Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2+) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2+ gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

SMARCA4-deficient undifferentiated gastric carcinoma: a case series and literature review.

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4. We herein report six cases of SMARCA4-deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities.

Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair.

BACKGROUND: We aimed to investigate clinicopathologic factors leading to different clinical outcomes in patients with deficient mismatch repair protein (d-MMR) gastric cancer (GC) treated with nivolumab plus chemotherapy (nivolumab chemotherapy). METHODS: This retrospective study included 28 patients with d-MMR advanced GC treated with first-line nivolumab chemotherapy. As a control group, 68 treated with first-line chemotherapy alone were included. Clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and PD-L1 combined positive score (CPS), were analyzed with regards to the efficacy outcomes. RESULTS: Progression-free survival (PFS) was longer (median PFS; not reached [NR] vs. 5.2 months, hazard ratio [HR] 0.28, P < 0.001), and overall survival (OS) tended to be longer (median OS; NR vs. 17.9 months, HR 0.43, P = 0.057) in patients treated with nivolumab chemotherapy than those treated with chemotherapy. The PFS benefit of nivolumab chemotherapy over chemotherapy was pronounced in the subgroup with a lower NLR (< 3.80 [median NLR]) (HR 0.10), whereas it was less prominent in patients with a high NLR (≥ 3.80) (HR 0.58). Among patients treated with nivolumab chemotherapy, PFS was worse in patients with a higher NLR (≥ 3.80) than in those with a lower NLR (< 3.80), and survival outcomes were similar between those with PD-L1 CPS ≥ 5 and < 5. CONCLUSION: Nivolumab chemotherapy was associated with better efficacy outcomes than chemotherapy alone among patients with d-MMR GC, but survival outcomes were poor even with nivolumab chemotherapy for those with a high NLR. Survival outcomes were not different according to PD-L1 CPS among d-MMR patients treated with nivolumab chemotherapy.

Discordant PD-L1 results between 28-8 and 22C3 assays are associated with outcomes of gastric cancer patients treated with nivolumab plus chemotherapy.

BACKGROUND: We evaluated the concordance/discordance of PD-L1 staining results between the 28-8 and 22C3 assays and its impact on the efficacy outcomes of advanced gastric cancer patients treated with nivolumab plus chemotherapy. METHODS: This retrospective study involved 143 gastric cancer patients treated with first-line nivolumab plus chemotherapy whose PD-L1 results with both 28-8 and 22C3 assays were available. The concordance/discordance between these assays and the inter-observer variability were evaluated for PD-L1 combined positive score (CPS) positivity. Discordant PD-L1 results were analyzed regarding survival outcomes. RESULTS: The agreement rates and Cohen's kappa values between the 28-8 and 22C3 assays were 78.3% and 0.56 (for CPS ≥ 1), 81.8% and 0.60 (for CPS ≥ 5), and 88.8% and 0.66 (for CPS ≥ 10), respectively. Inter-observer variability, as represented by the intra-class correlation coefficient, was 0.89 and 0.88 for the 28-8 and 22C3 assays, respectively. With PD-L1 CPS ≥ 5 defined as positive, 35 (24.5%) and 82 (57.3%) had concordantly positive and negative results, respectively, between the 28-8 and 22C3 assays, whereas 26 (18.2%) had discordant results. Progression-free survival was shorter for those who exhibited negatively concordant PD-L1 results and discordant PD-L1 positivity between the 28-8 and 22C3 assays relative to those with positively concordant PD-L1 results (P = 0.013). CONCLUSION: PD-L1 assays by 28-8 and 22C3 showed suboptimal concordance, while inter-observer variability was not critical in advanced gastric cancer. Discordant PD-L1 results between 28-8 and 22C3 assays may be associated with unfavorable efficacy outcomes in patients treated with nivolumab plus chemotherapy.

Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 plus Imatinib for Advanced Treatment-refractory Gastrointestinal Stromal Tumors.

PURPOSE: In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD-1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Advanced GIST patients whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3+3 dose escalation scheme was applied. PDR001 400 mg intravenously every 4 weeks plus imatinib (300 mg and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate (DCR) at 12 weeks. Exploratory biomarker analysis was performed based on PD-L1 immunohistochemistry, next-generation sequencing, and multiplexed immunohistochemistry. RESULTS: No dose-limiting toxicity was observed in the phase Ib part (n=10), and dose level 2 was selected as the recommended phase II dose. In the phase II part (n=29), there was no objective response and the DCR at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n=36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3-4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T cell density was associated with a favorable PFS, but to a limited degree. Tumor mutation burden and PD-L1 were not associated with better PFS. CONCLUSION: In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum for metastatic, recurrent, or unresectable gastric cancer.

BACKGROUND: We examined the impact of mismatch repair (MMR) status on efficacy of first-line fluoropyrimidine plus platinum (FP) chemotherapy in patients with HER2-negative metastatic, recurrent, or unresectable gastric cancer (mGC). METHODS: Patients with mGC receiving first-line FP between 2015 and 2018 at Asan Medical Center, Korea, were reviewed. We evaluated the clinical characteristics and the efficacy of chemotherapy according to MMR status in patients with available immunohistochemistry results. RESULTS: Of 895 patients, we analyzed 543 with available MMR protein expression results, and deficient MMR (dMMR) was detected in 4.4% (n = 24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p = 0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR. Objective response rate was 27.3% in dMMR and 34.3% in pMMR (p = 0.556). No difference in progression-free survival was noted between patients with dMMR and pMMR (median, 5.6 vs. 5.8 months, p = 0.266). Patients with dMMR tended to have better overall survival than those with pMMR although this difference was not statistically significant (median, 17.9 vs. 12.2 months, p = 0.183). CONCLUSIONS: Efficacy of first-line FP was not different by MMR status in mGC patients.

Adjuvant treatment for locally advanced gastric cancer: an Asian perspective.

Standard adjuvant treatment for locally advanced gastric cancer (LAGC) is regionally different. Whereas perioperative chemotherapy is the standard in Western populations, D2 gastrectomy followed by adjuvant chemotherapy has been the standard in East Asia. Recently, the pivotal phase 3 PRODIGY and RESOLVE studies have demonstrated survival benefits of adding neoadjuvant chemotherapy to surgery followed by adjuvant chemotherapy over up-front surgery followed by adjuvant chemotherapy in Asian patients. Based on these results, neoadjuvant chemotherapy is considered one of the viable options for patients with LAGC. In this review, various aspects of neoadjuvant chemotherapy will be discussed for its optimal application in Asia. Candidates for neoadjuvant chemotherapy should be carefully chosen in consideration of the inaccurate aspects of radiological clinical staging and its potential benefit over up-front surgery followed by a decision on adjuvant chemotherapy according to the pathological stage. Efforts should continuously be made to optimally apply neoadjuvant chemotherapy to patients with LAGC, considering various factors, including a more accurate radiological assessment of the tumor burden and the optimization of post-operative chemotherapy. Future neoadjuvant trials involving novel agents for Asian patients should be designed based on proven Asian regimens rather than adopting Western regimens.

Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFß) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors.

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGFß) monoclonal antibody, inhibits all TGFß isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFß, downregulation of TGFß-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from 'immune-excluded' to 'immune-infiltrated' phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFß1 was more consistently elevated followed by TGFß2, whereas TGFß3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFß alteration. However, further studies are needed to identify biomarkers of response.

Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial.

Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib-nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67+ proliferating CD8+ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib-nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709 .

Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable hepatocellular carcinoma (HCC), but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. We aimed to investigate the organ-specific response patterns among unresectable HCC patients treated with first-line atezolizumab-bevacizumab or lenvatinib. METHODS: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intraabdomen based on a radiological evaluation adopted from RECIST v 1.1. RESULTS: The median age was 60 years. Hepatitis B infection was the most common etiology (n = 270, 69.9%), and 291 (75.4%) patients had a viral etiology. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was overall higher in the atezolizumab-bevacizumab group than that in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9% and 33.3% vs. 15.0% for intrahepatic, lung, LN, and intraabdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6%, and 36.0% vs. 12.5%, respectively. CONCLUSION: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.

Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial.

BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.

Phase 1/2a Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, in Patients with Advanced Solid Tumors.

Purpose: To report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. Materials and Methods: In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of MTD determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. Results: A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥3 adverse events (AEs) were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The overall response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in 2 out of 6 patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. Conclusion: The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile. (NCT01497704 and NCT02711969).

GASTric Cancer HER2 Re-Assessment Study 2 (GASTHER2): HER2 Re-assessment for Initially HER2-Negative Advanced Gastric Cancer Patients after Progression on First-Line Treatment.

PURPOSE: Heterogeneous human epidermal growth factor receptor 2 (HER2) overexpression in gastric cancer may lead to a misdiagnosis of HER2 status. Accurate assessment of HER2 status is essential for optimal treatment as novel HER2-directed agents are being investigated in various clinical settings. We evaluated the usefulness of HER2 re-assessment following progression on first-line treatment in initially HER2-negative advanced gastric cancer (AGC) patients. MATERIALS AND METHODS: We enrolled 177 patients with baseline HER2-negative AGC and performed HER2 re-assessment after progression on first-line treatment from February 2012 to June 2016 at Asan Medical Center, Seoul, Korea. The re-assessed HER2 status was analyzed with baseline HER2 status and clinical characteristics. RESULTS: The median age was 54 years (range, 24 to 80 years), and 123 patients (69.5%) were men. Seven patients (4.0%) were HER2-positive on the re-assessment. Patients with baseline HER2 negativity confirmed by a single test (n=100) had a higher HER2-positive re-assessment rate compared to those who had repeated baseline testing (n=77) (5.0% vs. 2.6%). Among the patients with single baseline HER2 testing, the rate was higher in patients with baseline HER2 immunohistochemistry (IHC) 1+ compared to those with IHC 0 (13.4% vs. 3.6%). CONCLUSION: Overall, 4.0% of patients with baseline HER2-negative AGC were HER2-positive on re-assessment, and the HER2-positive re-assessment rate was higher among patients who had a single test at baseline. HER2 re assessment may be considered for initially HER2-negative patients to determine their eligibility for HER2-directed therapy, particularly if their HER2 negativity was determined by a single test, especially if they had a single baseline HER2 IHC 1+ test.

DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial.

BACKGROUND: The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. The PRODIGY trial showed the survival benefit of adding preoperative docetaxel, oxaliplatin, and S-1 (DOS) to surgery plus postoperative S-1 for LAGC patients. In this sub-analysis, we evaluated the benefit of preoperative DOS according to MMR status. METHODS: Among patients enrolled in the PRODIGY trial treated with either preoperative DOS followed by surgery and postoperative S-1 (CSC arm), or surgery and postoperative S-1 (SC arm) at Asan Medical Center (n = 249), those in the full analysis set with available tissue to assess MMR status were included in the present analysis. RESULTS: A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included (median age, 58 years [range, 27-75]), and 21 patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had D-MMR tumors. Progression-free survival and overall survival tended to be superior in the CSC arm than in the SC arm among D-MMR patients (HR 0.48 [95% CI 0.09-2.50]; log-rank P = 0.37 and HR 0.55 [95% CI 0.11-2.86]; log-rank P = 0.46, respectively), as well as among proficient MMR (P-MMR) patients (HR 0.68 [95% CI 0.46-1.03]; log-rank P = 0.07 and HR 0.75 [95% CI 0.49-1.14]; log-rank P = 0.17, respectively). CONCLUSION: Preoperative DOS followed by surgery and postoperative S-1 may be considered a treatment option for LAGC patients regardless of MMR status.

Clinical outcomes of Epstein-Barr virus (EBV)-associated metastatic and locally advanced unresectable gastric cancers (GCs) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy.

BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) is a distinct molecular subgroup showing excellent outcomes after surgery for localized disease. Prominent immune cell infiltration in EBVaGC reflects the immunogenicity of Epstein-Barr virus (EBV) and, as suggested by some investigators, responsiveness to immune checkpoint inhibitors in the palliative setting. However, few data are available on the prevalence, clinical characteristics, and prognosis of EBVaGC patients receiving palliative cytotoxic chemotherapy. METHODS: In this retrospective study, we identified 1061 patients with metastatic, recurrent, or locally advanced unresectable gastric cancer (GC) who started first-line fluoropyrimidine/platinum (FP) doublet chemotherapy with or without trastuzumab from January 2015 to August 2018. For 766 patients with available tumor tissue, the presence of EBV in cancer cells was evaluated by EBV-encoded RNA in situ hybridization and correlated with clinical characteristics and treatment outcomes. RESULTS: Among the patients evaluated (n = 766), 40 (5.0%) were EBV-positive. EBVaGC was associated with male sex (p = 0.009) and lower neutrophil-lymphocyte ratio (NLR < 2.46, p = 0.03). Efficacy of first-line FP chemotherapy, in terms of response rate ad progression-free survival (PFS), did not differ between EBVaGC and EBV-negative GC (overall response rate: 53.8% vs. 51.8%, p = 0.99; median PFS: 6.4 vs. 6.7 months, p = 0.90). However, overall survival tended to be better with EBVaGC than EBV-negative GC (16.4 vs. 14.0 months, p = 0.07). CONCLUSIONS: EBVaGC accounted for 5% of metastatic/unresectable GCs. While EBVaGC was not associated with better response to or PFS following first-line cytotoxic chemotherapy, it showed a trend toward better overall survival.

Clinicopathologic features and prognostic value of claudin 18.2 overexpression in patients with resectable gastric cancer.

Claudin 18.2 has emerged as a promising therapeutic target in gastric cancer based on phase 3 studies. However, clinicopathologic features associated with claudin 18.2 overexpression have not been comprehensively studied specifically for patients with resectable gastric cancer. This retrospective study included 299 patients with stage I-III resectable gastric cancer who underwent curative surgical resection. Possible associations between claudin 18.2 overexpression (moderate-to-strong expression in ≥ 75% by the 43-14A clone) and clinicopathologic features and survival outcomes were analyzed. There were 90 (30.1%), 96 (32.1%), and 113 (37.8%) patients with stage I, II, and III disease, respectively. Claudin 18.2 overexpression was noted in 139 out of 299 patients (46.5%). Claudin 18.2 overexpression was associated with a younger age, a lower invasion depth limited to the mucosa/submucosa, and less frequent lymphovascular invasion. Claudin 18.2 overexpression was also associated with Borrmann type 4 among patients with advanced gastric cancer and the diffuse histological type. Claudin 18.2 overexpression was not an independent factor for survival outcomes. In conclusion, claudin 18.2 was overexpressed in almost half of resectable gastric cancer patients. Claudin 18.2 overexpression was associated with some clinicopathological characteristics, but was not an independent prognostic factor in a localized setting.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial.

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/m2 per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m2) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m2) 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.

Tusamitamab Ravtansine in Patients with Advanced Solid Tumors: Phase I Study of Safety, Pharmacokinetics, and Antitumor Activity Using Alternative Dosing Regimens.

Purpose: Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m2 every 2 weeks (Q2W). Here we report results for two alternative schedules. Experimental Design: Adults ages ≥18 years (range, 34-73) with locally advanced/metastatic solid tumors (N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m2 [loading dose (LD)], then 100 mg/m2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W). Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W. Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m2 (LD) followed by 100 mg/m2 Q2W, and 170 mg/m2 Q3W as a fixed dose. (NCT02187848). Significance: The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer.