tbuckley/cabot-search huggingface dataset:
Phase 1b/II study of durvalumab (D) and tremelimumab (T) plus PET-adjudicated chemoradiation (CRT) in patients (Pts) with esophageal adenocarcinoma.
Authors: Geoffrey Yuyat Ku, Abraham Jing-Ching Wu, Nikhil Trivedi, Steven Brad Maron, Smita Suhas Joshi, David H. Ilson, Yelena Y. Janjigian, Marina Shcherba, Jia Li, Laura H. Tang, Randy Yeh, Smita Sihag, Bernard J. Park, David Randolph Jones, Daniela Molena
Journal: Journal of Clinical Oncology (2024)

355 Background: We previously evaluated adding D, an anti-PD-L1 antibody, to PET-directed CRT and found the combination to be safe and promising in terms of pathologic response and survival outcomes. 1 Here, we add T to the combination. Methods: Pts with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received T 300 mg ×1 and D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant T 300 mg ×1 and D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Initially, 6 Pts were enrolled to evaluate for toxicity; they received RT to 50.4 Gy. Subsequently, RT was lowered to 41.4 Gy to decrease the length of preop treatment (tx). Results: 16 pts have been enrolled. All Pts had clinical ≥T3 and/or N+ disease. PD-L1 CPS was ≥1 in 9 (60%) of 15 tested. 1 Pt (6%) had a microsatellite unstable (MSI) tumor. 9 (56%) Pts were PETr; 3 Pts (19%) were PETnr but had improved clinical symptoms and other PET parameters (MTV/TLG) and also continued with 5-FU/capecitabine and oxaliplatin during RT. Significant tx-related adverse events (AEs) are shown in the Table. Immune-related AEs (irAEs) were: gd 3 enterocolitis (1 Pt), gd 3/4 colitis (2 Pts, 12%), gd 1 diarrhea (1 Pt), gd 2 pruritis (1 Pt), gd 1 and gd 3 dermatitis (1 Pt each) and gd 2 arthralgias in 1 Pt. 1 Pt died of aspiration pneumonia while being treated for gd 4 colitis during CRT; 1 Pt developed gd 3 enterocolitis and cholecystitis during CRT, achieved a clinical CR and did not undergo surgery. He developed local recurrence and had surgery off-study 16 months after start of tx; 1 Pt developed a bone metastasis after CRT. 4 Pts are awaiting restaging post-CRT. Of 9 Pts who had surgery, 4 achieved a pCR (44%, including the MSI Pt) and 3 (33%) had ypN0 tumors and ³90% tx response. All 9 Pts have initiated/completed adjuvant D+T. Conclusions: The addition of D+T to induction FOLFOX and PET-directed CRT prior to surgery is feasible, although irAEs seem numerically higher than in our prior study of D and CRT. Pathologic response data are promising. Accrual is ongoing and updated data will be presented. 1. Ann Surg 2023;278:e511. Clinical trial information: NCT02962063 . [Table: see text]
Phase II study of GEN-001 in combination with avelumab in patients with PD-L1–positive locally advanced, or metastatic gastric cancer (GC) or gastroesophageal junction cancer (GEJC) who have progressed after second-line (2L) and beyond (GEN001-201 study).
Authors: Jeeyun Lee, Minkyu Jung, Keun-Wook Lee, Min-Hee Ryu, Minsuk Kwon, Kyung Mi Park, Young-Kwang Yoon, Mincheol Kim, Hansoo Park
Journal: Journal of Clinical Oncology (2024)

368 Background: The relationship between gut microbiota and the response to immune checkpoint inhibitors is likely due to cross-reactivity between microbial and tumor antigens, enhancing dendritic cell (DC) activation, antigen presentation, and inflammatory cytokine production. GEN-001 is a live biotherapeutic product (LBP) consisting of a lyophilized formulation of a strain of Lactococcus lactis. This study is designed to investigate the safety and efficacy of GEN-001 in combination with avelumab (the PD-L1 inhibitor) for patients with PD-L1 positive advanced GC/GEJC. Methods: This is an open-label, single arm, phase II clinical trial for PD-L1 positive (CPS ≥1) patients with unresectable, locally advanced, or metastatic GC/GEJC who have progressed after second-line and beyond. All patients were treated with GEN-001 (9x10 11 CFU, administered as oral once daily) in combination with avelumab (800 mg, administered as an intravenous infusion every two weeks) until progressive disease, unacceptable toxicity, death, or withdrawal. Tumor response was assessed every 8 weeks for 6 months and every 12 weeks thereafter. The primary endpoint was objective response (OR); secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Results: As of August 31, 2023, a total of 42 patients were enrolled. 37 patients have been assessed for response. The confirmed partial response (PR) and unconfirmed PR were achieved by 5 patients and 1 patient respectively, 8 patients have experienced as stable disease (SD). Median PFS and median OS were 1.73 months (95% confidence interval [CI]: 1.67-2.37 months) and 7.9 months (95% [CI]: 6.07-NE months). Treatment-related adverse events (TRAEs) of any grade occurred in 12 patients (28.6%) and Grade ≥3 TRAEs occurred in 2 patients (4.8%) out of 42 patients. Conclusions: Treatment of patients with GC/GEJC with GEN-001 in combination with avelumab in the ≥ 3L setting showed promising antitumor activities with an overall manageable safety profile. The results from this trial will be updated about its effects on clinical outcome, including survival, safety, and biomarker findings. Clinical trial information: NCT05419362 .
Regorafenib plus FOLFIRI with irinotecan dose escalated according to <i>UGT1A1</i> genotyping in patients with metastatic colorectal cancer.
Authors: Chao-Yuan Wang, Ching-Wen Huang, Hsiang-Lin Tsai
Journal: Journal of Clinical Oncology (2024)

125 Background: This multicenter, phase II, randomized, open-label, 2-arm parallel trial aims to compare the efficacy and safety profiles of regorafenib plus irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping with regorafenib alone in previously treated patients with metastatic colorectal cancer (mCRC). Methods: A total of 153 patients were planned to randomize at a ratio of 2:1 for receiving regorafenib plus FOLFIRI (arm A, 102 patients) or regorafenib alone (arm B, 52 patients), respectively. For both arms, regorafenib were given for 21 consecutive days (Day 1 to 21) of each 28-day cycle at a maintained dose of 120 mg. However, for arm A, patients received regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1 genotypes. FOLFIRI were on the first day of each 28-day cycle only. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and disease control rate (DCR), and adverse events (AEs). Results: Finally, a total of 116 patients were enrolled to be analyzed, including 74 in arm A and 42 in arm B. The significantly better PFS was observed in arm A, 4.8 and 3.0 months, respectively ( p = 0.016). Moreover, in patients with RAS wild type, the significantly better PFS was observed in arm A, 6.3 and 2.1 months, respectively ( p = 0.003). The OS was not significantly different between group A and B, 9.8 and 12.6 months, respectively ( p = 0.970). However, in patients with RAS wild type, the trend of better OS was observed in arm A, 14.3 and 6.9 months, respectively ( p = 0.158). The marginally significant better DCR was observed in arm A, 55.4% and 38.1%, respectively ( p = 0.055). The marginally significant better DCR was observed in arm A, 55.4% and 38.1%, respectively ( p = 0.055). Combination treatment of regorafenib plus FOLFIRI was independent favorable prognostic factor for PFS ( P = 0.008; hazard ratio [HR], 1.892; 95% CI, 1.182 – 3.027). Regarding severe AEs, there were no significant differences between the two groups (all P&gt;0.05). Conclusions: Combination treatment of regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1genotyping results in a significant better PFS and comparable AEs. Moreover, patients with RAS wild type of CRC would be more beneficial for this combination treatment.
Correlation of cancer testis antigen expression with high type-I interferon signal and prognosis in small bowel neuroendocrine tumors.
Authors: Reed I. Ayabe, Yongwoo David Seo, Brenda Melendez, Rossana Lazcano Segura, Brittany C. Fields, Khalida M. Wani, Sarah Johnson, Russell Witt, Manoj Chelvanambi, Courtney Hudgens, Sharia D. Hernandez, Nadim J. Ajami, Jennifer Ann Wargo, Alexander J. Lazar, Daniel M. Halperin, Jeannelyn Estrella, Jess Maxwell
Journal: Journal of Clinical Oncology (2024)

596 Background: Patients with small bowel neuroendocrine tumors (SBNET) frequently present with metastatic disease, and efficacy of available therapies, including immune checkpoint inhibitors (ICI), is limited. Toward developing novel immunomodulatory strategies, we evaluated the tumor immune microenvironment of SBNETs using bulk transcriptional and digital spatial profiling (DSP). Methods: Patients with SBNET who underwent surgical resection at MD Anderson Cancer Center from 2003-2016 were retrospectively analyzed. Overall survival (OS) was assessed using the Kaplan-Meier method and Cox proportional hazards model was used for multivariate analysis (MVA). Bulk transcriptional profiling was performed using the Nanostring PanCancer-Immune Panel. DSP was performed with whole human transcriptome using PanCK to segment tumor and adjacent stroma; 88 distinct regions were analyzed using differential gene expression and Reactome pathway enrichment pipelines. Results: Resected SBNETs from 42 patients were selected for transcriptional analysis. Unsupervised clustering of gene expression demonstrated dichotomization into high and low cancer testis antigen (CTA) expression. CTA-high patients (n=12) demonstrated elevated expression of type-I interferons (IFN) and CTAs such as PRAME, GAGE1, and MAGEA3 and had significantly longer OS compared to CTA-low patients (n=30; median OS not reached vs 1975 days, p=0.008). MVA controlling for age, sex, metastatic disease, and Ki-67% confirmed CTA-high status as an independent predictor of longer OS (hazard ratio [HR] 0.2, 95% confidence interval [CI] 0.05-0.83). A pilot DSP experiment with 4 CTA-high and 4 CTA-low tumors revealed higher expression of epigenetic modification genes (e.g., H3C1, H2BC8, p&lt;0.001) in CTA-high tumors with significant enrichment in epigenetic pathways (e.g., histone acetylation, DNA methylation). CTA-high tumors exhibited increased M2 macrophage presence (p=0.025) and increased stromal compartment NK cell activation (p=0.001). Conclusions: High expression of CTA and type-I IFN in resected SBNET is associated with longer survival, agnostic of stage or grade. While CTA expression has been implicated in tumor immunogenicity, this is the first work to identify a clinical signal in SBNET. Increased IFN in CTA-high tumors, corroborated by increased stromal NK cell activation, suggests an immune-mediated component of improved survival. Spatial transcriptomic analysis reveals epigenetic differences in CTA-high tumors and highlights the potential for combination epigenetic modifiers and immunotherapy in future trials.
Prognostic value of O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT) status in pancreatic neuroendrocrine tumors with capecitabine and temozolomide (CAPTEM).
Authors: Eduardo Terán Brage, Jorge Feito Pérez, Luis Miguel Navarro Martín, Roberto Andrés Escala Cornejo, María Mar Abad Hernández, Sofía Del Carmen, Álvaro López Gutiérrez, Belén Cigarral García, Rosario Vidal Tocino, Rebeca Lozano, Emilio Fonseca Sánchez
Journal: Journal of Clinical Oncology (2024)

598 Background: Loss of MGMT expression has been suggested as a predictor of response to alkylating agents in pancreatic neuroendocrine tumors (pNET), however, its determination is controversial. We aim to analyze the prognostic value of MGMT status assessed by immunohistochemistry (IHC) or pyrosequencing (PSQ) in patients with pNET receiving CAPTEM. Methods: Retrospective and unicentric analysis in patients (p) with pNET treated with CAPTEM from April 2008 to February 2023. MGMTdeficiency was determined by IHC and MGMT promoter methylation by PSQ. We analyzed patients’ characteristics, progression-free survival (PFS) and overall survival (OS) according to MGMT status. Results: 20p were included. Age (median): 62 [46-77]. Males (45%). Tumor grade (G): G1 (15%), G2 (55%) and G3 (20%). MGMT deficiency was detected in 12p (60%) and promoter methylation in 10p (50%). Results by IHC were consistent with PSQ in 10p (50%), with mismatches in 4p (methylated MGMT and positive IHC) and 6p (unmethylated MGMT and negative IHC). We reported a higher response rate in MGMT-deficient and MGMT-methylated p (Table) . In MGMT-deficient p we observed significantly better PFS (88m vs 11.1m; p=0.02, HR=0.21) and OS (141.9m vs 35.8m; p=0.03, HR=0.20). Also, in MGMT-methylated p we detected better PFS (88m vs 17.7m; p=0.20, HR=0.44) and OS (188.7m vs 141.9m; p=0.11, HR=0.28). A subanalysis was performed based on G, showing better PFS (88m vs 6.2m; p=0.03, HR=0.11) and OS (188.7m vs 35.8m; p&lt;0.01, HR=0.06) in those with G2 vs G3. There was a strong negative correlation between G and MGMT by PSQ; the higher G, the lower probability of promoter methylation r(16)= -0.62, p&lt;0.01. Conclusions: Our results support MGMT status, deficiency by IHC or promoter methylation by PSQ, as a potential prognostic biomarker in pNET treated with alkylating agents. However, it is necessary to evaluate its prognostic value in prospective studies. [Table: see text]
Phase I trial of intraperitoneal paclitaxel in patients with gastric adenocarcinoma and peritoneal carcinomatosis or positive peritoneal cytology.
Authors: Brian D. Badgwell, Mariela A. Blum-Murphy, Naruhiko Ikoma, Jeannelyn Estrella, Jenny Jing Li, Jitesh D. Kawedia, Paul F. Mansfield, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2024)

360 Background: The purpose of this Phase I trial was to evaluate the safety and toxicity of repeated normothermic intraperitoneal paclitaxel for patients with gastric cancer metastatic to the peritoneum. Methods: In patients with gastric adenocarcinoma and peritoneal carcinomatosis or positive peritoneal cytology, a Bayesian optimal interval design was used to prospectively identify the safety and tolerability of escalating doses of intraperitoneal paclitaxel administered as 3 weekly treatments followed by a 1-week break and then 3 additional weekly treatments. The primary objective was to define the maximum tolerated dose (MTD). Secondary objectives included determining the safety and tolerability of escalating doses of intraperitoneal paclitaxel and making a preliminary assessment of the anti-tumor activity based on the peritoneal carcinomatosis index (PCI) and overall survival (OS). Results: A total of 25 patients were treated between January 2020 and April 2023. The MTD for intraperitoneal paclitaxel was 100 mg/m 2 . Five patients (20%) had dose-limiting toxic effects at 100 mg/m 2 . Treatment-related grade 3-4 toxic effects included leukopenia in 8 patients (32%) and neutropenia in 8 (32%). Seven patients (28%) required a schedule change to every-other-week treatment. The PCI after intraperitoneal paclitaxel demonstrated progression in 5 patients (20%), stable disease in 5 (20%), and improvement in 10 (40%); 5 patients (20%) were not evaluable for PCI. Eight patients (32%) had resolution of their peritoneal disease, and 7 (28%) underwent attempted resection. The median OS from the time of diagnosis of metastatic disease was 17.9 months (95% CI 14.5-29.5) and from the date of treatment initiation was 10.3 months (95% CI 6.5-18.8). One-, 2-, and 3-year OS rates from the time of diagnosis of metastatic disease were 84%, 36%, and 22%, respectively. Pharmacokinetic analysis showed there was systemic absorption of paclitaxel and plasma AUC 0-∞ and C max was (13955 ± 6683 h.ng/ml) and (390 ± 191 ng/ml) respectively, while intraperitoneal concentration at the end of infusion was 232 ± 65 µg/ml. Conclusions: Paclitaxel may be safely administered at an intraperitoneal dose of 100 mg/m 2 . Neutropenia was common with weekly treatments, and we would recommend every-other-week treatment for future studies. Rates of resolution of peritoneal disease with multimodality therapy were promising, supporting future trials of this strategy and molecular profiling to identify factors associated with treatment response. Clinical trial information: NCT04220827 .
Efficacy and safety of trifluridine/tipiracil in combination with bevacizumab in older and younger patients with refractory metastatic colorectal cancer: A subgroup analysis of the phase 3 SUNLIGHT trial.
Authors: Julien Taieb, Gerald W. Prager, Marwan Fakih, Fortunato Ciardello, Eric Van Cutsem, Elena Elez, Felipe Melo Cruz, Lucjan S. Wyrwicz, Daniil Stroyakovskiy, Zsuzsanna Papai, Pierre-Guillaume Poureau, Gabor Liposits, Chiara Cremolini, Igor Bondarenko, Dominik Paul Modest, Lucas Roby, Valentine Barboux, Nadia Amellal, Josep Tabernero
Journal: Journal of Clinical Oncology (2024)

111 Background: SUNLIGHT, an international, open-label, randomized, phase 3 study comparing trifluridine/tipiracil (FTD/TPI) + bevacizumab (FTD/TPI + bev) to FTD/TPI monotherapy in patients with refractory metastatic colorectal cancer (mCRC), demonstrated a 3.3-month increase in overall survival from 7.5 months with FTD/TPI monotherapy to 10.8 months with FTD/TPI + bev (HR, 0.61; 95% CI: 0.49–0.77; P&lt;0.001). This subgroup analysis of SUNLIGHT examined efficacy and safety outcomes by age. Methods: In SUNLIGHT, patients with mCRC with ECOG PS of 0-1 and two prior treatment regimens were randomized to receive FTD/TPI + bev or FTD/TPI. A subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged &lt;65, 65-74, and ≥75 years. Results: Among 492 randomized patients (n=246 FTD/TPI + bev; n=246 FTD/TPI), 56%, 32%, and 12% were aged &lt;65, 65-74, and ≥75 years, respectively. Concerning overall survival, hazard ratios for FTD/TPI + bev vs FTD/TPI monotherapy were 0.65 (95% CI: 0.48–0.87), 0.64 (95% CI: 0.43–0.94), and 0.49 (95% CI: 0.27–0.90) in patients aged &lt;65, 65-74, and ≥75 years, respectively. Regardless of age, patients receiving FTD/TPI + bev experienced improved progression-free survival and improved time to worsening of ECOG PS to ≥2. Among FTD/TPI + bev treated patients, frequency of any-cause severe adverse events (AEs) was slightly higher in the 65-74 subgroup [69% (&lt;65); 80% (65-74); 67% (≥75 years)]. Frequency of grade 3 and 4 neutropenia was also slightly higher in the 65-74 subgroup [38% (&lt;65); 54% (65-74); 42% (≥75 years)]. AE-related discontinuation rates were similar across age subgroups [11.6% (&lt;65 years), 13.2% (65-74), and 16.7% (≥75 years)]. Conclusions: The results of this subgroup analysis demonstrate the efficacy benefit and tolerability of FTD/TPI + bevacizumab treatment regardless of age in refractory mCRC patients. Clinical trial information: NCT04737187 .
ZSAB-TOP: A phase 2 trial of tislelizumab (TIS) and ociperlimab (OCI) combined with gemcitabine and cisplatin (GemCis) as the first-line treatment for advanced biliary tract cancer (BTC).
Authors: Jia Fan, Jian Zhou, Guoming Shi, Xiaoyong Huang, Liang Ma, Jun-Ye Wang, Qiang Gao, Shuangjian Qiu, Huichuan Sun, Yinghong Shi, Xiao-Wu Huang, Xiaoying Wang, Yong Yi, Xiaodong Zhu, Cheng Huang, Zhenbin Ding, Yi Chen, Yi-Feng He, Yinghao Shen, Qiman Sun
Journal: Journal of Clinical Oncology (2024)

475 Background: GemCis has long been the standard-of-care for advanced BTC, however the prognosis remains poor. Combinations with immunotherapy and GemCis are being explored in BTC. This study aimed to evaluate the efficacy and safety of TIS (an anti-PD-1 antibody) and OCI (a TIGIT inhibitor) combined with GemCis as the first-line treatment for advanced BTC. Herein, the primary analysis results of this study were reported. Methods: In this open-label, single-arm, multicenter phase 2 study, systematic treatment-naïve pts with unresectable advanced BTC received TIS (200 mg, day1, Q3W), OCI (900 mg, day1, Q3W), and GemCis (Gem 1000 mg/m 2 and Cis 25 mg/m 2 on days 1 and 8 Q3W, up to 8 cycles). The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. A binomial exact test with a one-sided α of 0.05 was performed in the analysis of the primary endpoint to test the historical ORR of 25% with GemCis. If p≤0.05, the statistical superiority of the study treatment would be claimed. Results: A total of 45 pts were enrolled, with 75.6% having intrahepatic cholangiocarcinoma and 60.0% metastatic disease. As of 24 Aug 2023 (median follow-up, 8.0 months), 24.4% (11/45) pts remained on study treatment. Among the 41 pts in efficacy analysis set, confirmed ORR (cORR) was 48.8% (20/41, 95% CI, 32.9-64.9, p=0.0009), with 1 complete response. The statistical superiority was achieved. The subgroups of TIGIT + pts tended to have numerically higher cORR (Table). Median PFS was 7.7 months, with 6-month PFS rate of 67.6%. Median OS was not reached, and 6-month OS rate was 86.2%. Grade ≥3 treatment-related adverse events rate was 60% (27/45). Immune-mediated adverse events rate was 37.8% (17/45), which were mostly grade 1 and 2. Conclusions: The combination of TIS and OCI plus GemCis showed promising anti-tumor activity with manageable safety as the first-line treatment for advanced BTC. Clinical trial information: NCT05023109 . [Table: see text]