tbuckley/cabot-search huggingface dataset:
Relationship between the number of positive MSI markers and the efficacy of NIVO+IPI therapy in MSI-H gastric cancer: A subgroup analysis of NO LIMIT study (WJOG13320G/CA209-7W7).
Authors: Kenro Hirata, Hisato Kawakami, Shigenori Kadowaki, Akitaka Makiyama, Masahiro Tsuda, Naotoshi Sugimoto, Nozomu Machida, Hiroki Hara, Hidekazu Hirano, Taito Esaki, Yoshito Komatsu, Shuichi Hironaka, Yasutaka Chiba, Kei Muro
Journal: Journal of Clinical Oncology (2024)

386 Background: Although high instability of microsatellite lesion (MSI-H) is an established biomarker for response to immune checkpoint inhibitors, the relationship between the number of MSI markers and the efficacy of immune checkpoint inhibitors in MSI-H tumors has not been well elucidated. NO LIMIT (WJOG13320G/CA209-7W7) is a phase II trial of nivolumab plus low-dose ipilimumab (NIVO+IPI) for MSI-H advanced gastric or esophagogastric junction cancer (GC) in the first-line setting. 1 Here, we investigated the relationship between the number of positive MSI markers and the efficacy of NIVO+IPI in NO LIMIT study. Methods: Eligible patients were unresectable advanced, recurrent, or metastatic GC with confirmed as MSI-H with the MSI-IVD Kit (FALCO), where two or more of the five MSI markers are defined as positive. Nivolumab (240 mg) biweekly and ipilimumab (1 mg/kg) every six weeks were given until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and the association between number of positive MSI markers and clinical efficacy (ORR, PFS, OS). The analysis was performed 18 weeks after the first dose in the last patient, with a median follow-up of 9 months (range, 4.0-18.0). Results: The breakdown of MSI markers in the 29 patients enrolled in NO LIMIT was as follows: BAT-26 (26/26, 100%), NR-21 (25/29, 86.2%), BAT-25 (25/29, 86.2%), MONO-27 (29/29, 100%), NR-24 (27/29, 89.4%). Since most of the cases were positive for all five of them (the number of cases with 2, 3, 4, and 5 positive markers was 2, 2, 1, and 24, respectively), we dichotomized cases into group A (all five positive) and group B (the others). Response rates in groups A vs. B were 62.5% (15/24) vs. 60.0% (3/5), respectively. There was no difference in PFS or OS between the two groups. Conclusions: The number of MSI markers is not related to the efficacy of NIVO+IPI in NO LIMIT study. Further follow-up is needed to confirm the relationship between survival. 1. Muro K, et al. ESMO Congress 2023. Clinical trial information: jRCT2080225304 . [Table: see text]
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis 4-year (yr) follow-up.
Authors: Lin Shen, Yuxian Bai, Xiaoyan Lin, Wei Li, Jufeng Wang, Xiaochun Zhang, Hongming Pan, Chunmei Bai, Li Bai, Ying Cheng, Jingdong Zhang, Haijun Zhong, Yi Ba, Wenwei Hu, Rui-Hua Xu, Weijian Guo, Shukui Qin, Rui Wang, Stephen McCraith, Tianshu Liu
Journal: Journal of Clinical Oncology (2024)

318 Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. 1L NIVO + chemo is approved for advanced GC/GEJC/EAC in multiple countries, including China. We report 4-yr results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 49-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts (Table). The 4-yr OS rate was 25% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 21% vs 9% in all randomized pts. Objective response rate (ORR; 95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56–79) with NIVO + chemo vs 48% (36–60) with chemo; corresponding ORR in all randomized pts was 66% (55–76) and 45% (35–56). Responses were more durable with NIVO + chemo vs chemo both in pts with PD-L1 CPS ≥ 5 (median duration of response [mDOR; 95% CI] 12.5 mo [7.2–23.4] vs 6.9 mo [3.9–8.5]) and in all randomized pts (mDOR [95% CI] 12.5 mo [7.2–17.7] vs 5.6 mo [4.4–8.3]). No new safety signals were identified (Table). Conclusions: After 4 yrs of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo in Chinese pts, with an acceptable safety profile. These results are consistent with previous reports and with the overall study population with advanced GC/GEJC/EAC and further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]
Management of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemotherapy treatment in claudin-18.2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Analysis from the phase 3 SPOTLIGHT and GLOW studies.
Authors: Kohei Shitara, Rupesh Pophale, Maria Matsangou, Jung Wook Park, Mok Oh, Pranob P. Bhattacharya, Radhika Ranganath
Journal: Journal of Clinical Oncology (2024)

372 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed clinically meaningful, statistically significant improvement in PFS and OS using 1L zolbetuximab + chemotherapy vs placebo (PBO) + chemotherapy in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. N/V were the most common treatment-emergent adverse events (TEAEs) reported in the zolbetuximab arm of these studies. We report an analysis of the incidence and management of N/V in SPOTLIGHT and GLOW. Methods: In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6. In GLOW, pts (N = 507) were randomized 1:1 to zolbetuximab + CAPOX vs PBO + CAPOX. In both studies, neurokinin-1 receptor blockers (NK-1), selective serotonin receptor blockers (5-HT3), and other prophylactic antiemetic regimens were recommended to prevent and mitigate N/V per institutional care and guidelines. Results: A total of 279 pts in SPOTLIGHT and 253 pts in GLOW received zolbetuximab + chemotherapy. In SPOTLIGHT and GLOW combined, nausea occurred in 58% vs 18% of pts, and vomiting occurred in 43% vs 15% of pts in the first vs second zolbetuximab infusions, respectively; lower incidences of N/V were observed thereafter. During the first zolbetuximab infusion, the first episode of N/V occurred within 1 hour (median time, 48.0 min in SPOTLIGHT and 56.5 min in GLOW). Antiemetic usage and associated N/V rates are presented in the Table. The 96 pts in SPOTLIGHT and 52 pts in GLOW who had infusion modifications in cycle 1 due to TEAEs had numerically higher infusion rates than pts without infusion modifications; 85% of these modifications in SPOTLIGHT and 79% in GLOW were due to N/V. Zolbetuximab was discontinued within the first 9 weeks in 11 and 7 pts in SPOTLIGHT and 6 and 4 pts in GLOW due to nausea or vomiting, respectively. Conclusions: In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507 . [Table: see text]
MORPHEUS-EC: A phase Ib/II open-label, randomized study of first-line tiragolumab (tira) + atezolizumab (atezo) + chemotherapy (CT) in patients (pts) with esophageal cancer (EC).
Authors: Jong-Mu Sun, Yee Chao, Sung-Bae Kim, Sun Young Rha, T.R. Jeffry Evans, Andrew Strickland, Zev A. Wainberg, Ian Chau, Sharon Pelles-Avraham, Jaffer A. Ajani, Ritu Malhotra, Qingyuan Liu, Sijing Li, Edward Cha, Swapna Rahalkar, Simon Allen, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2024)

324 Background: TIGIT is a novel inhibitory immune checkpoint on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, e.g. PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. We report interim data from MORPHEUS-EC (NCT03281369) evaluating the combination of tira + atezo with CT in pts with untreated locally advanced unresectable or metastatic EC. Methods: Eligible pts (locally advanced unresectable, or metastatic EC with no prior systemic treatment; ECOG PS 0–1) were randomized to receive: cisplatin 80mg/m2 + 5-FU 800mg/m2/24 hours on Days 1–5 of each cycle (CT); atezo 1200mg + cisplatin + 5-FU (atezo + CT); or tira 600mg + atezo + cisplatin + 5-FU (tira + atezo + CT) in 21-day cycles. Primary endpoint: investigator (INV)-assessed objective response rate (ORR). Key secondary endpoints: INV-assessed progression-free survival (PFS), overall survival (OS), safety. Results: 152 pts were randomized to: CT (n=24; control); atezo + CT (n=65) or tira + atezo + CT (n=63). As of 14 Mar 2023, median follow-up was 8.7 months (mo) in the CT arm, 11.4 mo in the atezo + CT arm and 10.9 mo in the tira + atezo + CT arm. Pt characteristics were generally balanced between arms. ORR was 47.8% (CT) vs 53.8% (atezo + CT) vs 67.7% (tira + atezo + CT). Median PFS was 4.1 mo (CT) vs 6.8 mo (atezo + CT) vs 6.9 mo (tira + atezo + CT) (Table). ORR and PFS benefit was generally consistent across all pre-specified subgroups, including PD-L1 status. There was a numerical improvement in OS with tira + atezo + CT vs atezo + CT and CT alone (Table). Grade 3–5 adverse events (AEs) were 82.6% vs 83.1% vs 85.5% and treatment-related Grade 4/5 AEs were 4.3% vs 7.7% vs 14.5% for CT vs atezo + CT vs tira + atezo + CT. AEs leading to any tx discontinuation were 21.7%, 16.9% and 35.5%, respectively. Conclusions: Clinically meaningful improvements in INV-assessed ORR and PFS and a trend of improved OS were observed with tira + atezo + CT when compared with CT and atezo + CT. These results support the contribution of both tira and atezo in combination with CT. The safety profile was consistent with the known risks of the individual tx. Clinical trial information: NCT03281369 . [Table: see text]
Network meta-analysis of global trials of 1L therapies in locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
Authors: Manish A. Shah, Kohei Shitara, Sara Lonardi, Yee Chao, Kensei Yamaguchi, Bozena Kukielka-Budny, Min-Hee Ryu, Andrei Ungureanu, Mok Oh, Lawrence Chang, Hongbo Yang, Xinglei Chai, Pranob P. Bhattacharya, Maria Matsangou, Radhika Ranganath, Jaffer A. Ajani, Rui-Hua Xu
Journal: Journal of Clinical Oncology (2024)

325 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies reported statistically significant improvement in PFS and OS with 1L zolbetuximab (anti-claudin-18 isoform 2 [CLDN18.2]) + mFOLFOX6 or CAPOX in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. This network meta-analysis (NMA) indirectly compared the relative efficacy of 1L therapies. Methods: A systematic literature review of phase 2, 3, or unknown phase randomized, global trials of 1L therapies (capecitabine + cisplatin [CX]; capecitabine + oxaliplatin [CAPOX]; fluorouracil + cisplatin [CF]; oxaliplatin + folinic acid + fluorouracil [FOLFOX]; S-1 + cisplatin [SC]; nivolumab + CAPOX/FOLFOX; pembrolizumab + CF/CAPOX or CX; and zolbetuximab + CAPOX/FOLFOX) in adults with LA unresectable or mG/GEJ adenocarcinoma. To form a connected main network, FOLFOX and CAPOX were assumed equally efficacious and combined. In the latest publicly available data, hazard ratios (HRs) of PFS and OS for intent-to-treat (ITT) populations were extracted or reconstructed from Kaplan-Meier curves when not reported as inputs for Bayesian fixed-effects NMAs. Comparative effectiveness was reported using median HR and 95% credible intervals (CrIs). Results: Trials reporting ITT populations were included, resulting in 9 trials (6663 pts) for PFS analysis and 10 trials (6735 pts) for OS analysis representing 8 regimens. Pts were randomly assigned to an experimental arm vs FOLFOX/CAPOX. Pts on 1L zolbetuximab, nivolumab, or pembrolizumab in combination with CF/CAPOX or FOLFOX/CAPOX had significantly reduced risk of disease progression or death vs FOLFOX/CAPOX (Table). Zolbetuximab + FOLFOX/CAPOX had the highest probability of being ranked first in treatment efficacy for both PFS (probability =0.54) and OS (0.36); followed by pembrolizumab + CX (0.27) and pembrolizumab + CF/CAPOX (0.13) for PFS; and by pembrolizumab + CF/CAPOX (0.3) and nivolumab + FOLFOX/CAPOX (0.24) for OS. Conclusions: This NMA examined the relative benefit of different targeted therapies when combined with chemotherapy. Zolbetuximab + FOLFOX/CAPOX for CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma confers a significant PFS and OS benefit, similar to that achieved with PD-1/PD-L1 inhibitors + CF/CAPOX or FOLFOX/CAPOX. [Table: see text]
Microsatellite instability (MSI) in patients with gastric cancer (GC) and correlation with PD-L1 expression.
Authors: Henian Sun, Sergey Nered, Alexey Tryakin, Mikael Abgaryan, Elena Artamonova, Anna Stroganova, Ivan Stilidi
Journal: Journal of Clinical Oncology (2024)

389 Background: GC is a heterogeneous disease with a range of molecular subtypes. The TCGA (Cancer Genome Atlas) and ARCG (Asian Cancer Research Group) classified tumors with MSI status as a specific group. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) are playing a progressively important role in tumor immunology and cancer treatment. The present study investigated the relationship between MSI and PD-L1 expression. Methods: We analyzed GC patients who received treatment from September 2019 to March 2023 at N.N. Blokhin National Medical Research Center of Oncology. All patients were analyzed for microsatellite instability using PCR. PD-L1 expression was assessed based on a combined positive score (CPS) using PD-L1 IHC (immunohistochemistry) 22C3 pharmDx. Results: We studied 453 localized GC and 273 metastatic GC. Of the 726 tumors, 60 (8.26%) had MSI-H tumors. The frequency of MSI-H in localized and metastatic GC is 51 (11.26%) out of 453 and 9 (3.30%) out of 273 (p&lt;0.001). 106 patients were evaluated for expression PD-L1, 46 (43.40%) localized GC и 60 (56.60%) metastatic GC. PD-L1 is expressed in 45.28 % (48/106) of GC patients. PD-L1 CPS ≥ 1 was significantly associated with MSI-H status (P &lt; 0.05). Details about the correlation between MSI and the expression PD-L1 can be found in the table. Conclusions: The prevalence of MSI-H in localized GC is significantly higher than metastatic GC (11.26% vs. 3.30%, p&lt;0.001). A higher proportion showed PD-L1 expression (73.91%) in MSI-H than in MSS tumors, suggesting that MSI-H status is associated with PD-L1 (p&lt; 0.05). These results provide a basis for identifying GC patients who may benefit from anti-PD-1/PD-L1 therapy. [Table: see text]
Risk of relapse and patient selection for metastatic colorectal cancer liver surgery.
Authors: Madalena Machete, Pedro Azevedo, Francisco Lopes, Carlota Baptista, Inês Margarido, Carlota Branco, Jorge Correia, João Moreira Pinto, José António Pereira, Pedro Simões, Ana Faria Harrison, Tânia Abreu Rodrigues, Jose N. Teixeira, Jose Luis P. Coelho
Journal: Journal of Clinical Oncology (2024)

96 Background: Previous data on surgery for colorectal cancer (CRC) liver metastases (CRLM) documented improvement in overall survival (OS) and low perioperative mortality, but patient (pt) selection requires complex multidisciplinary work. Predictive scores such as the Comprehensive Evaluation of Relapse Risk (CERR) estimate relapse risk after surgery and help in the pre-operative decision. Objectives: This study aims to evaluate OS and progression-free survival (PFS) in a population of pts who had surgery for CRLM, and to analyse survival outcomes by risk groups, according to the CERR score. We identified individual, anatomic and biological factors with potential prognostic impact. Methods: We retrospectively analysed the medical records of pts who had CRLM surgery between January 2012 and December 2021 in two Portuguese reference centres. Outcomes for CRLM surgery were analysed by risk groups according to the CERR score of each pt (based on nodal status, preoperative CEA/CA 19.9 values, KRAS/BRAF status, presence of extrahepatic disease and modified tumour burden score). Univariate and multivariate survival analyses were performed with the log-rank test and Cox proportional-hazards regression models. Results: A total of 174 pts were included: 66,1% (n=115) male, mean age at CRLM diagnosis 62,1 (±11,5) years, 80,5% (n=140) with isolated liver metastases. Thirty-three pts (19%) had a second surgery, independently of the CERR score (chi-square p = 0,60). Eighteen (10,3%) pts had a CERR score of 0-1 (low-risk, LR), 96 (55,2%) of 2-3 (medium-risk, MR) and 60 (34,5%) of 4-5 (high-risk, HiR). With a median (MED) follow-up of 85,1 (15,6-186,5) months (mo), 100 (57.5%) pts have died. MED OS was 88,0 mo (95% confidence interval [CI] 40,6-135,4) for LR, 46,4 mo (95% CI 38,7-54,1) for MR and 30,7 mo (95% CI 23,1-38,4) for HiR pts (p=0,02); ECOG performance status was an independent prognostic factor (p=0,002) for OS. Median PFS was 88,0 mo (95% CI 6,9-169,0) for LR, 12,9 mo (95% CI 9,1-16,7) for MR and 7,7 mo (95% CI 5,9-9,4) for HiR pts (p&lt;0,001); positive resection margins and prior induction chemotherapy (CT) were additional independent negative prognostic factors for PFS (p&lt;0,001). Conclusions: These results suggest a significant association between relapse risk after surgery for CRLM and both OS and PFS. The CERR score can be used to select potential candidates for CRLM surgery and improve the impact of this intervention in pts with CRC. The link between induction CT and worse survival may reflect selection bias as these pts possibly had a higher volume of disease and therefore received initial systemic therapy. Prospective studies are required to confirm these results.
A phase II study of maintenance rucaparib in patients with platinum sensitive, advanced pancreatic cancer and a pathogenic germline or somatic variant in <i>BRCA1, BRCA2</i> or <i>PALB2</i>: A four year survival update.
Authors: Kim Anna Reiss, Mark H. O'Hara, Ursina R. Teitelbaum, Thomas Benjamin Karasic, Charles John Schneider, Caroline F. Pratz, Katherine L. Nathanson, Robert H. Vonderheide, Susan M. Domchek
Journal: Journal of Clinical Oncology (2024)

661 Background: We previously reported the results of a single arm, phase II study of maintenance rucaparib in patients with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2 or PALB2 variants (Reiss et al, JCO, 2021). We now report the five year follow-up of this trial. Methods: Patients with advanced PC and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 were enrolled in this single arm phase II study performed at the Abramson Cancer Center. Patients were required to have received ≥16 weeks of platinum-based treatment without evidence of platinum resistance, which was defined as growing lesions, new lesions or steadily rising tumor markers. Chemotherapy was discontinued and patients received rucaparib 600mg PO BID until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: Of 42 evaluable patients, seven (16.7%) remain progression-free for over four years (5 gBRCA2, 1 sBRCA2, 1 gPALB2) of whom four (9.5%) have been progression-free for five years. Two of these four patients discontinued rucaparib due to adverse events after three and four years of therapy, respectively, without signs or symptoms of progression to date. At the cutoff date, we observe an mPFS 12.9 months, mOS 24.3 months, ORR 41.6% (9 PRs, 6 CRs), noting that three patients converted from partial to complete response since our prior publication. Two patients with ongoing responses succumbed to treatment-related MDS/AML following 2.1 and 4.8 years on study, respectively. Prior to receiving rucaparib, these individuals had received 13 and 10 months of cytotoxic chemotherapy for pancreatic cancer, respectively. Conclusions: Here we report the four year progression-free survival rate of maintenance rucaparib in patients with BRCA or PALB2 related pancreatic cancer. Our data suggest that a select portion of this patient population achieves highly durable clinical remissions. This finding is further highlighted by two patients who have discontinued rucaparib for adverse events one and two years ago, respectively, and have not had biochemical or imaging evidence of progression to date. Given the cost and risk of treatment-related leukemia associated with PARP inhibition, this data highlights the need to better understand the highly variable biology of patients with PC and BRCA or PALB2 variants, and raises the possibility of whether a very small, select group may be cured by PARP inhibitors. Clinical trial information: NCT03140670 .