Doublet Chemotherapy Regimens Research Articles

Clinical Significance of the Peripheral Blood Neutrophil-to-Lymphocyte Ratio in Predicting Chemotherapy Outcomes for Small Cell Lung Cancer.

This study aims to assess the clinical significance of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) in predicting chemotherapy outcomes for patients with small cell lung cancer (SCLC). A cohort of 44 patients diagnosed with SCLC between January 2021 to June 2022 at Fuyang People's Hospital was selected for analysis. All patients in this group received a first-line platinum-based doublet chemotherapy regimen. In parallel, a control group consisting of 44healthy individuals undergoing routine physical examinations at the same hospital was also selected. Fasting venous blood samples were collected in the morning within one week before the initiation of chemotherapy, and a complete blood cell count was performed to calculate the NLR. The NLR in the plasma of patients with SCLC was significantly elevated compared to that of healthy individuals (P < 0.01). After two cycles of chemotherapy, there were no statistically significant differences in plasma NLR in SCLC patients compared to pre-chemotherapy levels (P > 0.05). However, in the subgroup of patients with a partial response (PR) to treatment, the NLR decreased to 2.625 (95% CI: 1.900, 3.625), down from a pre-chemotherapy level of 3.430 (2.688, 4.800) (Z = -3.127, P = 0.002). Conversely, in patients whose disease progressed (PD) following chemotherapy, the NLR increased to 3.880 (95% CI: 2.953, 5.223) from a pre-chemotherapy level of 2.060 (1.915, 2.968) (Z = -2.521, P = 0.012). The dynamic variations in the peripheral blood NLR before and after chemotherapy in patients with SCLC are strongly associated with the efficacy of first-line chemotherapy regimens. These changes in NLR levels may serve as a crucial indicator for predicting the effectiveness of first-line chemotherapy in patients with SCLC.

A real-world retrospective study to assess efficacy and safety of alectinib as adjuvant therapy in IB-IIIB NSCLC patients harboring ALK rearrangement.

Alectinib has demonstrated promising disease-free survival (DFS) benefit for early-stage non-small cell lung cancer (NSCLC) patients with ALK rearrangement positive in phase 3 ALINA trial. However, real-world evidence for the efficacy and safety of alectinib in early-stage ALK-positive NSCLC is limited. We retrospectively reviewed 68 patients with stage IB-IIIB ALK-positive NSCLC who underwent complete pulmonary resections from April 2010 to July 2023 at a single institution. 38 (55.9%) enrolled patients had N2 lymph node metastasis, and 17 (24.9%) patients had multi-station N2 metastasis. Patients were stratified into two groups according to the adjuvant treatment regimen, with 19 patients in the alectinib group and 49 patients in the chemotherapy group. There were no significant differences in clinicopathological characteristics between the two groups. After curative resection surgery, patients in alectinib group received oral alectinib at a dose of 600 mg twice daily and patients in chemotherapy group received platinum-based doublet chemotherapy regimen every 3 weeks for 4 cycles. The primary endpoint was 3-year DFS. The Kaplan-Meier method was used to estimate DFS and overall survival (OS). Safety analyses were conducted by comparing the incidence of adverse events between the two groups. At the last follow-up date (January 22th, 2024), A total of 1 (5.3%) and 28 (57.1%) DFS events were observed in alectinib group and chemotherapy group respectively. The 3-year DFS showed significant improvement in the alectinib group compared with chemotherapy group (91.7% vs 60.7%, P=0.051). In the IIIAN2 subgroup, the 3-year DFS rate in the alectinib group reached a satisfactory 87.5%. In both groups, the majority of AEs were graded as level 1 or 2, No grade 3-4 AEs were observed in alectinib group. Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.

Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer

BackgroundEvaluate the efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in treating locally advanced cervical cancer (LACC).MethodsRetrospective data was collected from LACC patients who were treated at our institution. These patients were categorized into three groups: the single-agent cisplatin (DDP) chemoradiotherapy group, the paclitaxel plus cisplatin (TP) chemoradiotherapy group, and the nanoparticle albumin-bound (nab-) paclitaxel combined with cisplatin (nPP) chemoradiotherapy group. The primary endpoints were overall survival (OS) and progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) and incidence of adverse events (AEs).ResultsA total of 124 patients were enrolled (32 in the DDP group, 41 in the TP group, and 51 in the nPP group). There were differences in OS (P = 0.041, HR 0.527, 95% CI 0.314–0.884) and PFS (P = 0.003, HR 0.517, 95% CI 0.343–0.779) between the three groups. Notably, the 2-year OS rate was significantly higher in the nPP group compared to the DDP group (92.2% vs. 85.4%, P = 0.012). The 2-year PFS rates showed a marked increase in the TP group (78.0% vs. 59.4%, P = 0.048) and the nPP group (88.2% vs. 59.4%, P = 0.001) relative to the DPP group, with multiple comparisons indicating that the 2-year PFS rate was significantly superior in the nPP group versus the DDP group (88.2% vs. 59.4%, P = 0.001). Moreover, the ORR was also significantly higher in the nPP group than in the DDP group (P = 0.013); and no statistically significant differences were found in the incidence of AEs among the groups (P > 0.05).ConclusionsIn LACC treatment, the two cisplatin-based doublet chemotherapy regimens are associated with better outcomes, with the nab-paclitaxel plus cisplatin regimen showing better efficacy than the paclitaxel plus cisplatin regimen. Furthermore, the AEs associated with these regimens were deemed tolerable. These findings could provide a reference for the clinical treatment of LACC. However, further prospective studies are needed to verify it.

Brief Report on Global Clinician Practices in the First-Line Management of Metastatic Non-Small Cell Lung Cancer

IntroductionIn the dynamic landscape of metastatic NSCLC (mNSCLC) management, marked by several frontline options and the integration of next generation sequencing (NGS) for informed decision-making, barriers persist despite advancements. This includes challenges in clinical trial recruitment. To gain global insights into clinicians’ practices, we conducted a survey on their testing and management approaches for patients with mNSCLC. MethodsThe survey, conducted from July 12 to August 20, 2023, utilized multiple-choice questions and qualitative research questions, employing the Likert Scale for comprehensive insights. ResultsA total of 127 individuals responded, with 72% affiliated with academic health systems, and 55% practicing in the USA. Regarding testing practices, 93% consistently ordered NGS for non-squamous histology, while 54% did so for squamous cell histology. Concurrent tissue and liquid biopsies were routinely ordered by 28%, while 39% reported ordering both testing platforms concurrently for select cases only. Respondents cited logistical barriers, such as insufficient tissue and lack of infrastructure, as the most common hindrance to molecular testing (76%), followed by reimbursement challenges (56%) and concerns about delayed turnaround time (50%). While most respondents were confident in interpreting NGS results, 22% lacked confidence. Concerning treatment decisions, 72% preferred awaiting molecular testing results before initiating systemic therapy. Less than 50% routinely referred patients for clinical trials in the frontline setting for mNSCLC. For patients with disease expressing high PD-L1 levels, most oncologists preferred pembrolizumab monotherapy. For disease with low PD-L1 expression, a platinum doublet chemotherapy regimen combined with pembrolizumab was favored. In disease cases with negative PD-L1 expression, a platinum doublet chemotherapy regimen with pembrolizumab was preferred. Key factors influencing oncologists' preferred immune checkpoint inhibitor (ICI) included experience with one ICI over another, preferred status per national guidelines, availability of trial data with a significant follow-up period, and consideration of drug cost. ConclusionAlthough this study demonstrates an improved awareness and adoption of ordering NGS for the management of mNSCLC, it underscores the persistence of various barriers that must be addressed to improve upon the quality of care for patients diagnosed with mNSCLC.

Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis

BackgroundTreatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed.ObjectiveA systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI).MethodsOutcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR).ResultsA total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results.ConclusionsHAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Najnoviji stavovi o prednostima primjene neoadjuvantne terapije kod pacijenata s uznapredovalim rakom želuca

Treatment for gastric cancer has multiple approaches and options across the world. Standard treatment for the Asian population comprises D2-gastrectomy and adjuvant chemotherapy. However, in Europe and North America, clinical trials have shown that perioperative chemotherapy, given to patients before surgery, could improve resection and survival rates significantly. Most recent studies have also discussed the advantages of doublet vs. triplet chemotherapy regimens. Furthermore, researchers have been comparing the effects of perioperative chemoradiotherapy as opposed to chemotherapy alone. The specific advantages of previously stated therapy options, as well as any novel treatments, should be researched more thoroughly in the future.

Comparison of bevacizumab plus doublet chemotherapy regimens in patients with metastatic or recurrent ovarian cancer.

e17537 Background: Ovarian cancer is the most common cause of death due to gynecological malignancies. Although the primary treatment is surgery, there are different chemotherapy regimens that can be used in metastatic disease. In this study, it was aimed to compare doublet chemotherapy regimens in combination with bevacizumab in patients with metastatic ovarian cancer. Methods: Our study was designed as a retrospective observational study. The clinical, pathological, radiological, and treatment characteristics of the patients were recorded. Survival analyzes were performed using the Kaplan-Meier method, and multivariate analysis using cox regression analysis. Results: 198 patients were included in the study. Median follow-up period after bevacizumab was 18.7 months. The most common pathological subtype was serous carcinoma (%85.9). Before bevacizumab treatment, 96% of patients received perioperative chemotherapy. The most common sites of metastasis were the peritoneum (94.5%), liver (43.9%), lung (18.7%), bone (4.5%), and brain (3%). In combination with bevacizumab, 92 (46.4%) patients used gemcitabine + carboplatin, 76 (38.4%) patients used paclitaxel + carboplatin, and 30 (15.2%) patients used gemcitabine + cisplatin. In the whole patient group, the rate of complete response was 18.7%, partial response 56.1%, stable disease 6.6%, and progressive disease 18.7%. The patients received a median of 9 cycles of bevacizumab and a median of 7 cycles of doublet chemotherapy. Median progression-free survival was 11.9 (95% CI, 9.2-14.5) months, and median overall survival was 24.7 (95% CI, 19.9-29.4) months. History of surgery before bevacizumab (p=0.006) and type of doublet chemotherapy (p=0.024) were found to be statistically significant factors affecting overall survival. The presence of brain metastases (p=0.062) had borderline significance. Conclusions: Doublet chemotherapy regimens with bevacizumab have been found to be effective and safe in the treatment of metastatic ovarian cancer in terms of survival. The combination of bevacizumab with gemcitabine + carboplatin was superior to other doublet chemotherapy regimens in terms of overall survival.

Real-world treatment trends and outcomes in elderly patients with metastatic colorectal cancer in the United States.

3591 Background: Prospective data to guide management of elderly patients with metastatic colorectal cancer (mCRC) is limited. Whether elderly patients derive the same degree of benefit from doublet chemotherapy as younger patients is not well understood. In this study we utilized real-world data from patients in the United States (US) to evaluate treatment trends and compare overall survival (OS) in younger versus older patients with mCRC who receive first-line (1L) chemotherapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was used to select patients ≥50 years old (yo) with mCRC treated with 1L fluoropyrimidine-based chemotherapy with or without the addition of targeted therapy. Overall survival from the initiation of 1L therapy, stratified by receipt of a doublet or single agent cytotoxic chemotherapy regimen was assessed independently within three age cohorts (50-69; 70-74, ≥75) using both a cox proportional hazard model and a propensity score weighted analysis to control for potential confounding variables. A subgroup analysis was performed in patients receiving bevacizumab as part of 1L therapy. Results: Of 14,440 patients who received 1L chemotherapy, 5,874 (40.7%) were ≥70 yo, including 3,656 (25.4%) who were 75 or older. Doublet chemotherapy was received by 7,505 (87.6%) patients age 50-64 yo, 1892 (85.3%) patients age 70-74 yo, and 2297 (62.2%) patients age 75 and above. In all three groups, multivariate analysis of single agent chemotherapy vs doublet chemotherapy showed a benefit to doublet chemotherapy with a hazard ratio of 1.14, (95% CI 1.04-1.24, p = 0.006), 1.22 (95% CI 1.05-1.42, p = 0.011) and 1.19 (95% CI 1.10-1.29, p &lt; 0.001), respectively. Similar results were noted when comparing doublet to single agent chemotherapy in the age 70-74 and ≥75 groups using a propensity score weighted analysis. In the subgroup of patients age ≥70 who received 1L bevacizumab, 2,604 received doublet chemotherapy and 441 received single agent chemotherapy. Median OS was 19 mos (95% CI: 18-20) vs 13 (95% CI: 11-15) vs with a propensity score weighted HR of 1.35 (95% CI 1.12-1.63, p = 0.001). Conclusions: A smaller percentage of patients over age 75 receive 1L doublet chemotherapy for mCRC in the US compared to patients age 50-69 or 70-74. Regardless of age, patients who receive doublet fluoropyrimidine-based chemotherapy appear to have improved overall survival compared to single agent chemotherapy. This retrospective US data is in contrast with recently presented data from a prospective phase III trial in Japan (JCOG1018). Elderly patients in the US should not be excluded from receiving doublet chemotherapy for mCRC without further prospective data.

Real-world outcomes of patients with advanced gastric cancer treated with FOLFIRI.

307 Background: Doublet chemotherapy regimens such as 5-fluorouracil and irinotecan (FOLFIRI) appear to be viable first-line treatment options in advanced gastric cancer (AGC). A phase III French intergroup study demonstrated a longer time to treatment failure, improved toxicity profile, and no difference in median OS when using FOLFIRI, compared to epirubicin, cisplatin, and capecitabine (ECX). Purpose: To investigate the real-world efficacy of FOLFIRI in AGC. Methods: Patients diagnosed with AGC in Alberta, Canada from 2012-2020 were identified by the Alberta Cancer Registry. Data points that could not be obtained automatically were obtained by retrospective chart review. Survival was compared by Log-Rank analysis or Cox Regression. Factors associated with FOLFIRI use were determined using logistical regression. Results: A total of 285 patients were analyzed. Eighty-four (29%) patients received FOLFIRI as first-line therapy, 69 received ECX (24%), 82 received CX (29%), 31 received EOX (11%), and 19 received FOLFOX (7%). Thirty-six (12.6%) received a subsequent line of therapy, most commonly FOLFIRI (52.8%). Age, sex, topography (cardia v. non-cardia), or morphology (adenocarcinoma v. signet ring cell v. NOS) did not influence the use of FOLFIRI in the first-line setting. Median overall survival with FOLFIRI was 5.8m vs. 7.4m (p = 0.12) when compared to the patients receiving all other regimens. Conclusions: FOLFIRI had comparable efficacy to other first-line regimens in patients with AGC.

256MO Decoding the cryptic stroma: Molecular cancer associated fibroblast 1 & 4 imaging allied with mesenchymal stroma to tumor content as a radiation dose bio-predictive signature to augur the future in locally advanced esophageal cancer

The multipotent cancer stem-cell differentiates into tumor cell and mesenchymal stromal cell. Depending on the favorability of the tumor microenvironment and the metabolic demand, the ratio of stromal cells to tumor cells differ in the tumor microenvironment. Our study corelates the stromal content in molecular CAF whole body imaging with stroma to tumor ratio and outcomes of locally advanced esophageal cancer patients subjected to different radiation doses with platinum-based doublet chemotherapy regimens.

Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity.

Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A. A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe. Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n=15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n=23) or modified FOLFIRINOX for pancreatic cancer (n=40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p=0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n=66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n=47). Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

Abstract 2566: Pre-clinical efficacy of the Wnt pathway inhibitor RXC004 in combination with anti-cancer therapies

Abstract Background: RXC004, a potent and selective inhibitor of the Wnt pathway regulator Porcupine, is being investigated in phase 2 studies in patients with advanced cancers (NCT04907851 and NCT04907539). Wnt pathway alterations, including loss-of-function RNF43 mutations and RSPO gene fusions, result in higher levels of the Wnt receptor Frizzled (Fzd) on the cell surface increasing Wnt-ligand dependent signaling. These alterations, which have been shown to be sensitive to Porcupine inhibitors, are implicated in colorectal, gastric and pancreatic cancer. Pre-clinical in vivo data on the effects of RXC004 in combination with clinically relevant anti-cancer therapies have not previously been described in genetically-defined models of cancer. Methods: RXC004 was evaluated as a monotherapy, and in combination with clinically relevant chemotherapy regimens, in an RSPO-fusion colorectal xenograft model (SNU-1411). RXC004, dosed at 5mg/kg QD (5 days on/2 days off), was evaluated in combination with either the clinically relevant colorectal triplet chemotherapy regimen (5-fluorouracil 5-FU (25mg/kg), irinotecan (50mg/kg) and oxaliplatin (5mg/kg)) or doublet chemotherapy regimen (5-FU (25mg/kg), irinotecan (50mg/kg)). Each chemotherapy regimen was dosed once a week for 3 to 4 weeks either alone or in combination with RXC004, which was dosed from day 8 onwards at 5mg/kg QD (5 days on/2 days off). Efficacy was measured by tumor volume and survival endpoint. In addition, RXC004 was studied in vitro, as monotherapy and in combination with a PARP inhibitor in genetically selected cell lines with both RSPO-fusion and RNF43 mutation. Combination and monotherapy effects on proliferation and effects on downstream signaling were investigated. Results: RXC004 in combination with the triplet chemotherapy regimen led to significantly increased survival compared to either treatment alone (p&amp;lt;0.005) and significant tumor volume reduction measured at Day 22 (p&amp;lt;0.001). RXC004 in combination with the doublet chemotherapy also increased survival compared to either treatment alone (p&amp;lt;0.05), and the combination led to significantly decreased tumor volume measured at Day 25 (p&amp;lt;0.05). RXC004 treatment in genetically defined cell lines with RSPO fusions or RNF43 mutations led to a significant reduction in BRCA1 and BRCA2 gene expression. In in vitro proliferation studies a synergistic effect of RXC004 and a PARP inhibitor was demonstrated in genetically defined cell lines. Conclusion: These data demonstrate that RXC004 in combination with clinically relevant standard of care chemotherapy regimens can lead to potential benefit over chemotherapy alone. The RXC004 induced downregulation of DNA repair pathway genes observed in vitro could contribute to the beneficial effect seen in combination with a PARP inhibitor in vitro as well as the combination effect observed in vivo with standard of care chemotherapy agents. Citation Format: James Kelly, Simon Woodcock, Inder Bhamra, Cliff Jones, Richard Armer, Jane Robertson, Caroline Phillips. Pre-clinical efficacy of the Wnt pathway inhibitor RXC004 in combination with anti-cancer therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2566.

Abstract 695: Patient derived organoids model lung adenocarcinoma metastases

Abstract Introduction: While lung cancer patient-derived xenografts (PDX) models predict response to therapy, PDX tumors rarely metastasize thus offering little personalized assessment of the biology of metastases. We hypothesize that the development of an in vivo patient-derived organoid (PDO) model will improve our understanding of the underlying genomic and transcriptomic alterations that help drive the biology of metastases for specific lung adenocarcinoma (LUAD) histologic subtypes. Methods: Fresh LUAD specimens were processed and cultured using optimized organoid culture conditions. Established PDOs were characterized by histologic analyses, RNA-sequencing and whole genomic sequencing (WGS). Response to therapy of PDOs was evaluated by treatment with combined chemotherapies, targeted therapies, or co-culturing with patient-matched peripheral blood mononuclear cells (PMBC) in vitro and/or in vivo. The metastatic capabilities of PDOs were assessed in vivo using intracardiac injection and scoring for tumor outgrowth in distant organs using in vivo bioluminescence imaging system. Metastatic tumors from specific organs were isolated, PDOs reestablished, and those tumors underwent additional genomic and transcriptomic characterization. Phylogenetic analyses of tumor metastatic progression and putative metastasis markers were investigated by WGS and RNA-sequencing. Results: We successfully generated 14 PDOs from early-stage (I-II) primary LUAD specimens and 12 from human LUAD metastatic sites (brain, bone and pleural effusion). All PDOs recapitulate genetic alterations and transcriptomic signatures of their original tumors. Moreover, we found that individual PDOs exhibit distinct responses to different chemotherapy regimens and targeted therapies. Pre-treatment of PDOs with low doses of platinum-based doublet chemotherapy regimens activated patient-matched tumor specific T cells and enhanced PD-1 checkpoint inhibitor Nivolumab induced CD8+ T cell-mediated tumor killing. Importantly, utilizing our in vivo PDO metastasis model we successfully developed a platform to evaluate: 1) metastatic potential, 2) response to targeted therapies, 3) tumor evolution with respect of genomic instability, tumor phylogeny, and colonization, and 4) molecular signatures promoting tumor metastases. Conclusion: Our PDO system reliably models human LUAD in vitro and in vivo, by recapitulating histologic architectures, genomic alterations and transcriptomic signatures of the parent LUAD. Using LUAD PDOs we have successfully created multiple platforms to assess response to chemo- and targeted- therapies, develop an in vivo PDO metastasis model to assess tumor evolution, and use of patient matched PMBCs and PDOs to assess immune-priming strategies for individual patient tumors. Citation Format: Yuan Liu, David Jones. Patient derived organoids model lung adenocarcinoma metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 695.

Randomized phase 2 study evaluating efficacy and safety of inupadenant in combination with chemotherapy in adults with metastatic non–small cell lung cancer (mNSCLC) who progressed on immunotherapy.

TPS9158 Background: In cancer, the accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via the high affinity A2A receptor (A2AR), causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. This results in increased tumor cell survival and immune escape (Blay 1997; Merighi 2003; Muller-Haegele 2014). Therefore, inhibiting A2AR could reverse immunosuppression and re-establish immune surveillance in the tumor microenvironment. Inupadenant is an antagonist of the A2AR with potent inhibition of A2AR even at the high concentrations of adenosine present in the tumor microenvironment. Ongoing clinical studies have established inupadenant as a molecule with a favorable safety profile with preliminary evidence of clinical activity in multiple tumor types, including durable PRs in patients who have exhausted standard treatment options (Buisseret 2021). The standard treatment for patients without a driving mutation who progress on first-line IO is a platinum-based doublet chemotherapy regimen. Carboplatin plus Pemetrexed (C+P) is the preferred chemotherapy in nonsquamous mNSCLC. Study A2A-005 will evaluate the efficacy of inupadenant in combination with C+P as a second-line therapy in adult patients with nonsquamous mNSCLC (post-IO). A successful outcome from study A2A-005 will help address a high unmet need for this patient population and could lead to new therapeutic options. Methods: This is a 2-part study. The first part is an open label dose-finding part to determine the safety and recommended Phase 2 dose (RP2D) of inupadenant in combination with C+P (N = 40). In Part 2, 150 patients will be randomized 1:1 to inupadenant or placebo, both in combination with C+P. Tumor response will be determined according to RECIST 1.1 criteria and safety findings will be reviewed by the Safety Review Committee (for Part 1) and the Data Monitoring Committee (for Part 2). Key eligibility criteria include 1) mNSCLC of nonsquamous pathology, 2) have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy, and have progressed (IO/IO combination therapy is allowed), 3) have measurable disease as defined by RECIST v1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. Primary endpoints are RP2D (for Part 1) and PFS (for Part 2). Secondary endpoints include change in tumor size, ORR, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. The study will be conducted in approximately 11 countries in North America and Europe. Clinical trial information: EudraCT 2021-005487-22.

Elevated levels of CA125 (MUC16) in metastatic gastric cancer as a strong predictor of poor survival

Introduction: CA125 is an extracellular domain of MUC16 glycoprotein. The clinical significance of serum CA125 has been most extensively studied in ovarian cancer. The significance of serum CA125 in gastric cancer has not been fully elucidated. There is evidence that MUC16 overexpression is associated with poor survival in patients with metastatic gastric cancer. We have not found any research papers on the correlation between the levels of serum CA125 and MUC16 overexpression.Objective: The objective of the study was to assess the effects of elevated CA125 levels in patients with metastatic cancer on the long‑term results (time to disease progression and overall survival).Materials and methods: CA125 was determined in the serum before the start of first‑line chemotherapy in 75 patients (45 males and 30 females) with metastatic gastric cancer. The mean age of the patients was 61,3 (26,7–84,9) years. Synchronous metastases were observed in 85 % of patients: 57,3 % in the peritoneum, 37,3 % in the liver, 5,4 % at other sites. Palliative gastrectomy and metastasectomy were performed in 28 % and 20 % of patients, respectively. Monotherapy, doublet and triplet chemotherapy regimens were used in 6,7 %, 58,7 % and 36,0 % of patients, respectively.Results: the analysis showed that elevated levels of CA125 (&gt; 37 IU/mL) were associated with a significant reduction in median time to progression (3,5 months (CI 2,87–9,53) vs 6,2 months, р = 0.001 (CI 2,02–4,9)) and overall survival (5,1 months (CI 6,07–28,1) vs 17,1 months (CI 3,5–6,67), р = 0.001). One‑factor ANOVA showed that factors with the strongest effects on the survival rates included the location of metastases (peritoneum), tumor histology (adenocarcinoma/signet ring cell carcinoma), the use of palliative gastrectomy and metastasis resection. A multi‑factor ANOVA showed that the only favorable prognostic factors in terms of overall survival rates were normal CA125 levels (HR 0,39 (95 % CI 0,18–0,84), р = 0.001) and the use of palliative gastrectomy (HR 0,23 (95 % CI 0,1–0,58), р = 0.001). The use of triplet chemotherapy regimens allowed to slightly improve the overall survival rates in the group of patients with elevated CA125 levels; however, the differences were not statistically significant (6,7 months vs 4Ю0 months, p = 0.29).Conclusion: Elevated levels of CA125, which reflect MUC16 overexpression to a certain extent, is a strong independent predictor of poor outcome in metastatic gastric cancer. Currently, a possible way to overcome this negative impact is to use more intensive chemotherapy regimens. However, further research should be aimed at finding adequate targets and ways of neutralizing the negative impact of MUC16 overexpression in patients with metastatic gastric cancer.

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling

BackgroundPemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling. MethodsA total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models. Results157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186. ConclusionsThis study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.

Evaluation of prescribing trends in patients with gastrointestinal cancers; A prospective observation study

Background: To Evaluate the prescribing trends in patients with gastrointestinal cancers; A prospective observational study in Bharath Hospital and Institute of Oncology, Mysuru.&#x0D; Methodology: Six hundred and seventy eight patients were screened and 111 were enrolledinto the study based on inclusion and exclusion criteria and the same was taken for further analysis.&#x0D; Results: Out of 111 patients with gastrointestinal carcinoma, 66 patients (54%) are between age of 41-50 years. In these study 78 patients (70.3%) were males, 91 patients (81.98%) are from rural area, in our study 69 patients were (62.16%) illiterate. In this study, the prevalence of GI cancer was 16.37% was observed. Doublet chemotherapy regimen (18.11%) was frequently prescribed, in which 71.11% of patients who received FOLFOX and ECF had carcinoma of GI while paclitaxel + carboplatin (8.10%). Singlet regimen 5-Flurouracil (1.80%), Capecitabine (0.90%) were highly prescribed among the different cancer types. The most commonly prescribed supportive care medications Palenosetron (90.99%) dexamethasone (90.99%) and ranitidine (23.42%), filgrastim (83.33%) were prescribed among all cycles of chemotherapy.&#x0D; Conclusion: Prevalence of gastrointestinal cancer in the study was 16.37% and more male were diagnosed gastrointestinal cancers.

Real-World Outcomes of Gemcitabine, Cisplatin, and Nab-Paclitaxel Chemotherapy Regimen for Advanced Biliary Tract Cancer: A Propensity Score-Matched Analysis

Background/AimsAdvanced biliary tract cancer (BTC) is associated with poor survival. A recent phase II study of triplet combination chemotherapy, including gemcitabine, cisplatin, and nanoparticle albumin-bound (nab)-paclitaxel, has shown promising results. This study aimed to compare the efficacy of triplet and standard doublet chemotherapy in a real-world setting.MethodsPatients with advanced BTC treated with triplet and doublet chemotherapy regimens were recruited. The propensity-score nearest neighbor matching method with a ratio of one-to-one was used to create a matched cohort for comparison. Progression-free survival (PFS), overall survival (OS), and safety profiles were examined in both groups.ResultsA total of 68 patients (n=34 per group) were included in the matched cohort, and their baseline characteristics were well balanced. Survival outcomes in the triplet chemotherapy group were not better than those in the doublet chemotherapy group, with a median PFS of 7.5 months (95% confidence interval [CI], 4.1 to 10.9) versus 7.2 months (95% CI, 5.6 to 8.9) (hazard ratio [HR], 0.93; 95% CI, 0.53 to 1.62; p=0.793) and a median OS of 13.7 months (95% CI, 8.8 to 18.7) versus 12.2 months (95% CI, 8.4 to 16.0) (HR 0.73; 95% CI, 0.38 to 1.41; p=0.354), respectively. In addition, the treatment-related severe adverse events, such as neutropenia, were more common in the triplet chemotherapy group.ConclusionsGemcitabine, cisplatin, and nab-paclitaxel did not improve the PFS or OS compared to that achieved by standard chemotherapy in patients with advanced BTC. The benefits of triplet chemotherapy in advanced BTC require examination in large randomized controlled trials.Key Words Biliary tract cancer; Gemcitabine; Cisplatin; Albumin-bound paclitaxel

Trıplet or Doublet Chemotherapy Regimens in Metastatic Gastric Cancer

Chemotherapy is the most important treatment option for patients diagnosed at an advanced stage. Chemotherapy both prolongs survival and increases the quality of life. Today, there is still no definite information about whether doublet or triplet chemotherapy should be chosen in empirical therapy. Therefore, we designed our study to evaluate first-line treatment options in metastatic gastric cancer.Our study is retrospective and involves five centers in Turkey. Inclusion criteria were the presen

Gastric cancer: Russian clinical guidelines

Gastric cancer remains one of the most common malignancies in Russia. Despite steady decrease of gastric cancer incidence it still reaches 24.65 per 100 000 population (crude rate) in 2019 with about 36 000 new cases annually. More than 29 000 people die of gastric cancer every year. High mortality rate is mostly caused by an extremely significant proportion of patients with metastatic disease which reached 40.1% in 2019. The majority of cases is related to Helicobacter pylori infection, salty diet, tobacco exposure as well as hereditary syndromes. Staging of locally advanced gastric cancer includes contrast-enhanced computed tomography of the thorax, abdomen and pelvis as well as diagnostic laparoscopy with peritoneal washings. In patients with inoperable or disseminated cancer of the stomach additional analysis for HER2, microsatellite instability and PD-L1 status is recommended. Endoscopic or laparoscopic resection remains the mainstay of treatment in patients with early cancer. Laparoscopic gastrectomy in patients with locally advanced cancer is reserved for high-volume centers with extensive experience with the procedure. Recently, perioperative cytotoxic therapy became the standard of treatment in patients with locally advanced gastric cancer. FLOT regimen is recommended while FOLFOX6 or XELOX are considered possible in the elderly or frail patients. Drug therapy includes standard doublet or triplet chemotherapy regimens for metastatic disease with trastuzumab for HER2(+++) patients. Patients with MSI-H tumors can be treated with pembrolizumab starting with 2nd line while nivolumab is reserved for the 3rd and further lines regardless of PD-L1 status. Importantly, this year guidelines include multimodal prehabilitation including physical exercise, nutritional support and psychological counselling as a possibility in all patients in need of surgery. Also standardized enhanced recovery protocols are recommended for usage during the perioperative period.