Network Meta-analysis of Randomized Controlled Trials in Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: Comparisons Involving Ramucirumab.

PURPOSE: With relatively few direct comparisons among treatment options for previously treated advanced gastric cancer or gastroesophageal junction (GEJ) cancer, network meta-analysis (NMA) may inform evidence-based decision-making. Ramucirumab plus paclitaxel (RAM + PTX) is a preferred regimen in guideline recommendations. NMA of key outcomes may further characterize the relative clinical value of RAM + PTX. METHODS: A systematic literature review of randomized controlled trials of adult patients with previously treated advanced gastric/GEJ cancer informed a NMA which compared overall survival, progression-free survival, and discontinuations due to adverse events. Comparisons were reported relative to placebo/best supportive care (BSC) when possible, otherwise relative to RAM + PTX. RESULTS: The base-case NMA focused on second-line treatment only, from 19 of 28 studies identified. For overall survival, seven of 16 regimens were favorable relative to placebo/BSC, with RAM + PTX as the most favorable. For progression-free survival, five of 14 regimens were unfavorable relative to RAM + PTX. For discontinuations due to adverse events, two of 13 regimens were similar to placebo/BSC: ramucirumab monotherapy and fluorouracil; relative to RAM-PTX, all regimens were similar except ramucirumab monotherapy which was favorable and irinotecan + cisplatin which was unfavorable. CONCLUSION: This NMA of trials of previously treated gastric/GEJ cancer suggests that RAM + PTX has one of the more favorable clinical profiles.

Dexamethasone is non-inferior to antihistamine plus dexamethasone premedication in preventing ramucirumab plus nab-paclitaxel infusion-related reactions in gastric cancer: a multicenter retrospective study.

PURPOSE: Ramucirumab (RAM) is recommended as premedication with H1-receptor antagonists (H1RA) to prevent infusion-related reactions (IRRs). However, RAM is a human antibody with a low incidence of IRRs. We evaluated the noninferiority of non-H1RA (dexamethasone [DEX] alone) premedication to H1RA (plus DEX) premedication in terms of IRRs in patients with gastric cancer receiving RAM plus nanoparticle albumin-bound paclitaxel (nab-PTX). METHODS: This was a noninferiority, multicenter, retrospective trial conducted in three Japanese centers to assess the incidence of IRRs in patients receiving RAM plus nab-PTX for gastric cancer between 2018 and 2023. Patients with gastric cancer receiving RAM plus nab-PTX were divided into groups with and without H1RA premedication. The incidence of IRRs was compared between the two groups. RESULTS: Ninety patients were evaluated, with non-H1RA and H1RA premedications in 43 and 47 cases, respectively. After the first dose of RAM, IRRs were not observed in either group. IRRs during the overall doses were 0% for non-H1RA premedication and 2.1% for H1RA premedication (90% confidence interval (CI): -5.6%-1.3% for each comparison). The upper limit of the 90% CI (1.3%) did not exceed the noninferiority margin (Δ) of + 10% and therefore met the noninferiority criteria. CONCLUSION: RAM plus nab-PTX for gastric cancer with DEX premedication may be possible without H1RA premedication.

Ramucirumab-induced ascites with endothelial growth factor receptor mutation-positive non-small cell lung cancer: Two case reports.

Ramucirumab (RAM) has been approved for the treatment of non-small cell lung cancer (NSCLC). Here, we report two cases of RAM-induced ascites with epidermal growth factor receptor-mutant NSCLC. Patient 1, a 72-year-old man, developed ascites 20 months after erlotinib (ERL) and RAM administration, which resolved after their discontinuation and performing paracentesis. Patient 2, an 83-year-old woman, developed ascites 9 months after ERL and RAM administration, which resolved after RAM discontinuation and furosemide administration. Ramucirumab administration can cause ascites due to increased hepatic sinusoidal pressure. Clinicians should be aware of RAM-induced ascites in patients with NSCLC and should appropriately manage it.

A Case of Ramucirumab for Radiation Necrosis Following Stereotactic Radiotherapy for Brain Metastases From Lung Cancer.

It is well known that bevacizumab is effective against radiation necrosis in the brain (hereafter referred to as brain necrosis). Herein, we report a case of brain necrosis in a patient treated with a regimen that included ramucirumab, an anti-vascular endothelial growth factor (VEGF) inhibitor. A woman in her 40s presented with five brain metastases from lung adenocarcinoma at the initial diagnosis. Each metastasis was treated with stereotactic radiotherapy. Subsequent magnetic resonance imaging showed increased oedema surrounding the lesion in the left frontal lobe, leading to a diagnosis of radiation-induced brain necrosis. Docetaxel + ramucirumab was chosen for third-line chemotherapy. During treatment, perioperative brain necrotic oedema diminished. Furthermore, anti-VEGF inhibitor regimens should be considered for reducing oedema associated with radiation necrosis of the brain, as they can be utilized alongside chemotherapy for the primary tumor.

Effect of baseline anemia on the efficacy of docetaxel and ramucirumab for advanced non-small cell lung cancer treatment.

BACKGROUND: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting. METHODS: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation. RESULTS: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups. CONCLUSIONS: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms.

Paclitaxel/Ramucirumab versus Paclitaxel in 2nd-Line Therapy of Advanced Esophageal Squamous Cell Carcinoma: Randomized Phase II IKF-AIO-RAMOS Trial.

INTRODUCTION: In squamous cell carcinoma of the esophagus (ESCC), therapeutical options in 2nd-line treatment are scarce with immune checkpoint inhibition being the only approved one. Ramucirumab/paclitaxel is an approved 2nd-line treatment in metastatic esophagogastric adenocarcinoma. We assessed safety and efficacy of ramucirumab/paclitaxel for ESCC. METHODS: This prospective, randomized, open-label, multicenter, phase II trial evaluated paclitaxel (80 mg/m2 days 1, 8, 15) plus ramucirumab (8 mg/kg days 1, 15) (investigational arm A) versus paclitaxel alone (80 mg/m2 days 1, 8, 15) (standard arm B), both q4w, in advanced/metastatic ESCC refractory or intolerant to fluoropyrimidine and platinum-based drugs. Primary endpoint was overall survival (OS) rate at 6 months. RESULTS: From 3/2019 to 4/2021, 21/186 planned patients were included (arm A 11 patients; arm B 10 patients) in 9 German centers. Due to slow accrual, the study was terminated prematurely. OS at 6 months was 72.7% for ramucirumab/paclitaxel and 50.0% for paclitaxel. The study design did not allow statistical comparison of the arms. PFS (3.8 vs. 3.5 months), OS (12.1 vs. 9.2 months), ORR (18.2% vs. 20.0%) and DCR (54.5% vs. 60.0%) were comparable in both arms. Most common treatment-related adverse events (TRAEs) in arm A were leucopenia (54.5%), fatigue (27.3%), and peripheral sensory neuropathy (18.2%). 27.3% in arm A and 50.0% in arm B had TRAEs ≥ grade 3. CONCLUSION: Ramucirumab/paclitaxel shows an acceptable tolerability and numerically improved OS at 6 months. Due to the small number of patients, the current trial must be considered exploratory and more data are needed in this indication.

Efficacy of chemotherapy for patients with gastric cancer with early recurrence during or after adjuvant chemotherapy with S-1 alone: a multicenter retrospective study.

This study aimed to survey the efficacy of chemotherapy regimens in the real world setting and explore the most promising regimen for patients experiencing early recurrence for gastric cancer. We retrospectively reviewed the clinical course of 207 patients with gastric cancer, who developed early recurrence during or within 6 months after completing S-1 adjuvant therapy at 19 Japanese institutions between 2012 and 2016. The treatment regimens after recurrence were fluoropyrimidines plus platinum-based regimens (FP) in 91 (44%) patients, paclitaxel-based regimens (PTX) in 102 (49%), and irinotecan-based regimens (IRI) in 14 (7%). The overall response and disease control rates were 28.7% and 54.1%. Median progression-free survival (PFS) and overall survival (OS) were 5.1 and 12.9 months, respectively. In the FP, PTX, and IRI regimens, the median PFS and OS were 5.9, 4.1, 4.1 months and 12.8, 12.9, and 11.8 months, respectively. The combination of PTX and ramucirumab showed survival comparable to capecitabine plus platinum. Multivariate analyses for OS showed that recurrence during adjuvant chemotherapy and undifferentiated histological type were independent poor prognostic factors. Although the prognosis of patients with early recurrence even with adjuvant S-1 was poor, PTX plus ramucirumab therapy could be a potential treatment option.

Efficacy and safety of ramucirumab in gastric or gastroesophageal cancer: A systematic review and meta-analysis.

BACKGROUND: Ramucirumab is considered a potential treatment for gastric or gastroesophageal cancer; however, its safety has not been evaluated. This meta-analysis aimed to evaluate the efficacy and safety of ramucirumab for treating gastric or gastroesophageal cancer. METHODS: The databases of PubMed, Embase, and Cochrane Library were searched through October 2023. The search focused on randomized controlled trials (RCTs) comparing ramucirumab (with or without chemotherapy) to a placebo (with or without chemotherapy) in patients with gastric or gastroesophageal cancer. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were pooled. RESULTS: Seven RCTs with a total of 2613 patients were included. Compared with placebo (with or without chemotherapy), ramucirumab (with or without chemotherapy) significantly improved OS (HR: 0.90, 95% CI: 0.82-0.99, p = 0.030), PFS (HR: 0.74, 95% CI: 0.60-0.90, p = 0.003), ORR (OR: 1.39, 95% CI: 1.15-1.67, p < 0.001), and DCR (OR: 1.91, 95% CI: 1.38-2.63, p < 0.001). However, ramucirumab (with or without chemotherapy) also increased the incidence of decreased appetite (OR: 1.29, 95% CI: 1.09-1.53, p = 0.004), diarrhea (OR: 1.39, 95% CI: 1.01-1.91, p = 0.05), hypertension (OR: 3.13, 95% CI: 2.03-4.83, p < 0.00001), and bleeding or hemorrhage (OR: 2.34, 95% CI: 1.93-2.85, p < 0.00001). CONCLUSIONS: Ramucirumab (with or without chemotherapy) can improve OS, PFS, ORR and DCR in patients with gastric or gastroesophageal cancer. However, it may also increase the incidence of specific AEs.

Efficacy and safety of ramucirumab for gastric or gastro-esophageal junction adenocarcinoma: a systematic review and meta-analysis.

PURPOSE: Based on the comparison of ramucirumab monoclonal antibody with control treatments in randomized controlled trials, this study aims to elucidate the role of ramucirumab monoclonal antibody in cancer therapy and its potential side effects, providing scientific evidence for clinical treatment. METHODS: PubMed, Embase, Cochrane, and Web of Science were searched systematically to obtain the trials on ramucirumab in the treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma up to April 13, 2023. We included randomized controlled trials (RCTs) evaluating the efficacy and safety of ramucirumab as monotherapy and in combination with other chemotherapy agents as interventions for treating gastric or gastroesophageal junction (GEJ) adenocarcinoma. RESULTS: After screening 2200 studies, we finally included 8 eligible studies (involving a total of 3,283 participants). Meta-analysis results showed that compared to the control group, ramucirumab monotherapy significantly improved overall survival (OS) (hazard ratio [HR] = 0.77, 95% confidence interval [CI] [0.67, 0.89]) and progression-free survival (PFS) (HR = 0.48, 95% CI [0.40, 0.58]). Similar results were obtained for ramucirumab combined with paclitaxel. In the treatment combining ramucirumab with paclitaxel, compared to monotherapy, three severe adverse reactions (grade ≥ 3) were observed with significantly increased risks (OR > 2). These include proteinuria (OR = 5.37, 95% CI [1.22, 23.54]), hypertension (OR = 4.02, 95% CI [2.63, 6.14]), and gastrointestinal perforation (OR = 4.64, 95% CI [1.00, 21.60]). Subgroup analysis further indicated that ramucirumab is effective in both non-East Asian and East Asian populations, with East Asian patients more prone to developing proteinuria, while having a lower incidence of hypertension. Additionally, ramucirumab demonstrated comparable efficacy between first-line and second-line treatments, with a higher incidence of proteinuria observed in second-line therapy. CONCLUSION: Ramucirumab significantly improves the prognosis of patients with gastric or gastroesophageal junction adenocarcinoma. When used in combination with paclitaxel, close monitoring of adverse reactions such as proteinuria (especially in East Asian populations), hypertension (especially in non-East Asian populations), and gastrointestinal perforation is essential.

A Retrospective Analysis of the Efficacy of Oral Dexamethasone in Combination With Docetaxel Plus Ramucirumab Therapy for Previously Treated Lung Cancer.

INTRODUCTION: Docetaxel plus ramucirumab (DTX + RAM) therapy is a standard treatment for previously treated lung cancer, but many adverse events have been reported. This retrospective study was conducted to examine if the side effects of DTX + RAM therapy can be minimized by the combined use of oral dexamethasone (DEX), and to assess the therapeutic effect of DTX + RAM in patients with recurrent lung cancer. METHODS: Forty patients with relapsed non-small cell lung cancer who underwent DTX + RAM therapy were divided into two groups based on the concomitant use of oral DEX, and the therapeutic effects and toxicities in the two groups were compared. RESULTS: The objective response rate (ORR) was significantly better in the DEX group (P = 0.0203). The median progression-free survival (PFS) was 5.20 months vs 2.87 months (P = 0.064) in the DEX and non-DEX groups, respectively. However, the median overall survival (OS) was significantly better in the DEX group (15.17 months vs 7.37 months, P = 0.0317). The frequency of fluid retention within six months of the start of treatment was 10.0% vs 42.5% in the DEX and non-DEX groups, respectively, with the fluid retention rate being significantly higher in the non-DEX group (P = 0.039).Conclusion: Concomitant use of oral DEX during DTX + RAM therapy may facilitate the long-term continuation of treatment and contribute to OS prolongation.

Ramucirumab plus FOLFIRI or irinotecan as second-line treatment for patients with gastroesophageal adenocarcinoma: a review and meta-analysis of an emerging option.

Introduction: The aim of this study was to provide a review of the clinical evidence for use of ramucirumab (RAM) plus folinic acid (leucovorin), fluorouracil (5-FU), and irinotecan (FOLFIRI) or irinotecan as second-line treatment in gastroesophageal adenocarcinoma (GEA). Methods: A systematic and comprehensive search of PubMed was performed to identify phase 2 clinical trials or retrospective studies using RAM plus FOLFIRI or irinotecan in GEA, including abstracts from major congresses, in addition to published manuscripts. An aggregated review and meta-analysis was performed to assess the effectiveness (overall response rate [ORR] as primary outcome) and safety data of RAM plus FOLFIRI or irinotecan. ORR for each study was calculated with 95% confidence interval estimated from normal approximation. To generate the combined ORR with 95% confidence interval, random-effects meta-analysis was conducted to synthesize response data from available studies. Results: Six studies were identified with non-overlapping populations, 3 phase 2 clinical trials and 3 retrospective studies. Across these studies the ORR ranged from 22% to 38%, and pooled ORR was 25.4%. Two of the 3 studies reported better ORR in patients pretreated with taxanes followed by RAM plus FOLFIRI. Treatment with RAM plus FOLFIRI or irinotecan was well tolerated. Neutropenia and diarrhea were the most common adverse events reported across studies. Conclusion: The studies examined in this review suggest that RAM plus FOLFIRI or irinotecan have activity in previously treated GEA irrespective of prior-taxane use. Overall, RAM plus FOLFIRI or irinotecan was well tolerated with no new safety concerns identified beyond established profiles for these regimens.

Synthesis of chitosan polyethylene glycol antibody complex for delivery of Imatinib in lung cancer cell lines.

Lung cancer is known as the most common cancer. Although the Ramucirumab antibody is a second-line treatment for lung cancer, the high interstitial fluid pressure limits the antibody's performance. In this way, Imatinib is a chemotherapeutic drug to reduce the interstitial fluid pressure. Up to now, unfortunately, both Ramucirumab and imatinib have not been reported in one nanosystem for cancer therapy. To fulfill this shortcoming, this paper aims to design a chitosan nanocarrier that loads imatinib and attaches to Ramucirumab for selective bonding to A549. Therefore, this paper aims to develop a polymeric nanosystem for non-small cell lung cancer (NSCLC) treatment. In first, the chitosan polyethylene glycol nanoparticle is synthesized, loaded with imatinib, and then targeted using Ramucirumab. Afterwards, the CS-PEG-Ab-Im by FTIR, TEM, DLS, zeta potential, and TGA techniques are characterized. The size of CS-PEG-Ab-Im was 25-30 nm, its surface charge was 13.1 mV, and the shape of CS-PEG-Ab-Im was nearly spherical and cylindrical. The therapeutic potential of CS-PEG-Ab-Im was assessed using the A549 cell line. According to the obtained results, the cell viability was 48% after 48 h of treatment of A549 cells using the IC50 concentration of CS-PEG-Ab-Im (100 nanomolar). Moreover, the apoptosis and cell cycle arrest percentages were increased by 3 and 6 times, respectively, as compared to free imatinib. Furthermore, the release rate of imatinib from CS-PEG-Ab-Im in an acidic medium was 17% during 1 h, indicating five times the imatinib release in the natural medium. Eventually, the result of flow cytometry indicates the more apoptotic effect of nanosystem to free imatinib and CS-PEG-Ab. Besides, cell arresting result exhibits the CS-PEG-Ab-Im and causes cell arrested at G1 by %8.17. Thus, it can be concluded that CS-PEG-Ab-Im can be an ideal nanosystem in NSCLC treatment.

Successful Treatment with Ramucirumab Plus Erlotinib following Osimertinib-induced Interstitial Lung Disease: A Case Report.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are key drugs for patients with EGFR mutation-positive non-small-cell lung cancer, and osimertinib is the standard treatment. Although drug-induced interstitial lung disease (ILD) is a remarkable adverse event of EGFR-TKIs, evidence regarding the continuation and re-challenge of EGFR-TKIs after drug-induced severe ILD is lacking. This is the first report of successful switching to ramucirumab plus erlotinib after osimertinib-induced severe ILD in an 81-year-old woman with stage IV lung adenocarcinoma harboring the EGFR L858R mutation in exon 21. These findings suggest that ramucirumab plus erlotinib may be a viable treatment option for osimertinib-induced severe ILD.

Ramucirumab in second­line advanced colorectal cancer therapy: A study on therapeutic outcomes and hepatic sinusoidal platelet aggregation.

The present study investigated the role of ramucirumab (RAM) in treating liver metastases (LMs) as a second-line or salvage treatment in patients with advanced CRC. Of the 36 patients, 21 (58%) received RAM plus folinic acid, fluorouracil and irinotecan (FOLFIRI) as second-line treatment, whereas 15 (42%) received it in a salvage setting. The median overall survival time was 23 months [95% confidence interval (CI), 12-34 months] for those in the second-line treatment group and 8 months (95% CI, 5-19 months) for those in the salvage treatment group. Of the 36 patients, 14 (39%) underwent surgical resection of LMs during chemotherapy. A total of 6 patients underwent surgical resection for LMs for the first time during second-line RAM plus FOLFIRI (RAM-LM); of the remaining 8 patients, 6 underwent resection of LMs during first-line bevacizumab (BEV)-based chemotherapy (BEV-LM). Immunohistochemical analysis of CD42b showed that the platelet aggregation score (CD42b score), which ranges from 0 (absence of deposition) to 3 (presence of linear deposition), tended to decrease with the increasing duration of treatment with both RAM and BEV. Although there was no significant difference in the mean duration of anti-VEGF antibody treatment between the BEV-LM and RAM-LM groups, the median CD42b score was higher in the RAM-LM group (median CD42b score, 3; range, 0-3) compared with that in the BEV-LM group (median CD42b score, 1; range, 0-3; P=0.01), suggesting that RAM induces a different degree of platelet aggregation in liver sinusoids compared to BEV.

Influence of Previous Therapy for Neutropenia Caused by Combination Therapy of Ramucirumab and Docetaxel.

In the present study, the influence of previous immune checkpoint inhibitor (ICI) therapy with ramucirumab (RAM) + docetaxel (DTX) therapy on the occurrence of severe neutropenia in patients with non-small cell lung cancer (NSCLC) was evaluated, taking into account the influences of cytotoxic chemotherapy used in pretreatment. The study participants included patients who received a combination therapy of RAM and DTX as cancer chemotherapy for NSCLC. The influences of previous ICI treatment and pretreatment with cytotoxic anticancer agents on the development of grade ≥ 3 neutropenia were analysed. A total of 89 patients, including 50 with and 39 without a history of ICI treatment, were analysed. Kaplan-Meier curves showed a significant difference in the influence of previous ICI treatment on the development of grade ≥ 3 neutropenia (p = 0.006). Moreover, Cox regression analysis identified a history of ICI treatment and prophylactic administration of G-CSF as factors associated with the development of grade ≥ 3 neutropenia (p = 0.018 and p < 0.001, respectively). This study found that previous treatment with ICIs reduced the incidence of grade ≥ 3 neutropenia after RAM + DTX therapy in patients with NSCLC, regardless of the influences of pretreatment with cytotoxic anticancer agents.

Trifluridine/tipiracil with and without ramucirumab for advanced gastric cancer: a comparative observational study.

The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment. This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081). The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030). The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC. Further investigation via randomized trials is warranted to confirm these findings.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Ramucirumab Beyond Disease Progression After Paclitaxel Plus Ramucirumab in Gastric Cancer: A Phase II Trial.

BACKGROUND/AIM: Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in September 2017 and trifluridine/tipiracil in August 2019. The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of paclitaxel plus ramucirumab (PTX+RAM) as second-line chemotherapy, has been under debate. PATIENTS AND METHODS: A single-center phase II study was conducted in patients with unresectable advanced or recurrent gastric cancer previously treated with fluoropyrimidines and platinum, who received PTX+RAM as second-line therapy and irinotecan plus ramucirumab (IRI+RAM) as third-line therapy after treatment failure (UMIN000022956). RESULTS: Eleven patients were enrolled from July 2016 to July 2018. Enrolment was discontinued due to difficulties in case ascertainment because of expanded third-line treatment options (originally planned for 53 patients). The median progression-free survival (the primary endpoint) of the IRI+RAM was 3.98 months [95% confidence interval (CI)=1.78-NA]. Among secondary endpoints, the transition rate to IRI+RAM was 45%, the rate of 8-week treatment continuation for IRI+RAM was 100%, the response rate for IRI+RAM was 0%, the median overall survival (OS) for PTX+RAM was 13.53 months (95%CI=1.61-24.36), and the median OS for IRI+RAM was 9.99 months (95CI=4.5-NA). CONCLUSION: The transition rate from PTX+RAM to IRI+RAM was reasonable. Ramucirumab beyond progressive disease may be beneficial for patients who are able to transition to IRI+RAM.