Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.

A meta-analysis of efficacy and safety data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in adult patients with RAS wild-type metastatic colorectal cancer by sidedness.

The first-line treatment choice of EGFRIs plus doublet chemotherapy vs. bevacizumab plus doublet chemotherapy remains a topic of interest for patients with left-sided RAS WT mCRC. We conducted a systematic literature review and meta-analysis of clinical trial data published between 2015 and 2024. We evaluated the relative efficacy and safety of first-line EGFRIs plus doublet chemotherapy (FOLFIRI or FOLFOX) vs. bevacizumab plus doublet chemotherapy for patients with RAS WT left-sided mCRC, as well as in all- and right-sided tumors. We identified eight trials with 2624 patients. Five trials reported outcomes by tumor sidedness. In the left-sided population, overall survival (OS) (Hazard Ratio (HR) = 0.80, 95% Confidence Interval (CI): 0.71-0.90) and objective response rate (ORR) (Odds ratio [OR]=1.61, 95% CI: 1.30-1.99) favored EGFRI plus chemotherapy, while no statistically significant differences were observed for progression-free survival (PFS) (HR=0.93, 95% CI: 0.84-1.04) or resection rate (RR). Similar results were found in the all-sided population. In the right-sided population, PFS favored bevacizumab plus chemotherapy (HR=1.45, 95% CI: 1.19-1.78), while no statistically significant differences were observed for OS (HR=1.17, 95% CI: 0.95-1.44), ORR (OR=0.99, 95% CI: 0.69-1.41), and RR. Early tumor shrinkage in the all-sided population favored EGFRI plus chemotherapy (OR=1.72; 95% CI: 1.36-2.17); limited data precluded evaluation by sidedness. Safety was available in 6 trials for all-sided tumors and 1 trial for left-sided tumors, each demonstrating typical class-specific adverse events. This most comprehensive meta-analysis indicates a benefit for first-line EGFRI plus chemotherapy over bevacizumab plus chemotherapy in patients with left-sided RAS WT mCRC.

Claudin 18.2 as a novel therapeutic target.

Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial.

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 report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

Efficacy and Safety of Trifluridine/Tipiracil-Containing Combinations in Colorectal Cancer and Other Advanced Solid Tumors: A Systematic Review.

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.

Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Zolbetuximab for Claudin18.2-positive gastric or gastroesophageal junction cancer.

Claudins (CLDNs) are a family of major membrane proteins that form components of tight junctions. In normal tissues, CLDNs seal the intercellular space in the epithelial sheets to regulate tissue permeability, paracellular transport, and signal transduction. Claudin18.2 (CLDN18.2), a member of the CLDN family, is expressed specifically in gastric mucosal cells in normal tissue, and its expression is often retained in gastric cancer cells. CLDN18.2 is ectopically expressed in many cancers other than gastric cancer such as esophageal cancer, pancreatic cancer, biliary tract cancer, non-small-cell lung cancer, and ovarian cancer. Structurally, CLDN18.2 is localized on the apical side of the cell membrane and has extracellular loops capable of binding monoclonal antibodies. Upon malignant transformation, CLDN18.2 is exposed to the cell surface of the whole membrane, which enables the binding of monoclonal antibodies. Based on these characteristics, CLDN18.2 was considered to be optimal for target therapy, and zolbetuximab was developed which is a first-in-class chimeric immunoglobulin G1 monoclonal antibody highly specific for CLDN18.2. It binds to CLDN18.2 on the tumor cell surface and stimulates cellular and soluble immune effectors that activate antibody-dependent cytotoxicity and complement-dependent cytotoxicity. Recently, zolbetuximab combined with chemotherapy demonstrated a survival benefit in patients with CLDN18.2-positive and HER-2-negative gastric or gastroesophageal junction cancers in the global phase III SPOTLIGHT and GLOW trials. From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.

Potential Efficacy of Shiunko for Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody-Induced Skin Fissure: A Single Institutional Case Series.

PURPOSE: Anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) is the key drug for RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). However, anti-EGFR mAb-induced skin fissures often affect a patient's quality of life. Shiunko, a traditional Japanese topical herbal medicine, is used for burns and dermatitis and may potentially have wound-healing effects. Herein, we report cases of patients with mCRC who were treated with Shiunko for anti-EGFR mAb-induced skin fissure. METHODS: We retrospectively reviewed consecutive patients with mCRC who received an anti-EGFR mAb-containing regimen and were treated with Shiunko twice a day for skin fissures at the National Cancer Center Hospital East between March 2022 and December 2022. Skin fissures were assessed at baseline and at every visit until 28 days after Shiunko initiation according to CTCAE v5.0. RESULTS: Among the 11 patients, 5 patients were female; the median age was 61 (range, 43-79) years. The median treatment duration with anti-EGFR mAb before Shiunko initiation was 13.1 (range, 6-52) weeks. Skin moisturizer and topical steroids were applied for skin fissures in 11 and 5 patients, respectively. All patients had grade 2 skin fissures at baseline of Shiunko initiation. Two weeks after Shiunko initiation, complete recovery was noted in 4 patients and improvement to grade 1 was noted in 6 patients. There were no Shiunko-related adverse events. Ten patients continued anti-EGFR mAb treatment until disease progression, while 1 patient discontinued anti-EGFR mAb treatment due to severe eruptions. CONCLUSION: Shiunko could be a treatment option for anti-EGFR mAb-induced skin fissure. Further studies are warranted to investigate the efficacy and safety of Shiunko for anti-EGFR mAb-induced skin fissure.

Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer: a plain language summary of the DESTINY-Gastric01 study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the publication about the DESTINY-Gastric01 study, which was published in the New England Journal of Medicine in May 2020. The study included 187 adults in Japan and South Korea with gastric cancer or gastroesophageal junction cancer that had high levels of a protein called HER2 (HER2-positive). All the participants' cancer had spread to nearby or distant parts of the body and had worsened after receiving at least 2 previous cancer treatments or treatment combinations. The researchers wanted to know whether a drug called trastuzumab deruxtecan (T-DXd) could improve participants' cancer more than standard chemotherapy drugs. WHAT WERE THE RESULTS?: Researchers in this study found that just over half (51%) of participants who received T-DXd had their cancer shrink significantly or disappear, compared to around 1 out of 7 participants (14%) who received standard chemotherapy. In addition, T-DXd reduced the risk of death by 41% compared to standard chemotherapy. Half of the participants who received T-DXd had died after 12.5 months. Half of the participants who received standard chemotherapy had died after 8.4 months. Just under half (44%) of participants who received T-DXd had serious medical problems during the study, also called serious adverse events, compared to about a quarter (24%) of participants who received standard chemotherapy. Of the participants who received T-DXd, 1 out of 10 (10%) got interstitial lung disease or pneumonitis that was potentially related to the study treatment. None of the participants who received standard chemotherapy got interstitial lung disease or pneumonitis. WHAT DO THE RESULTS MEAN?: T-DXd could be a treatment option for people who have HER2-positive gastric cancer that has been previously treated without success.

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas. METHODS: This multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy's Law criteria, and all cases of overdose were reported on the case report forms. RESULTS: A total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1). CONCLUSION: This expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.

Quantitative Analysis of the Concentration of Trifluridine in Tumor Hypoxic Regions Using a Novel Platform Combining Functional Endoscopy and Mass Spectrometry.

Hypoxic regions in solid tumors are highly resistant to drugs and thus represents an obstacle in drug discovery. Currently, however, there are technical barriers in sampling human hypoxic tumors and examining drug delivery with high sensitivity and accuracy. Herein, we present a new platform combining functional endoscopy and highly sensitive liquid chromatography-mass spectrometry (LC-MS) to assess drug delivery to hypoxic regions. Because oxygen saturation endoscopic imaging (OXEI), a functional endoscopy, can evaluate lesions and hypoxia in real-time by simultaneously acquiring a pseudocolor map of oxygen saturation and conventional endoscopic images, this platform can be used to evaluate drug delivery with human samples from hypoxic regions. As the first clinical application of this platform, the relationship between hypoxic regions and the concentration of trifluridine (FTD) incorporated into DNA was evaluated in patients with advanced gastric cancer treated with FTD/tipiracil (FTD/TPI; n = 13) by obtaining and analysis of tissue samples by OXEI and LC-MS and vascular maturity index by CD31/α-SMA staining ex vivo. The results showed that the concentration of FTD was significantly higher in the normoxic region than in the hypoxic region (P < 0.05) and there were significantly more immature vessels in hypoxic regions than in normoxic regions (P < 0.05). These results indicate that the platform was sufficiently sensitive to evaluate differences in drug anabolism in different oxygenic regions of human tumor tissue. This new platform allows quantitative drug analysis in hypoxic regions and is expected to initiate a new era of drug discovery and development.

Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study.

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.

Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

BACKGROUND: Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. METHODS: Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). RESULTS: The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. CONCLUSIONS: Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

Neoadjuvant chemotherapy for locally advanced gastric cancer in Japan: Consensus meeting at the 77th general meeting of the Japanese Society of Gastroenterological Surgery.

Treatment strategy for locally advanced gastric cancer differs worldwide. Neoadjuvant chemotherapy (NAC) is considered one of the promising treatment options for locally advanced gastric cancer, even in Japan, and clinical trials have been conducted or are ongoing. A consensus meeting was organized at the 77th general meeting of the Japanese Society of Gastroenterological Surgery in 2022, in which the current status and future prospects of NAC for locally advanced gastric cancer were discussed. Participants at the meeting looked forward to the results of the JCOG1509 trial, providing solid evidence regarding NAC. The optimal indications and regimens for NAC were also debated. Patients with cStage III gastric cancer are the main targets of NAC in Japan, and a doublet regimen of S-1 and oxaliplatin was preferred by the participants. However, the feasibility of a triplet regimen with S-1, oxaliplatin, and docetaxel, and that with 5-FU, leucovorin, oxaliplatin, and docetaxel has been demonstrated, and these could become treatment options in Japan. Other points of discussion include perioperative chemotherapy to avoid peritoneal recurrence and for patients with dMMR/MSI-high tumors. The panel regarded NAC as a promising treatment option, and NAC will become the standard treatment for cStage III gastric cancer in Japan if an ongoing clinical trial successfully demonstrates its efficacy.

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial.

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.

Efficacy and safety of trifluridine/tipiracil plus ramucirumab in comparison with trifluridine/tipiracil monotherapy for patients with advanced gastric cancer-single institutional experience.

BACKGROUND: Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy. METHODS: We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients. RESULTS: Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups. CONCLUSIONS: Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials.

Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649.

PURPOSE: In CheckMate 649, first-line nivolumab plus chemotherapy prolonged overall survival versus chemotherapy in patients with advanced/metastatic non-human epidermal growth factor receptor 2 (HER2)-positive gastric/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC). We present exploratory patient-reported outcomes (PROs). METHODS: In patients (N = 1,581) concurrently randomly assigned 1:1 to nivolumab plus chemotherapy or chemotherapy and in those with tumor PD-L1 expression at a combined positive score (CPS) of ≥5, health-related quality of life (HRQoL) was assessed using the EQ-5D and Functional Assessment of Cancer Therapy-Gastric (FACT-Ga), which included the FACT-General (FACT-G) and Gastric Cancer subscale (GaCS). The FACT-G GP5 item assessed treatment-related symptom burden. Longitudinal changes in HRQoL were assessed using mixed models for repeated measures in the PRO analysis population (randomly assigned patients with baseline and ≥1 postbaseline assessments). Time to symptom or definitive deterioration analyses were also conducted. RESULTS: In the PRO analysis population (n = 1,360), PRO questionnaire completion rates were mostly >80% during treatment. Patient-reported symptom burden was not increased with nivolumab plus chemotherapy versus chemotherapy. Mean improved changes from baseline were greater with nivolumab plus chemotherapy versus chemotherapy for FACT-Ga total, GaCS, and EQ-5D visual analog scale in patients with a CPS of ≥5; results were similar for the overall PRO analysis population. In CPS ≥5 and all randomly assigned populations, nivolumab plus chemotherapy reduced the risk of symptom deterioration versus chemotherapy, on the basis of FACT-Ga total score and GaCS; time to definitive deterioration was longer, and the risk of definitive deterioration in HRQoL was reduced with nivolumab plus chemotherapy across EQ-5D and most FACT-Ga measures (hazard ratio [95% CI] <1). CONCLUSION: Compared with chemotherapy alone, first-line nivolumab plus chemotherapy showed stable or better on-treatment HRQoL in patients with advanced/metastatic non-HER2-positive GC/GEJC/EAC and also showed decreased risk of definitive HRQoL deterioration.