Chemotherapy In First-line Treatment Research Articles

Outcomes of patients with intermediate-risk neuroblastoma presenting with motor deficits relating to intraspinal tumor extension: A report from the Children's Oncology Group study ANBL0531.

Tumor invasion of the spinal canal is detected radiographically in approximately 15% of patients with newly diagnosed neuroblastoma (NB). The optimal clinical approach to maintain excellent survival outcomes while minimizing long-term sequelae is yet to be defined. Patients with intermediate-risk neuroblastoma (IR-NB) and radiographically identified intraspinal tumors who were treated on the Children's Oncology Group study ANBL0531 were studied prospectively to evaluate neurologic outcomes related to cord compression. Patients were defined as being symptomatic versus asymptomatic based on reporting of neurologic motor deficits at diagnosis. Patient characteristics, tumor biology, chemotherapy treatment, surgical interventions, and neurologic and disease outcomes are reported. Of the 92 patients with intraspinal tumors, 42 (46%) were symptomatic and most (73%) had complete resolution of symptoms. Age, degree of motor deficit, and duration of symptoms at diagnosis were not associated with complete resolution. While symptomatic patients were more likely to undergo upfront laminectomy, laminectomy was not associated with improvement of motor symptoms. Administration of additional chemotherapy beyond initial treatment assigned per protocol to achieve the treatment end point was not associated with achieving symptom resolution. Patients presenting with motor deficits due to intraspinal tumor had excellent survival and favorable neurologic outcomes, with the majority reporting complete resolution of motor symptoms regardless of severity and duration of symptoms at diagnosis or neurosurgical intervention. Prompt diagnosis and initiation of first-line chemotherapy treatment remain priority, while neurosurgical intervention should be reserved for patients with rapid neurologic deterioration. Biology-based therapy and tumor response should continue to be used to maintain favorable outcomes.

Guidelines versus real-world data in metastatic bladder cancer: A population-based study on first-line chemotherapy treatment patterns

BackgroundFor patients with metastatic bladder cancer (mBC) palliative chemotherapy is one of the main treatment options. Real-world insights into outcomes are available, but a comprehensive overview of specific treatment details like number of chemotherapy cycles received and (reasons for) adjustments is lacking. MethodsA population-based study was conducted, including all patients diagnosed with mBC in the Netherlands between 2016 and 2021 who started chemotherapy as initial treatment. Data on patient, tumor, and treatment characteristics, including number of cycles, adjustments and reasons for adjustments, and survival were collected from the Netherlands Cancer Registry. Treatment patterns and outcomes were analyzed descriptively. Logistic regression analysis was used to identify factors associated with receiving the full guideline-recommended treatment (4–6 cycles). ResultsA total of 684 patients started first-line chemotherapy, mostly carboplatin-based (54%). Of these patients, 35% did not receive the full course of treatment. Among these patients who received <4 cycles, 24% died within one month of stopping treatment. Male sex and good performance status were independently associated with receiving the full course of treatment. Among patients who did receive a full course of treatment, half still had adjustments to their treatment schedule, which mainly included dose reductions due to side effects. ConclusionsAmong patients with mBC starting first-line chemotherapy, only a small majority received the recommended number of cycles, and treatment adjustments were common. This suggests that adhering to recommended treatment is challenging, emphasizing the importance of integrating insights on treatment discontinuation and modifications into the shared decision-making process and guideline development.

Cost-effectiveness analysis of tislelizumab plus chemotherapy versus standard chemotherapy in first-line treatment for extensive-stage small cell lung cancer: perspectives from the United States and China.

Tislelizumab combined with chemotherapy has shown significant clinical benefits in improving overall survival compared to chemotherapy alone for patients with extensive-stage small-cell lung cancer (ES-SCLC). This study aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy versus standard chemotherapy as a first-line treatment for ES-SCLC from the US payer perspective and the perspective of the Chinese healthcare system. We conducted an economic evaluation using a Markov state-transition model, reflecting the US payer perspective and the perspective of the Chinese healthcare system. Baseline patient characteristics and essential clinical data were obtained from the RATIONALE-312 trial. The costs and utilities were derived from open-access databases and published literature. The primary outcomes measured included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB). Uncertainties in the model were addressed by probabilistic sensitivity analysis (PSA) and one-way sensitivity analysis (OWSA). In the base-case analysis, the addition of tislelizumab to chemotherapy provided an incremental gain of 0.16 QALYs at an additional cost of $7430.73, resulting in an ICER of $46,132.33 per QALY. Although above the willingness-to-pay (WTP) threshold of China of $38,042.49 per QALY, the cost-effectiveness was marginal, with an INHB of - 0.03 QALYs and an INMB of $- 1303.06. In the US, despite a slightly higher effectiveness gain of 0.28 QALYs, the increased cost of $45,157.35 resulted in an unfavorable ICER of $163,885.06 per QALY, exceeding the US WTP threshold of $150,000.00. PSA showed probabilities of cost-effectiveness of tislelizumab plus chemotherapy at 17.18% in China and 40.41% in the US. Tislelizumab combined with chemotherapy was not a cost-effective first-line treatment option for ES-SCLC in China or the US; however, the margin of cost-effectiveness was narrow.

Immune checkpoint inhibitors for first-line treatment of advanced esophageal squamous cell carcinoma

Immunotherapy has revolutionized the treatment landscape of esophageal squamous cell carcinoma. He etal. present the final results of the randomized phase 3 ESCORT-1st trial, confirming positive survival outcomes when adding the anti-PD1 inhibitor camrelizumab to first-line chemotherapy treatment in Chinese patients with esophageal squamous cell cancer.1.

Efficacy and safety analysis on the combination of camrelizumab with nab-paclitaxel and cisplatin-based chemotherapy in first-line treatment of advanced or metastatic esophageal squamous cell carcinoma.

205 Background: Nab-paclitaxel has indicated good efficacy during the multi-line esophageal squamous cell carcinoma (ESCC) treatment. Our study summarized the efficacy and safety of the first-line combination treatment of camrelizumab with nab-paclitaxel and platinum in advanced or metastatic ESCC patients. This could provide evidence of the positive effects of using nab-paclitaxel. Methods: We included patients with advanced or metastatic ESCC who received camrelizumab in association with nab-paclitaxel and cisplatin for 3-6 cycles as first-line therapy. The patients were recruited from the First Hospital of Jilin University between August 2021 and December 2023. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), PFS, and OS rates at 12, 18, and 24 months, including safety. Results: 43 patients were included in this study, they were assessed based on the therapeutic effect, with 72.1% [95% CI,58.1%-86.1%]ORR and 100% DCR. The median PFS was 25.5 months, and the median OS was not achieved. The OS rates were 96.8%, 86.4%, and 78.6% at 12 months, 18 months, and 24 months, respectively. In contrast, the PFS rates were 90.1%, 75.8%, and 68.3%, respectively. Grade 3 or above treatment-related adverse reactions (TRAEs) occurred in nine patients (20.9%). No patient developed severe grade 5 TRAEs. Conclusions: During the first-line treatment of advanced or metastatic ESCC, applying nab-paclitaxel in associated with camrelizumab and cisplatin -based therapy showed a positive effect. Therefore, the results exhibit an extension of OS and PFS with manageable safety and no new TRAEs.

PALC-02. PALLIATIVE RADIOTHERAPY FOR HAEMOSTASIS IN CHILDREN WITH CEREBRAL METASTATIC HAEMORRHAGE

Abstract BACKGROUND Among children, bleeding from brain metastases is rare. Bleeding could be caused by: cancer, treatments and chemotherapy/other drugs such as Bevacizumab, NSAIDs and anticoagulants. We report a case of brain RT after metastases bleeding. METHODS A 14-years-old boy with a negative previous medical history presented to the Emergency Department with seizures and loss of consciousness. Full-body CT scan revealed brain and renal haemorrhages and a right testicular lesion. Serum βhCG was 223,773 mIU/mL. Neurosurgical bleeding control and right orchiectomy were performed: the histopathology revealed a metastatic mixed non-seminomatous germ cell neoplasia of the testis. First-line chemotherapy (4 cycles of Cisplatin/Etoposide/Ifosfamide) and second-line treatments (Paclitaxel/Ifosfamide/Cisplatin and Gemcitabine/Paclitaxel/Oxaliplatin) were performed. Suddenly, he presented with left-sided hyposthenia and partial left hemibody seizure. CT scan revealed 2 haemorrhagic brain lesions, one in each hemisphere. Surgery was not feasible. We started anti-oedema and anti-epileptic therapy, and whole brain RT (WBRT, 36 Gy/12 fx, BEDα/β= 10 Gy= 46.8 Gy). After 5 days from the start, RT had a 7-day stop because of acute oedema and clinical deterioration. Fourth-line chemotherapy was administered with CarboPEB (1st of further 4 cycles), and then WBRT was restarted. At the end of WBRT a stereotactic RT boost to both the haemorrhagic lesions was delivered (20 Gy/10 fx, BEDα/β= 10 Gy= 24.0 Gy). As of today, eight months after the end of therapy, the patient is free from disease and βhCG is negative. CONCLUSION Palliative RT in children is a non-conventional indication, but potentially effective at providing rapid haemostasis, especially in selected cases (surgery not feasible/contraindicated, adult-type histologies, …) and it is ensuring a good tumor control and low-grade acute toxicities. Hypofractionation is suggested to balance patient comfort and treatment effectiveness, especially when life expectancy is short. The optimal RT schedule, dose and fractionations need to be further investigated.

CO162 Systematic Literature Review (SLR) and Meta-Analysis of Crizotinib Versus Conventional Chemotherapy in First-Line Treatment for ROS-1 Rearranged Non-Small Cell Lung Cancer

CO162 Systematic Literature Review (SLR) and Meta-Analysis of Crizotinib Versus Conventional Chemotherapy in First-Line Treatment for ROS-1 Rearranged Non-Small Cell Lung Cancer

A phase 2/3 study of fianlimab, cemiplimab, plus chemotherapy versus cemiplimab plus chemotherapy in first-line treatment of advanced non-small cell lung cancer.

TPS8660 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Anti–programmed cell death-1 (PD-1) therapies have improved outcomes in patients with NSCLC; however, most patients do not respond or only respond for a limited time. The combination of cemiplimab (anti–PD-1) and chemotherapy has been studied for the first-line treatment of advanced NSCLC (aNSCLC), regardless of programmed cell death-ligand 1 (PD-L1) status. While the standard of care continues to evolve for NSCLC, one approach to potentially improve outcomes is the combination of checkpoint inhibitors (IO) with chemotherapy. Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab are both high-affinity, fully human IgG4 monoclonal antibody IO therapies that have shown promising clinical activity when combined in patients with aNSCLC in a Phase 1 study (NCT03005782). This ongoing study will further investigate the combination of fianlimab + cemiplimab + chemotherapy. Methods: This is a randomized, multicenter, Phase 2/3 study of fianlimab + cemiplimab + platinum-doublet chemotherapy (chemo) versus cemiplimab + chemo in patients with unresectable stage IIIB/IIIC or stage IV NSCLC irrespective of PD-L1 expression levels (NCT05800015). This study will be conducted globally at approximately 210 sites. Patient eligibility criteria: ≥18 years old; squamous or non-squamous histology with stage IIIB, IIIC, or IV disease; valid PD-L1 result; ≥1 radiographically measurable lesion by computed tomography/magnetic resonance imaging; Eastern Cooperative Oncology Group performance status ≤1; adequate organ and bone marrow function. The Phase 2 portion will be used to determine the fianlimab dose selected for the Phase 3 portion: patients will be randomized 1:1:1 to receive fianlimab high dose + cemiplimab 350 mg + chemo (Arm A), fianlimab low dose + cemiplimab 350 mg + chemo (Arm B), or cemiplimab 350 mg + chemo + placebo (Arm C), Q3W IV. In Phase 3, patients will be randomized 1:1 into one of two treatment arms (either Arm A or Arm B, and Arm C) based on findings from Phase 2. The primary endpoint of Phase 2 is objective response rate (ORR) per blinded independent central review. The primary endpoint of Phase 3 is overall survival. The secondary endpoints include efficacy (ORR, disease control rate, time to tumor response, duration of response, progression-free survival, and overall survival), safety and tolerability, immunogenicity (anti-drug antibodies and neutralizing antibodies against fianlimab or cemiplimab in serum), patient-reported outcomes, and pharmacokinetics. This study and a parallel study of fianlimab + cemiplimab in patients with aNSCLC with tumors expressing PD-L1 ≥50% (NCT05785767) are currently open for enrollment. Clinical trial information: NCT05800015 .

A rapid assessment tool for systemic treatment outcomes in colorectal cancer with deep bidirectional transformers.

e15567 Background: Retrospective investigations involving cancer treatment encounter the challenge of manually reviewing voluminous imaging reports to identify the best responses and the timing of disease progression. Here, we employed natural language processing, specifically deep bidirectional transformers, to automate the extraction of treatment response data. Methods: Data were sourced from the Yonsei Cancer Data Library database, focusing on patients with stage II-IV colorectal cancer at the Yonsei Cancer Center from Jan 1, 2010, to Dec 31, 2020. Imaging reports from 6,574 patients were gathered, amounting to 97,119 CT readings. Among these, 9,000 CT reports corresponding to 2,859 patients were randomly subjected to multilabel manual labeling by four radiology experts, based on the RECIST version 1.1 classification (CR/NED, PR, SD, PD). The pretrained BERT-base-uncased model was employed and fine-tuned for the downstream tasks of multilabel classification. 6,765 reports were used for training, while the remaining 1,000 reports were divided equally between the validation and test sets. Additionally, an algorithm for integrating and extracting treatment response data was also implemented. Clinical data were meticulously collected for 47 patients with stage IV early-onset colorectal cancer (EOCRC) receiving palliative first-line chemotherapy. The primary objective was to evaluate the model’s accuracy in predicting the timing of disease progression events within a ±30-day window. Secondary objectives focused on the model’s ability to identify the best response and its timing within a ±45-day window. Results: The evaluation of the classification accuracy across 1,000 individual CT reports, categorized as CR/NED (319), PR (86), SD (272), and PD (298), revealed accuracy with an AUROC of 0.956 and an F1 score of 0.823. All EOCRC patients were initially diagnosed with stage IV disease, and 45 out of 47 (95.7%) underwent metastasectomy either before initiating chemotherapy or during the first-line chemotherapy treatment. In clinical evaluation, the model demonstrated 72.3% (95% Confidence Interval [CI], 59.5-85.1) accuracy in predicting the day of disease progression within a ±30-day window. It achieved 55.3% (95% CI, 41.1-69.5) accuracy in predicting the best response category and its timing within ±45-days. Notably, the model was more accurate in predicting CR/NED at 72% compared to SD and PR, which had accuracy of 27.3% and 15.4%, respectively. Conclusions: Our model demonstrated high performance in classifying CT reports, which is expected to provide rapid insights into patient progress and improve clinical decision-making. However, the complexity involved in integrating and extracting data result in slight constraints in performance. This emphasizes the need for further research into multimodal large language models that can integrate a wider variety of clinical data.

Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells.

Acute myeloid leukemia is the second most frequent type of leukemia in adults. Due to a high risk of development of chemoresistance to first-line chemotherapy, the survival rate of patients in a 5-year period is below 30%. One of the reasons is that the AML population is heterogeneous, with cell populations partly composed of very primitive CD34+CD38- hematopoietic stem/progenitor cells, which are often resistant to chemotherapy. First-line treatment with cytarabine and idarubicin fails to inhibit the proliferation of CD34+CD38- cells. In this study, we investigated Metformin's effect with or without first-line conventional chemotherapy, or with other drugs like venetoclax and S63845, on primitive and undifferentiated CD34+ AML cells in order to explore the potential of Metformin or S63845 to serve as adjuvant therapy for AML. We found that first-line conventional chemotherapy treatment inhibited the growth of cells and arrested the cells in the S phase of the cell cycle; however, metformin affected the accumulation of cells in the G2/M phase. We observed that CD34+ KG1a cells respond better to lower doses of cytarabine or idarubicin in combination with metformin. Also, we determined that treatment with cytarabine, venetoclax, and S63845 downregulated the strong tendency of CD34+ KG1a cells to form cell aggregates in culture due to the downregulation of leukemic stem cell markers like CD34 and CD44, as well as adhesion markers. Also, we found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience

IntroductionFirst-line systemic therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemoimmunotherapy trials failed to show a clear benefit over chemotherapy alone. We used real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy, or combination chemoimmunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). Materials and MethodsWe used the National Cancer Database to identify patients with stage IV mUC diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. ResultsIn our cohort of 4,169 patients, multivariable analysis identified increasing age (RRR: 1.07, 95%CI, 1.06–1.08) and comorbidity burden (, as independent predictors of receiving immunotherapy. Treatment at an academic facility was associated with increased likelihood of combination treatment (RRR: 1.29, 95%CI, 1.01–1.65). After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95%CI, 0.62–0.83) was associated with improved survival compared to chemotherapy. ConclusionsPatients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Utilization of chemoimmunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy.

Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study

In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P=0.0170), pain (-2.24, 95% CI:-4.30 to-0.17; P=0.0337), fatigue (-2.24, 95% CI:-4.46 to-0.02; P=0.0479), constipation (-3.27, 95% CI-5.49 to-1.05; P=0.0039), QLQ-OES18 pain (-1.77, 95% CI-3.11 to-0.43; P=0.0097), trouble swallowing saliva (-2.09, 95% CI:-3.77 to-0.42; P=0.0146), and choked when swallowing (-3.23, 95% CI:-5.60 to-0.86; P=0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P=0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P<0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

Fisetin and/or capecitabine causes changes in apoptosis pathways in capecitabine-resistant colorectal cancer cell lines

Capecitabine is recommended as one of the first-line chemotherapy treatments for advanced or metastatic colorectal cancer. Researches have been conducted on capecitabine’s impact on the viability of human colon cancer cells and its potential to induce apoptosis. However, even in cases initially responsive to treatment, the development of acquired resistance significantly limits its efficacy. Challenges still exist in effectively treating patients with chemotherapy, and developing new cytotoxic drugs is hindered by drug resistance. Fisetin alters the cell cycle, inducing apoptosis, inhibiting cancer cell proliferation, and enhancing the therapeutic effectiveness of chemotherapy drugs. This work aims to create a plan for reversing capecitabine resistance. For this purpose, the role of capecitabine and/or fisetin combinations in cell proliferation and apoptosis has been determined in both wild-type and capecitabine-resistant HT29 cells (CR/HT29). We developed capecitabine-resistant cell line from wild-type HT29 cells. This study demonstrated the effects of capecitabine, fisetin, and their combinations on both resistant and wild-type cells through experiments including cell survival skills, cell proliferation, wound healing, colony formation, hoechst staining, and western blot analysis. We established capecitabine-resistant cell lines. P-gp expression increased in CR/HT29 cells. Capecitabine effects on a CR/HT29 cells less than wild-type HT29 cells. The combination of fisetin and capecitabine in cell proliferation caused greater reductions in wild-type HT29 cells than in capecitabine-resistant cells. Fisetin has also additive effects on the apoptotic pathway in CR/HT29 cells. This study provides new perspectives on the combination of capecitabine and/or flavonoid treatment in resistant cells.Graphical abstract

Prognostic impact of age in advanced non-small cell lung cancer patients undergoing first-line checkpoint inhibitor immunotherapy and chemotherapy treatment

BackgroundResearch on the association between age and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy combined with chemotherapy as first-line setting is limited. The aim of study is to determine the influence of age on the progress-free survival (PFS) and overall survival (OS) in those patients after adjusting for potential confounders. MethodsA total of 207 advanced NSCLC patients treated with immunotherapy combined with chemotherapy in the first-line treatment in Guangxi Medical University Cancer Hospital from March 10, 2019, to December 31, 2022, was retrospectively analyzed. χ2 (categorical variables) was used to analyze the differences among the different age groups. Cox regression and Kaplan–Meier analyses were used to assess the association between age and clinical outcomes. P values < 0.05 (two-sided) were considered statistically significant. ResultsThe mean age of the cohort was 58.8 ± 10.3 years. The percentages of patients < 65, 65–69, 70–74, and ≥ 75 years were 66.7 %, 19.3 %, 9.2 % and 4.8 %, respectively. Compared to the aged < 65 years group, the HR for the risk of disease progression for each group are 0.67 (95 %CI = 0.40–1.12, P = 0.125), 0.66 (95 %CI = 0.31, 1.43, P = 0.298), and 2.27 (95 %CI = 0.80, 6.45, P = 0.124), respectively, with no significant differences in the results. And the HR for risk of death for the 65–69 years and 70–74 years groups was 1.16 (95 %CI = 0.64–2.08, P = 0.628) and 0.93 (95 %CI = 0.39–2.23, P = 0.879), respectively. The difference has no statistical significance. Whereas in patients aged ≥ 75, there is an increased risk of death after adjusted confounders with HR = 4.83 (95 %CI = 2.06–11.35). The difference was statistically significant (P < 0.001). Trend test indicates that with advancing age, the patient's risk of death increases (HR = 1.33, 95 % CI = 1.02–1.75, P = 0.034). ConclusionAge may not be the primary factor influencing the efficacy of immunotherapy combined with chemotherapy, but particular attention should be given to the elderly population.

Abstract 4911: PAIRWISE: Deep learning-powered personalized medicine approach identifies actionable drug combinations in B cell lymphoma

Abstract Combination drug therapies offer promise for improving cancer treatment. However, identifying actionable drug combinations for specific cancer subtypes and individual patients remains challenging due to the vast number of possibilities. Existing approaches like high-throughput screening (HTS) and rule-based drug additions have limitations in their ability to predict clinically translatable synergistic combinations. Therefore, advanced machine learning focused on patient-centric modelling have the potential to optimize combination therapies. PAIRWISE is a patient-centric deep learning-powered drug combination recommendation platform. Given gene expression along with chemical structures and targets from a set of two drugs being applied, the output is the binary combination outcome. PAIRWISE introduces a new approach of representing tumor genomics using the unsupervised pretraining design on 11K TCGA tumors. The power of PAIRWISE is derived from knowledge-guided transfer learning by learning from in vitro experiments with drug-drug-cell interactions and cellular heterogeneity. PAIRWISE can accurately predict combination synergy with area under the curve (AUC) &amp;gt; 0.85 across 10 tissue types in a large dataset of 200K in vitro drug combinations and significantly outperform all state-of-the-art methods. Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Finding optimal combination therapy for each DLBCL patient is a critical unmet need. As independent validation, we applied PAIRWISE to an external HTS study of Bruton Tyrosine Kinase inhibitor (BTKi) combinations (Griner et al., 2014), confirming the reproducibility and accuracy of high-confidence predictions (AUC = 0.72). PAIRWISE was also applied to transcriptomic data of 29 DLBCL cell lines (Bal et al., 2022) and predicted BTKi-containing combinations across ABC subtypes with higher synergy scores than GCB (P = 0.02). This is consistent with expected better overall efficacy of BTK inhibitors in ABC subtype (Younes et al., 2019; Davis et al., 2010; Wilson et al., 2015). To predict opportunities in DLBCL, PAIRWISE was used to identify BTKi partners for an additional 211 anti-cancer drugs using 562 published ex vivo DLBCL samples (Schmitz et al., 2018). PAIRWISE effectively identified novel DLBCL sub-population with significantly higher response scores for predicted BTKi combinations and favorable survival. Notably, patients predicted as responsive had significantly better outcomes upon first-line chemotherapy treatments than non-responsive ones (P &amp;lt; 0.0001). Collectively, we demonstrate that PAIRWISE is a highly efficient and generalizable framework that enables confident predictions of pairwise drug combinations at disease subtype level, with the potential of informing treatment options and clinical trial design. Citation Format: Chengqi Xu, Jake Cohen-Setton, Zhouyang Shen, Marta Milo, Ilkay US, Ben Sidders, Jude Fitzgibbon, Heng Pan, Olivier Elemento, Krishna Bulusu. PAIRWISE: Deep learning-powered personalized medicine approach identifies actionable drug combinations in B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4911.

Immune Checkpoint Inhibitor Plus Chemotherapy as First-Line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer: A Systematic Review and Meta-Analysis.

Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is effective in advanced gastric or gastroesophageal junction (G/GEJ) cancer. This study aims to evaluate the clinical effect of first-line immunotherapy in combination with chemotherapy for advanced G/GEJ cancer. Methods: PubMed, Web of Science, Embase and Cochrane databases were systematically searched from the inception of the databases to December 2021. Randomized trials comparing ICI plus chemotherapy with chemotherapy in first-line treatment for advanced G/GEJ cancer were included. The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Analyses were performed in Stata 14.0 software. The study protocol was registered with PROSPERO, number CRD42022300907. Results: Five trials were included for analysis, involving 2, 814 patients. ICI plus chemotherapy can significantly improve OS (hazards ratio [HR], 0.86; 95% CI 0.78-0.94; P = .002), PFS (HR, 0.79; 95% CI 0.63-0.99; P ＜ .001) and ORR (relative ratio [RR], 1.20; 95% CI 1.11-1.30; P < .001). In safety analyses, there were no significant differences in incidence of all AEs, treatment-related adverse event (TRAE), TRAE of grade 3 or higher, serious TRAE and TRAE leading to death between two arms (P > .05). Conclusions: ICI plus chemotherapy is more effective first-line treatment for advanced G/GEJ cancer in contrast to chemotherapy regrading to improving OS, PFS and ORR, without increasing TRAE risk. This study will redefine the role of ICI in combination with chemotherapy in the first-line setting for G/GEJ cancer, and provide reference for clinical treatment.

Concomitant Immunotherapy and Metastasis-Directed Radiotherapy in Upper Tract Urothelial Carcinoma: A Biomarker-Driven, Original, Case-Based Proof-of-Concept Study.

Metastatic upper tract urothelial carcinoma (mUTUC) has a poor prognosis. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in patients with metastatic urothelial carcinoma. However, data supporting the use of ICIs in patients with mUTUC are limited. A promising synergy between ICI and concomitant radiotherapy (RT) has been reported in patients with mUTUC. Our research involved a case-based investigation and emphasized the successful integration of different specialists' skills. Observed after partial urethrectomy procedures for muscle-invasive upper tract urothelial carcinoma (UTUC), the radiological detection of lung metastases prompted us to implement cisplatin-based first-line chemotherapy and molecular characterization in the treatment process. We uncovered alterations in the ERBB2 and FGFR3 genes and mismatch repair deficiency at a molecular level. First-line chemotherapy treatment led to a stable disease, and the patient was started on maintenance immunotherapy with Avelumab. Subsequently, an increase in the size of the lung nodules was described, and the patient received radiotherapy for three lung lesions in combination with immunotherapy. After 3 months, a restaging CT scan reported a complete response, which is still ongoing. We discuss the mechanisms driving RT/ICI synergy and the molecular profile of mUTUC as factors that should be considered in therapeutic strategy planning. Molecular insight enhances the originality of our study, providing a nuanced understanding of the genetic landscape of mUTUC and paving the way for targeted therapeutic strategies. The therapeutic armamentarium expansion encourages the design of a multimodal and personalized approach for each mUTUC patient, taking into account tumor heterogeneity and molecular profiling.

1507TiP Phase Ib multicenter study of trastuzumab deruxtecan (T-DXd) and immunotherapy with or without chemotherapy in first-line treatment of patients (pts) with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (OE): DESTINY-Lung03

1507TiP Phase Ib multicenter study of trastuzumab deruxtecan (T-DXd) and immunotherapy with or without chemotherapy in first-line treatment of patients (pts) with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (OE): DESTINY-Lung03

The Effect of Chemotherapeutic Agents on Survival in Metastatic Non-Small-Cell Lung Cancer with KRAS Mutation

Abstract Introduction KRAS mutation is observed in up to 30% of non-small-cell lung cancer (NSCLC) cases and is corelated with a poor prognosis. In the cases with KRAS p.G12C mutation and first-line chemotherapy (± immunotherapy) resistance, a targeted drug option is available. Objectives Our study aimed to examine the correlation between first-line chemotherapy agents and treatment response in patients with KRAS-mutated metastatic NSCLC. Materials and Methods Retrospective database searches were performed on cases diagnosed with metastatic NSCLC at our center between January 2019 and December 2021 that were found to be KRAS mutation positive using the next-generation sequencing (NGS) approach. The cases were classified into five subgroups based on the chemotherapy regimens (platinum + gemcitabine, platinum + taxane, platinum + pemetrexed, platinum + vinorelbine, and others). The clinical and demographic data of 41 cases were analyzed retrospectively, and survival analyses were performed using the Kaplan–Meier method. Results Thirty-seven of 41 patients (90.2%) were males, and 27 (65.9%) had adenocarcinoma histology. The most prevalent mutation was KRAS G12C, with 12 cases (29.2%), followed by KRAS G12V, with 9 cases (21.9%). Other mutations were as follows: KRAS G12D 4 (9%), KRAS G13C 3 (7.3%), KRAS G12A 2 (4.8%), KRAS G12R 2 (4.8%), KRAS Q61H 2 (4.8%), KRAS Q61L 2 (4.8%), KRAS V14I 2 (4.8%), KRAS A146T 1 (2.4%), KRAS G13G 1 (2.4%), and KRAS G1C 1 (2.4%). The median progression-free survival (mPFS) for all groups was 4.6 months (95% confidence interval [CI]: 2.7-6.5), and there were no statistically significant differences between the groups (p = 0.121). The median overall survival (mOS) for all groups was 9.3 months (95% CI: 3.8–14.5), and there were no statistically significant differences between the groups (p = 0.805). Conclusions OS and PFS analyses showed no differences between platinum + taxane, platin + pemetrexed, platinum + gemcitabine, and platin + vinorelbine used in first-line treatments for KRAS mutant NSCLC cases. We believe that patient-specific characteristics may be a determining factor in selecting chemotherapy for this patient population.

Anti-PD-1 Monoclonal Antibodies (mAbs) Are Superior to Anti-PD-L1 mAbs When Combined with Chemotherapy in First-Line Treatment for Metastatic Non-Small Cell Lung Cancer (mNSCLC): A Network Meta-Analysis.

Platinum-based chemotherapy combined with anti-PD-1 or PD-L1 monoclonal antibodies (mAbs) is now standard first-line therapy for mNSCLC patients without sensitizing driver mutations. Anti-PD-1 and anti-PD-L1 mAbs are considered to be equivalent in efficacy. In the absence of head-to-head randomized control trials (RCTs), we utilized network meta-analysis (NWM) to provide an indirect comparison of their efficacy. A systematic literature review and NWM were performed using RCTs that investigated anti-PD-1 or PD-L1 mAbs ± chemotherapy in patients with mNSCLC in the first-line setting. The primary outcome was comparative overall survival (OS), while secondary outcomes were comparative progression-free survival (PFS), objective response rate (ORR), and rate of grade 3 and higher toxicities. We identified 24 RCTs. Patients treated with anti-PD-1 mAb + chemotherapy compared with anti-PD-L1 mAb + chemotherapy showed superior mOS, mPFS, and ORR with a similar rate of grade 3 and higher toxicities. This difference in mOS was most pronounced in the PD-L1 TPS 1-49% population. The two mAbs were equivalent as single agents. Anti-PD-1 mAb + chemotherapy improved mOS when compared to anti-PD-1 mAb monotherapy, whereas anti-PD-L1 mAbs + chemotherapy did not when compared to anti-PD-L1 mAb monotherapy. Head-to-head RCTs are warranted in the future.