Platinum Combination Chemotherapy Research Articles

Advances in the treatment of gastroenteropancreatic poorly differentiated neuroendocrine carcinoma at our hospital.

595 Background: Overall survival after first-line chemotherapy for metastatic or recurrent gastroenteropancreatic poorly differentiated neuroendocrine carcinoma (GEP-NEC) is reported to be less than 1 year. Platinum drugs in combination with etoposide or irinotecan have been used as first-line chemotherapy for GEP-NEC patients, but no standard treatment has been established for second-line and subsequent chemotherapy. Recently, however, we have seen patients with a good prognosis after treatment based on comprehensive cancer genomic profiling (CGP). We retrospectively reviewed GEP-NEC patients treated with chemotherapy. Methods: Patient background, treatment regimen, overall survival, and toxicity were evaluated in 20 GEP-NEC patients who started first-line platinum combination chemotherapy at our hospital between October 2016 and September 2022. Results: Median age was 71 (48 to 81) years, 16 were male, and primary sites were esophagus in 2 patients, stomach in 7 patients, small intestine in 2 patients, large intestine in 6 patients, and pancreas in 3 patients. Five patients had an adenocarcinoma component. Stage III, IV, and recurrence were observed in 2, 16, and 2 patients, respectively. Progression-free survival and overall survival after first-line chemotherapy were 4.0 (2.3 to 7.0) and 8.1 (4.7 to 17.0) months, respectively. Grade 3 or higher toxicity was observed in 13 patients. No differences in overall survival were observed in chemotherapy regimen including etoposide or irinotecan and cisplatin or carboplatin. Patients who underwent CGP had significantly longer survival. After second-line chemotherapy, a regimen containing irinotecan, 5-FU, paclitaxel, ramucirumab, and nivolumab was used, and overall survival was 5.2 (1.8 to NA) months. There were 4 of 20 patients who survived for more than 1000 days after first-line chemotherapy. Durable responses were observed in colonic NEC patients harboring the POLE P286R mutation treated with nivolumab and in those harboring the BRAF V600E mutation treated with cetuximab and encorafenib. Conclusions: Overall survival of GEP-NEC patients treated with platinum combination chemotherapy was very poor at only 8 months. However, in some cases, long-term survival has been achieved with molecular targeted therapy based on CGP results.

Genomic profile and clinical feature of esophageal squamous cell carcinoma, focusing on MSI, TMB, and HRD status: Analysis with the national database of Japan.

412 Background: In Japan, cancer genome profiling (CGP) testing has been widely used from 2019, and genomic and clinical information integrated into national database (C-CAT database) is now available for secondary use for innovative research. In esophageal squamous cell carcinoma (ESCC), more than 500 patients (as of December 2022) have already undergone CGP testing. MSI-H and TMB-H ESCC are rare, and information is lacking. Using C-CAT data base, we analyzed the clinical and genomic characteristics of ESCC, especially focusing on MSI, TMB, and HRD status. Methods: We retrospectively reviewed data on 535 cases with ESCC enrolled in C-CAT between June 2019 and December 2022. The clinical features, genomic variants classified as oncogenic/pathogenic, MSI/TMB status and response to treatment (response rate; RR and time to treatment failure; TTF) were evaluated. Results: Oncogenic/pathogenic variants were detected in 527 cases (98%), and the Top 5 gene mutations were TP53 (94.6%), CDKN2A (56.6%), CDKN2B (43.7%), CCND1 (42.6%), and FGF19 (38.9%), in order of prevalence. No patient had MSI-H, and number of patients with TMB-H (≥10 Muts/Mb) and HRD were 82 (15%) and 15 (13%), respectively. Regarding the efficacy of first-line chemotherapy (IO-containing regimen in 5 cases, 0.9 %), the TTF was significantly shorter in TMB-H cases than in TMB-L cases (11.8 vs 17.5 weeks, p=0.006). No difference in response to anti-PD-1 antibody was observed depending on TMB status (RR, TMB-L 19 % vs. TMB-H 12 %). Patients with BRCA1/2 mutations tended to respond better to first-line chemotherapy including platinum drugs, although there was no difference in response to treatment with or without other HRR mutations. The percentages of cases delivered new treatments based on CGP testing was 6.8%. The percentage of cases with HRD or TMB-H suggested new treatment based on GCP testing was significantly higher than those without them. Conclusions: Patients with BRCA1/2 mutations are more sensitive to platinum combination chemotherapy and may be good candidates for PARP inhibitors in ESCC. Since TMB-H patients are resistant to standard chemotherapies, we should promote the development of immunotherapy and molecular-based targeted therapies for this population.

Thrombotic risk of platinum combination chemotherapy with and without immune checkpoint inhibitors for advanced non-small cell lung cancer: a nationwide inpatient database study

ObjectivesTo determine the associated thromboembolism risk with adding immune checkpoint inhibitors (ICI) to platinum combination chemotherapy compared with platinum combination chemotherapy alone in patients with advanced non-small cell lung cancer.Materials and methodsThis study identified 75,807 patients with advanced non-small cell lung cancer from the Japanese Diagnosis Procedure Combination database who started platinum combination chemotherapy between July 2010 and March 2021. The incidence of venous thromboembolism (VTE), arterial thromboembolism (ATE), and all-cause mortality within 6 months after commencing platinum combination chemotherapy was compared between patients receiving chemotherapy with ICI (ICI group, n = 7,177) and without ICI (non-ICI group, n = 37,903). Survival time analysis was performed using the overlap weighting method with propensity scores to adjust for background factors. The subdistribution hazard ratio for developing thromboembolism was calculated using the Fine-Gray model with death as a competing risk. The hazard ratio for all-cause mortality was also calculated using the Cox proportional hazards model.ResultsOverall, VTE and ATE occurred in 761 (1.0%) and 389 (0.51%) patients, respectively; mortality was 11.7%. Propensity score overlap weighting demonstrated that the subdistribution hazard ratio (95% confidence interval) for VTE and ATE in the ICI group was 1.27 (1.01–1.60) and 0.96 (0.67–1.36), respectively, compared with the non-ICI group. The mortality hazard ratio in the ICI group was 0.68 (0.62–0.74).ConclusionThe addition of ICI to platinum combination therapy was associated with a higher risk of VTE compared with platinum combination therapy alone, while the risk of ATE might be comparable.

ENGOT-EN20/GOG-3083/xport-EC-042: A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with P53 wild-type, advanced or recurrent endometrial carcinoma.

TPS5627 Background: Patients (pts) with first-line metastatic or recurrent endometrial cancer (EC) have a poor prognosis. Selinexor is an oral XPO1 inhibitor, which leads to nuclear accumulation of tumor suppressor proteins, including p53. Selinexor is FDA-approved for use in multiple myeloma and diffuse large B-cell lymphoma, and has shown clinical activity in previously treated, advanced EC. Molecular characterization of EC is critical in directing treatment for advanced and recurrent disease. Of the EC molecular subtypes, TP53 wild type (wt) tumors represent 50% of advanced and recurrent tumors. A recent phase 3 study in maintenance after chemotherapy found that, despite the primary endpoint (PFS) not reaching statistical significance, prolonged PFS of oral once-weekly selinexor versus placebo (13.7 months and 3.7 months, respectively) was observed in a prespecified exploratory subgroup analysis of patients with advanced or recurrent TP53wt EC. Methods: XPORT-EC-042 (NCT05611931) is a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of selinexor as maintenance therapy in pts with TP53wt advanced or recurrent EC, who have achieved a partial response or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completing at least 12 weeks of platinum combination chemotherapy ±immunotherapy for primary stage IV or recurrent disease. Eligible pts must be ≥18 years of age, have histologically confirmed EC, and TP53 wt disease based on NGS sequencing assessed by Foundation Medicine. Pts will be randomized 1:1 with either selinexor 60 mg or placebo once weekly in 28-day cycles until progressive disease, toxicity, or 3 years if in complete response. A total of 220 pts will be enrolled at sites across the United States, Canada, Europe, and Israel. The primary objective is to compare PFS in pts treated with selinexor compared to placebo based on RECIST v1.1 criteria as assessed by the Investigator. Key secondary objective is overall survival. Other secondary objectives are safety, time to first subsequent therapy, time to second subsequent therapy, time from randomization until the second progression event (PFS2), and PFS by a blinded independent central review. Patient enrollment is ongoing. Clinical trial information: NCT05611931 .

S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma–final results of the randomized AIO MATEO phase II trial

Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints. From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P= 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P= 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%). S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

HF01-17 MOBILIZE THE TROOPS! MILITARY INVOLVEMENT IN THE HISTORY OF TESTICULAR CANCER

You have accessJournal of UrologyCME1 Apr 2023HF01-17 MOBILIZE THE TROOPS! MILITARY INVOLVEMENT IN THE HISTORY OF TESTICULAR CANCER Kit Yuen, Alexis Steinmetz, Phillip Rappold, and Ronald Rabinowitz Kit YuenKit Yuen More articles by this author , Alexis SteinmetzAlexis Steinmetz More articles by this author , Phillip RappoldPhillip Rappold More articles by this author , and Ronald RabinowitzRonald Rabinowitz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003243.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testicular cancer is a rare malignancy that has become a manageable disease, assisted by the study of the large number of such tumors found in World War II (WWII) soldiers. METHODS: A literature review of textbook chapters, manuscripts, online texts, and peer-reviewed articles was performed for historical descriptions of testis tumors and its treatments. RESULTS: Saint Donat in 1696 described a testis teratoid tumor as a “fetal monstrosity”. Testicular tumor pathology was first documented by British physicians Percival Pott and Astley Cooper in the mid to late 1700s. In 1794, Scottish surgeon Benjamin Bell described the presentation of a testis tumor as a firm painless fleshy enlargement. If treatment with mercury failed, orchiectomy was done. It wasn’t until 1910 that French urologist Maurice Chevassu reported radical orchiectomy. Diagnosis, staging, and evaluation of response to therapy was propelled forward with the discovery of tumor marker human chorionic gonadotropin in 1927. Radiation was introduced to treat testicular cancer in the 1940s. Testis cancer, a tumor of young men, was found in high frequency in the military. Prior to WWII, case series of more than 50 subjects were rare. From examining more than 900 soldiers with testis tumors, the histopathology was established in 1946. In 1950, two large military studies reported that RPLND improved survival compared to orchiectomy alone. In 1952, a modified classification system was published by Frank Dixon and Robert Moore in the first Armed Forces Institute of Pathology (AFIP) tumor atlas. Fathollah Mostofi, along with other military pathologists, contributed greatly to the field; in 1972 he led a group to devise a standardized World Health Organization (WHO) classification system. Until the advent of platinum combination chemotherapy, metastatic disease was bleak and uniformly fatal, with a 90% mortality rate within 1 year. Chemosensitivity was first demonstrated in the 1950s with actinomycin combined with methotrexate. In 1974, a regimen of cisplatin, vinblastine with bleomycin was introduced by Lawrence Einhorn and John Donahue at Indiana University for advanced testicular cancer with greatly improved survival. RPLND templates were further refined with lymph node mapping studies, which decreased morbidity significantly. CONCLUSIONS: World War II brought together young men with testis cancer, a rare disease that ignited fifty years of basic and clinical research resulting in one of the greatest oncological success stories. The military contributed greatly to the diagnosis, histopathology and management of testicular cancer. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e261 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kit Yuen More articles by this author Alexis Steinmetz More articles by this author Phillip Rappold More articles by this author Ronald Rabinowitz More articles by this author Expand All Advertisement PDF downloadLoading ...

Indoxyl Sulfate Promotes Metastatic Characteristics of Ovarian Cancer Cells via Aryl Hydrocarbon Receptor–Mediated Downregulation of the Mas Receptor

Although platinum-combination chemotherapy shows a high response rate at the primary site, epithelial ovarian cancer (EOC) treatment remains challenging because of tumor recurrence and metastasis. Recent studies have revealed that chemotherapy paradoxically promotes cancer cell survival, proliferation, and metastasis, although the reason for this remains unclear. The underlying molecular mechanisms that contribute to chemotherapy-induced metastasis need to be elucidated to establish effective therapeutic strategies. Acute kidney injury is a known side effect of cisplatin treatment, and kidney dysfunction results in the accumulation of uremic toxins in the serum. The present study aimed to investigate whether indoxyl sulfate (IS), a representative uremic toxin, affects the pathophysiology of EOC. In this study, IS reduced the expression of Mas receptor (MasR) in cultured human EOC cells. Both knockdown of the aryl hydrocarbon receptor (AhR), which is an intracellular IS receptor, and inhibition of AhR function suppressed IS-mediated downregulation of MasR in SK-OV-3 cells. IS induced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an AhR-dependent manner. Inhibition of the STAT3 pathway or reactive oxygen species production suppressed the IS-mediated reduction of MasR. IS stimulated cell migration and invasion of SK-OV-3 cells in an AhR-dependent manner. Cisplatin-nephropathy model mice exhibited elevated levels of serum IS accompanied by elevated levels of blood urea nitrogen and serum creatinine. Furthermore, intraperitoneal administration of IS in mice promoted tumor growth and metastasis. Finally, we found that the MasR agonist Ang-(1-7) suppressed the IS-mediated effects on cell proliferation, migration, and invasion of SK-OV-3 cells. However, the knockdown of MasR expression by specific small interfering RNA in the absence of IS resulted in only minimal promotion of cell migration and invasion. These findings demonstrate that IS promotes malignancy in ovarian cancer via AhR-mediated downregulation of MasR function, whereas Ang-(1-7) attenuates this effect, thereby suggesting that Ang-(1-7) could provide a future treatment strategy for this cancer type.

Perspectives on the future of urothelial carcinoma therapy: chemotherapy and beyond

ABSTRACT Introduction Despite recent developments in the landscape of urothelial carcinoma (UC) treatment, platinum combination chemotherapy still remains a milestone. Recently immunotherapeutic agents have gained ever-growing attractivity, particularly in the metastatic setting. Novel chemotherapeutic strategies and agents, such as antibody-drug conjugates (ADCs), and powerful combination regimens have been developed to overcome the resistance of most UC to current therapies. Areas covered Herein, we review the current standard-of-care chemotherapy, the development of ADCs, the rationale for combining therapy regimens with chemotherapy in current trials, and future directions in UC management. Expert opinion Immunotherapy has prompted a revolution in the treatment paradigm of UC. However, only a few patients experience a long-term response when treated with single-agent immunotherapies. Combination treatments are necessary to bypass resistance mechanisms and broaden the clinical utility of current options. Current evidence supports the intensification of standard-of-care chemotherapy with maintenance immunotherapy. However, the optimal sequence, combination, and duration must be determined to achieve individual longevity with acceptable health-related quality of life. In that regard, ADCs appear as a promising alternative for single and combination strategies in UC, as they specifically target the tumor cells, thereby, theoretically improving treatment efficacy and avoiding extensive off-target toxicities.

Upregulation of the Long Noncoding RNA CASC10 Promotes Cisplatin Resistance in High-Grade Serous Ovarian Cancer.

Despite initial responses to first-line treatment with platinum and taxane-based combination chemotherapy, most high-grade serous ovarian carcinoma (HGSOC) patients will relapse and eventually develop a cisplatin-resistant fatal disease. Due to the lethality of this disease, there is an urgent need to develop improved targeted therapies against HGSOC. Herein, we identified CASC10, a long noncoding RNA upregulated in cisplatin-resistant ovarian cancer cells and ovarian cancer patients. We performed RNA sequencing (RNA-seq) in total RNA isolated from the HGSOC cell lines OVCAR3 and OV-90 and their cisplatin-resistant counterparts. Thousands of RNA transcripts were differentially abundant in cisplatin-sensitive vs. cisplatin-resistant HGSOC cells. Further data filtering unveiled CASC10 as one of the top RNA transcripts significantly increased in cisplatin-resistant compared with cisplatin-sensitive cells. Thus, we focused our studies on CASC10, a gene not previously studied in ovarian cancer. SiRNA-mediated CASC10 knockdown significantly reduced cell proliferation and invasion; and sensitized cells to cisplatin treatment. SiRNA-mediated CASC10 knockdown also induced apoptosis, cell cycle arrest, and altered the expression of several CASC10 downstream effectors. Multiple injections of liposomal CASC10-siRNA reduced tumor growth and metastasis in an ovarian cancer mouse model. Our results demonstrated that CASC10 levels mediate the susceptibility of HGSOC cells to cisplatin treatment. Thus, combining siRNA-mediated CASC10 knockdown with cisplatin may represent a plausible therapeutic strategy against HGSOC.

PSY1-2 Combined immunotherapy for non-small cell lung cancer

First-line treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor. In addition, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte-associated protein-4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. It is expected as a treatment aiming for long-term survival. The differences in the positioning of immunotherapy for NSCLC from other cancer types are as follows: (1) In patients with positive driver gene alteration such as EGFR gene mutation or ALK translocation, anti-PD-(L)1 antibody alone is ineffective, and (2) The positioning of anti-CTLA-4 antibody has not yet been determined.

KEYNOTE-365 cohorts E and F: Phase 1b/2 study of pembrolizumab + lenvatinib combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).

TPS215 Background: Standard of care for noncurative adenocarcinoma mCRPC is docetaxel or the next-generation hormonal agents (NHAs) abiraterone and enzalutamide. However, approximately 20% of patients develop t-NE after treatment for adenocarcinoma mCRPC; t-NE is associated with shorter survival, and it has no standard of care beyond combination platinum chemotherapy. The vascular endothelial growth factor (VEGF)/fibroblast growth factor receptor (FGFR) inhibitor lenvatinib inhibits proliferation and angiogenesis in preclinical models of adenocarcinoma prostate cancer. The phase 2 KEYNOTE-199 trial showed some antitumor activity with pembrolizumab monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC. VEGF/FGFR inhibition combined with PD-1 inhibition may have enhanced benefit in mCRPC, for adenocarcinoma and possibly as a new treatment option for t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate different pembrolizumab combination therapies in several patient populations with mCRPC. Cohort E will enroll patients with confirmed adenocarcinoma of the prostate without small cell histology, per investigator. Cohort F will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort F requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score of 0 or 1. Both cohorts will receive pembrolizumab 200 mg IV every 3 weeks + oral lenvatinib 20 mg once daily until disease progression, withdrawal of consent, prespecified alanine aminotransaminase or aspartate aminotransaminase level increase, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

A Multicenter, Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non–Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study)

BackgroundFirst-line treatment of non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death–1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte–associated protein–4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC. Patients and MethodsChemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events. ConclusionIf the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.

Chemotherapy with nivolumab in advanced gastro-oesophageal adenocarcinoma

Platinum and fluoropyrimidine combination chemotherapy forms the basis of first-line systemic treatment for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma, and apart from the addition of trastuzumab for the 15% of patients whose tumours are HER2-positive,1 there has been very little progress over the past two decades. The median overall survival (OS) of patients with advanced disease is around 11 months.2

Real-world outcomes of second-line ramucirumab plus paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A nationwide retrospective study in Korea (KCSG-ST19-16).

4056 Background: Ramucirumab as monotherapy or in combination with paclitaxel is a second-line treatment option recommended for patients with locally advanced unresectable or metastatic gastroesophageal junction (GEJ) or gastric adenocarcinoma. However, real-world data of large samples focused on ramucirumab plus paclitaxel in gastric cancer are limited. We conducted a nationwide retrospective study to evaluate the efficacy, safety, and factors potentially associated with survival in patients with gastric or GEJ adenocarcinoma who received second-line ramucirumab plus paclitaxel in a real-world setting. Methods: The study population comprised all patients with gastric or GEJ cancer who received ramucirumab plus paclitaxel in South Korea between May 1, 2018, and December 31, 2018. We included patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum and fluoropyrimidine-containing combination chemotherapy. Results: A total of 1,063 patients with advanced gastric or GEJ adenocarcinoma who received ramucirumab plus paclitaxel were included. The objective response rate and disease control rate were 15.1% and 57.7%, respectively; the median progression-free survival was 4.03 months (95% CI, 3.80–4.27), and the median overall survival was 10.3 months (95% CI, 9.33–10.73). The common treatment-related adverse events (TRAEs) at any grade were neutropenia (44.7%), anemia (41.8%), neuropathy (29.1%), fatigue (25.9%), and anorexia (25.0%). Grade 3 or higher TRAEs with incidences of ≥5% were neutropenia (35.1%) and anemia (10.5%). Adverse events of special interest were infrequent, including hypertension (2.1%) and proteinuria (3.0%). Based on multivariate analysis, overall survival was negatively associated with Eastern Cooperative Oncology Group performance status ≥2, weight loss in the previous 3 months ≥10%, GEJ of primary tumor, poor or unknown histology grade, number of metastatic sites ≥3, presence of peritoneal metastasis, no prior gastrectomy, and time to second-line since first-line treatment < 6 months. Conclusions: Our large-scale, nationwide, real-world data analysis of an unselected real-world population added evidence for the efficacy and safety of second-line ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Clinical trial information: NCT04192734.

A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin.

Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin-paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cells and suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.

Ability of the Glasgow Prognostic Score to predict the tolerability and efficacy of platinum-combination chemotherapy among elderly patients with advanced non-small cell lung cancer.

Background : Although platinum-combination chemotherapy is widely used to treat advanced non-small cell lung cancer (NSCLC), not all elderly patients benefit from this regimen. In this retrospective study, we aimed to evaluate whether the Glasgow Prognostic Score (GPS), an indicator of systemic inflammation and malnutrition, could predict the tolerability and efficacy of platinum-combination chemotherapy among elderly patients with NSCLC. Methods : The eligibility criteria included patients aged ≥ 70 years with NSCLC treated with first-line platinum-combination chemotherapy at Shimane University Hospital between January 2015 and December 2018. Results : Thirty-two patients with NSCLC (median age, 74 years) were included. The GPS scores were 0-1 for 19 patients and 2 for 13 patients. Four chemotherapy cycles were completed by 57.9% and 30.8% of patients in the GPS 0-1 and GPS 2 groups, respectively. The GPS 0-1 group experienced better outcomes than the GPS 2 group (response rate : 26% vs. 15%, P = 0.67 ; median progression-free survival : 4.1 vs. 2.1 months, P = 0.0026 ; median overall survival : 22.8 vs. 9.6 months, P = 0.0092). Conclusions : Platinum-combination chemotherapy demonstrated promising efficacy among elderly NSCLC patients with a GPS 0-1. Therefore, GPS may be crucial in determining whether treatments recommended for younger patients are suitable for older patients with NSCLC. J. Med. Invest. 68 : 260-264, August, 2021.

Ramucirumab plus paclitaxel as second-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma: a nationwide real-world outcomes in Korea study (KCSG-ST19-16).

Background:Ramucirumab as monotherapy or in combination with paclitaxel is a second-line treatment option recommended for patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, real-world data from large study cohorts focused on ramucirumab plus paclitaxel in gastric cancer are limited.Methods:The study population comprised all patients with gastric or GEJ cancer who received ramucirumab plus paclitaxel in South Korea between 1 May 2018 and 31 December 2018. We included patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum and fluoropyrimidine-containing combination chemotherapy.Results:In total, 1063 patients were included in the present study. The objective response rate and disease control rate were 15.1% and 57.7%, respectively. The median progression-free survival was 4.03 months (95% confidence interval, 3.80–4.27) and the median overall survival was 10.03 months (95% confidence interval, 9.33–10.73). Grade 3 or higher treatment-related adverse events with incidence of ⩾5% were neutropenia (35.1%) and anemia (10.5%). Based on multivariable analysis, overall survival was negatively associated with Eastern Cooperative Oncology Group performance status ⩾2, weight loss ⩾10% in the previous 3 months, GEJ of primary tumor, poor or unknown histologic grade, number of metastatic sites ⩾3, presence of peritoneal metastasis, no prior gastrectomy, and time to second-line since first-line treatment <6 months.Conclusion:Our large-scale, nationwide, real-world data analysis of an unselected real-world population adds evidence for the efficacy and safety of second-line ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.

Neoadjuvant treatment for newly diagnosed advanced ovarian cancer: where do we stand and where are we going?

Newly diagnosed high grade serous epithelial ovarian cancer (EOC) patients are treated with radical surgery followed by adjuvant platinum and taxane combination chemotherapy. In EOC patients where upfront surgery is contraindicated for medical reasons (e.g., comorbidities or poor performance status), or where complete cytoreduction cannot be achieved, neoadjuvant chemotherapy (NACT) prior to interval debulking surgery (IDS), and adjuvant chemotherapy is an alternative therapeutic option. There is currently a lack of consensus about who are the best candidates to receive NACT, and some authors have even suggested that this approach could be harmful in a subset of patients via promotion of early chemoresistance. Standard and novel imaging techniques together with a better molecular characterization of the disease have the potential to improve selection of patients, but ultimately well designed randomised clinical trials are needed to guide treatment decisions in this setting. The advent of new and effective treatment options (antiangiogenics and PARP inhibitors), now approved for use in the first line and relapse settings has opened the way to clinical trials aiming to investigate these agents as substitute or in addition to chemotherapy in the neoadjuvant setting in molecularly selected EOC patients. Here, we will review the evidence supporting the use of NACT in newly diagnosed EOCs, data highlighting the importance of its use in selected patients, new imaging methodologies and biomarkers that can guide patient selection.

Combined chemotherapy of platinum and fluorouracil promotes T cell-mediated antitumor immunity.

The two-drug combined chemotherapy of platinum and fluorouracil has been reported to efficiently kill tumor cells as the first-line treatment for advanced gastric cancer. However, the effect of these drugs on T cells remains unclear. Here, we showed that T cells including CD4+ T cells and CD8+ T cells of the patients with advanced gastric cancer after platinum and fluorouracil chemotherapy exhibited enhanced ex vivo proliferation ability as compared to that before chemotherapy. In addition, platinum and fluorouracil also promoted the differentiation of human T cells into Th1 and Th9 subtypes and cytotoxic T lymphocytes (CTLs) in vitro and in vivo. Accordingly, the combination therapy greatly suppressed tumor growth with increased tumor infiltration of Th1, Th9, and CTL cells in a mouse tumor model. Moreover, in activated T cells, long-term treatment with these two drugs further facilitates T cell activation along with promoted nuclear factor-κB (NF-κB) activation. Our findings demonstrate a previously unidentified function of platinum and fluorouracil combination chemotherapy in promoting T cell-mediated antitumor immunity.

Variants of SLC22A16 Predict the Efficacy of Platinum Combination Chemotherapy in Advanced Non-small-cell Lung Cancer.

Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored. This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes. Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model. A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.