3-week Cycle Research Articles

Development of a tool to assess the compliance of canteen menus with the Mediterranean Diet

Abstract The Mediterranean Diet (MD) is one of the healthiest food patterns associated with important health benefits. Acknowledging this, it’s important to understand how the dietary patterns of the consumers align with the MD. Over time, different authors have formulated several indexes for this purpose. However, current indexes lack standardization, and they only evaluate the quality of the diet of individuals to be used by health professionals and political decision-makers. Although there are indexes to assess the food options at the restaurants, none of them assess the menu compliance with the MD. Due to the importance of the food services in the food choices and dietary patterns of the consumers, this research developed an index to assess the alignment of the food availability with the MD key points. To address this gap, after reviewing the existing indexes in the literature, the authors created a tool that assesses the degree of compliance of menus with the MD - MedCIn. This index is divided into 4 dimensions, the first one assesses the availability (part A) and variety (part B) of the food/food groups. The second dimension assesses the nutritional quality of the menus based on the nutritional declaration, the third dimension assesses the food portions and culinary options, and the fourth dimension allows the verification of the previous information on site. Although the use of all dimensions allows for a more comprehensive menu evaluation, dimension one can be used as a first approach MD compliance. The index is meant to be applied in a 4-week cycle, though it can be adapted for each food service. Validation of this tool included construct validity, internal consistency and inter-rater reliability, all of which returned high values (alpha-Cronbach=0.88; Coheńs Kappa=0.92). The researchers consider this a reliable tool to easily assess compliance of menus with MD key points, allowing for the identification of issues to be addressed and improved

Neoadjuvant intratumoral plasmid interleukin-12 electro-gene-transfer and nivolumab in patients with operable locoregionally advanced melanoma.

Intratumoral (IT) TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of interleukin-12 (IL-12) within the tumor microenvironment (TME). This study evaluated neoadjuvant TAVO-EP combined with intravenous (IV) nivolumab followed by surgery and adjuvant nivolumab in patients with operable locoregionally advanced melanoma. The neoadjuvant phase comprised up to 3 Χ 4-week cycles where TAVO-EP was given IT on days 1, 8, and 15 (optional) concurrently with 480 mg nivolumab IV on day 8 of each 4-week cycle. Surgery followed, and adjuvant nivolumab was initiated after surgery. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathological response (MPR; pCR or near pCR). Sixteen patients were enrolled and the preoperative radiological response rate was 63%. One patient declined surgery after experiencing a significant clinical response. Among the remaining 15 patients, pCR rate was 60% and MPR was 80%. No patient with MPR has had disease recurrence with a median follow-up from the date of surgery of 15.4 months. At baseline, most patients exhibited low CD8+ TIL, PD-L1 and IFN-γ gene expression signature. There was enhanced immune activation following treatment in the TME and blood including increased immune-related gene expression, CD8+ TIL and proliferating immune cell subsets. The clinical efficacy of neoadjuvant IT TAVO-EP + nivolumab is promising with 80% of patients achieving an MPR. Evidence of potent immune activation both systemically and within the TME along with a favorable safety profile supports the activity of local IL-12 and anti-PD1 based regimens.

Combination of anlotinib and sintilimab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma: a single-arm prospective study

To investigate whether blocking both programmed cell death protein and vascular endothelial growth factor receptor could offer superior anticancer activity in these patients without compromising safety. In this study, patients were administered oral anlotinib (12 mg/day) on days 1–14 and intravenous sintilimab (200 mg) on day 1 of a 3-weekly cycle. The primary endpoints included the objective response rate and disease control rate. The secondary endpoints included overall survival (OS) and safety. Ten eligible patients were enrolled between June 2019 and May 2022, and eight patients underwent radiographic assessments. The results showed an objective response rate of 50% (partial and complete response in four and zero patients, respectively) and a disease control rate of 100%; four patients demonstrated stable disease for at least 8 weeks. The median OS was 4.37 (in our study, the score was 7), and the OS rate at 12 months was 37.5%. The Kaplan–Meier survival curve showed that the group with high blood glucose levels had a significantly shorter duration of survival than those with normal blood glucose levels. Adverse events of grade 3 and higher occurred in 50% of patients, and the most common severe adverse events included tumor pain (50%), hypertension (37.5%), tumor hemorrhage (25%), and decreased appetite (25%). The combination of anlotinib and sintilimab showed promising efficacy in controlling tumor size. However, the disappointing OS rate suggests that anti-vascular endothelial growth factor receptor agents should be used cautiously after radical radiation therapy. The combination used in this study demonstrated a toxicity profile comparable to that of other agents used in this setting. These findings warrant further investigation into the potential clinical utility of this combination.

Phase II Trial of Adjuvant S-1 Following Neoadjuvant Chemotherapy and Surgery in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: The PIECE Trial.

Neoadjuvant chemotherapy followed by surgery (NAC-S) is the standard therapy for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan. The aim of this phase II trial was to assess the efficacy and safety of the addition of adjuvant S-1 after R0 resection in ESCC patients who received NAC-S. Key eligibility criteria included clinical stage IB-III (without T4 disease) ESCC, age 20-75years, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received adjuvant therapy with four cycles of S-1 (80mg/m2/day) administered orally for 4 weeks of 6-week cycles. The primary endpoint was 3year relapse-free survival (RFS). If the lower confidence limit for 3year RFS was >50%, we judged that the primary endpoint of this study was met. A total of 52 patients were enrolled between January 2016 and January 2019. Two patients were excluded from analysis; five patients were determined to have R1 or R2 resection, and seven patients did not receive adjuvant S-1. The 3-year RFS and overall survival rates in the intention-to-treat population were 72.3% (90% confidence interval [CI] 59.9-81.5) and 85.0% (90% CI 73.9-91.6), indicating that the primary endpoint was met. Grade ≥3 adverse events with an incidence ≥10% included neutropenia (13.2%), anorexia (13.2%), and diarrhea (10.5%). There were no treatment-related deaths. Adjuvant S-1 after NAC-S showed promising efficacy with a manageable safety profile for patients with resectable ESCC and warrants further evaluation in larger studies.

Phase II Trial of Gemcitabine and nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation.

The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients 12-30 years with recurrent osteosarcoma and measurable disease. A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 weekly x 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response. Eighteen patients received 56 total cycles (median 2, range 1 - 12). Two patients (11%) experienced confirmed partial response, and 6 (33%) received > 2 cycles. The PFS-4 was 28% (95% CI 13-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs, and 10 had ctDNA identified. All 8 patients with MYC amplification at study-entry experienced disease progression. Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.

Spa Therapy Efficacy in Mental Health and Sleep Quality Disorders in Patients with a History of COVID-19: A Comparative Study.

The COVID-19 pandemic has left behind mental health issues like anxiety, depression, and sleep disorders among survivors. This study assessed the efficacy of spa therapy in enhancing psychological well-being and sleep quality in individuals with chronic arthro-rheumatic, respiratory, and otorhinolaryngological diseases, including COVID-19 recoverees. Our prospective observational study included 144 Caucasian subjects from three Italian spas who underwent a 2-week spa therapy cycle, involving balneotherapy and/or inhalation treatments. Symptoms were assessed with the Visual Analogue Scale (VAS), psychological well-being with Depression Anxiety Stress Scales-21 items (DASS-21), and sleep quality with the Insomnia Severity Index (ISI). Significant reductions in VAS scores for arthro-rheumatic, respiratory, and otorhinolaryngological symptoms were observed after spa therapy, as well as for DASS-21 and ISI scores for sleep quality, transitioning to less severe insomnia categories. Females had more pronounced improvements in DASS-21 scores and sleep quality. Subjects with and without prior SARS-CoV-2 infection experienced significant reductions in anxiety, depression, and stress, with more pronounced improvements in those without prior infection. COVID-19 survivors also showed significant ISI score improvements. Spa therapy is a promising complementary treatment for improving mental health and sleep quality in chronic disease patients, including COVID-19 survivors.

Brief Report: Phase II Trial of Regorafenib and Oral Methotrexate in Previously Treated Advanced KRAS-Mutant NSCLC

IntroductionThere are no standard targeted treatment options for advanced KRAS-mutant NSCLC beyond KRAS G12C inhibitors. A computational model identified regorafenib and low-dose methotrexate as synergistic in preclinical models of KRAS-mutant NSCLC. This study evaluated the efficacy and safety of the combination in previously treated advanced KRAS-mutant NSCLC. MethodsThis single-arm phase II study included regorafenib 80 to 120 mg daily and oral methotrexate dose escalated to tolerability from 10 to 20 mg twice weekly during the first cycle. Both agents were administered on weeks 1 to 3 of each 4-week cycle. The primary end point was progression-free survival. ResultsIn total, 18 patients with KRAS-mutant NSCLC were enrolled. Five patients received regorafenib at a 120 mg starting dose with four discontinuing due to toxicity; subsequently, 13 patients were treated at an 80 mg starting dose, with eight dose-escalating to 120 mg after the first cycle. Median progression-free survival was 3.7 months (95% confidence interval 1.8–8.6) and median overall survival was 10.4 months (95% confidence interval 5.2–30.3). The objective response rate was 16.7% and the 8-week disease control rate was 66.7%. Grade 3 treatment-related adverse events occurred in 11 patients, most often oral mucositis (n = 2) and asymptomatic lipase increase (n = 2). One patient developed asymptomatic grade 4 lipase increase. ConclusionsCombination treatment of regorafenib and oral methotrexate in patients with KRAS-mutant NSCLC was limited due to toxicity, and the study did not meet its primary end point. Computational modeling may aid in repurposing therapeutic options though caution must be exercised with tolerability.

Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

779. IMMUNE CHECKPOINT INHIBITOR WITH CHEMOTHERAPY (CISPLATIN+5FU) FOR ADVANCED ESOPHAGEAL CANCER

Abstract Background First-line chemotherapy for advanced esophageal carcinoma results in poor outcomes. Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma according to the KEYNOTE-590. We studied 17patients for the unresectable esophageal cancer and gastroesophageal junction adenocarcinoma cases treated with pembrolizumab and chemotherapy at our hospital between November 2023 and May 2024. Methods 17 patients with advanced carcinoma of the thoracic esophagus having either T4 tumor or distant lymph node metastasis were enrolled in this study. pembrolizumab 200mg/m2 and CDDP 80 mg/m2 was administered on days 1 and 5-FU 800 mg/m2 was administered on days 1-5 intravenously 3corse in 3-week cycles. Results Back ground: Averaged Age 76 (55-86), male: female =16:1, location (Ce: Ut: mt: Lt: Jz =1:1:6:6:3), strength 71mm (30-120), Stage (IVA: IVB= 7:10), Pathology (SCC: AD= 16:1), Times (3 courses completed: uncompleted: ongoing=9:3:5), Response PR:SD:PD: unknown=6:1:2:8, Toxicity: iRAE: liver dysfunction: Febrile neutropenia=4:2:6, The incidence of Grade 3 or higher adverse events was 3/15. One toxicity-related death occurred. We performed conversive esophagectomy for 2 patients. After chemotherapy: operation: radiation: observation: death:=2:2:10:3 Conclusion and discussion Due to the small number of cases, it is unclear whether the treatment was safe in a single center. I would like to consider increasing the number of cases. We will show one toxicity-related death and two conversive operation.

357. OUTCOMES OF TWO-COURSE NEOADJUVANT CHEMOTHERAPY WITH DOCETAXEL, CISPLATIN, AND 5-FLUOROURACIL ON ADVANCED ESOPHAGEAL CANCER: A SINGLE INSTITUTION STUDY

Abstract Background The CROSS trial established neoadjuvant chemoradiotherapy (CRT) as a cornerstone in treating esophageal cancer, making it the standard approach worldwide. However, in Japan, the JCOG1109 trial, a three-arm study, redefined the standard by showing the superiority of neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and 5-fluorouracil (DCF) over the conventional cisplatin and 5-fluorouracil (CF) regimen. Notably, it found no significant difference between neoadjuvant CRT with CF and CF. This trial adopted a 3-week cycle of 3 courses for the DCF regimen. Nonetheless, subsequent findings by Makino et al. suggested no difference in outcomes between 2-course and 3-course DCF regimens. This report presents the results of a 2-course neoadjuvant DCF regimen at our institution. Method This study included esophageal cancer patients who underwent esophagectomy after a 2-course NAC-DCF regimen at Okayama University Hospital from January 2014 to December 2019. Eligible participants were 20 to 80 years old, with a performance status of 0–1, histologically confirmed esophageal squamous cell carcinoma (ESCC), and adequate organ function. The stages ranged from cT1-4a N0-3 M0. We evaluated recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) using the Kaplan-Meier method and explored histopathological factors associated with RFS through COX regression analysis. Results Out of 209 cases, 63 were eligible. The median follow-up was 71 months, with 17 instances of recurrence observed, categorized as lymphatic (6 cases), hematinic (3 cases), local (2 cases), dissemination (2 cases), and multiple (4 cases). The 5-year RFS was 64.5%, and the 5-year OS was 65.8%. Univariate analysis identified pathological T, N, Stage, and chemotherapy response grade as significant factors related to RFS, with multivariate analysis highlighting pathological N as an independent factor. Kaplan-Meier analysis demonstrated significant survival differences across N stages, particularly between N1 and N2. Conclusion Our findings from the 2-course neoadjuvant DCF regimen highlight pathological N stage as a crucial independent predictor of recurrence in ESCC patients treated with NAC-DCF. Specifically, patients above N2 exhibited notably poorer prognoses, underscoring the need for adjuvant treatment strategies.

Cost-utility analysis of romiplostim for the treatment of chronic primary immune thrombocytopenia in China.

This study aimed to assess the cost-utility of romiplostim (ROMI) compared to eltrombopag (EPAG) as a second-line treatment for chronic primary immune thrombocytopenia (cITP) in Chinese adults. A decision tree-embedded Markov model with a lifetime horizon was used to estimate the quality-adjusted life years (QALYs) and costs for ROMI versus EPAG from the perspective of the Chinese health care system. The model was driven by platelet response with a 4-week cycle. Both QALYs and costs were discounted 5% per year. Clinical data comparing ROMI and EPAG were obtained by matching-adjusted indirect comparison (MAIC), utilizing individual patient data on ROMI and published Chinese Phase III trial data on EPAG. Costs were reported in 2022 US dollars and included drug acquisition costs, monitoring costs, bleeding-related costs, and costs associated with adverse events. Deterministic and probabilistic sensitivity analyses were performed. The CEA model indicated that treatment with ROMI resulted in an average of $4,344.4 higher costs for 0.004 QALYs. One-way sensitivity analysis (OSA) indicated that the model was most sensitive to the high bleeding rate in response (Markov stage) for EPAG and ROMI. Probabilistic sensitivity analysis (PSA) indicated that ROMI was likely to be cost effective in 0.16% cases at a willingness-to-pay threshold of $12039.1 (China per capita GDP in 2022) per QALY. If the price of ROMI is either lower than or equal to that of EPAG, ROMI could likely be considered cost-effective as a second-line treatment for Chinese adults with cITP.

Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study

IntroductionEftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+ and CD8+) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC. MethodsAfter confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally. ResultsThirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti–PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment. ConclusionsEfti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.

Improving Patient-Centered Care for End-Stage Renal Disease Patients at a Community Palliative Setting.

End-stage renal disease (ESRD) is a complex medical condition growing fastest in Americans 65 years and older. Despite its chronic nature, fewer than 10% of these patients have had advanced care planning. A chart audit (n = 20) of the palliative patients at a community palliative program revealed that no patient had a conversation about prognostication, 10% (n = 2) about the burden of kidney disease, 30% (n = 6) had coordination of care with the nephrologist, and 35% (n = 7) had engaged in end-of-life planning. This project aimed to increase patient-centered care for ESRD patients to 80% in 90 days. The project utilized the Plan-Do-Study-Act quality improvement model in four 2-week rapid cycles with 2 focus improvement areas. The 2 core interventions were patient screening for preferences and values and providing the right care for palliative management utilizing a checklist. At the end of the project, patient-centered right care for ESRD increased from a baseline of 24% to 94%. Patient engagement scores increased from a baseline of 3.2 to 4.9 on a 5-point Likert scale, with 5 being the highest supporting a shared decision model of care in improving patient-centered right care.

Modelling Adverse Events in Patients Receiving Chronic Oral Corticosteroids in the UK.

Oral corticosteroids (OCS) are effective anti-inflammatory agents used across a range of conditions. However, substantial evidence associates their use with increased risks for adverse events (AEs), causing high burden on healthcare resources. Emerging biologics present as alternative agents, enabling the reduction of OCS use. However, current modelling approaches may underestimate their effects by not capturing OCS-sparing effects. In this study, we present a modelling approach designed to capture the health economic benefits of OCS-sparing regimens and agents. We developed a disease-agnostic model using a UK health technology assessment (HTA) perspective, with discounting of 3.5% for costs and outcomes, a lifetime horizon, and 4-week cycle length. The model structure included type 2 diabetes mellitus, established cardiovascular disease, and osteoporosis as key AEs and drivers of morbidity and mortality, as well as capturing transient events. Quality-adjusted life-years (QALYs), life-years, and costs were determined for OCS-only and OCS-sparing treatment arms. Outcomes were determined using baseline 50% OCS-sparing, considering several OCS average daily doses (5, 10, 15mg). A treatment regimen with 50% OCS dose-sparing led to lifetime incremental cost savings per patient of £1107 (95% confidence interval £1014-£1229) at 5mg, £2403 (£2203-£2668) at 10mg, and £19,501 (£748-£51,836) at 15mg. Patients also gained 0.033 (0.030-0.036) to 0.356 (0.022-2.404) QALYs dependent on dose. The benefits of OCS sparing were long-term, plateauing after 35-40years of treatment. We present a modelling approach that captures additional long-term health economic benefits from OCSsparing that would otherwise be missed from current modelling approaches. These results may help inform future decision making for emerging OCS-sparing therapeutics by comparing them against the cost of such treatments.

Mecapegfilgrastim for prophylaxis of febrile neutropenia in children and adolescents with rhabdomyosarcoma or Ewing sarcoma: a prospective, single-arm, pilot study

BackgroundThe chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES.MethodsIn this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 μg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 109/L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile.ResultsIn total, 2 of the 30 (6.7%, 95% CI: 0.82–22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28–45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 109/L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0–5 years and the 13–18 years groups, and 2 patients experienced FN in the 6–12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0–5 years, 6–12 years, and 13–18 years groups, respectively.ConclusionMecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted.Trial registrationThis clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

17 CDK4/6 inhibition with Abemaciclib in in patients (pts) with previously treated advanced renal carcinoma (RCC)

Abstract Background Preclinical data suggests rationale for CDK4/6 alone and in combination with HIF-2 inhibitors; single agent activity for CDK4/6 inhibitors in RCC has not been reported. Abemaciclib is an oral CDK4/6 inhibitor approved in combination with hormonal therapy for metastatic breast cancer. In our phase 1b clinical trial (NCT04627064), we investigated the safety and clinical efficacy of abemaciclib monotherapy in pts with advanced pretreated RCC with clear cell component. Methods In this single center trial, adult pts with advanced RCC with a clear cell component and ECOG status of ≤1 progressing after at least one prior regimen including immunotherapy and a VEGF TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. Primary objective was to evaluate the objective response rate (ORR) of abemaciclib with secondary endpoint of safety. First imaging was performed after 2 cycles. Response assessed per RECIST 1.1 and toxicity per CTCAE v5.0. Results 11 pts (10 clear cell RCC and 1 translocation RCC) were enrolled between 12/31/2020 and 10/03/2023. Median age was 62 years (range 54-68) with 18% (n=2) showing sarcomatoid features. 73% (n=8) had IMDC intermediate risk disease and one patient had translocation RCC (tRCC) with a clear cell component. Median number of prior therapies was 4 (range 1-9). Seven patients received 2 cycles and 4 patients received &amp;lt; 2 cycles. ORR was 0% (0/11; 8 progressive disease, 1 stable disease in tRCC stopping for clinical progression, 2 pts not evaluable with clinical progression). 27% (n=3) experienced grade ≥3 treatment-related adverse events (diarrhea n=1, nausea n=1, neutropenia n=1). Conclusions In pts with heavily pretreated RCC, abemaciclib had manageable toxicity profile but no clinically meaningful activity as monotherapy. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2 inhibitors.

Pembrolizumab with platinum-based chemotherapy with or without epacadostat as first-line treatment for metastatic non-small cell lung cancer: a randomized, partially double-blind, placebo-controlled phase II study

BackgroundThe combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC.MethodsECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C.Results178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7–36.7) than the PBO + P + C group (44.8%; 95% CI 34.1–55.9), with a difference of − 18.5% (95% CI − 32.0 – (− 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C.ConclusionsAddition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination.Trial registrationNCT03322566. Registered October 26, 2017.

Split-Dose Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Carcinoma: A Systematic Literature Review and Network Meta-Analysis

BackgroundGemcitabine plus cisplatin (GC) is a highly active and commonly used regimen in locally advanced/metastatic urothelial carcinoma (la/mUC). With GC, cisplatin is dosed at 70 mg/m2 on day 1 of a 3-week cycle; however, for many patients, impaired renal or cardiac function, neuropathy, or poor performance status (PS) can preclude the use of cisplatin. A promising alternative is split-dose GC, in which the cisplatin dose is divided over 2 days. MethodsWe conducted a systematic literature review (SLR) and network meta-analysis (NMA) to better understand treatment patterns and comparative effectiveness and safety of split-dose GC vs gemcitabine plus carboplatin (GCa), GC, and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). ResultsAmong 120 identified studies, 16 studies representing 1,767 patients included split-dose GC. Common reasons for choosing split-dose GC were impaired renal function, age > 70 years, comorbidities, and physician preference. Split-dose GC had objective response rates (ORRs) of 39%-80%, median progression-free survival (PFS) of 3.5-9.9 months, and median overall survival (OS) of 8.5-18.1 months. Discontinuation rates due to adverse events were 5%-38%. In the NMA, ORR with split-dose GC was significantly higher than with GCa. PFS and OS for split-dose GC were similar to that observed with the other regimens (GCa, GC, and MVAC). ConclusionsThis is the first SLR and NMA of split-dose GC in la/mUC. Despite heterogeneity in the limited studies included, split-dose GC demonstrated comparable effectiveness and safety profile to those seen with other regimens. Split-dose GC thus has the potential to extend the la/mUC population eligible to receive cisplatin-based regimens and warrants further prospective study.

Population Pharmacokinetic Modeling of Adavosertib (AZD1775) in Patients with Solid Tumors.

Adavosertib (AZD1775) is a potent small-molecule inhibitor of Wee1 kinase. This analysis utilized pharmacokinetic data from 8 Phase I/II studies of adavosertib to characterize the population pharmacokinetics of adavosertib in patients (n = 538) with solid tumors and evaluate the impact of covariates on exposure. A nonlinear mixed-effects modeling approach was employed to estimate population and individual parameters from the clinical trial data. The model for time dependency of apparent clearance (CL) was developed in a stepwise manner and the final model validated by visual predictive checks (VPCs). Using an adavosertib dose of 300 mg once daily on a 5 days on/2 days off dosing schedule given 2 weeks out of a 3-week cycle, simulation analyses evaluated the impact of covariates on the following exposure metrics at steady state: maximum concentration during a 21-day cycle, area under the curve (AUC) during a 21-day cycle, AUC during the second week of a treatment cycle, and AUC on day 12 of a treatment cycle. The final model was a linear 2-compartment model with lag time into the dosing compartment and first-order absorption into the central compartment, time-varying CL, and random effects on all model parameters. VPCs and steady-state observations confirmed that the final model satisfied all the requirements for reliable simulation of randomly sampled Phase I and II populations with different covariate characteristics. Simulation-based analyses revealed that body weight, renal impairment status, and race were key factors determining the variability of drug-exposure metrics.