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Background: Women are predisposed to develop intolerance to cancer chemotherapy. Sarcopenia and chemotherapy are mutually related. Women are generally intolerable to chemotherapeutics such as 5-fluorouracil. Although adjuvant oxaliplatin-based chemotherapy, e.g. CAPOX is commonly used to treat colorectal cancer, its effects on patients in terms of sarcopenia and sex remain unknown. We investigated sex disparities in the impacts of CAPOX on body composition in this study., Methods: We conducted a prospective study on diagnostic metrics used for sarcopenia in colorectal cancer patients receiving adjuvant CAPOX. Evaluations of the nutritional status by the Mini-Nutritional Assessment (MNA), gait speed, grip strength, skeletal muscle mass, fat mass, and bone mineral content using a body composition analyzer were performed in the first, fourth, and eighth cycles of CAPOX (first, second, and third measurements, respectively)., Results: Among 80 eligible patients, 61 completed four CAPOX cycles. The median differences in MNA, gait, grip strength, muscle mass, fat mass, and bone mineral content between the first and second measurements for men (n = 35) and women (n = 26) were + 10.5% and + 2.9% (p = 0.067), + 4.5% and - 2.6% (p = 0.16), + 1.8% and + 2.8% (p = 0.66), + 2.7% and + 1.3% (p = 0.021), + 4.5% and + 3.5% (p = 0.59), and + 3.3% and + 0.0% (p = 0.006), There were no sex differences in comparisons of the above metrics between the first and third measurements in 34 patients who completed eight CAPOX cycles (19 wen and 15 women)., Conclusions: Early cycles of adjuvant CAPOX may have a negative impact on the postoperative recovery of several metrics for diagnosing sarcopenia in women., (© 2024. The Author(s).)

Purpose: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC)., Methods: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0., Results: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs., Conclusions: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens., Methods: In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m 2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes., Results: Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of -5.2% and -3.3%; both were >-10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1-3 severity., Conclusions: Zuberitamab (375 mg/m 2 ) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL., Trial Registration Number: Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite promising outcomes of treatment with anti-programmed cell death (PD)-1/PD-ligand (L)1 agents in combination with platinum-doublet chemotherapy (PDC) in the first-line setting, a significant unmet medical need remains in patients with PD-L1-unselected non-small cell lung cancer (NSCLC)., Methods: This multicenter, open-label, phase 1b study comprising dose-confirmation and dose-expansion parts investigated the combination of spartalizumab and various PDC regimens, with or without canakinumab, in treatment-naïve patients with PD-L1-unselected, metastatic NSCLC. The primary objectives were to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of spartalizumab, with or without canakinumab, in combination with PDC in the dose-confirmation part and antitumor activity of spartalizumab in the dose-expansion part., Results: The MTD/RDE of spartalizumab was 300 mg every 3 weeks (Q3W) when administered with either gemcitabine (1250 mg/m 2 )/cisplatin (75 mg/m 2 ) (group A; no dose-limiting toxicities [DLTs]), pemetrexed (500 mg/m 2 )/cisplatin (group B; 2 DLTs: grade 2 posterior reversible encephalopathy syndrome and grade 4 hyponatremia), or paclitaxel (200 mg/m 2 )/carboplatin area under the curve 6 min*mg/mL (group C; 1 DLT: grade 4 neutropenic colitis). The RDE of canakinumab combined with spartalizumab and pemetrexed/cisplatin (group E; no DLTs) was 200 mg Q3W (no dose-expansion part was initiated). No new safety signals were identified. In groups A, B, C, and E, the overall response rates were 57.6%, 55.3%, 51.5%, and 57.1%, respectively. Group B compared with other groups had the longest median progression-free survival (10.4 months vs. 6.2-7.5 months), overall survival (29.7 months vs. 16.1-21.0 months), and duration of response (30.1 months vs. 6.0-8.2 months)., Conclusions: The combination of spartalizumab and PDC, with or without canakinumab, was well tolerated across treatment groups. The antitumor activity across treatment groups was comparable with that of pembrolizumab and pemetrexed combination. Canakinumab did not appear to improve the antitumor activity when combined with spartalizumab, pemetrexed and cisplatin., Trial Registration: The trial was registered in Clinicaltrials.gov with identifier no. NCT03064854. Date of Registration: 06 February 2017., (© 2024. The Author(s).)

Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8-13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety., (© 2024. The Author(s).)

Abstract: Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A "mutation score" was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points ("Beat-AML intermediate") vs 1+ points ("Beat-AML adverse"). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined "Beat-AML favorable-risk" group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Currently, several randomized controlled trials (RCTs) have been conducted to investigate the efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy as a first-line treatment for advanced or recurrent endometrial cancer; however, the optimal treatment strategy remains undetermined., Methods: A comprehensive search of online databases was conducted to identify RCTs published until December 31, 2023. Network meta-analysis was performed to evaluate PFS, OS, TRAEs, irAEs, and the ranking of different treatment regimens., Results: A total of 2702 patients from five RCTs (six reports) were included in the analysis. The combination therapy of ICIs significantly prolonged PFS (HR = 0.69, 95%CI 0.63-0.76, p < 0.0001) and OS (HR = 0.73, 95%CI 0.63-0.85, p < 0.0001) in the overall population. Among the different ICIs combinations evaluated, Durva-Olap-CP exhibited superior efficacy for both PFS and OS outcomes. In the pMMR population, both Durva-Olap-CP and Pembro-CP significantly reduced the risk of disease progression or death compared to Avelu-CP and Atezo-CP treatments; however, no significant differences were observed among various ICI combination therapies in patients with dMMR. In the dMMR population, Dostar-CP demonstrates a 42.2% probability of achieving first rank in terms of PFS, whereas in the pMMR population, Pembro-CP exhibits a 60% likelihood of securing the top position. Importantly, the toxicity associated with ICIs combination therapy was manageable and well-tolerated., Conclusions: The combination of ICIs and chemotherapy as first-line treatment for advanced or recurrent endometrial cancer has demonstrated superior survival outcomes compared to chemotherapy alone. Durva-Olap-CP exhibited the most favorable PFS and OS benefits in the overall population. In patients with dMMR, Dostar-CP showed the greatest improvement in PFS, while Pembro-CP demonstrated the most pronounced PFS benefit in patients with pMMR., (© 2024. The Author(s).)

Background: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting., Methods: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation., Results: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups., Conclusions: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms., (© 2024. The Author(s).)

Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy., Patients and Methods: Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point., Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively., Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Background: Exploration of novel combination mode of pyrotinib and chemotherapy for heavily pretreated HER2-positive metastatic breast cancer (MBC) and how to balance survival benefits and compliance are still urgent problems in clinical practice. The current single-arm prospective phase II study aimed to evaluate the efficacy and safety of pyrotinib in combination with metronomic oral etoposide in heavily pretreated HER2-positive MBC., Methods: HER2-positive MBC patients previously treated with trastuzumab were enrolled to receive oral pyrotinib 400 mg per day and metronomic oral etoposide 50 mg per day d1-21 every 28 days, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and safety., Results: 22 patients were enrolled with a median of 4 prior treatment regimens for MBC. During the follow-up of 20 evaluable patients, the median PFS was 9.0 months (95% CI, 7.6-10.4 months), and the median OS was 27.0 months (95%CI, 20.9-33.1 months). The ORR was 30% (6/20), the DCR was 80% (16/20), and the CBR was 65% (13/20). The most common grade 3 adverse events (AEs) included nausea (15%), vomiting (15%), diarrhea (5%), anemia (5%), and peripheral neuropathy (5%). No grade 4 or lethal AEs were observed., Conclusion: The combination of pyrotinib with metronomic oral etoposide has achieved promising clinical benefits in heavily pretreated HER2-positive MBC, with acceptable and manageable toxicity., Trial Registration: Registry number: NCT03923179. Registered April 18, 2019., (© 2024. The Author(s).)

Background: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients., Methods: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause., Results: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation., Conclusions: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma., Methods: The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0-4 weeks) and 180 mg once daily (5-8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614., Results: Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9-44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort., Conclusions: TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma., Competing Interests: Conflicts of interest T.M. declares research funding from Astellas Pharma Inc., Daiichi-Sankyo Biotech Co. Ltd., and Kowa Company, and holds stocks from Renascience Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A platinum-based concurrent chemoradiotherapy (CCRT) is the standard treatment for refractory cervical cancer (CC). However, the recurrence of disease and the occurrence of metastasis remain prevalent. We observed the long-term efficacy and safety of bevacizumab combined with neoadjuvant chemotherapy (NACT) and CCRT in refractory CC. A total of 62 patients with refractory CC were enrolled in this study from January 2016 to December 2019. The NACT regimen included bevacizumab (7.5 mg/kg), docetaxel (75 mg/m2), and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. The CCRT regimen included bevacizumab (7.5 mg/kg) and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. A dose of 45-50 Gy was prescribed for external beam radiotherapy (EBRT), while 30-35 Gy in 4-5 fractions was prescribed for brachytherapy (BT). Among the patients, 21 patients (33.9%) were at stages IIB-IIIB, 8 patients (12.9%) were at stage IIIC1, 19 patients (30.6%) were at stage IIIC2, and 14 patients (22.6%) were at stage IVB. Pelvic, para-aortic, supraclavicular, and inguinal lymph node metastases were discovered in 41 patients (66.1%). The median follow-up was 49.8 months (12.3-82.7 months). The median tumor volumes pre-treatment, after NACT, and before BT were 84.64 ± 53.15 cm3, 1.64 ± 13.15 cm3, and 0 ± 1.5 cm3, respectively. Complete clinical response (cCR) rates after NACT and EBRT were 35.5% and 66.1%, respectively. Four years after the diagnosis, the overall survival (OS) rate was 78.6%, the local region-free survival (LRFS) rate was 91.3%, the disease-free survival (DFS) rate was 70.6%, and the distant metastasis-free survival (DMFS) rate was 81.4%. A total of 29 patients (46.8%) experienced grade 3/4 hematological toxicity, 3 patients (4.8%) experienced grade 3 gastrointestinal toxicities, and none experienced grade 5 adverse events. Bevacizumab combined with NACT and CCRT significantly improved cCR and OS in refractory CC with acceptable toxicity.

Background: Breast cancer patients have an increased risk of cardiometabolic disease and for many patients, adjuvant therapy causes an altered lipid profile, insulin resistance and inflammation. Previous follow-up studies are inconclusive regarding the duration of therapy-induced inflammation. We examined the acute and persistent changes of adjuvant chemotherapy on inflammatory and metabolic health markers in breast cancer patients., Methods: Plasma levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α, high-sensitivity C-reactive protein (hsCRP) and metabolic health parameters were analyzed before, shortly after and every six months up to two years after adjuvant chemotherapy treatment in 51 postmenopausal early breast cancer (EBC) patients, as well as in 41 healthy age- and BMI-matched controls. A target-specific multiplex assay was applied for cytokine measurements., Results: Before initiation of adjuvant therapy, plasma IL-8 levels were higher in EBC patients (31%, p = 0.0001). Also, a larger proportion of the patients had a hsCRP level above 2 mg/L (41%) compared to the controls (17%, Χ 2  = 5.15, p = 0.023). Plasma levels of all five cytokines, but not hsCRP, were significantly increased after compared to before adjuvant chemotherapy (15-48% increase; all p ≤ 0.05). Already six months after ending chemotherapy treatment, all plasma cytokine levels were significantly reduced and close to pre-chemotherapy levels. Adjuvant chemotherapy caused a worsened lipid profile (increased triglycerides, lower HDL levels), insulin resistance and increased plasma insulin levels that remained high during the first year after chemotherapy., Conclusion: Postmenopausal women with EBC have temporarily increased plasma levels of pro-inflammatory cytokines after adjuvant chemotherapy. Although transient, the therapy-induced increase in plasma cytokine levels, together with dyslipidemia and insulin resistance, may contribute to cardiometabolic risk in breast cancer patients treated with adjuvant chemotherapy., Trial Registration: The clinical trial (registration number NCT03784651) was registered on www., Clinicaltrials: gov on 24 December 2018., (© 2024. The Author(s).)

Purpose: Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis., Patients and Methods: This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry., Results: With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%-56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%-76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%-81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively]., Conclusions: Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings., (©2024 American Association for Cancer Research.)

Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option., Patients and Methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm A1), oleclumab [recommended phase II dose (RP2D)] with GnP (arm A2), or oleclumab (RP2D) with durvalumab plus GnP (arm A3). Primary objectives were safety (escalation) and objective response rate (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS)., Results: During escalation, 1/11 patients from cohort B (oleclumab 3,000 mg) experienced two dose-limiting toxicities. Oleclumab's RP2D was 3,000 mg. During expansion, grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. The objective response rate was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs. A3; P = 0.650). PFS [HR = 0.72; 95% confidence interval (CI), 0.47, 1.11] and OS (HR = 0.75; 95% CI, 0.50-1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution., Conclusions: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: As we delve into the intricate world of venetoclax combination therapy in relapsed or refractory acute myeloid leukemia (AML), our exploration not only aims to contribute to the current body of knowledge but also strives to inform future research directions, clinical decision-making, and the ongoing evolution of therapeutic strategies in the relentless pursuit of improved outcomes for patients facing this formidable hematologic malignancy., Methods: We systematically searched PubMed, Embase, and Cochrane databases from inception to November 2023 for English-language studies on venetoclax combination therapy in relapsed/refractory AML. We excluded duplicate published studies, incomplete studies, those with incomplete data, animal experiments, literature reviews, and systematic studies. Meta-analysis was performed using STATA 15.1., Results: Out of 58 identified articles, seven were included in the meta-analysis. The pooled complete remission (CR) rate was 15.4%, and the composite complete remission (CRc) rate was 35.7%. The partial remission (PR) rate was 2.6%, while the non-remission (NR) rate was 24.4%. The minimal residual disease status in CRc patients (MRD-CRc) rate was 39.4%, and the morphologic leukemia-free state (MLFS) rate was 10.3%. Incidence of adverse events included diarrhea (10.0%), nausea (4.3%), vomiting (2.6%), hypokalemia (16.4%), hypomagnesemia (0.8%), decreased appetite (4.2%), fatigue (9.1%), febrile neutropenia (39.6%), and thrombocytopenia (28.4%). Subgroup analysis based on combined drugs revealed varying CR and CRc rates. the combination of venetoclax and azacitidine + demonstrates superior outcomes, displaying the highest rates of CR at 31.3% and CRc at 62.7%. In contrast, venetoclax and idasanutlin exhibits a moderate CR rate of 6.1% and a CRc rate of 26.5%, while venetoclax and mivebresib shows the lowest CR rate at 3.3% and a moderate CRc rate of 8.0%., Conclusion: In conclusion, while venetoclax combination therapies, particularly with azacitidine + , show promise in achieving favorable treatment responses in relapsed/refractory AML patients, a comprehensive evaluation of safety profiles is essential. Nevertheless, it is essential to underscore the markedly increased incidence rates of febrile neutropenia and thrombocytopenia observed among adverse events., (© 2024. The Author(s).)

Objective: Immune checkpoint inhibitor (ICI) therapy activates the immune system to recognize and eliminate cancer cells that have escaped surveillance. This study aimed to compare the treatment outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without ICI., Methods: Data from 69 advanced and recurrent cervical cancer patients treated with first-line ICI plus platinum and paclitaxel (N = 33) or first-line platinum and paclitaxel (N = 36) were reviewed between March 2020 and January 2023 in this retrospective study. Patients chose treatment based on the actual disease condition, patient willingness, and medical advice. Additionally, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were calculated, and adverse events were gained., Results: There was no difference in baseline data between patients receiving the two different treatments (all P > 0.05). Complete response rate (18.2% vs. 8.3%; P = 0.294), ORR (48.5% vs. 30.6%; P = 0.127), and DCR (81.8% vs. 72.2%; P = 0.345) tended to ascend in patients treated with ICI plus platinum and paclitaxel compared to those treated with platinum and paclitaxel, although there was no statistical significance. In patients treated with ICI plus platinum and paclitaxel, the median PFS was 10.3 months and the median OS was not reached. Meanwhile, the median PFS and OS were 7.7 and 16.9 months in patients treated with platinum and paclitaxel. PFS (P = 0.036) and OS (P = 0.033) were increased in patients treated with ICI plus platinum and paclitaxel versus those treated with platinum and paclitaxel, which was verified by multivariate Cox regression analyses (both P < 0.05). No difference was observed in the occurrence of adverse events between patients receiving the two different treatments (all P > 0.05)., Conclusion: First-line ICI plus platinum and paclitaxel yields better treatment responses, longer survival, and non-differential adverse events versus first-line platinum and paclitaxel in advanced and recurrent cervical cancer patients., (© 2024. The Author(s).)

Background: Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor., Methods: This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25 mg/kg HLX22 (a novel anti-HER2 antibody) + HLX02 (trastuzumab biosimilar) + oxaliplatin and capecitabine (XELOX) (group A), 15 mg/kg HLX22 + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC)., Findings: Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n = 18), B (n = 17), and C (n = 18). With 14.3 months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2 months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2 months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE., Conclusions: Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety., Funding: Shanghai Henlius Biotech, Inc., Competing Interests: Declaration of interests F.Y., H.Y., Jing Li, Q.W., and J. Zhu are employees of Shanghai Henlius Biotech, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Multimodal two-stage hepatectomy (mTSH) is used in patients with bilobar colorectal liver metastases (CRLM) that cannot be treated with one surgical procedure due to insufficient future liver remnant. Interval chemotherapy has been proposed to improve disease control in CRLM patients undergoing mTSH. We here present a narrative review of clinical studies on mTSH including the use of interval chemotherapy in patients with CRLM., Methods: A systematic literature search of the PubMed databases as well as the ClinicalTrials.gov registry was performed., Results: The use of interval chemotherapy during mTSH was reported in 23 studies and applied in 595 out of 1,461 patients with CRLM. Two studies report on the actual effects of this treatment, one study describes a trend towards improved disease progression rate. No serious adverse events caused by interval chemotherapy were observed. There is currently no randomized clinical trial investigating the efficacy and safety of interval chemotherapy during mTSH., Conclusion: The currently available data indicate that interval chemotherapy does neither impair liver hypertrophy during mTSH nor cause procedure-associated complications in patients with CRLM. Results from randomized clinical trials on the potential positive effect on disease control are not yet available., (© 2024. The Author(s).)

The effect of immune-based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273., (© 2024. The Author(s).)

Purpose: Combined immunotherapy (ipilimumab + nivolumab) has improved survival in stage IV melanoma patients, making Health-related Quality of Life (HrQoL) crucial due to potential immune-related adverse events (irAEs). Previous studies treated HrQoL as secondary/explorative endpoint, and no specific HrQoL questionnaire for melanoma patients on immune checkpoint inhibitor (ICI) therapy exists. This study aimed to gather specific HrQoL data during combined ICI therapy, tracking changes during and after treatment, and examining associations with gender, irAEs, and treatment response., Methods: 35 melanoma patients (22 males, 13 females) undergoing combined ICI were surveyed using the Short-form 36 questionnaire (SF-36), the Inflammatory Bowel Disease Questionnaire - Deutsch (IBDQ-D), and the distress thermometer (DT). HrQoL was evaluated during treatment, after six months, and at the onset of autoimmune colitis., Results: irAEs occurred in 51.4% of patients, with colitis being the most common (26.1%). 45.7% had progressive disease. SF-36 showed stable HrQoL during treatment and follow-up. Women had worse HrQoL on the physical component scale than men (p = 0.019). Patients with progression showed worse HrQoL over time in physical (p = 0.015) and mental health scales (p = 0.04). IBDQ-D showed constant HrQoL throughout treatment and follow-up. Distress on DT remained constant, with women reporting higher levels of distress., Conclusion: HrQoL remained stable during and after therapy. Female gender and disease progression negatively impacted HrQoL. The development of irAEs was not associated with HrQoL, though this may not apply to severe irAEs like colitis, which were not assessed., (© 2024. The Author(s).)

Background: Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy., Methods: In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded., Results: A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group., Conclusions: Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC., Method: This study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint., Discussion: This proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC., Competing Interests: Author JW was employed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. JW has no role in the study design and interpretation of results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Li, Wang, Yang, Wang and Cao.)

Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2- stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4-5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer.Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009., (© 2024. The Author(s).)

Introduction: Several trials of perioperative immunotherapy for resectable non-small cell lung cancer (NSCLC) reported positive results. They were designed to adjuvant, neoadjuvant and sandwich (neoadjuvant plus adjuvant) immunotherapy with immune checkpoint inhibitors and chemotherapy (CT). The differences between neoadjuvant and sandwich modalities were unclear., Method: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, WHO ICTRP and major international conferences., Results: We analyzed 8 studies involving 3429 patients, including 6 neoadjuvant plus adjuvant (Neo-Adj) and 2 neoadjuvant (Neo) trials. Neo-Adj had better event-free survival (EFS) (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.45-0.71) than CT. There existed no difference between Neo-Adj and Neo in EFS (HR = 0.87, 95% CI: 0.53-1.46) and overall survival (OS) (HR = 1.04, 95% CI: 0.38-2.57). Neo might have lower incidence of treatment-related adverse events (TRAEs) (relative risk [RR] = 0.96, 95% CI: 0.87-1.12) than Neo-Adj. Subgroup analysis of PD-L1 ≥ 50% suggested that EFS of Neo-Adj (HR = 0.46, 95% CI: 0.27-0.76) and Neo (HR = 0.24, 95% CI: 0.06-0.89) was better than CT, and Neo-Adj potentially caused shorter EFS than Neo (HR = 1.92, 95% CI: 0.46-7.84)., Conclusions: Our results suggest that Neo-Adj and Neo have similar EFS for patients with PD-L1 < 1% or 1-49%. However, patients with PD-L1 ≥ 50% may obtain more EFS benefit from Neo than Neo-Adj. Neo might present a more favorable assessment than Neo-Adj when evaluating OS. Moreover, adding adjuvant immunotherapy may increase toxicity., (© 2024. The Author(s).)

Background: Using granulocyte colony-stimulating factor (G-CSF) after completing chemotherapy reduces the duration of neutropenia and infections. However, the efficacy and safety of prophylactic pegfilgrastim in acute lymphoblastic leukemia (ALL) patients have not yet been evaluated after intensive cytotoxic chemotherapy compared to the daily G-CSF. This study aimed to evaluate the efficacy of pegfilgrastim for ALL patients who received intensive chemotherapy compared with a short-acting G-CSF., Patients and Methods: Clinical data of 145 patients treated with hyper-CVAD, modified VPDL/VPD, or KALLA 1406/1407 regimen were retrospectively evaluated. Pegfilgrastim or the short-acting G-CSF was selected according to the clinician's discretion. Patients not receiving pegfilgrastim were treated with the short-acting G-CSF., Results: The median age of enrolled patients was 45 years. Sixty newly diagnosed ALL patients were treated with hyper-CVAD regimen, while KALLA and VPDL regimens were administered to 39 and 46 patients, respectively. Among the 60 patients treated with hyper-CVAD, 20 patients received pegfilgrastim. Patients who received pegfilgrastim had a significantly shorter duration of neutropenia and hospitalization and reduced incidence of severe infections compared to patients receiving the short-acting G-CSF. Consistent results were also confirmed in an analysis targeting only patients who achieved remission during hyper-CVAD induction therapy. There was no significant difference in neutrophil recovery ability and hospitalization duration when the daily short-acting G-CSF was used prophylactically after completing hyper-CVAD, KALLA, and VPDL regimens as induction therapy., Conclusion: Using pegfilgrastim after hyper-CVAD therapy was more effective than the short-acting G-CSF in terms of infection, neutropenia recovery, and hospitalization in patients with newly diagnosed ALL., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: In the context of multiple myeloma (MM), early use of the immunomodulatory drug lenalidomide has led to an increased population of patients with lenalidomide-refractory MM in early-line settings, but their outcomes are not well characterized. Herein, we report treatment patterns, survival outcomes, prognostic variables, and attrition rates for patients with proteasome inhibitor-exposed, lenalidomide-refractory MM, treated with 1 to 3 prior lines of therapy (LOT). From 12 767 patients with MM in the Flatiron Health database between January 2016 and April 2022, 1455 met the inclusion criteria. The most common subsequent treatments were triplet combinations (41.6% of patients); daratumumab/pomalidomide/dexamethasone was the most common treatment regimen (13.2%). Median real-world progression-free survival (RW-PFS) and overall survival (OS) were 6.5 months and 44.4 months, respectively. RW-PFS was similar in patients with 1, 2, or 3 prior LOT. International Staging System stage III, Eastern Cooperative Oncology Group performance status of 1, hemoglobin <12 g/dL, high-risk cytogenetics, and refractoriness to anti-CD38 antibody at baseline were associated with worse RW-PFS and OS. Outcomes remained similar for patients who received National Comprehensive Cancer Network-preferred treatments and those who received treatments after 2020. In 561 patients with 1 prior LOT at inclusion, the cumulative attrition rate from LOT 2 to 5 was 85%, which included 25% patients who died and 60% with no further treatment. Patients with lenalidomide-refractory MM who have received 1 to 3 prior LOT have poor outcomes and progress rapidly through available therapies, highlighting the need for more effective treatments early in the disease course, before patients are lost to attrition., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Optimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma in their first relapse remains poorly defined. We therefore undertook a randomized phase 2 study to evaluate the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) in this patient population. The overall response rate (ORR) for POM-DEX was 43.6%, and for IXA-POM-DEX, it was 63.2%. The depth of response, measured by the attainment of at least a very good partial response, favored triplet therapy over doublet therapy (28.9% vs 5.1%; P = .0063). A preplanned interim analysis after 75% of the progression events had occurred demonstrated an improvement in progression-free survival (PFS) that favored IXA-POM-DEX and that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI], 4.8-13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI, 7.7-26.0 months; hazard ratio, 0.437; upper 90% bound = 0.657). The ORR and median PFS for 26 of 30 eligible patients who crossed over from the doublet to the triplet therapy at disease progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the 2 groups. More hematologic toxicities were seen with the triplet therapy, but nonhematologic adverse events were similar between the 2 arms. Our data support further testing of this all-oral triplet therapy in comparison with current standard triplet therapy in the context of phase 3 studies for patients with LEN-refractory disease at first relapse. This trial was registered at www.clinicaltrials.gov as #NCT02004275., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Twice-weekly carfilzomib (27 mg/m2) plus lenalidomide and dexamethasone (KRd27) is a standard of care in relapsed/refractory multiple myeloma (RRMM). Once-weekly carfilzomib regimens have shown clinical benefits with improved patient convenience. This open-label, phase 3, multicenter, randomized study aimed to demonstrate noninferiority of the overall response rate (ORR) for once-weekly carfilzomib (56 mg/m2) plus Rd (KRd56) vs twice-weekly KRd27 in RRMM. A total of 454 patients were randomized (1:1) to receive carfilzomib as once-weekly 30-minute infusions of 56 mg/m2 (KRd56; n = 228) or twice-weekly 10-minute infusions of 27 mg/m2 (KRd27; n = 226). Baseline characteristics were balanced between groups. ORR was 82.5% (95% confidence interval [CI], 76.9-87.2) in the once-weekly group vs 86.3% (95% CI, 81.1-90.5) in the twice-weekly group (risk ratio, 0.954 [95% CI, 0.882-1.032]) and did not meet the threshold for statistical significance of noninferiority (P = .0666). Complete response (CR) or better was obtained in 46.9% of patients in the once-weekly arm and 36.3% in the twice-weekly arm. The proportions of patients who achieved CR and were also assessed negative for minimal residual disease were 21.5% and 18.1%, respectively (odds ratio, 1.235 [95% CI, 0.775-1.970]). Progression-free survival was comparable between groups (hazard ratio, 0.945 [95% CI, 0.617-1.447]). The safety profile was similar for both groups. In conclusion, although statistical significance for noninferiority of ORR was not achieved, the efficacy and safety of once-weekly KRd56 were similar to those of twice-weekly KRd27, and once-weekly KRd56 may be an effective and convenient treatment option for patients with RRMM. This trial was registered at www.ClinicalTrials.gov as #NCT03859427., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Anlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC., Methods: Locally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common., Conclusions: Anlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted., (© 2024. The Author(s).)

Purpose: Ramucirumab (RAM) is recommended as premedication with H 1 -receptor antagonists (H 1 RA) to prevent infusion-related reactions (IRRs). However, RAM is a human antibody with a low incidence of IRRs. We evaluated the noninferiority of non-H 1 RA (dexamethasone [DEX] alone) premedication to H 1 RA (plus DEX) premedication in terms of IRRs in patients with gastric cancer receiving RAM plus nanoparticle albumin-bound paclitaxel (nab-PTX)., Methods: This was a noninferiority, multicenter, retrospective trial conducted in three Japanese centers to assess the incidence of IRRs in patients receiving RAM plus nab-PTX for gastric cancer between 2018 and 2023. Patients with gastric cancer receiving RAM plus nab-PTX were divided into groups with and without H 1 RA premedication. The incidence of IRRs was compared between the two groups., Results: Ninety patients were evaluated, with non-H 1 RA and H 1 RA premedications in 43 and 47 cases, respectively. After the first dose of RAM, IRRs were not observed in either group. IRRs during the overall doses were 0% for non-H 1 RA premedication and 2.1% for H 1 RA premedication (90% confidence interval (CI): -5.6%-1.3% for each comparison). The upper limit of the 90% CI (1.3%) did not exceed the noninferiority margin (Δ) of + 10% and therefore met the noninferiority criteria., Conclusion: RAM plus nab-PTX for gastric cancer with DEX premedication may be possible without H 1 RA premedication., (© 2024. The Author(s).)

Purpose: This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma., Methods and Materials: Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m 2 , once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS)., Results: All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%., Conclusions: Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer., (© 2024. The Author(s).)

Background: Treatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC., Methods: This retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted., Results: A total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5-13.1) and 5.4 (95% CI: 3.8-7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016)., Conclusion: Lenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers., (© 2024. The Author(s).)

Background: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC)., Methods: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety., Results: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported., Conclusion: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy., (© 2024. The Author(s).)

Background: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population., Materials and Methods: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR)., Results: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred., Conclusion: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Sarcopenia or skeletal muscle depletion is a poor prognostic factor for gastric cancer (GC). However, existing cutoff values of skeletal muscle index (SMI) for defining sarcopenia have been found to have limitations when clinically applied. This study aimed to determine the optimal cutoff for SMI to predict severe toxicities of chemotherapy and overall survival (OS) in patients with advanced GC., Methods: Patients with metastatic gastric adenocarcinoma who received first-line palliative chemotherapy between January 2014 and December 2021 at Queen Mary Hospital, Hong Kong, were included in this study. The SMI was determined via a pre-chemotherapy computed tomography scan. Optimal cutoff points of SMI were identified by recursive partitioning analysis. Univariate and multivariate analyses evaluating risk factors of severe chemotherapy toxicities and OS were also performed., Results: A total of 158 patients (male: 108 (68.4%), median age: 65.3) were included. The SMI cutoff to define low SMI was ≤33 cm2/m2 for males and ≤28 cm2/m2 for females; 30 patients (19.0%) had low SMI. Patients with low SMI had a higher incidence of hematological toxicities (63.3% vs 32.0%, P = .001) and non-hematological toxicities (66.7% vs 36.7%, P = .003). Multivariable analysis indicated that low SMI and low serum albumin (≤28 g/L) were independent predictive factors of hematological toxicity, while low SMI and neutrophil-lymphocyte ratio ≥5 were predictive factors of non-hematological toxicity. Moreover, patients with low SMI had a significantly shorter OS (P = .011), lower response rate to chemotherapy (P = .045), and lower utilization of subsequent lines of treatment (P < .001)., Conclusions: Using pre-chemotherapy SMI cutoff (≤33 cm2/m2 for males and 28 cm2/m2 for females) one can identify individuals with a higher risk of severe chemotherapy toxicities and worse prognosis., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers., Methods: A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety., Results: Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively., Conclusion: The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation., Clinicaltrials.gov Identifier: NCT03162510., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC)., Methods: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS)., Results: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group., Conclusion: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308)., (© The Author(s) 2024. Published by Oxford University Press.)

Background: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported., Materials and Methods: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated., Results: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95)., Conclusion: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer., Clinicaltrials.gov Id: NCT03189719., (© The Author(s) 2024. Published by Oxford University Press.)

Background: To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of chemotherapy., Methods: Electronic medical records for patients receiving chemotherapy were reviewed for adverse events and treatment modifications. Log-binomial regression models were used to estimate relative risks (RRs) with 95% CIs to examine associations between chemotherapy modifications, patient characteristics, and treatment modalities., Results: Delays in chemotherapy initiation (7%) were for surgical complications (58%), personal reasons (16%), and other (26%; port malfunction, infections, and obtaining extra imaging). Delays during chemotherapy (38%) were for infections (20%), neutropenia (13%), and personal reasons (13%). Dose reductions (38%) were for neuropathy (36%), unknown causes (9%), anemia (9%), and neutropenia (8%). Early treatment discontinuations (23%) were for neuropathy (29%). Patients receiving paclitaxel/nab-paclitaxel (RR 2.05; 95% CI, 1.47-2.87) and an anthracycline (RR 1.89; 95% CI, 1.39-2.57) reported more dose delays during chemotherapy. Black race (RR 1.46; 95% CI, 1.07-2.00), stage 3 (RR 1.79; 95% CI, 1.09-2.93), and paclitaxel/nab-paclitaxel receipt (RR 1.39; 95% CI, 1.02-1.90) increased the likelihood of dose reduction. Both Black race (RR 2.06; 95% CI, 1.35-3.15) and receipt of paclitaxel/nab-paclitaxel (RR 1.93; 95% CI, 1.19-3.13) increased the likelihood of early discontinuation. Patients receiving anthracyclines had higher rates of hospitalizations during chemotherapy (RR: 1.79; 95% CI, 1.11-2.89)., Conclusion: Toxicities are the most common reason for treatment modifications and need close monitoring in high-risk groups for timely intervention. Dose reductions and early treatment discontinuations occurred more for Black patients and need further study., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Acute myeloid leukemia (AML) is a heterogenous and complex blood cancer requiring aggressive treatment. Early identification and prediction of the complications following treatment is vital for effective disease management., Aims: We explored associations between plasma protein levels and fever- and infection-related complications in 26 AML patients during chemotherapy-induced neutropenia., Material and Methods: Longitudinal plasma profiling was conducted using data-dependent mass spectrometry analysis., Results: Mass spectrometry-based plasma profiling data correlated well with laboratory parameters, including C-reactive protein, and revealed a broader inflammation protein network associated with fever- and infection-related complications., Discussion and Conclusion: These data indicate the potential of longitudinal plasma profiling in AML patients for identifying and predicting complications that may aid in improved disease monitoring and treatment., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

The traditional treatment for small-cell lung cancer (SCLC) has been traditional systemic platinum-containing chemotherapy because the response rate is 50-90%. Durvalumab is an immune checkpoint inhibitor that blocks the binding of programmed cell death protein 1 and programmed cell death 1 ligand 1. Durvalumab combined with traditional chemotherapy agents has been recommended as the first-line treatment for extensive-stage SCLC, but its use may cause immune-related adverse events. Autoimmune encephalitis is a rare and potentially fatal neurological adverse event. This current case report describes a male patient in his late 50s with ES-SCLC who developed autoimmune encephalitis associated with durvalumab treatment after three cycles of combination chemotherapy. This current case furthers the understanding of autoimmune encephalitis caused by durvalumab treatment., Competing Interests: Declaration of conflicting interestAll authors declare no conflicts of interest.

Background: Randomized controlled trials (RCTs) have unequivocally established the therapeutic advantages of combining immune checkpoint inhibitors (ICIs) with chemotherapy in the treatment of early-stage non-small cell lung cancer (NSCLC). Presently, numerous perioperative immunotherapy regimens centered around the integration of ICIs and chemotherapy have undergone clinical trials. Nonetheless, due to the absence of direct comparative RCTs among these treatment regimens, this study aims to employ Bayesian network meta-analysis to ascertain the optimal combination of ICIs and chemotherapy., Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, Web of Science databases, and major international conference publications up to April 10, 2024. This comprehensive search yielded a total of 1434 studies. Following a rigorous screening process that involved evaluating the studies for relevance, methodological quality, and alignment with our research objectives, 8 studies were carefully selected for inclusion in the final analysis. Based on these curated search results, a systematic review and network meta-analysis were conducted., Results: 8 RCTs were included, encompassing 7 treatments and involving 3699 operable NSCLC patients at stages I-III. Compared to chemotherapy alone, perioperative immunotherapy demonstrated higher efficacy. The combination of toripalimab and chemotherapy showed the most significant improvement in event-free survival (EFS) (HR= 0.40; 95% CI, 0.28-0.58). The regimen that most notably enhanced overall survival (OS) was Nivolumab combined with chemotherapy (HR = 0.62; 95% CI, 0.36-1.07). In terms of pathological complete response (pCR), the combination of Toripalimab and chemotherapy exhibited the highest benefit (OR = 32.89; 95% CI, 7.88-137.32). Regarding the improvement in R0 resection, Pembrolizumab plus chemotherapy performed most prominently(OR=2.15; 95% CI, 1.30-3.56). In terms of the incidence of grade 3 or higher adverse events, durvalumab combined with chemotherapy had the lowest incidence (OR = 1.05; 95% CI, 0.79-1.38), while the incidence for other regimens was higher than chemotherapy alone., Conclusion: The efficacy of perioperative immunotherapy plus chemotherapy in patients with early NSCLC is significantly improved compared to chemotherapy alone. Although there is a certain risk of adverse events, the safety is within a controllable range. After a comprehensive evaluation of five endpoints in this study, it is believed that the combination of Toripalimab or Nivolumab with chemotherapy may be the optimal immunotherapy regimen for the treatment of stage Ib-IIIb NSCLC. These findings will help guide the design of clinical treatment plans and ICIs selection., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42024536799., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Wang, Yue, Chen, Zhu, Cui, Zhang, Jin and Xiao.)

Background: Tumor lysis syndrome (TLS) is a potentially life-threatening condition resulting from the rapid destruction of malignant cells, leading to electrolyte imbalances and severe complications, such as acute kidney injury, arrhythmias, and seizures. TLS can be managed through hyperhydration, urate-lowering treatments, and a steroid prophase strategy., Aims: This study aims to explore the impact of fractionated rituximab, an anti-CD20 antibody, on the occurrence and severity of TLS during the initial cycle in patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL)., Methods: Data was retrospectively collected from 94 of 186 patients., Results: Among the 94 patients included in the analysis, the median age was 70. Histologies were diffuse large B-cell lymphoma (75%), Burkitt lymphoma (13%) and high-grade B-cell lymphoma (8%). The majority were at an advanced stage (93%) with a high IPI score (75%). Most patients received anthracycline-containing regimens (72%) and prophylactic allopurinol (83%) and/or rasburicase (26%). Steroid prophase was administered to 82% of patients. The study identified one clinical TLS case and six laboratory TLS cases. Significant TLS factors included BL histology, elevated baseline LDH (⟩500 U/l), and rasburicase usage. Infusion reactions were rare (3%). Median progression-free survival was 2.6 years, and 2-year overall survival was 33%, irrespective of TLS occurrence., Conclusion: In this real-life study, clinical TLS occurrence was low (1%). TLS appeared more frequent in BL but did not impact overall survival. Fractionated initial rituximab dosing in addition to preventive strategies is a feasible approach in preventing clinical TLS, warranting further prospective investigation., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Objective: Comparing the efficacy of transarterial chemoembolization (TACE) combined with lenvatinib plus tislelizumab (TLT) with TACE combined with lenvatinib (TL) for unresectable hepatocellular carcinoma, particularly in determining which patients can benefit more from the TLT treatment., Methods: From March 2021 to September 2023, a total of 169 patients from three centers were included in this study, with 103 patients receiving TLT and 66 patients receiving TL. The Kaplan-Meier method was utilized to evaluate the cumulative overall survival (OS) and progression-free survival (PFS) between the two groups and were assessed using the log-rank test. Subgroup analysis on tumor number, maximum tumor diameter, presence of portal vein thrombosis, AFP level, and Child-Pugh class were conducted., Results: The median OS was 26 months in the TLT group, and 20 months in the TL group. The median PFS was 14 months in the TLT group and 9 months in the TL group. The Kaplan-Meier curve demonstrated a significantly superior OS and PFS in the TLT group compared to the TL group. Subgroup analysis showed that for patients with a maximum tumor diameter greater than 7 cm, AFP > 400 ng/ml and accompanied by portal vein tumor thrombus, and Child-Pugh class A, there was a statistically significant difference in OS between TLT and TL groups., Conclusions: OS and PFS were significantly improved in patients who received TLT compared to those who received TL, patients with a largest tumor diameter greater than 7 cm, AFP > 400 ng/ml, Child-Pugh class A and PVTT appeared to derive more benefit., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Wen, Xue, Dang, Nan, Wang, Li, Feng and Chen.)