: June 2024

4144

Background: Microsatellite instability (MSI-H) occurs in the setting of Lynch syndrome (LS), which is caused by germline pathogenic variants (gPV) in mismatch repair (MMR) genes. The incidence and implications of somatic MMR variants without LS gPV in PC is unknown. We present a large cohort of patients (pts) with somatic only MMR variants and PC, and outline clinico-genomic descriptors, MSI-H prevalence, MMR methylation status, and response to ICB, comparing these features with a LS PC cohort. We also present microsatellite status (MS) orthogonal testing strategies. Methods: Institutional databases queried to identify pts with somatic MMR variants or LS gPVs and PC consented to matched tumor-normal NGS from 2012-2023. Clinico-genomic data abstracted from medical record. MiMSI used to assess MS stable (MSS) and indeterminate (MSI-I) PC. MMR status determined by immunohistochemistry (IHC). Composite MSI-H adjudicated as loss of MMR protein expression by IHC or MSI-H interpretation by MSISensor or MiMSI. Zygosity status assessed with FACETs. Exploratory mutational signature analysis performed on tumor mutation burden-high (TMB-H > 10) tumors with deconstructSigs. MMR methylation analyses underway. Results: N=55/4,626 (1.2%) pts with PC and MMR variant: N=23 somatic MMR variant only (Somatic Cohort) and N=32 LS Cohort. In Somatic Cohort, 10 (43%) MSI-H cases; 6 reclassified as MSI-H by MiMSI (N=2 MSI-I; N=4 MSS). Zygosity status: 11 (48%) biallelic, 11 (48%) monoallelic, 1 (4%) indeterminate. Of 11 monoallelic cases, 3 MSI-H. N=7/14 (50%) evaluable pts had dominant MSI-H mutational signatures. In LS Cohort, 17 (59%) MSI-H cases; 5 reclassified as MSI-H by MiMSI (N=4 MSI-I; N=1 MSS). Zygosity status (N=27 evaluable): 9 (33%) biallelic, 15 (56%) monoallelic, 3 (11%) indeterminate. Of 15 monoallelic cases, 4 MSI-H. N=7/15 (44%) evaluable pts had dominant MSI-H signatures. N=20 pts received ICB (N= 14 LS; N= 6 Somatic Cohort). Median ICB duration: 27.7 months (95% confidence interval (CI) 11.5, -). Overall response rate: 50% in both cohorts; similar duration of response. Conclusions: MSI-H arises due to somatic and germline oncogenesis at similar rates in ~1% of PC. MMR methylation analyses may provide further insight into the mechanisms of MSI-H. Orthogonal MS testing key to inform accurate MS status. MiMSI valuable in classifying low-cellularity specimens. Pts with MSI-H PC treated with ICB derive durable benefit, irrespective of germline or somatic etiology. [Table: see text]
Early-onset appendiceal adenocarcinoma (EOAA): 10-year experience from a single center.
Authors: Gujarathi Rushabh , Belmont Erika , Rodman Christopher , Bansal Varun Vivek , Setia Namrata , Alpert Lindsay , Hart John , Moller Mecker , Eng Oliver S. , Lee Grace , Chin Janet , Amin Manik A. , Polite Blase N. , Liao Chih-Yi , Turaga Kiran , Shergill Ardaman
Published: June 2024

4178

Background: The incidence of early-onset (age <50) gastrointestinal cancers, including early onset Appendiceal Adenocarcinoma (EOAA) is on the rise, however reported data on etiology, treatment, and outcomes is scarce. Here we present outcomes for EOAA patients treated at a single high-volume center. Methods: Records of patients (pts) with EOAA were reviewed. Clinicopathological and genomic data were abstracted. Pts aged 18 - 49 years at diagnosis with Appendiceal Adenocarcinoma (AA) seen at UCMC between 2013 - 2023 were included. The primary outcome of Overall survival (OS) was analyzed using univariable Cox proportional hazards regression analysis. Results: 116/492 (23.6%) appendix cancer pts seen at UCMC had early-onset disease. 45 pts met eligibility (Table). 10/20 (50%) pts with localized disease had recurrence after hemicolectomy (median recurrence free survival = 41.6 months; 95% CI, 34.3 – NR; follow-up = 46.42 months). 22/44 (50%) pts had mucinous AA, 21 (47.7%) goblet cell AA, and 1 (2.33%) had poorly differentiated AA. In 35 pts with metastatic/recurrent disease, mOS was 35.93 months (95% CI, 28.4 – NR). Lymphovascular (LVI) or perineural invasion (PNI) (HR, 6.41; 95% CI, 2.10 – 19.59, p = 0.001), lymph nodes metastasis (HR, 13.11; 95% CI, 3.53 – 48.68; p < 0.001), and grade 3 disease (vs. grade 1; HR, 5.28; 95% CI, 1.43 – 19.51, p = 0.01) were prognostic for worse OS in univariable analysis. Cytoreductive surgery (CRS), irrespective of completeness, was associated with improved OS (HR = 0.21; 95% CI, 0.09 – 0.53; p < 0.001). Next Generation Sequencing results were available in 20 cases: KRAS (n = 10, 50%), TP53(n = 7, 35%), GNAS (n = 6, 30%), SMAD4 (n = 4, 20%), and MYC (n = 3, 15%) were frequently altered. Alterations with potential therapeutic targets were seen in 12/20 (60%) cases. 10 pts had germline testing with 2 (20%) pathogenic alterations detected: SDHA(H447Mfs*23) and CHEK2 (T367Mfs*15). The pt with CHEK2 mutation had AA as the only malignancy, was the youngest (age 26.17) and passed away 17.26 months after diagnosis. Conclusions: A considerable number of patients with AA may have early-onset disease. A median OS of about 3 years in this young and vulnerable patient population is alarming. As in late-onset disease, EOAA is often incidentally diagnosed. LVI or PNI may be associated with poorer outcomes and deserve additional consideration for risk stratification. Many patients have targetable genomic alterations and should be included in clinical trials where current enrollment is often unsatisfactory for AA. Germline mutation testing in patients with EOAA should be widely implemented. [Table: see text]
Association between activating GNAS mutations and outcomes with chemotherapy in metastatic appendiceal adenocarcinoma.
Authors: Gujarathi Rushabh , Rodman Christopher , Bansal Varun Vivek , Belmont Erika , Setia Namrata , Alpert Lindsay , Hart John , Moller Mecker , Eng Oliver S. , Lee Grace , Chin Janet , Amin Manik A. , Polite Blase N. , Liao Chih-Yi , Turaga Kiran , Shergill Ardaman
Published: June 2024

4179

Background: Data regarding predictive biomarkers in Appendiceal Adenocarcinoma (AA) is scarce. GNAS mutations, frequent in mucinous AA, have been linked with poor objective response (OR) to chemotherapy. We hypothesize that activating GNAS mutations are associated with differential outcomes for metastatic AA treated with chemotherapy. Methods: We reviewed the records of AA patients (pts) seen between 2013 and 2023. Pts who received 5-Flurouracil/Capecitabine (5-FU/Cape) based chemotherapy for at least 3 months (m) in the metastatic/recurrent setting (no chemotherapy for localized AA in prior 12 m) and had data available for GNAS mutations were included. The primary outcome was disease event-free survival (dEFS): the time from first dose of 5-FU/Cape given for metastatic/recurrent AA to the earliest disease event: death, radiographic recurrence in pts with complete cytoreduction (CC0), or clinical/radiographic progression. The secondary outcome was overall survival (OS). Associations between GNAS status, clinicopathologic features, and study outcomes were assessed using univariable and multivariable (for variables with p values < 0.2) Cox proportional hazards regression analysis. Results: 48 pts were eligible. GNAS activating mutations (excluding variants of uncertain significance) were seen in 18/48 (37.5%), all at the R201 hotspot ( R201H = 15, R201C= 3). Clinicopathologic characteristics between activating GNAS mutated ( GNASmt) and GNAS wild-type ( GNASwt) groups are compared in Table 1. Over a median follow-up of 29.83 m, GNASmt pts had worse dEFS (adjusted HR [aHR], 5.62; 95% CI, 1.65 – 19.12; p = 0.006), after adjusting for CC0 reduction, histology (mucinous vs. non-mucinous), and synchronous metastases (vs. metachronous). CC0 reduction (aHR, 0.43; 95% CI, 0.21 – 0.88; p = 0.02) and synchronous metastases (aHR, 0.30; 95% CI, 0.12 – 0.74; p = 0.009) were also associated with improved dEFS. There was no significant difference in OS between GNASmt vs. GNASwt pts (HR, 0.82; 95% CI, 0.39 – 1.73; p = 0.61). Conclusions: GNAS mutated metastatic AAs show worse disease event free survival with chemotherapy which aligns with historic OR data. A previously reported survival benefit of GNAS mutations in AA, likely due to favorable disease at baseline (see table), is negated in the setting of metastatic disease treated with chemotherapy. Evaluating GNAS status as a predictive biomarker for AA is warranted. [Table: see text]