Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer.

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1-4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7-11. Treatment combining 1 mg kg-1 nivolumab with 3 mg kg-1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma.

Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.

APC/PIK3CA mutations and ß-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.

BACKGROUND: Aberrant WNT/ß-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, ß-catenin repressors. Tankyrase inhibitors block WNT/ß-catenin signaling and colorectal cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven ß-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor-resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity. METHODS: Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582. RESULTS: Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active ß-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor-resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a ß-catenin-independent manner. CONCLUSIONS: APC/PIK3CA mutations and ß-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

Intratumor transforming growth factor-ß signaling with extracellular matrix-related gene regulation marks chemotherapy-resistant gastric cancer.

Drug-tolerant persister (DTP) cells remain following chemotherapy and can cause cancer relapse. However, it is unclear when acquired resistance to chemotherapy emerges. Here, we compared the gene expression profiles of gastric cancer patient-derived cells (GC PDCs) and their respective xenograft tumors with different sensitivities to 5-fluorouracil (5-FU) by using immunodeficient female BALB/c-nu mice. RNA sequencing analysis of 5-FU-treated PDCs demonstrated that DNA replication/cell cycle-related genes were transiently induced in the earlier phase of DTP cell emergence, while extracellular matrix (ECM)-related genes were sustainably upregulated during long-term cell survival in 5-FU-resistant residual tumors. NicheNet analysis, which uncovers cell-cell signal interactions, indicated the transforming growth factor-ß (TGF-ß) pathway as the upstream regulator in response to 5-FU treatment. This induced ECM-related gene expression in the 5-FU-resistant tumor model. In the 5-FU-resistant residual tumors, there was a marked upregulation of cancer cell-derived TGF-ß1 expression and increased phosphorylation of SMAD3, a downstream regulator of the TGF-ß receptor. By contrast, these responses were not observed in a 5-FU-sensitive tumor model. We further found that TGF-ß-related upregulation of ECM genes was preferentially observed in non-responders to chemotherapy with 5-FU and/or oxaliplatin among 22 patient-derived xenograft tumors. These observations suggest that chemotherapy-induced activation of the TGF-ß1/SMAD3/ECM-related gene axis is a potential biomarker for the emergence of drug resistance in GCs.

Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair.

Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.

Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial.

BACKGROUND: We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC). METHODS: Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported. CONCLUSIONS: In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). CLINICAL TRIAL REGISTRATION: NCT03694522.

Bemarituzumab plus mFOLFOX6 as first-line treatment in East Asian patients with FGFR2b-overexpressing locally advanced or metastatic gastric/gastroesophageal junction cancer: subgroup of FIGHT final analysis.

BACKGROUND: In the FIGHT study (NCT03694522) bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 showed clinically meaningful efficacy in patients with FGFR2b-positive (2+/3+ membranous staining by immunohistochemistry) locally advanced unresectable/metastatic gastric/gastroesophageal cancer (G/GEJC). A meaningful proportion of patients in FIGHT were enrolled in East Asia, reflecting global epidemiology of G/GEJC. METHODS: This subgroup analysis of the global, phase 2, double-blind FIGHT study included all patients enrolled in East Asian sites. Patients were randomized 1:1 to bemarituzumab-mFOLFOX6 (15 mg/kg and one 7.5 mg/kg dose on cycle 1, day 8) or matching placebo-mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: The East Asian subgroup comprised 89 patients (57% of overall study population); 45 were randomized to bemarituzumab-mFOLFOX6 and 44 to placebo-mFOLFOX6. Median PFS (95% confidence interval [CI]) was 12.9 months (8.8-17.9) with bemarituzumab-mFOLFOX6 and 8.2 months (5.6-10.3) with placebo-mFOLFOX6 (HR 0.50, 95% CI 0.29-0.87); median OS (95% CI) was 24.7 months (13.8-33.1) vs 12.9 months (9.3-21.4), respectively (HR 0.56, 95% CI 0.32-0.96). Treatment benefit was more pronounced in patients with FGFR2b-positive G/GEJC in ≥ 10% of tumor cells. No new safety signals were reported. CONCLUSION: In East Asian patients with FGFR2b-positive advanced/metastatic G/GEJC enrolled in the global FIGHT study, bemarituzumab-mFOLFOX6 showed clinically meaningful outcomes over placebo-mFOLFOX6.

Cetuximab every 2 weeks versus standard weekly dosing administration schedule.

Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence.

Cetuximab is a drug for patients with colorectal cancer or cancer of the head and neck. It is usually administered once a week. However, studies have shown that cetuximab given once every 2 weeks instead has similar clinical benefits and side effects. Based on this evidence, the every 2 weeks dosing schedule has been approved for use in USA and Japan. The every 2 weeks dosing schedule is a convenient alternative to the weekly schedule. It may result in fewer hospital visits, improved patient quality of life, reduced healthcare costs and more flexibility for medical staff. This review summarizes the current evidence and benefits for the every 2 weeks dosing schedule.

Analysis of Adverse Events Associated with Trastuzumab Deruxtecan in Patients with Gastric and Breast Cancer: A Retrospective Study.

Trastuzumab deruxtecan (T-DXd) has displayed demonstrable efficacy and manageable toxicity in previously treated patients with advanced gastric and breast cancer, and it has been approved in Japan. However, there is a lack of data on the optimal management in clinical practice. Therefore, we assessed the adverse event (AE) profiles of T-DXd in patients with advanced gastric or breast cancer to provide guidance for appropriate management. This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We reviewed the medical records of patients with advanced gastric or breast cancer who received T-DXd between May 2020 and December 2021. AEs occurring within the first three cycles of T-DXd were evaluated according to Common Terminology Criteria for Adverse Events version 5.0. Thirty-six patients were enrolled (gastric: n = 19, breast: n = 17). All 15 males had gastric cancer, whereas 4 and 17 females had gastric and breast cancer, respectively. Interstitial lung disease (ILD) occurred in five patients (14%), but no patients had severe ILD. Gastrointestinal (GI) toxicities, including nausea (61%), vomiting (22%), decreased appetite (33%), and diarrhea (39%), were the most common AEs. The incidence of GI toxicities did not differ by cancer type; however, nausea was significantly more common in females (81 vs. 33%; p < 0.01). T-DXd was safely administered in clinical practice in patients with previously treated advanced gastric or breast cancer. The management of GI toxicities is important in the clinical implementation of T-DXd.

Clinical outcomes and prognostic factors of concurrent chemoradiotherapy for anal squamous cell carcinoma in Japan.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan. METHODS: Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45 Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC). RESULTS: This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact. CONCLUSIONS: The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.

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.

Exploratory analysis of serum HER2 extracellular domain for HER2 positive gastric cancer treated with SOX plus trastuzumab.

BACKGROUND: The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer. METHODS: sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes. RESULTS: 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1 ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7 months, p = 0.359. mOS: 35.5 vs 20.6 months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7 months, p = 0.095. mOS: 65.0 vs 17.8 months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively. CONCLUSIONS: Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer.

Clinical utility of the carcinoembryonic antigen level in patients with stage III colon cancer after surgery and adjuvant chemotherapy.

PURPOSE: The association between perioperative and post-adjuvant carcinoembryonic antigen (CEA) levels and recurrence and prognosis remains unclear. We aimed to evaluate whether perioperative CEA levels are an integral component of the assessment of recurrence and prognosis of patients with stage III colon cancer (CC). METHODS: This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2005 to 2013. We enrolled patients with stage III CC who underwent complete resection of a primary tumor and received adjuvant chemotherapy. We analyzed the association between perioperative and post-adjuvant CEA levels and recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 564 consecutive patients were included in the analysis. The RFS and OS of patients with high postoperative CEA levels were significantly worse than those of patients with normal postoperative CEA levels. In the multivariate analysis, high postoperative CEA levels were associated with shorter RFS and OS. The number of risk factors, postoperative CEA levels, and T/N-stage all had a cumulative effect on RFS and OS. CONCLUSIONS: High postoperative CEA levels and the number of risk factors are associated with recurrence and worse prognosis for patients with stage III CC.

Neoadjuvant chemotherapy for borderline resectable colorectal cancer liver metastases: a single-institution retrospective study.

INTRODUCTION: This study aimed to extract prognostic factors in patients undergoing neoadjuvant chemotherapy (NAC) for borderline resectable colorectal liver metastasis (BR-CRLM) (tumor size ≥5 cm, number of tumors ≥4, or resectable extrahepatic diseases) and assess validity of this strategy. MATERIALS AND METHODS: Since 2010, patients with BR-CRLM were treated with hepatectomy after six cycles of NAC. Prognostic factors of these patients were evaluated using clinicopathological data. RESULTS: Of 650 patients who underwent initial hepatectomy for CRLM from 2010 to 2018, 246 BR-CRLM cases underwent hepatectomy after NAC (BR-NAC). The 5-year recurrence-free survival rate was 16.7% and the 5-year overall survival rate (5y-OS) was 52.9%. Number of tumors ≥6, carcinoembryonic antigen (CEA) level ≥25 ng/mL, tumor diameter ≥5 cm, and progressive disease (PD) after NAC were identified as independent poor prognostic factors for OS. Patients were divided into four groups according to the number of risk factors, and prognoses of the four groups were well stratified. CONCLUSION: In patients with BR-NAC, number of tumors ≥6, CEA ≥25 ng/mL, tumor diameter ≥5 cm, and PD after NAC were independent poor prognostic factors. Patients with three or four risk factors showed poor prognosis and may need to switch chemotherapy.

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer. METHODS: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety. RESULTS: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group. CONCLUSIONS: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Prognostic Impact of Tumor Markers (CEA and CA19-9) on Patients with Resectable Colorectal Liver Metastases Stratified by Tumor Number and Size: Potentially Valuable Biologic Markers for Preoperative Treatment.

BACKGROUND: Although patients with resectable colorectal liver metastasis (CLM), a population with good prognosis, have been treated with upfront surgery, some patients have had a poor prognosis. This study aimed to investigate biologic prognostic factors in patients with resectable CLMs. METHODS: This single-center retrospective study enrolled consecutive patients who underwent liver resection for initial CLMs at the Cancer Institute Hospital between 2010 and 2020. The study defined CLMs as resectable (tumor size < 5 cm; < 4 tumors; no extrahepatic metastasis) or borderline resectable (BR). Preoperative chemotherapy was administered to patients with BR CLMs. RESULTS: During the study period, 309 CLMs were classified as resectable without preoperative chemotherapy and 345 as BR with preoperative chemotherapy. For the 309 patients with resectable CLMs, the independent poor prognostic factors associated with overall survival in the multivariable analysis were high tumor marker levels (CEA ≥ 25 ng/mL and/or CA19-9 ≥ 50 U/mL; (hazard ratio [HR], 2.45; p = 0.0007), no adjuvant chemotherapy (HR, 1.69; p = 0.043), and age of 75 years or older (HR, 2.09; p = 0.012). The 5-year survival rates for the patients with high tumor marker (TM) levels (CEA ≥25 ng/mL and/or CA19-9 ≥50 U/mL) were significantly worse than for those with low TM levels (CEA < 25 ng/mL and CA19-9 < 50 U/mL) (55.3% vs. 81.1%; p <0.0001) and similar to the rate for those with BR CLMs (52.1%; p = 0.864). Postoperative adjuvant chemotherapy had an impact on prognosis only in the high-TM group (HR, 2.65; p = 0.007). CONCLUSIONS: High TM levels have a prognostic impact on patients with resectable CLMs stratified by tumor number and size. Perioperative chemotherapy improves long-term outcomes for patients with CLM and high TM levels.

Adding Induction Chemotherapy Before Chemoradiotherapy with Total Mesorectal Excision and Selective Lateral Lymph Node Dissection for Patients with Poor-Risk, Locally Advanced, Mid-to-Low Rectal Cancer May Improve Oncologic Outcomes: A Propensity Score-Matched Analysis.

BACKGROUND: This study aimed to investigate whether the addition of induction chemotherapy before chemoradiotherapy (CRT) and total mesorectal excision (TME) with selective lateral lymph node dissection improves disease-free survival for patients with poor-risk, mid-to-low rectal cancer. METHODS: The authors' institutional prospective database was queried for consecutive patients with clinical stage II or III, primary, poor-risk, mid-to-low rectal cancer who received neoadjuvant treatment followed by TME from 2004 to 2019. The outcomes for the patients who received induction chemotherapy before neoadjuvant CRT (induction-CRT group) were compared (via log-rank tests) with those for a propensity score-matched cohort of patients who received neoadjuvant CRT without induction chemotherapy (CRT group). RESULTS: From 715 eligible patients, the study selected two matched cohorts with 130 patients each. The median follow-up duration was 5.4 years for the CRT group and 4.1 years for the induction-CRT group. The induction-CRT group had significantly higher rates of 3-year disease-free survival (83.5 % vs 71.4 %; p = 0.015), distant metastasis-free survival (84.3 % vs 75.2 %; p = 0.049), and local recurrence-free survival (98.4 % vs 94.4 %; p = 0.048) than the CRT group. The pathologically complete response rate also was higher in the induction-CRT group than in the CRT group (26.2 % vs 10.0 %; p < 0.001). Postoperative major complications (Clavien-Dindo classification ≥III) did not differ significantly between the two groups (12.3 % vs 10.8 %; p = 0.698). CONCLUSIONS: The addition of induction chemotherapy to neoadjuvant CRT appeared to improve oncologic outcomes significantly, including disease-free survival, for the patients with poor-risk, mid-to-low rectal cancer who underwent TME using selective lateral lymph node dissection.

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors.

BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Efficacy of aluminum chloride in severe regorafenib-associated hand-foot skin reactions: a single-arm trial.

BACKGROUND: Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib. METHODS: The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride. RESULTS: In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed. CONCLUSIONS: Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR. TRAIL REGISTRATION: ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.

Incidence and risk factors for venous thromboembolism in the Cancer-VTE Registry stomach cancer subcohort.

BACKGROUND: The Cancer-VTE Registry was a large-scale, multicenter, prospective registry designed to investigate real-world data on venous thromboembolism (VTE) incidence and risk factors in adult Japanese patients with solid tumors. This pre-specified subgroup analysis aimed to estimate the incidence of VTE, including VTE types other than symptomatic VTE, and identify risk factors of VTE in stomach cancer from the Cancer-VTE Registry. METHODS: Stage II-IV stomach cancer patients who planned to initiate cancer therapy and underwent VTE screening within 2 months before registration were enrolled. RESULTS: Of 1,896 patients enrolled, 131 (6.9%) had VTE at baseline, but 96.2% were asymptomatic. Female sex, age ≥ 65 years, VTE history, and D-dimer > 1.2 µg/mL were independent risk factors of VTE at baseline. Notably, patients with D-dimer > 1.2 µg/mL at the time of cancer diagnosis had an approximately 20-fold risk of VTE. During follow-up, event incidences were symptomatic VTE, 0.3%; incidental VTE requiring treatment, 1.1%; composite VTE, 1.4%; bleeding, 1.6%; cerebral infarction/transient ischemic attack/systemic embolic events, 0.7%; and all-cause death, 15.0%. The incidence of all-cause death was higher in patients with VTE vs without VTE at baseline (adjusted hazard ratio 1.67; 95% confidence interval 1.21-2.32; p = 0.002). CONCLUSIONS: VTE prevalence at the time of cancer diagnosis was not negligible and was extremely high when the patients had high D-dimer. VTE screening by D-dimer before starting cancer treatment is advisable, even for asymptomatic patients, regardless of whether the patient is undergoing surgery or chemotherapy. TRIAL REGISTRATION: UMIN000024942.