Optimal Treatment Sequence Research Articles

Evolving Standards of Care in the Management of Localized Colorectal Cancer.

The treatment of patients with localized rectal cancer is complex and requires input from a multidisciplinary team. Baseline local staging and mismatch repair protein testing are vital to develop individualized treatment plans. There are multiple options in terms of treatment modalities and sequencing, including transanal excision, short-course radiation, long-course chemoradiation, chemotherapy doublet or triplet, nonoperative management, and immune checkpoint blockade for patients with mismatch repair deficient tumors. While localized colon cancer is typically treated with surgical resection and consideration of adjuvant chemotherapy, emerging data suggest that neoadjuvant chemotherapy may be beneficial in patients with higher-risk disease. Quality-of-life considerations are imperative to prevent potential chronic effects on psychosocial health, neuropathy, fertility, and bowel, bladder, and sexual function. The omission of radiation or surgery can mitigate these toxicities without diminishing oncologic outcomes. The optimal treatment plan and sequence is not a one-size-fits-all approach but rather should be personalized to the patient's disease burden, tumor location, comorbidities, and preferences.

Informing optimal treatment (tx) sequences for platinum-eligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in the United States: Results of a clinical simulation modeling exercise.

e13514 Background: Platinum-based chemotherapy (PBT) followed by avelumab (AVE) as first-line (1L) maintenance for patients with nonprogressive disease (PBT ± AVE) is the standard of care in la/mUC. This study compared the overall survival (OS) and cost-effectiveness of the tx sequence of PBT ± AVE followed by enfortumab vedotin (EV) or other therapies, including immuno-oncology (IO), in second line (2L; ie, PBT + 2L EV/IO or PBT + AVE + 2L EV/IO) vs 1L EV + pembrolizumab (PEM) for PBT-eligible patients (PBTp) from a US commercial payer perspective. Methods: A partitioned survival model compared outcomes with PBT ± AVE and EV + PEM among PBTp. Inputs included progression-free survival and OS, time to tx discontinuation, adverse event (AE) incidence, and health utilities and costs. Efficacy inputs were sourced and extrapolated from patient data in JAVELIN Bladder 100 (data cut: Jun 4, 2021), AVENANCE real-world study (1), and published data (EV-302 trial). Safety data were sourced from US prescribing information. Drug, subsequent tx, disease management, and AE management costs (2023 USD) were calculated. The optimal tx sequencing scenario assumed 80% of patients starting PBT were eligible to receive AVE (2023 Flatiron data cut; (2)), 70% of patients progressing on PBT ± AVE would start 2L, and 70% of those would be eligible for EV. Outcomes included life-years (LYs), quality-adjusted LYs (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Scenarios and probabilistic sensitivity analyses (PSAs) were conducted to assess uncertainty. Results: LY, QALY, costs, and ICER modeling outcomes are shown in the Table. Use of EV in 2L after PBT ± AVE is associated with 0.76 lower QALYs, but given the large cost saving, it represents a cost-effective use of resources at the $150,000/QALY willingness to pay (WTP) threshold. PSAs showed that PBT ± AVE is likely to be more cost-effective over a broad and relevant WTP threshold range ($0-500,000/QALY). Results were sensitive to drug acquisition costs and eligibility to receive AVE and 2L EV. Conclusions: Based on this simulation exercise, the use of 2L EV after PBT ± AVE achieves considerable survival benefit at substantially lower costs vs 1L EV + PEM in PBTp with la/mUC. Given the shift toward value-based care in oncology, such analyses are becoming increasingly relevant to guide clinical decision-making. There is a need to assess tx alternatives that balance healthcare costs while optimizing outcomes in patients with la/mUC. 1. Barthélémy et al, J Clin Oncol 2024;42[suppl 4]: Abstract 561. 2. Moon et al, J Clin Oncol 2023;41[suppl 16]: Abstract 4567. [Table: see text]

Challenges in IBD Research 2024: Pragmatic Clinical Research.

Pragmatic clinical research is 1 of the 5 focus areas of the Challenges in IBD Research 2024, a multidisciplinary effort by scientists, clinicians, patients, and funders to identify priorities for patient-centric research. This summary provides a comprehensive overview of current gaps in inflammatory bowel disease (IBD) clinical research and actionable approaches to address them. This review is focused on identifying research that is needed to achieve the best outcomes for patients in clinical practice. Research gaps include understanding the needs of understudied patient groups and addressing barriers to care so all patients receive optimal care, validating and using biomarkers to enable early diagnosis and result in better outcomes for adults and children with IBD, and determining the optimal sequencing of treatments (medical, surgical, adjunct) in children and adults. Inclusive pragmatic research is needed to address these gaps and lead to improvements in patient care and outcomes for all populations of patients with IBD.

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. Inaddition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Abstract PO4-04-10: Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial

Abstract BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard of care for hormone receptor-positive (HR+)/Human Epidermal Growth Factor 2 negative (HER2-) metastatic breast cancer (MBC); no consensus actually exists for second-line (2L) treatments. The HERMIONE-13 trial evaluates the adopted therapeutic options after CDK4/6i failure and the potential factors that influence these choices. METHODS: HERMIONE-13 is a retrospective and prospective multicentric observational trial involving 15 Italian Centers. Information about therapies after disease progression to CDK4/6i from January 2016 until December 2020 was collected for the present analysis, aiming at evaluating which are the clinical criteria guiding the choice of 2L therapy after CDK4/6i failure. RESULTS: 114 pts have been enrolled: 14 pts (12.3%) received neoadjuvant treatment, 80 (70.2%) adjuvant therapy, of whom 46 (57.5%) chemotherapy (CT)+ endocrine therapy (ET) and 33 (41.3%) ET alone. Among the 79 pts treated with adjuvant ET, 44 pts (55.7%) showed primary or secondary endocrine resistance. 39 pts (34.2%) received first-line (1L) CDK 4/6i in combination with Fulvestrant (F), the remaining with aromatase inhibitors (AIs). Median duration of 1L CDK4-6i was 10.4 months (interquartile range (IQR) 4.7-17.4). Median age at 2L start was 59.5 years (IQR 51-68). As 2L therapy, 79 pts (69.3%) received CT±targeted therapy (TT) and 35 (30.7%) ET±TT. Visceral metastases at the beginning of 2L were documented in 46 pts (40.4%). Comorbidities were present in 48 (42.9%) of the pts, mainly cardiac diseases (25, 22.3%); 71 pts (63.4%) showed a 1L-related adverse events (AEs) (NA: 2 pts), mainly hematological toxicity (60, 53.6%). Among 79 pts treated with adjuvant ET, 60 (76%) were addressed to 2L CT±TT, while 19 (24%) to an ET-based therapy. A longer duration of 1L was observed in pts treated with 2L ET±TT (12.5 months, 7.2-22.2) in comparison with those treated with CT±TT (8.7 months, 4.2-14.9). The majority of pts treated with 1L F+CDK 4/6i underwent 2L CT-based treatment, as summarized in Table 1. Analyzing the population treated with 2L CT±TT, we observed that median age was 58 years (49-67), slightly lower than that of pts treated with ET±TT (63, 54-69). Among pts with visceral metastases, 30 pts (65.2%) were addressed to 2L CT±TT and 16 pts (34.8%) to ET±TT; CT±TT was also the favorite choice for the majority of pts with concomitant disease (33, 68.8%) and with previous CDK4/6i-related toxicity (47, 66.2%). Among age, visceral metastases, comorbidities, adjuvant treatment, duration of 1L therapy, use of 1L F and 1L related AEs, univariate analysis revealed that previous use of adjuvant ET (p=0.021), 1L F (p< 0.001), duration of 1L treatment (p=0.043) and age at 2L start (p=0.053) are all factors influencing the choice of 2L therapy. At the multivariate logistic regression model, only the use of F in association with CDK4/6i as 1L treatment and age at 2L therapy were associated with the choice between ET±TT vs CT± TT, with a backward selection, as summarized in table 2. CONCLUSION: The preliminary results of our study suggest that previous F in combination with CDK4/6i is a statistically confirmed predictor of choice for subsequent CT, whereas the increase in age is significantly associated with the choice for ET. Further research is needed to investigate the optimal sequencing of treatments following CDK4/6i and to determine predictive factors of response to 2L therapies. Table 1 2L choices in 1L F+CDK 4/6i pts. Table 2 Statistical model with the significant variables. Citation Format: Marina Elena Cazzaniga, Emanuela Rossi, Antonella Turla, Massimo Ambroggi, Alice Baggi, Rossana Berardi, Fulvio Borella, Serena Capici, Federica Cicchiello, Luigi Coltelli, Ugo De Giorgi, Antonella Ferro, Ornella Garrone, Monica Giordano, Elisabetta Landucci, Marco Mazzotta, Gabriella Moretti, Raffaella Palumbo, Francesca Fulvia Pepe, Patrizia Vici, Fable Zustovich, Viola Cogliati. Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-10.

OPT-In; Optimized Patient Treatment Outcomes in Plaque Psoriasis: A 3-Year State-Transition Treatment-Sequencing Model in the Italian Setting.

There are several treatment options for plaque psoriasis (PsO), but uncertainty remains around the optimal sequencing of treatments. The aims of this study were to investigate how adopting a best-treatment-first treatment sequence impacts patient outcomes and healthcare systems and to quantify the cost of treatment failure to the healthcare system. A 3-year state-transition treatment-sequencing model which identifies all possible treatment sequences in PsO was adapted to the Italian healthcare setting. Treatments considered in the model are those with European Medicines Agency marketing authorization and reimbursement in Italy as of December 2022. Italian market share data (2019-2021) and list prices (2022) informed the current prescribed sequences; these sequences were compared against all possible sequences to determine opportunities for improvement. Both the national perspective in Italy as well as the local perspective from seven regions were considered. The cost of treatment failure was informed through a questionnaire circulated to Italian dermatologists. Overall, 1284 possible treatment sequences are possible when four lines of treatment are considered for patients with moderate-to-severe PsO in Italy. Within the estimated range of treatment failures across those sequences (0.97-2.56 per patient over 3 years), current prescribing behavior from the national perspective suggests patients will face 1.44 failures on average; this highlights the potential for improvement. For every treatment failure, the cost borne by the Italian National Healthcare Service (NHS) is €676.80. Overall, prescribing more optimized treatment sequences results in a 22.95% reduction in failures with a 2.27% increase in costs. The regional analyses found similar trends. Results suggest that selecting the most effective treatment sequences for incident patients provides the greatest opportunity to reduce treatment failures and maximize patient outcomes with a modest impact on costs. While regional variations exist, there is room for improvement across the board, which could translate to more efficient local healthcare systems.

Current Therapeutic Sequencing in Chronic Lymphocytic Leukemia.

The treatment landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is constantly changing. CLL patients can be divided into three risk categories, based on their IGHV mutational status and the occurrence of TP53 disruption and/or complex karyotype. For the first-line treatment of low- and intermediate-risk CLL, both the BCL2 inhibitor venetoclax plus obinutuzumab and the second generation BTK inhibitors (BTKi), namely acalabrutinib and zanubrutinib, are valuable and effective options. Conversely, venetoclax-based fixed duration therapies have not shown remarkable results in high-risk CLL patients, while continuous treatment with acalabrutinib and zanubrutinib displayed favorable outcomes, similar to those obtained in TP53 wild-type patients. The development of acquired resistance to pathway inhibitors is still a clinical challenge, and the optimal treatment sequencing of relapsed/refractory CLL is not completely established. Covalent BTKi-refractory patients should be treated with venetoclax plus rituximab, whereas venetoclax-refractory CLL may be treated with second generation BTKi in the case of early relapse, while venetoclax plus rituximab might be used if late relapse has occurred. On these grounds, here we provide an overview of the current state-of-the-art therapeutic algorithms for treatment-naïve patients, as well as for relapsed/refractory disease.

Sequencing of Anti-CD19 Therapies in the Management of Diffuse Large B-Cell Lymphoma.

Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant are directed against the B-cell antigen cluster of differentiation 19 (CD19). The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. Although CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable using current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies for CD19-directed therapy is hampered by the exclusion of patients who have received prior CD19-directed therapies from major clinical trials. Antigen escape, which is attributed to mechanisms including epitope loss and defective cell surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy, and retrospective analyses indicate that some patients with disease relapse after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T has been limited to small case series. Prospective studies and detailed analyses are needed to understand how pretreatment and posttreatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy to fully maximize treatment strategies.

Immune Therapies in AL Amyloidosis-A Glimpse to the Future.

Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.

The Real-Life Impact of Primary Tumor Resection of Synchronous Metastatic Colorectal Cancer-From a Clinical Oncologic Point of View.

The complex medical care of synchronous metastatic colorectal (smCRC) patients requires prudent multidisciplinary planning and treatments due to various challenges caused by the primary tumor and its metastases. The role of primary tumor resection (PTR) is currently uncertain; strong arguments exist for and against it. We aimed to define its effect and find its best place in our therapeutic methodology. We performed retrospective data analysis to investigate the clinical course of 449 smCRC patients, considering treatment modalities and the location of the primary tumor and comparing the clinical results of the patients with or without PTR between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs. A total of 63.5% of the 449 smCRC patients had PTR. Comparing their data to those whose primary tumor remained intact (IPT), we observed significant differences in median progression-free survival with first-line chemotherapy (mPFS1) (301 vs. 259 days; p < 0.0001; 1 y PFS 39.2% vs. 26.6%; OR 0.56 (95% CI 0.36-0.87)) and median overall survival (mOS) (760 vs. 495 days; p < 0.0001; 2 y OS 52.4 vs. 26.9%; OR 0.33 (95% CI 0.33-0.53)), respectively. However, in the PTR group, the average ECOG performance status was significantly better (0.98 vs. 1.1; p = 0.0456), and the use of molecularly targeted agents (MTA) (45.3 vs. 28.7%; p = 0.0005) and rate of metastasis ablation (MA) (21.8 vs. 1.2%; p < 0.0001) were also higher, which might explain the difference partially. Excluding the patients receiving MTA and MA from the comparison, the effect of PTR remained evident, as the mOS differences in the reduced PTR subgroup compared to the reduced IPT subgroup were still strongly significant (675 vs. 459 days; p = 0.0009; 2 y OS 45.9 vs. 24.1%; OR 0.37 (95% CI 0.18-0.79). Further subgroup analysis revealed that the site of the primary tumor also had a major impact on the outcome considering only the IPT patients; shorter mOS was observed in the extrapelvic IPT subgroup in contrast with the intrapelvic IPT group (422 vs. 584 days; p = 0.0026; 2 y OS 18.2 vs. 35.9%; OR 0.39 (95% CI 0.18-0.89)). Finally, as a remarkable finding, it should be emphasized that there were no differences in OS between the smCRC PTR subgroup and metachronous mCRC patients (mOS 760 vs. 710 days, p = 0.7504, 2 y OS OR 0.85 (95% CI 0.58-1.26)). The role of PTR in smCRC is still not professionally justified. Our survey found that most patients had benefited from PTR. Nevertheless, further prospective trials are needed to clarify the optimal treatment sequence of smCRC patients and understand this cancer disease's inherent biology.

Sequencing Treatments in Patients with Advanced Well-Differentiated Pancreatic Neuroendocrine Tumor (pNET): Results from a Large Multicenter Italian Cohort.

Background: The optimal treatment sequencing for advanced, well-differentiated pancreatic neuroendocrine tumors (pNETs) is unknown. We performed a multicenter, retrospective study to evaluate the best treatment sequence in terms of progression-free survival to first-line (PFS1) and to second-line (PFS2), and overall survival among patients with advanced, well-differentiated pNETs. Methods: This multicenter study retrospectively analyzed the prospectively collected data of patients with sporadic well-differentiated pNETs who received at least two consecutive therapeutic lines, with evidence of radiological disease progression before change of treatment lines. Results: Among 201 patients, 40 (19.9%) had a grade 1 and 149 (74.1%) a grade 2 pNET. Primary tumor resection was performed in 98 patients (48.8%). First-line therapy was performed in 128 patients with somatostatin analogs (SSA), 35 received SSA + radioligand therapy (RLT), 21 temozolomide-based chemotherapy, and 17 SSA + targeted therapy. PFS was significantly longer in patients with grade 1 pNETs compared to those with grade 2, in patients who received primary tumor surgery, and in patients treated with RLT compared to other treatments. At multivariate analysis, the use of upfront RLT was independently associated with improved PFS compared to SSA. Second-line therapy was performed in 94 patients with SSA + targeted therapy, 35 received chemotherapy, 45 SSA + RLT, and 27 nonconventional-dose SSA or SSA switch. PFS was significantly longer in patients treated with RLT compared to other treatments. At multivariate analysis, the type of second-line therapy was independently associated with the risk for progression. OS was significantly longer in patients who received primary tumor surgery, with Ki67 < 10%, without extrahepatic disease, and in patients who received SSA-RLT sequence compared to other sequences. Conclusions: In this large, multicenter study, RLT was associated with better PFS compared to other treatments, and the SSA-RLT sequence was associated with the best survival outcomes in patients with pNETs with Ki67 < 10%. Primary tumor surgery was also associated with improved survival.

A review of perioperative treatment strategies with immunotherapy and tyrosine kinase inhibitors in resectable and stage IIIA-N2 non-small cell lung cancer.

Stage IIIA-N2 non-small cell lung cancer (NSCLC) is a heterogeneous group with different potential therapeutic approaches. Treatment is typically multimodal with either surgical resection after neoadjuvant chemotherapy and/or radiation or concurrent chemotherapy and radiation if unresectable. Despite the multimodal treatment and early stage, cure rates have traditionally been low. The introduction of immunotherapy changed the treatment landscape for NSCLC in all stages, and the introduction of immunotherapy in early-stage lung cancer has improved event free survival and overall survival. Tyrosine Kinase inhibitors (TKIs) have also improved outcomes in early-stage mutation-driven NSCLC. Optimal treatment choice and sequence is increasingly becoming based upon personalized factors including clinical characteristics, comorbidities, programmed death-ligand 1 (PD-L1) score, and the presence of targetable mutations. Despite encouraging data from multiple trials, the optimal multimodal sequence of stage IIIA-N2 NSCLC treatment remains unresolved and warrants further investigation. This review article summarizes recent major clinical trials of neoadjuvant and adjuvant treatment including stage IIIA-N2 NSCLC with a focus on immunotherapy and TKIs.

Stereotactic Radiosurgery and Stereotactic Fractionated Radiotherapy in the Management of Brain Metastases.

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM patients have changed. Considering and addressing the fact that patients with BM are living longer, the need to provide effective local control while preserving quality of life and neurocognition is fundamental. Over the past decade, SRS and SRT have become a more commonly chosen treatment option for BM. Despite significant advances in the treatment of BM, numerous questions remain regarding patient selection and optimal treatment sequencing. Clinical trials are critical to advancing our understanding of BM, especially as more therapeutic alternatives become available. Therefore, it is imperative for interdisciplinary teams to improve their understanding of the latest advances in SRS-SRT. This review aims to comprehensively explore SRS and SRT as treatments for BM, covering clinical considerations in their application (e.g., patient selection and eligibility), managing limited and multiple intact BM, addressing brainstem metastases, exploring combination therapies with systemic treatments, and considering the health economic perspective.

Hairy cell leukemia 2024: Update on diagnosis, risk-stratification, and treatment-Annual updates in hematological malignancies.

Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogenous group of mature lymphoid B-cell disorders characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment. Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11c, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral bone marrow infiltration and the presence of BRAFV600E somatic mutation. Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood, and the immunoglobulin heavy chain variable region gene mutational status. VH4-34 positive HCL cases are associated with a poor prognosis, as well as HCL with TP53 mutations and HCL-V. Patients should be treated only if HCL is symptomatic. Chemotherapy with risk-adapted therapy purine analogs (PNAs) are indicated in first-line HCL patients. The use of chemo-immunotherapy combining cladribine (CDA) and rituximab (R) represents an increasingly used therapeutic approach. Management of relapsed/refractory disease is based on the use of BRAF inhibitors (BRAFi) plus R, MEK inhibitors (MEKi), recombinant immunoconjugates targeting CD22, Bruton tyrosine kinase inhibitors (BTKi), and Bcl-2 inhibitors (Bcl-2i). However, the optimal sequence of the different treatments remains to be determined.

Sequential combination of sonic hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma.

Sonic hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC). However, the use of these drugs is limited by adverse events, and relapse at discontinuation in around one-half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially as resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined. We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation. We present a case series of patients with laBCCs who achieved complete response after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist. Eleven patients were included. SHHis were prescribed for a median 5 months (range 4-11). Consolidation RT was performed after complete response to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events. SHHi treatment followed by consolidation RT after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.

Sequence of Epinephrine and Advanced Airway Placement After Out-of-Hospital Cardiac Arrest

While epinephrine and advanced airway management (AAM) (supraglottic airway insertion and endotracheal intubation) are commonly used for out-of-hospital cardiac arrest (OHCA), the optimal sequence of these interventions remains unclear. To evaluate the association of the sequence of epinephrine administration and AAM with patient outcomes after OHCA. This cohort study analyzed the nationwide, population-based OHCA registry in Japan and included adults (aged ≥18 years) with OHCA for whom emergency medical services personnel administered epinephrine and/or placed an advanced airway between January 1, 2014, and December 31, 2019. The data analysis was performed between October 1, 2022, and May 12, 2023. The sequence of intravenous epinephrine administration and AAM. The primary outcome was 1-month survival. Secondary outcomes were 1-month survival with favorable functional status and prehospital return of spontaneous circulation. To control imbalances in measured patient demographics, cardiac arrest characteristics, and bystander and prehospital interventions, propensity scores and inverse probability of treatment weighting (IPTW) were performed for shockable and nonshockable initial rhythm subcohorts. Of 259 237 eligible patients (median [IQR] age, 79 [69-86] years), 152 289 (58.7%) were male. A total of 21 592 patients (8.3%) had an initial shockable rhythm, and 237 645 (91.7%) had an initial nonshockable rhythm. Using IPTW, all covariates between the epinephrine-first and AAM-first groups were well balanced, with all standardized mean differences less than 0.100. After IPTW, the epinephrine-first group had a higher likelihood of 1-month survival for both shockable (odds ratio [OR], 1.19; 95% CI, 1.09-1.30) and nonshockable (OR, 1.28; 95% CI, 1.19-1.37) rhythms compared with the AAM-first group. For the secondary outcomes, the epinephrine-first group experienced an increased likelihood of favorable functional status and prehospital return of spontaneous circulation for both shockable and nonshockable rhythms compared with the AAM-first group. These findings suggest that for patients with OHCA, administration of epinephrine before placement of an advanced airway may be the optimal treatment sequence for improved patient outcomes.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

P1037 Treatment sequences and time on specific treatments in patients with inflammatory bowel disease under advanced treatment – a German claims data analysis

Abstract Background The number of advanced therapies (ADT) approved for the treatment (Tx) of inflammatory bowel disease (IBD) in is increasing, however, yet no guidance on optimal sequencing of treatments is available in Germany (and elsewhere). This study aims to investigate applied Tx sequences of ADT in claims data based on real-world setting across Germany in patients (pts) with IBD. Methods A retrospective healthcare claims data analysis was conducted using claims data from approx. 4.5 Mio pts within German statutory health insurance, including pts diagnosed with Crohn’s disease (CD) and ulcerative colitis (UC) from 2014 to 2021. Pts were followed up for at least 6 months after the first prescription of ADT (index date) if not deceased. A pre-index period of at least 12 months was applied to only include pts naïve to ADT. The study assessed Tx sequences and time to next treatment (TTNT) among other parameters. Data was not adjusted to disease severity and only descriptively reflects real world Tx patterns within the database. Results The database included 15.041/18.361 pts with CD/UC. Pts with CD/UC starting ADT between 2014 to 2021 received either Adalimumab (ADA: 923/337), Infliximab (IFX: 616/419), Ustekinumab (UST: 113/25) or Vedolizumab (VDZ: 139/248). In an analysis of ADT sequences and TTNT defined as start of first line (1L) Tx to start of second line (2L) Tx we found that during the observation period the majority of pts (71.4%) have not switched to 2L Tx yet. In 1L, ADA was observed as the preferred Tx in CD pts (51.5%) followed by IFX (34.4%), VDZ (7.8%) and UST (6.3%), in UC pts IFX (40.7%) was mostly prescribed as 1L followed by ADA (32.8%), VDZ (24.1%) and UST (2.4%). The proportion (%) of pts not switched to 2L Tx within one year for CD/UC were: ADA (83.6/70.3), IFX (79.0/73.1), UST (93.5/96.0) and VDZ (85.4/86.6). Within three years proportions of pts not switched to 2L Tx changed for CD/UC: ADA (68.1/54.5), IFX (57.8/56.8), UST (82.5/72.0) and VDZ (72.7/73.0) (table1). For pts who had a switch to a different ADT, the switch occurred within one year in over 50% of all pts. Most Tx switches (45.8%) were observed in pts who received IFX as 1L Tx, both in the UC and CD population. The majority of CD pts that received 2L Tx were switched to UST (35.7%), while in UC, a high proportion of pts were switched to VDZ (44.3%). Further Tx pathways and proportions of switches are summarized in Figure 1. Conclusion The study found that most IBD pts started ADT with ADA or IFX, but unadjusted time on 1L data may suggest a trend towards superior TTNT of VDZ and UST in UC and CD. Data should be interpreted carefully, as pts for &amp;gt;1L are limited and UST and VDZ were approved during the study period.

P610 Ustekinumab demonstrates superior treatment persistence over anti-TNF in Crohn’s disease patients previously treated with vedolizumab

Abstract Background With the rise in biologic therapies to manage moderate to severe inflammatory bowel disease (IBD), determining the optimal treatment sequence has become crucial. This aids in the selection of the next biologic agent after prior exposure or unresponsiveness to a previous regimen. Vedolizumab (VDZ) is a gut-specific α4β7-integrin inhibitor recognized for its efficacy in treating moderate to severe IBD. Yet, only a few studies have assessed the comparative effectiveness of alternative biologics, such as ustekinumab (UST) and antitumor necrosis factor agents (anti-TNF), following VDZ exposure. Methods In our retrospective study conducted at Chang Gung Memorial Hospital at Linkou, a leading 3700-bed medical facility in Taiwan, we examined 110 IBD patients who underwent treatment with UST or anti-TNF agents (including adalimumab and infliximab) from May 2019 to September 2023. UST's standard maintenance dosing in Taiwan is every 12 weeks. We utilized Kaplan-Meier analysis and Cox proportional hazards models to evaluate the 52-week treatment retention of UST versus anti-TNF. Results Of the 110 participants, 40 were diagnosed with ulcerative colitis (UC), and 70 with Crohn’s disease. The demographics between the anti-TNF and UST groups regarding age, gender, and body mass index were comparable. The primary reason for vedolizumab discontinuation in both groups was secondary non-response (Table 1). UST exhibited a notably higher 52-week retention in overall IBD (HR: 5.36, 95% CI: 1.84-15.62, P = 0.002, Figure 1a) and in Crohn’s disease patients (HR: 10.75, 95% CI: 1.34-86, P = 0.025, Figure 1b) compared to anti-TNF. While UST also showed superior persistence at 52 weeks in UC patients, the difference was not statistically significant (HR: 2.25, 95% CI: 0.63-8, P = 0.211, Figure 1c). At the 52-week mark, 73.5% of the anti-TNF group and 81% of the UST group were not on steroids. Secondary non-response was the predominant cause for discontinuation of the current biologic. Notably, UST required more frequent dose adjustments than anti-TNF. The safety profile of both treatments was comparable. Conclusion UST showed superior treatment persistence, compared to anti-TNF in Crohn's disease patients who had previously been exposed to vedolizumab. However, UST required more frequent dosing adjustments compared to anti-TNF.

Modeling the Synergistic Impact of Yttrium 90 Radioembolization and Immune Checkpoint Inhibitors on Hepatocellular Carcinoma.

The impact of yttrium 90 radioembolization (Y90-RE) in combination with immune checkpoint inhibitors (ICIs) has recently gained attention. However, it is unclear how sequencing and dosage affect therapeutic efficacy. The purpose of this study was to develop a mathematical model to simulate the synergistic effects of Y90-RE and ICI combination therapy and find the optimal treatment sequences and dosages. We generated a hypothetical patient cohort and conducted simulations to apply different treatments to the same patient. The compartment of models is described with ordinary differential equations (ODEs), which represent targeted tumors, non-targeted tumors, and lymphocytes. We considered Y90-RE as a local treatment and ICIs as a systemic treatment. The model simulations show that Y90-RE and ICIs administered simultaneously yield greater benefits than subsequent sequential therapy. In addition, applying Y90-RE before ICIs has more benefits than applying ICIs before Y90-RE. Moreover, we also observed that the median PFS increased up to 31~36 months, and the DM rates at 3 years decreased up to 36~48% as the dosage of the two drugs increased (p < 0.05). The proposed model predicts a significant benefit of Y90-RE with ICIs from the results of the reduced irradiated tumor burden and the associated immune activation and suppression. Our model is expected to help optimize complex strategies and predict the efficacy of clinical trials for HCC patients.