Search

Purpose: This study aims to compare the economic- and patient-reported outcomes between outpatient home-based and inpatient hospital-based chemotherapy in advanced colorectal cancer patients.Methods: A total of 80 patients from Severance Hospital in Seoul, Korea, who had stage III colorectal cancer and underwent home-based (n = 40) or hospital-based chemotherapy (n = 40) with a FOLFOX regimen between January 2007 and April 2008 were enrolled. Patient satisfaction data were collected by a self-administered questionnaire survey. Based on hospital charge records, average cost (in 2008 Korean won (KW)) per chemotherapy session was estimated and compared between home- and hospital-based chemotherapy from a societal perspective.Results: Patients receiving chemotherapy at home showed higher satisfaction with their treatment (mean satisfaction score 3.58 ± 0.15, 5-point Likert-type scale, with a higher score indicating higher satisfaction) than did those treated at the hospital (3.23 ± 0.21; p < 0.01). After adjusting for differences in baseline characteristics between the two groups using multivariate analysis, those receiving home-based chemotherapy still showed significantly higher satisfaction than those undergoing hospital-based therapy (β = 0.271, p < 0.001). Additionally, home-based therapy reduced the cost per chemotherapy session by 16.6%, compared with hospital-based treatment (1,694,216 versus 2,030,383 KW, 1,200 KW ≈ 1 US dollar). The largest cost reduction was attributable to medical costs (-201,122 KW), followed by caregiver's opportunity costs (-135,000 KW).Conclusions: Higher satisfaction and lower economic cost for home-based chemotherapy suggests that home-based chemotherapy could be a popular and cost-effective treatment option for colorectal cancer patients who are eligible for home-based chemotherapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the activity and the safety of a combination regimen of capecitabine and doxorubicin as salvage chemotherapy in advanced gastric cancer patients who had undergone one or two prior chemotherapy regimens. Patients received capecitabine, 2,500 mg/m2/day PO for 14 days (D1–14) and doxorubicin, 30 mg/m2 IV on day 1 every 3 weeks until disease progression. The response was evaluated according to RECIST criteria, and the toxicity was evaluated by NCI-CTC (version 2.0). Forty-five patients were enrolled. Twenty-six patients were treated as second-line chemotherapy and the remaining patients as third-line chemotherapy. A total of 152 cycles of chemotherapy (median 2, range 1–12) were administered. Median dose intensities of capecitabine and doxorubicin were 11,326 and 9.6 mg/m2/week, respectively. The overall response rate was 6.7% (95% CI, 4.1–12.5%) and the disease control rate was 46.7% (95% CI, 28.6–87.1%) according to an intent-to-treat analysis. The median progression-free survival was 11.3 weeks (95% CI, 5.6–16.7 weeks). The median overall survival was 29.1 weeks (95% CI, 18.3–39.9 weeks) with one-year survival rate of 24%. Severe (grade III/IV) hematologic and non-hematologic toxicity was uncommon and included nausea/vomiting in five (11.1%), neutropenia in two (4.4%), anemia in one (2.2%), and hand-foot syndrome in one patient (2.2%). The combination of capecitabine and doxorubicin is a feasible salvage regimen in advanced pre-treated gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose: Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin.Methods: Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m(2 )capecitabine twice daily on days 1-14 and a dose of 100 mg/m(2) irinotecan infused over 90 min on days 1 and 8, every 3 weeks.Results: The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5-58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8-8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9-9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0-15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%).Conclusions: The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin. [ABSTRACT FROM AUTHOR]

Purpose: The nProfiler 1 Stomach Cancer Assay (nProfiler1), designed to predict responses to fluorouracil-based adjuvant chemotherapy, measures the expression of four gastric cancer target genes (GZMB, WARS, SFRP4, and CDX1). The randomized phase III POST trial aimed to compare the efficacies of two adjuvant S-1-based doublet chemotherapies: S-1 plus cisplatin (SP) and S-1 plus docetaxel (DS). This study aimed to validate the nProfiler1 assay using a distinct cohort from the POST trial., Materials and Methods: The nProfiler1 assay stratifies patients into three groups (low-risk, intermediate-risk, and high-risk) using the prognostic single-patient classifier and two groups (chemotherapy-benefit and no-benefit) using the predictive single-patient classifier. The nProfiler1 assay was applied to formalin-fixed paraffin-embedded slides obtained from the POST trial. Disease-free survival (DFS) and overall survival (OS), including 5-year survival rates, were calculated for the enrolled patients., Results: Of the 153 patients in the POST trial, 118 were included in the post-hoc analysis. With a median follow-up of 57.9 months, no significant difference in DFS or OS was observed between the SP and DS groups. The prognostic single-patient classifier predicted the OS in the SP group (p=0.0425) but not in the DS group (p=0.5940). The chemotherapy-benefit group exhibited numerically longer DFS than the no-benefit group in the SP and DS groups., Conclusion: The nProfiler1 assay offers valuable insights into the prognosis and efficacy of adjuvant chemotherapy based on fluorouracil plus platinum doublet regimens but not docetaxel-containing regimens. Further validation with larger patient cohorts and different regimens is warranted.

Background: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited., Methods: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data., Results: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy., Conclusion: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer., Trial Registration: NCT02746796., (© 2024. The Author(s).)

Purpose: Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS)., Methods: A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL)., Results: INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports., Conclusion: Regorafenib improves survival compared with placebo in refractory AGOC.

Purpose: Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC)., Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity., Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D., Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods : A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results : While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions : This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

Background: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting., Methods: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m 2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m 2 for 2 h every 21 days and capecitabine 1000 mg/m 2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed., Findings: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy., Interpretation: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer., Funding: Ono Pharmaceutical and Bristol Myers Squibb., Competing Interests: Declaration of interests Y-KK is a consultant for ALX Oncology, Amgen, Blueprint Medicines, Bristol Myers Squibb, DAE HWA Pharmaceutical, Macrogenics, Novartis, Surface Oncology, and Zymeworks. MT receives honoraria from Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Intuitive Surgical, Johnson & Johnson, Eli Lilly, Medtronic, Olympus, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceuticals, and Yakult Honsha and receives institutional research funding from Ono Pharmaceutical. NB receives honoraria from Bristol Myers Squibb Japan, Daiichi Sankyo, Ono Pharmaceutical, and Taiho Pharmaceutical and receives institutional research funding from Ono Pharmaceutical and Takeda Pharmaceuticals. HCC is an employee of MDBiolab; is a consultant for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Gloria Biosciences, Eli Lilly, Merck Serono Pharmaceutical, MSD, Quintiles, Taiho Pharmaceutical, and Zymeworks; receives speakers fees from Foundation Medicine, Eli Lilly, and Merck Serono; and receives institutional research funding from Amgen, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Eli Lilly, Merck Serono, MSD, Taiho Pharmaceutical, and Zymeworks. J-SC receives research funding from Amgen, Astellas Pharma, AstraZeneca, Janssen, Merck, MSD Oncology, Ono Pharmaceutical, Roche, Senhwa Biosciences, and TTY Biopharm. L-TC is independent director of ScinoPharm; receives honoraria from ACT Genomics, AstraZeneca, Bristol Myers Squibb, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, PharmaEngine, SynCoreBio, and TTY Biopharm; is a consultant for AstraZeneca, Bristol Myers Squibb, CStone Pharmaceuticals, Ipsen Pharma, Eli Lilly, MSD, Ono Pharmaceutical, Onward Therapeutics, Taivex Therapeutics, and TTY Biopharm; receives institutional research funding from ACT Genomics, Celgene, Novartis, OBI Pharma, Pfizer, Polaris Pharmaceuticals, SynCoreBio, and TTY Biopharm; and holds patents, royalties, and other intellectual property related to anti-α-enolase monoclonal antibody from HuniLife Biotechnology. M-HR receives honoraria from AstraZeneca, Bristol Myers Squibb, DAE HWA Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; is a consultant for AstraZeneca, Bristol Myers Squibb, DAE HWA Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical. TO receives honoraria and institutional research funding from Daiichi Sankyo. SYR is a consultant for Amgen, Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eisai, Eutilex, Indivumed, LG Chem, MSD Oncology, and Ono Pharmaceutical; receives speakers fees from Amgen, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Union Chimique Belge Japan, Eisai, Eli Lilly, and MSD Oncology; and receives research funding from Amgen (paid to their institution), ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daichii Sankyo, Eisai, Indivumed, Eli Lilly, MSD Oncology, Roche–Genentech, Sillajen, and Zymeworks. TY receives honoraria from Bristol Myers Squibb, Johnson & Johnson, Janssen, Ono Pharmaceutical, and Taiho Pharmaceutical. MS receives honoraria from Chugai Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, and Taiho Pharmaceutical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The JAVELIN Bladder 100 phase 3 trial demonstrated the efficacy and safety of avelumab administered as first-line (1L) maintenance treatment in patients with advanced urothelial carcinoma (UC) without disease progression after 1L platinum-based chemotherapy. This study provides the first real-world data from Korea regarding avelumab 1L maintenance treatment, comprising data obtained from a nationwide expanded access program (EAP)., Methods: This open-label EAP was conducted at five centers from September 2021 until June 2023. Eligible patients had unresectable locally advanced or metastatic UC and were progression free after 1L platinum-based chemotherapy. Patients received avelumab 10 mg/kg intravenously every 2 weeks per local prescribing information. Safety and effectiveness were assessed by treating physicians according to routine practice., Results: Overall, 30 patients were enrolled. At initial UC diagnosis, 20 patients (66.7%) had stage 4 disease and 12 (40.0%) had visceral metastases. The most common 1L chemotherapy regimen was gemcitabine + cisplatin (21 patients; 70.0%). All but one patient (96.7%) had received 4-6 cycles of 1L chemotherapy. The median interval from end of 1L chemotherapy to start of avelumab was 4.4 weeks. Median duration of avelumab treatment was 6.2 months (range, 0.9-20.7); nine patients (30.0%) received >12 months of treatment. Adverse events related to avelumab occurred in 21 patients (70.0%) and were grade ≥3 or classified as serious in three patients (10.0%). Median progression-free survival was 7.9 months (95% CI, 4.3-13.1). Overall survival was not analyzed because only one patient died., Conclusion: Results from this EAP demonstrated the clinical activity and acceptable safety of avelumab 1L maintenance treatment in Korean patients with advanced UC, consistent with previous studies., Competing Interests: SHP has served in consulting or advisory roles for Janssen; reports honoraria from Merck, Ono Pharmaceutical, and Pfizer; and reports research funding from Ono Pharmaceutical and Sanofi. SYR reports advisory roles and speaker services for and has received research funding from Merck. HKS has received research funding from Astellas, AstraZeneca, Basilea, Janssen, Merck, MSD, Ono-BMS, and Roche; and reports consulting, advisory roles, and speaker services for Astellas, Boehringer Ingelheim, Janssen, MSD, Ono-BMS, and Roche. BK has served in advisory roles for ABL Bio, AstraZeneca, CbsBioscience, Cellid, Genexine, Handok, Merck, MSD, and Trial Informatics; reports speaker services from AstraZeneca, Merck, and MSD; and served as coordinating principal investigator for AstraZeneca, MSD, and Ono Pharmaceutical. MK has served in consulting or advisory roles for Eisai, Ipsen, MSD, Ono-BMS, and Yuhan. Y-HH reports employment at Merck Ltd., Seoul, Republic of Korea, an affiliate of Merck KGaA. J-LL reports stock and other ownership interests in Amgen, Black Diamond Therapeutics, Innovent Biologics, Johnson & Johnson/Janssen, Karyopharm Therapeutics, Merck, and Zymeworks; reports honoraria from Astellas, AstraZeneca, BMS, MSD, and Pfizer; has served in consulting or advisory roles for AstraZeneca, BMS, GI Innovation, Merck, MSD, Oscotec, Pfizer, and Sanofi; and has received institutional research funding from Amgen, AstraZeneca/MedImmune, Bayer Schering Pharma, BMS, GI Innovation, Janssen, MSD, Novartis, Pfizer, Roche/Genentech, and Seagen. 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. The authors declare that this study received funding from Merck Ltd. The funder had the following involvement in the study: providing administrative roles for the present study., (Copyright © 2024 Park, Shin, Rha, Beom, Seo, Keam, Kim, Hong, Yoon and Lee.)

Background: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations., Methods: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting., Findings: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis., Interpretation: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting., Funding: AstraZeneca and Daiichi Sankyo., Competing Interests: Declaration of interests BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, and Lilly. He has received academic travel support from Amgen. He is an inventor on two institutional patents at MSK (US62/685,057 and US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. He is supported by the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. FM-B reports institutional grants or contracts from Aileron, AstraZeneca, Bayer, Calithera, Curis, CytomX, Daiichi Sankyo, Debiopharm, eFFECTOR, Genentech, Guardant, KLUS, Novartis, Puma Biotechnology, Taiho, and Takeda; personal consulting fees from AbbVie, Aduro, Alkermes, AstraZeneca, Calibr (a division of Scripps Research), Daiichi Sankyo, Debiopharm, EcoR1 Capital, eFFECTOR, F Hoffmann-La Roche, GT Apeiron, Genentech, Harbinger Health, IBM Watson, Infinity, Jackson Laboratory, Kolon Life Science, LegoChem Biosciences, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer, Protai, Samsung Bioepis, Seattle Genetics, Tallac, Tyra Biosciences, Xencor, and Zymeworks; personal meeting or travel support from the Cholangiocarcinoma Foundation, the European Organisation for Research and Treatment of Cancer, and the European Society for Medical Oncology; and personal participation on a data safety monitoring board or advisory board for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm, Loxo Oncology, Mersana, OnCusp, Puma Biotechnology, Seattle Genetics, Sanofi, Silverback, Spectrum, Theratechnologies, and Zentalis. AB reports grants or contracts from AstraZeneca/Daiichi Sankyo, Eli Lilly, Genentech/Roche, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius/Menarini, and Sanofi; consulting fees from BioTheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech/Roche, Immunomedics/Gilead, Innocrin Pharma, Merck, Novartis, Pfizer, Philips, Puma Biotechnology, Radius Health, Radius/Menarini, Sanofi, and Spectrum Pharmaceuticals; institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo/AstraZeneca, Genentech, Eli Lilly, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius Health, and Sanofi; personal participation on a data safety monitoring board or advisory board for AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Gilead, Lilly, Menarini, Merck, Mersana, Novartis, Pfizer, and Sanofi; other personal financial or non-financial interests for AstraZeneca, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Mersana, Novartis, Pfizer, and Sanofi. YN reports institutional grants or contracts from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Eisai, Ono, Pfizer, and Taiho; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Guardant, MSD, Nihon Kayaku, Novartis, Ono, PDR Pharma, Pfizer, Taiho, and Takeda. SS reports personal participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, GlaxoSmithKline, MSD, Novartis, Seagen, and T-One Therapeutics. PA reports institutional grants or contracts from Roche; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Amgen and Synthon; support for attending meetings and/or travel from Amgen, Daiichi Sankyo, MSD, Pfizer, and Roche; personal participation on a data safety monitoring board or advisory board for Amcure, Boehringer Ingelheim, Deloitte, Eisai, G1 Therapeutics, Gilead, Lilly, MacroGenics, Menarini, Novartis, Radius, Roche, and Servier. GC reports grants or contracts from Merck; consulting fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Ellipsis, Gilead, Lilly, Menarini, Merck, Novartis, Pfizer, Roche, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Gilead, Lilly, Novartis, Pfizer, and Relay; support for attending meetings or travel from Daiichi Sankyo. MdM reports institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and MSD; and other personal financial or non-financial interests for AbbVie, Achilles, Amunix, Arcus, BioNTech, Catalym, Dizal, Furmo, Genentech, Janssen, Loxo, MSD, Novartis, Numab, PharmaMar, Replimune, Roche, and Seagen. MK reports stock or stock options from Athenex, CRISPR, Eli Lilly, Natera, and Pfizer. D-YO reports personal grants or contracts from Array, AstraZeneca, Basilea, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier; and participation on a data safety monitoring board or advisory board for Arcus, ASLAN, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, MSD, Novartis, Taiho, Turning Point, Yuhan, and Zymeworks. MK's current affiliation is Breast Medical Oncology, LifeBridge Health, Baltimore, MD, USA. JOP reports personal grants or contracts from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier; personal support for attending meetings and/or travel from Minneamrita; personal participation on a data safety monitoring board or advisory board for Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), ImmuneOncia, MediRama, MedPacto Merck, Merck Sereno, MedPacto, and Servier. SP-V reports institutional grants or contracts from AstraZeneca and IMCore Hoffman LaRoche; institutional participation on data safety monitoring board or advisory board for Amgen and Daiichi Sankyo; and other personal financial or non-financial interests for Amgen, AstraZeneca, Bristol Myers Squibb, Clovis, GlaxoSmithKline, Novartis, Oxford Biotherapeutics, PEP Therapy, and Roche. SYR reports institutional grants or contracts from ABL Bio, ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, BeiGene, Bold Therapeutics, Daiichi Sankyo, Eisai, Ipsen, Leap Therapeutics, MacroGenics, MedPacto, Merck KGaA, MSD, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical, and Zymeworks; consulting fees from Individumed and LG Biochem; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Daiichi Sankyo, Eisai, Lilly, and MSD; and participation on a data safety monitoring board or advisory board for Amgen. TS reports personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharm, Ono Pharmaceutical, Taiho, Takara Bio, Takeda, and Yakult Honsha; institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead, HUTCHMED, Merck Biopharm, Ono Pharmaceutical, Parexel, Taiho, and Yakult Honsha; and personal participation on a data safety monitoring board or advisory board for Takara Bio. IS reports institutional grants or contracts from AstraZeneca, Genentech, Incyte, MSD, Orion, Pfizer, Puma Biotechnology, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; support for attending meetings or travel from AstraZeneca, Incyte, and Merck/Pfizer; and other financial or non-financial interests for AstraZeneca, Genentech, Incyte, MSD, Orion, Pfizer, Puma Biotechnology, and Roche. FM reports other personal financial or non-financial interests for AstraZeneca. AS reports personal stock or stock options for AstraZeneca and other financial or non-financial interests for AstraZeneca. KKM reports other personal financial or non-financial interests for AstraZeneca. CS reports personal participation in advisory boards or travel grants from AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F Hoffmann-La Roche Ltd, Gilead, Lilly, MediTech, MSD, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma Biotechnology, SeaGen, Synthon Biopharmaceutical, and Zymeworks. IA declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Background: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC., Methods: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan)., Results: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy., Conclusions: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression., Trial Registration: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732)., (© 2024. The Author(s).)

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC 50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI 50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the β-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the β-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yong-Chul Kim reports financial support was provided by Gwangju Institute of Science and Technology. Eun Yi Cho reports financial support was provided by Korea Ministry of Small and Medium Enterprises and Startups. Soo-Youl Kim, Yong-Chul Kim has patent issued to MDbiopharm Corp. If there are other authors, they 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 © 2023 Elsevier Inc. All rights reserved.)

Background: The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma is unknown. We assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastro-oesophageal adenocarcinoma., Methods: The KEYNOTE-585 study is a multicentre, randomised, placebo-controlled, double-blind, phase 3 study done at 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0-1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumour stage, and chemotherapy backbone. Primary endpoints were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT03221426, and is closed to accrual., Findings: Between Oct 9, 2017, and Jan 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47·7 months (IQR 38·0-54·8), pembrolizumab was superior to placebo for pathological complete response (52 [12·9%; 95% CI 9·8-16·6] of 402 vs eight [2·0%; 0·9-3·9] of 402; difference 10·9%, 95% CI 7·5 to 14·8; p<0·00001). Median event-free survival was longer with pembrolizumab versus placebo (44·4 months, 95% CI 33·0 to not reached vs 25·3 months, 20·6 to 33·9; hazard ratio [HR] 0·81, 95% CI 0·67 to 0·99; p=0·0198) but did not meet the threshold for statistical significance (p=0·0178). Median overall survival was 60·7 months (95% CI 51·5 to not reached) in the pembrolizumab group versus 58·0 months (41·5 to not reached) in the placebo group (HR 0·90, 95% CI 0·73 to 1·12; p=0·174). Grade 3 or worse adverse events of any cause occurred in 312 (78%) of 399 patients in the pembrolizumab group and 297 (74%) of 400 patients in the placebo group; the most common were nausea (240 [60%] vs 247 [62%]), anaemia (168 [42%] vs 158 [40%]), and decreased appetite (163 [41%] vs 172 [43%]). Treatment-related serious adverse events were reported in 102 (26%) and 97 (24%) patients. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group (interstitial ischaemia, pneumonia, decreased appetite, and acute kidney injury [n=1 each]) and two (<1%) patients in the placebo group (neutropenic sepsis and neutropenic colitis [n=1 each])., Interpretation: Although neoadjuvant and adjuvant pembrolizumab versus placebo improved the pathological complete response, it did not translate to significant improvement in event-free survival in patients with untreated, locally advanced resectable gastric or gastro-oesophageal cancer., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests KS reports research funding to their institution from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, Merck Sharp & Dohme, Amgen, and Eisai, consulting fees from Eli Lilly, Bristol-Myers Squibb, Takeda Pharmaceutical, Novartis, Abbive, Daiichi Sankyo, Taiho Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, Merck Sharp & Dohme, Astellas, Guardant Health Japan, and Janssen, and honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, and Janssen; SYR reports research funding to their institution from Amgen, Astellas, Daiichi Sankyo, Eisai, Merck, Roche, Zymework, Indivumed, Merck Sharp & Dohme, Ono Pharmaceutical, Bristol-Myers Squibb, and AstraZeneca, consultancy fees from Amgen, Astellas, Daiichi Sankyo, Eisai, LG Biochem, Indivumed, Merck Sharp & Dohme, Ono Pharmaceutical, Bristol-Myers Squibb, and AstraZeneca, and fees for speaker bureau from Eli Lilly, Eisai, Daiichi Sankyo, Merck Sharp & Dohme, Ono Pharmaceutical, and Bristol-Myers Squibb; LSW, PY, JX, SA, MO, HYab, Y-KP, TO, and NK report research funding to their institution from Merck Sharp & Dohme; S-EA-B reports research funding to their institution from Celgene, Eli Lilly, Sanofi, German Cancer Aid, German Research Foundation, German Federal Ministry of Education and Research, Roche, Vifor Pharma, Eurozyto, Immutep, Ipsen, Bristol-Myers Squibb, Merck Sharp & Dohme, and AstraZeneca, fees for speakers' bureau participation from Eli Lilly, AIO, Bristol-Myers Squibb, and MCI Group, fees for consulting or advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Daiichi Sankyo, and Eli Lilly Germany, and stock ownership in Institut fir Klinische Grebsforschung and Immutep; TY reports honoraria from Merck Sharp & Dohme, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, AstraZeneca, TREUMO, Otsuka, Covidien, Johnson & Johnson, Olympus, and Intuitive; HYas reports research funding to their institution from Merck Sharp & Dohme, and honoraria from Chugai Pharma; MDB reports research funding to their institution from Merck Sharp & Dohme, honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Eli Lilly, and Servier, reimbursement for travel from Daiichi, and participation on an advisory board for Novartis; SL reports research funding to their institution from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, Merck Sharp & Dohme, Pfizer, Roche, and Servier, consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Daichii Sankyo, Incyte, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Servier, and Astellas, and honoraria from Amgen, Bristol-Myers Squibb, Incyte, GlaxoSmithKline, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Pierre-Fabre, Roche, Servier; JT reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F Hoffman-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspira, IQVIA, Eli Lilly, Menarini, Merck Serono, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc, and Tolremo Therapeutics, honoraria from HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource, and stock options in Oniria Therapeutics; EVC reports research funding to their institution from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier, and fees for advisory board consulting for Abbvie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichi, GlaxoSmithKline, Incyte, Ipsen, Eli Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks; YYJ reports research funding to their institution from Merck Sharp & Dohme, the National Cancer Institute, the US Department of Defense, Cycle of Survival, Fred's Team, Rgenix, Bayer, Roche, Bristol-Myers Squibb, and Eli Lilly, fees for advisory board participation from Rgenix, Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck Sharp & Dohme, Daiichi Sankyo, Zymeworks, SeaGen, Basilea Pharmaceutical, Astra Zeneca, and equity in Rgenix; XF, C-SS, and PB are employees of and own stock options in Merck Sharp & Dohme; D-YO reports research funding to their institution from AstraZeneca, Novartis, Array, Eli Lilly, Servier, Beigene, Merck Sharp & Dohme, and Handok; and Y-JB reports research funding to their institution from Merck Sharp & Dohme and fees for consulting from Astellas, Amgen, Samyang Biopharm, Hanmi, and Daewoong., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20 + B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10 -4 ) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20 + B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile., (© 2024. The Author(s).)

Purpose: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC)., Patients and Methods: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cβ inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety., Results: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08)., Conclusion: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Purpose: BVAC-B is an autologous B cell- and monocyte-based immunotherapeutic vaccine that contains cells transfected with a recombinant human epidermal growth factor receptor 2 (HER2) gene and loaded with the natural killer T cell ligand alpha-galactosylceramide. Here, we report the first BVAC-B study in patients with HER2-positive advanced gastric cancer., Materials and Methods: Patients with advanced gastric cancer refractory to standard treatment with HER2+ immunohistochemistry ≥ 1 were eligible for treatment. Patients were administered low (2.5×107 cells/dose), medium (5.0×107 cells/dose), or high dose (1.0×108 cells/dose) of BVAC-B intravenously four times every 4 weeks. Primary endpoints included safety and maximum tolerated BVAC-B dose. Secondary endpoints included preliminary clinical efficacy and BVAC-B-induced immune responses., Results: Eight patients were treated with BVAC-B at low (n=1), medium (n=1), and high doses (n=6). No dose-limiting toxicity was observed, while treatment-related adverse events (TRAEs) were observed in patients treated with medium and high doses. The most common TRAEs were grade 1 (n=2) and grade 2 (n=2) fever. Out of the six patients treated with high-dose BVAC-B, three had stable disease with no response. Interferon gamma, tumor necrosis factor-α, and interleukin-6 increased after BVAC-B treatment in all patients with medium and high dose, and HER2-specific antibody was detected in some patients., Conclusion: BVAC-B monotherapy had a safe toxicity profile with limited clinical activity; however, it activated immune cells in heavily pretreated patients with HER2-positive gastric cancer. Earlier treatment with BVAC-B and combination therapy is warranted for evaluation of clinical efficacy.

Background: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC)., Methods: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m 2 or dose level 2, 80 mg/m 2 ) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis., Results: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival., Conclusions: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Neuregulin 1 ( NRG1 ) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block ® ' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

Trastuzumab is used to treat HER2-amplified metastatic gastric cancer; however, most patients become trastuzumab-resistant within a year. Knowledge of the mechanisms underlying trastuzumab resistance is required to overcome this limitation. Here, we aimed to elucidate this resistance mechanism using four trastuzumab-resistant (TR) cell lines and investigate the efficacy of HER2-targeted therapies to overcome treatment resistance. Each TR cell line had different phenotypic characteristics. Interestingly, HER2 expression remained as high as the parental cell lines in TR cell lines, suggesting that HER2-targeted agents were still useful. As expected, three tyrosine kinase inhibitors (lapatinib, neratinib, and tucatinib) and one antibody-drug conjugate (trastuzumab deruxtecan: T-DXd) exhibited good antitumor effects against TR cell lines. We further investigated the potential biological mechanism of T-DXd. When treated with trastuzumab or T-DXd, HER2 or its downstream signals were disrupted in parental cell lines, but not in TR cell lines. Moreover, T-DXd induced the expression of pH2A.X and cPARP and caused cell cycle arrest in the S or G2-M phase in TR cell lines. T-DXd showed promising antitumor activity in both parental and TR cell lines, suggesting that it is a potential candidate for overcoming trastuzumab resistance., (© 2023. The Author(s).)

Background: Evidence for the efficacy of combined PD-1 and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastro-oesophageal cancer is scarce. The first interim analysis of the randomised, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, we report results from protocol-specified subsequent interim analyses of KEYNOTE-811., Methods: The randomised, phase 3 KEYNOTE-811 trial involved 168 medical centres in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastro-oesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator or participant-initiated withdrawal. Randomisation used a block size of four and was stratified by region, PD-L1 status, and chemotherapy. Dual primary endpoints were progression-free and overall survival, analysed by intention to treat. Safety was assessed in all randomly assigned patients who received at least one dose of study treatment according to the treatment received. KEYNOTE-811 is registered with ClinicalTrials.gov (NCT03615326) and is active but not recruiting., Findings: Between Oct 5, 2018, and Aug 6, 2021, 698 patients were assigned to pembrolizumab (n=350) or placebo (n=348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 (82%) of 350 patients in the pembrolizumab group and 304 (88%) of 346 in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28·3 months [IQR 19·4-34·3] in the pembrolizumab group and 28·5 months [20·1-34·3] in the placebo group), median progression-free survival was 10·0 months (95% CI 8·6-11·7) in the pembrolizumab group versus 8·1 months (7·0-8·5) in the placebo group (hazard ratio [HR] 0·72, 95% CI 0·60-0·87; p=0·0002). Median overall survival was 20·0 months (17·8-23·2) versus 16·9 months (15·0-19·8; HR 0·87 [0·72-1·06]; p=0·084). At the third interim analysis (median follow-up 38·4 months [IQR 29·5-44·4] in the pembrolizumab group and 38·6 months [30·2-44·4] in the placebo group), median progression-free survival was 10·0 months (8·6-12·2) versus 8·1 months (7·1-8·6; HR 0·73 [0·61-0·87]), and median overall survival was 20·0 months (17·8-22·1) versus 16·8 months (15·0-18·7; HR 0·84 [0·70-1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 (58%) of 350 patients in the pembrolizumab group versus 176 (51%) of 346 patients in the placebo group. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group and three (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhoea (165 [47%] in the pembrolizumab group vs 145 [42%] in the placebo group), nausea (154 [44%] vs 152 [44%]), and anaemia (109 [31%] vs 113 [33%])., Interpretation: Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests YYJ reports research funding to their institution from MSD, the US National Cancer Institute, the US Department of Defense, Cycle of Survival, Fred's Team, Rgenix, Bayer, Genentech/Roche, Bristol-Myers Squibb, and Eli Lilly; fees for advisory board participation from Inspira, Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck Sharp & Dohme, Daiichi Sankyo, Zymeworks, SeaGen, Basilea Pharmaceutical, and AstraZeneca; and equity in Inspira. AK reports research funding to their institution from AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, and MSD; consulting fees from Zymeworks, MSD, and Astellas Pharma; and honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Ono Pharmaceutical, Eli Lilly, and Taiho Pharmaceutical. YB, JX, PY, LSW, YO, MB, HCC, and S-KQ report research funding to their institutions from Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD). SL reports research funding to their institution from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier; consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Daichii Sankyo, Incyte, Lilly, Merck Serono, MSD, Servier, and Astellas; and honoraria from Amgen, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, and Servier. JPM reports grants from MSD, Bristol-Myers Squibb, Zymeworks, Astellas, Bayer, and Diachii; honoraria from MSD, Astellas, Bayer, and Bristol-Myers Squibb; and reimbursement for travel from MSD, Daichii, and BMS. LS reports research funding to their institution from MSD, Beijing Xiantong Biomedical Technology, Qiku Pharmaceutical Co, Zaiding Pharmaceutical (Shanghai) Co, Jacobio Pharmaceuticals Co, Beihai Kangcheng (Beijing) Medical Technology Co, Boehringer Ingelheim, Harbour, and Merck; and consulting fees from Harbour and Merck. KS reports research funding to their institution from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, MSD, Amgen, and Eisai; consulting fees from Eli Lilly and Company, Bristol-Myers Squibb, Takeda Pharmaceutical, Novatis, AbbVie, Daiichi Sankyo, Taiho Pharmaceutical, GSK, Amgen, Boehringer Ingelheim, MSD, Astellas, Guardant Health Japan, and Janssen; and honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, and Janssen. EVC reports research funding to their institution from Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Rocher, and Servier; and fees for advisory board consulting for Array, AstraZeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho. JT reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F Hoffman-La Roche, Genentech, HalioDx SAS, Hutchison MediPharma International, Ikena Oncology, Inspira, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc, and Tolremo Therapeutics; honoraria from Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and stock options in Oniria Therapeutics. KL, C-SS, and PB are employees of and own stock options in MSD. SYR reports research funding to their institution from Amgen, Astellas, Daiichi Sankyo, Eisai, Merck, Roche, Zymework, Indivumed, MSD, Ono, Bristol-Myers Squibb, and AstraZeneca; consultancy fees from Amgen, Astellas, Daiichi Sankyo, Eisai, LG Biochem, Indivumed, MSD, Ono, Bristol-Myers Squibb, and AstraZeneca; and fees for speakers bureaus from Lilly, Eisai, Daiichi Sankyo, MSD, Ono, and Bristol-Myers Squibb., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Evidence on whether prior antibiotic (pATB) administration modulates outcomes of programmed cell death protein-1 (PD-1) inhibitors in advanced gastric cancer (AGC) is scarce. In this study, we find that pATB administration is consistently associated with poor progression-free survival (PFS) and overall survival (OS) in multiple cohorts consisting of patients with AGC treated with PD-1 inhibitors. In contrast, pATB does not affect outcomes among patients treated with irinotecan. Multivariable analysis of the overall patients treated with PD-1 inhibitors confirms that pATB administration independently predicts worse PFS and OS. Administration of pATBs is associated with diminished gut microbiome diversity, reduced abundance of Lactobacillus gasseri, and disproportional enrichment of circulating exhaustive CD8 + T cells, all of which are associated with worse outcomes. Considering the inferior treatment response and poor survival outcomes by pATB administration followed by PD-1 blockade, ATBs should be prescribed with caution in patients with AGC who are planning to receive PD-1 inhibitors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma., Methods: KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m 2 per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m 2 ) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m 2 ) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m 2 ) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete., Findings: Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n=790) or placebo plus chemotherapy (placebo group; n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group; 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cutoff was 31·0 months (IQR 23·0-38·3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12·9 months [95% CI 11·9-14·0] vs 11·5 months [10·6-12·1]; hazard ratio [HR] 0·78 [95% CI 0·70-0·87]; p<0·0001), in participants with a PD-L1 CPS of 1 or higher (13·0 months [11·6-14·2] vs 11·4 months [10·5-12·0]; 0·74 [0·65-0·84]; p<0·0001), and in participants with a PD-L1 CPS of 10 or higher (15·7 months [13·8-19·3] vs 11·8 months [10·3-12·7]; 0·65 [0·53-0·79]; p<0·0001). The most common grade 3-5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified., Interpretation: Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma., Funding: Merck Sharp and Dohme., Competing Interests: Declaration of interests All authors report funding to their institution from Merck Sharp and Dohme to support the conduct of this study. All authors received medical writing and editorial support for the preparation of this manuscript from Merck Sharp and Dohme. SYR reports grants from Amgen, Astellas, Daiichi Sankyo, Eisai, Merck, Roche, Zymeworks, Indivumed, MSD, Ono/Bristol Myers Squibb, AstraZeneca, BI, Taiho, Lilly, SN Bioscience, and SRF; has received honoraria as an invited speaker for Lilly, Eisai, Daiichi Sankyo, MSD, and Ono/Bristol Myers Squibb; has participated on advisory boards for Amgen and Indivumed; and has served as an advisor for Astellas, Daiichi Sankyo, Eisai, LG Biochem, Merck Sharpe Dohme, Ono/Bristol Myers Squibb, and AstraZeneca. D-YO reports grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, Merck Sharpe Dohme, and Handok; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, and Merck Sharpe Dohme. M-HR reports research grants from AstraZeneca; consulting fees from Bristol Myers Squibb, Ono, Lilly, Merck Sharpe Dohme, Novartis, Daiichi Sankyo, AstraZeneca, Sanofi, and Astellas; and has received honoraria for lectures, presentations, speakers bureaus, or educational events from Bristol Myers Squibb, Ono, Lilly, Merck Sharpe Dohme, Novartis, Daiichi Sankyo, AstraZeneca, Sanofi, and Astellas. FR reports research grants paid to his institution from Roche, Merck Serono, Amgen, Merck Sharpe Dohme, Bristol Myers Squibb, Lilly, Celgene, Sanofi-Aventis, Servier, AstraZeneca, Bayer, Astellas, and Organon; has received consulting fees and honoraria for lectures, presentations, speakers bureaus, or educational events from Roche, Merck Serono, Amgen, Merck Sharpe Dohme, Bristol Myers Squibb, Lilly, Celgene, Sanofi-Aventis, Servier, and Bayer; has received travel expenses from Roche, Amgen, Merck Sharpe Dohme, Bristol Myers Squibb, Servier, and Bayer; and has participated on a data safety monitoring board or advisory boards for Roche, Merck Serono, Amgen, Merck Sharpe Dohme, Bristol Myers Squibb, Lilly, Celgene, Sanofi-Aventis, Servier, and Bayer. GVA reports participation on advisory boards for Merck Sharpe Dohme. MG has received honoraria for lectures, presentations, speakers bureaus, or educational events from Pfizer, Merck, Bristol Myers Squibb, and Merck Sharpe Dohme; received payment for expert testimony from AstraZeneca, Bristol Myers Squibb, and Merck Sharpe Dohme; and has received travel expenses from Tecnofarma. K-KS reports research grants paid to his institution from Merck Sharpe Dohme, Roche, AstraZeneca, and BioNTech; has received consulting fees from Nouscom; has received honoraria for lectures, presentations, speakers bureaus, or educational events from Merck Sharpe Dohme, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, Nouscom, Roche, and Servier; has received travel expenses from Merck Sharpe Dohme, Merck KGaA, Nouscom, Roche, and Servier; and has received honoraria for participation on advisory boards for Bayer, Merck Sharpe Dohme, Merck KGaA, Roche, and Mirati Therapeutics. FMC has received honoraria for lectures from Merck Sharpe Dohme; participated on advisory boards for Jansen and Bayer; and has served on a steering committee for Novartis. ZAW reports grants from Bristol Myers Squibb and Arcus; has received consulting fees from Amgen, AstraZeneca, Daiichi, Bayer, Bristol Myers Squibb, Merck, Ipsen, Arcus, Astellas, Pfizer, and Seagen; has received travel expenses from Amgen and Merck; and has participated on advisory boards or data safety monitoring boards for Pfizer, Daiichi, and Compass. LY, SB and PB report full-time employment by Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ, USA), and stock ownership in Merck. LSW reports consulting fees from Amgen; and has received honoraria for lectures, presentations, speakers bureaus, or educational events from Novartis, Bristol Myers Squibb, Merck Sharpe Dohme, Roche, and Amgen. PY, YB, JLee, MGF, JLi, MAL, TC, SQ, SL, and HP declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

PF-06804103 is an anti-HER2 antibody-drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15-5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). Ninety-three patients enrolled in P1 (n = 47: HER2+ gastric cancer = 22, HER2+ breast cancer = 25) and P2 [n = 46: HER2+ breast cancer = 19, hormone receptor (HR)+ HER2-low breast cancer = 27] received PF-06804103. Four patients (3.0- and 4.0-mg/kg groups, n = 2 each) had DLTs (mostly Grade 3). Safety and efficacy results showed a dose-response relationship. Adverse events (AE) leading to treatment discontinuation (44/93, 47.3%) included neuropathy (11/93, 11.8%), skin toxicity (9/93, 9.7%), myalgia (5/93, 5.4%), keratitis (3/93, 3.2%), and arthralgia (2/93, 2.2%). Two (2/79, 2.5%) patients (P1, 4.0- and 5.0-mg/kg groups, n = 1 each) achieved complete response; 21 (21/79, 26.6%) achieved partial response. In P2, ORR was higher in HER2+ compared with HR+ HER2-low breast cancer [3.0 mg/kg: 16.7% (2/12) vs. 10.0% (1/10); 4.0 mg/kg: 47.4% (9/19) vs. 27.3% (3/11)]. PF-06804103 demonstrated antitumor activity; however, AEs led to discontinuation in 47.3% of patients. Safety and efficacy were dose-dependent., (©2023 The Authors; Published by the American Association for Cancer Research.)