Sequential Regimen Research Articles

Hepatic arterial infusion chemotherapy combined with systemic therapy sequentially or simultaneously for advanced hepatocellular carcinoma.

The goal of this study was to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with targeted therapy and PD-(L)1 blockade (triple therapy), either sequentially (SE) or simultaneously (SI), in the treatment of Barcelona Clinic Liver Cancer (BCLC) stageC hepatocellular carcinoma (HCC). From January1, 2018, to June1, 2022, 575patients with BCLC stageC HCC who underwent SE or SI triple therapy were retrospectively enrolled. Propensity score matching (PSM; 1:1) was performed to eliminate possible confounder imbalances across cohorts. We used the Kaplan-Meier method and a log-rank test to compare the overall survival (OS) and progression-free survival (PFS) rates between the SI and SE groups. The tumor response and the incidence of adverse events (AEs) were reported. After PSM, 182patients in each of the two groups were matched. The median OS in the SI group was significantly longer than that in the SE group (28.8 vs. 16.1months; P = 0.002), and the median PFS was significantly improved in the SI versus SE group (9.6 vs. 7.0months; P = 0.01). The objective response rate based on the mRECIST was higher in the SI group (58% vs. 37%; P < 0.001). The total incidences of grade3-4 AEs were 111/182 (60.9%) and 128/182 (70.3%) in the SE and SI groups, respectively. No grade5 AEs were reported in either group. Simultaneous HAIC plus targeted therapy and PD-(L)1 blockade significantly improved outcomes compared to the sequential regimen in patients with BCLC stageC HCC, with no unexpected AEs. The patients who received hepatic arterial infusion chemotherapy combined with targeted therapy and PD-(L)1 blockade simultaneously have a better prognosis than those who received it sequentially.

CTNI-61. PRELIMINARY RESULTS OF A PHASE I/II TRIAL OF SELINEXOR AND TEMOZOLOMIDE IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).

Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer.

The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.

Mosaic and mixed HIV-1 glycoprotein nanoparticles elicit antibody responses to broadly neutralizing epitopes.

An effective human immunodeficiency virus 1 (HIV-1) vaccine will most likely have to elicit broadly neutralizing antibodies (bNAbs) to overcome the sequence diversity of the envelope glycoprotein (Env). So far, stabilized versions of Env, such as SOSIP trimers, have been able to induce neutralizing antibody (NAb) responses, but those responses are mainly strain-specific. Here we attempted to broaden NAb responses by using a multivalent vaccine and applying a number of design improvements. First, we used highly stabilized SOSIP.v9 trimers. Second, we removed any holes in the glycan shields and optimized glycan occupancy to avoid strain-specific glycan hole responses. Third, we selected five sequences from the same clade (B), as we observed previously that combining Env trimers from clade A, B and C did not improve cross-reactive responses, as they might have been too diverse. Fourth, to improve antibody (Ab) responses, the Env trimers were displayed on two-component I53-50 nanoparticles (NPs). Fifth, to favor activation of cross-reactive B cells, the five Env trimers were co-displayed on mosaic NPs. Sixth, we immunized rabbits four times with long intervals between vaccinations. These efforts led to the induction of cross-reactive B cells and cross-reactive binding Ab responses, but we only sporadically detected cross-neutralizing responses. We conclude that stabilized HIV-1 Env trimers that are not modified specifically for priming naive B cells are unable to elicit strong bNAb responses, and infer that sequential immunization regimens, most likely starting with specific germline-targeting immunogens, will be necessary to overcome Env's defenses against the induction of NAbs. The antigens described here could be excellent boosting immunogens in a sequential immunization regimen, as responses to bNAb epitopes were induced.

Improved Outcomes in Myelofibrosis after Allogeneic Stem-Cell Transplantation in the Era of Ruxolitinib Pretreatment and Intensified Conditioning Regimen—Single-Center Analysis

(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. (2) Methods: In this retrospective, single-center study, we compared allo-HSCT outcomes in 36 adult patients with MF transplanted at two-time intervals (2001–2015 versus 2016–2021). (3) Results: The estimated median overall survival was 48.9 months (95%CI 0.00–98.2) in the cohort transplanted before 2016 and not reached in the more recent years (p = 0.04) due to markedly lower non-relapse mortality (p = 0.02). The 3-year relapse incidence was low in both cohorts (11.1% and 12.5%, p &gt; 0.99). When comparing only subgroups within the more recent cohort based on the presence or absence of total body irradiation (TBI) or the use of sequential regimens, OS and PFS were comparable. (4) Conclusion: Pretreatment with ruxolitinib, intensified conditioning, and the preferential use of haploidentical related instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allo-HCT in MF in recent years.

Comparing long-term efficacy and safety of GP versus TPF sequential chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a propensity score-matched analysis

PurposeTo evaluate the long-term efficacy and safety of GP and TPF sequential chemotherapy regimens in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC).MethodsFrom 2005 to 2016, a total of 408 LA-NPC patients treated with GP or TPF sequential chemoradiotherapy were retrospectively included. Propensity Score Matching (PSM) was employed to balance the baseline variables. Survival outcomes and acute toxicities were compared between both groups.ResultsA total of 230 patients were selected by 1:1 PSM. At a median follow-up of 91 months, no significant differences were observed between the matched GP and TPF groups regarding 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregionally relapse-free survival (83.4% vs. 83.4%, P = 0.796; 75.6% vs. 68.6%, P = 0.301; 86.7% vs. 81.1%, P = 0.096; and 87.4% vs. 87.2%, P = 0.721). Notable disparities in adverse effects were identified, with higher incidences of grade 3/4 thrombocytopenia in the GP group while grade 3/4 leukopenia and neutropenia in the TPF group. Though not recorded in our cohort, combined with the FAERS database, thrombotic adverse reactions are a concern for the GP regimen, while the TPF regimen requires vigilance for life-threatening adverse reactions such as septic shock, acute respiratory distress syndrome, and laryngeal edema.ConclusionNo significant difference in long-term outcomes was observed between the GP and TPF sequential chemotherapy regimens for LA-NPC. Differences in adverse effects should be noted when choosing the regimen.

Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B

Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (<LLOQ) in a subset of patients. The B-Together study investigated if sequential bepirovirsen and pegylated interferon-α-2a (Peg-IFN) therapy can reduce relapse rates and improve response rates. In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA <LLOQ for 24 weeks after planned end of Peg-IFN treatment, in the absence of newly initiated antiviral therapy. The intent-to-treat population included 108 participants (Arm 1, n= 55; Arm 2, n= 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms. Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse. This phase IIb study investigated whether sequential therapy with bepirovirsenfollowed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens. NCT04676724.

Results from a phase I study of 4-l-[131I]iodo-phenylalanine ([131I]IPA) with external radiation therapy in patients with recurrent glioblastoma (IPAX-1).

Glioblastoma (GBM), the most common malignant brain tumor, is associated with devastating outcomes. IPAX-1 was a multicenter, open-label, single-arm phase I study to evaluate carrier-added 4-L-[131I]iodo-phenylalanine ([131I]IPA) plus external radiation therapy (XRT) in recurrent GBM. A total of 10 adults with recurrent GBM who had received first-line debulking surgery plus radio-chemotherapy, were randomized to a single-dose regimen (1f; 131I-IPA 2 GBq before XRT); a fractionated parallel dose regimen (3f-p; 3 131I-IPA 670 MBq fractions, in parallel with second-line XRT), or a fractionated sequential dose regimen (3f-s; 3 131I-IPA 670 MBq fractions before and after XRT). Metabolic tumor responses were determined using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography, while single-photon emission computed tomography was used to guide [131I]IPA tumor dosimetry. All dose regimens were well tolerated. Organ-absorbed radiation doses in red marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease was observed in 4 of the 9 patients at 3 months post-treatment (3-month follow-up [FU], 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month FU, 6 patients demonstrated metabolic stable disease. Median progression-free survival was 4.3 months (95% confidence interval [CI]: 3.3-4.5), while median overall survival was 13 months (95% CI: 7.1-27). Single or fractionated doses of [131I]IPA plus XRT were associated with acceptable tolerability and specific tumor targeting in patients with recurrent GBM, warranting further investigation.

Investigation of the synergistic effect mechanism underlying sequential use of palbociclib and cisplatin through integral proteomic and glycoproteomic analysis.

Chemoresistance largely hampers the clinical use of chemodrugs for cancer patients, combination or sequential drug treatment regimens have been designed to minimize chemotoxicity and resensitize chemoresistance. In this work, the cytotoxic effect of cisplatin was found to be enhanced by palbociclib pretreatment in HeLa cells. With the integration of liquid chromatography-mass spectrometry-based proteomic and N-glycoproteomic workflow, we found that palbociclib alone mainly enhanced the N-glycosylation alterations in HeLa cells, while cisplatin majorly increased the different expression proteins related to apoptosis pathways. As a result, the sequential use of two drugs induced a higher expression level of apoptosis proteins BAX and BAK. Those altered N-glycoproteins induced by palbociclib were implicated in pathways that were closely associated with cell membrane modification and drug sensitivity. Specifically, the top four frequently glycosylated proteins FOLR1, L1CAM, CD63, and LAMP1 were all associated with drug resistance or drug sensitivity. It is suspected that palbociclib-induced N-glycosylation on the membrane protein allowed the HeLa cell to become more vulnerable to cisplatin treatment. Our study provides new insights into the mechanisms underlying the sequential use of target drugs and chemotherapy drugs, meanwhile suggesting a high-efficiency approach that involves proteomic and N-glycoproteomic to facilitate drug discovery.

Cholangiocarcinoma, sequential chemotherapy, and prognostic tests.

Routine blood tests are prognostic tests for patients with cholangiocarcinoma. New drug regimens may produce a median overall survival of 2 years or more. This single practice, IRB-approved, phase II trial examines prognostic tests, Kaplan-Meier survival, and univariate Cox regression analyses. Eligibility requires: intent-to-treat; signed consent; advanced measurable intrahepatic cholangiocarcinoma, with or without resistance to the test drugs; any adult age; performance status 0-2; and expected survival of ≥ 6 weeks. Biweekly treatment, with 1/3 of standard dosages in mg/M2, includes: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hours; Leucovorin 180; Irinotecan 80; and on day 2, Oxaliplatin 40. On progression, drugs are added on day 2: first, Docetaxel 25 precedes Oxaliplatin, with or without Mitomycin C 6 after Oxaliplatin. The next sequential additions are day 1, Cetuximab 400 total mg, then 200 mg weekly, and then Bevacizumab 10 mg/kg is substituted for Cetuximab (FDA IND# 119005). For 35 patients, 19 with 1-2 lines of prior therapy, resistant tumors, and 16 no prior therapy, survival at 24-months is ≥ 72 and ≥ 58%, respectively. For 14 patients aged ≥ 70 years, ≥ 63% survive 24 months, P = 0.28. Validated tests that predict ≤ 6-month survivals find median survival times of 17-months through > 2-years when compared to patients with favorable tests: Neutrophils lymphocyte ratio > 3.0, HR = 6.54, P < 6.4x10-3; absolute neutrophil count > 8000/μl, HR = 4.95, P < 6.5x10-3; serum albumin < 3.5 g/dl, HR = 4.10, P < 0.03; and lymphocyte monocyte ratio< 2.1, HR = 1.6, P = 0.50. Overall, the 76 (60-90)% of patients with 0-2 out of 4 high risk tests survive ≥ 24 months, (P = 7.1x10-3). Treatments produce neither hospitalization, neutropenic fever, severe enteritis, nor severe neuropathies. Two-year survival is replicable and predictable. Findings warrant phase III validation tests of sequential regimens, re-challenge with recombination, low dosages, and blood tests that are associated with lethal mechanisms that impair response and survival.

DIPG-46. TOTAL THERAPY FOR DIFFUSE MIDLINE GLIOMAS: A SEQUENTIAL, INTENSIVE, MULTI-AGENT COMBINATION PLATFORM IS A POTENT TREATMENT STRATEGY

Abstract BACKGROUND Diffuse Midline Glioma (DMG) has a dire prognosis, with a mortality rate nearing 100%. In the past, children diagnosed with Acute Lymphoblastic Leukemia (ALL) faced a similar prognosis until multi-agent chemotherapy revolutionized their survival rates. We hypothesized that implementing a comprehensive treatment strategy for DMG could yield similar efficacy. This study aimed to test the safety and efficacy of sequential, intensive, multi-agent combinations targeting epigenetic/chromatin modification (CBL0137-Panobinostat, CP), polyamine metabolism (DFMO-AMXT1501, DA), and the NF-κB pathway (ACT001) in preclinical DMG models. METHODS/RESULTS Maximum tolerated dose studies, which integrated comprehensive biochemical and hematological analyses with clinical data, tested different treatment durations and drug sequences. Tolerable doses and drug sequences were assessed in the aggressive patient-derived SU-DIPGVI orthotopic model for activity. In total six different drug combination sequences were tested for impact on survival. One particular sequence – DA/ACT001/CP – was significantly more effective compared with both vehicle and other regimens. This specific sequential regimen resulted in a 50% tumour regression rate with surviving animals maintaining tumor-free status &amp;gt; 1 year, compared with 81-day survival in controls. This 5-agent treatment sequence (DA/ACT001/CP) was next tested in the HSJD-DIPG007 orthotopic model with a significant extension of survival (119 days) compared with single or two-agent treatments (vehicle-59 days, DA-86 days, ACT001-66 days, CP-62 days, DA/ACT001-93 days). Further enhancement of this treatment regimen through addition of radiotherapy significantly extended survival to 130 days, with one-third of the cohort showing sustained tumor regression and remaining tumor-free (by Xenogen imaging) for &amp;gt; 220 days. CONCLUSIONS There are no effective therapies for DMG. Single and combination regimens in vivo often extend survival by days or weeks but do not generally eliminate tumors. Our “Total Therapy” strategy, inspired by successful ALL therapies, suggests that multi-agent sequential combination therapy can induce profound responses and unprecedented long-term survival in DMG animal models.

Comparison of the efficacy of immunotherapy at different time points during the perioperative period for stage II-III NSCLC.

e20009 Background: The application of immune checkpoint inhibitors (ICIs) in early-stage lung cancer is fraught with unresolved issues, and there are no clinical studies directly comparing the efficacy of ICIs used in neoadjuvant, adjuvant, and neoadjuvant followed by adjuvant therapy across different perioperative time points in non-small cell lung cancer (NSCLC). Consequently, the optimal timing for immunotherapy in surgically resectable NSCLC remains uncertain. Methods: This study encompassed 536 patients with stage II-III NSCLC, diagnosed and treated across multiple centers from January 2019 to December 2022. Clinical data for all patients ultimately included in the study were retrospectively collected. The primary endpoints evaluated were event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) . Secondary endpoints included pathological complete response (pCR) and major pathological response (MPR). Propensity score matching was utilized to mitigate confounding factors, comparing the efficacy of ICIs across different treatment modalities and time dimensions during the perioperative period of lung cancer. Results: The integration of neoadjuvant ICIs with chemotherapy was observed to significantly enhance pCR ( p &lt; 0.001), MPR ( p &lt; 0.001), EFS ( p = 0.002), and OS ( p &lt; 0.001) in comparison to neoadjuvant chemotherapy alone. Similarly, the combination of adjuvant ICIs with chemotherapy markedly improved DFS ( p = 0.034) and OS ( p = 0.021) relative to adjuvant chemotherapy alone. Building on these insights, we further delineated the efficacy of ICIs across distinct temporal dimensions within the perioperative interval, categorizing patients into three groups: neoadjuvant ICIs plus chemotherapy, adjuvant ICIs plus chemotherapy, and a sequential regimen of neoadjuvant followed by adjuvant ICIs plus chemotherapy. The analysis revealed no significant differences in DFS and OS among the three patient groups for stage II NSCLC. In contrast, for stage III NSCLC, both neoadjuvant ( p = 0.015) and sequential treatment approaches ( p = 0.047) demonstrated significantly improved DFS outcomes compared to the adjuvant protocol, with no substantial statistical difference noted between the neoadjuvant and sequential treatments ( p = 0.274). Furthermore, the sequential regimen outperformed the adjuvant strategy in OS ( p = 0.020). However, when comparing the neoadjuvant strategy with either the adjuvant ( p = 0.054) or sequential approaches ( p = 0.717), there were no statistically significant variances detected. Conclusions: For individuals with resectable stage III NSCLC, perioperative administration of neoadjuvant and sequential adjuvant ICIs appears to confer enhanced survival advantages. Future efforts should focus on refining treatment strategies for early-stage NSCLC, aiming to deliver enhanced survival benefits to patients.

Abstract PO4-01-12: Efficacy of neoadjuvant dose-dense versus standard chemotherapy regimens in ER+ HER2-negative breast cancer: a single-center matched-cohort study. Exploratory analysis of immune markers

Abstract Introduction: Dose-dense adjuvant CT improves long-term outcomes, which has been proved in clinical trials and meta-analysis. However, the efficiency of thе modern dose dence (dd) anthracycline-taxane (A-T) sequential regimens in the neoadjuvant (NA) setting of ER+HER2- breast cancer (BC) has not been assessed. Tumour-infiltrating lymphocytes (TILs) play a key role in the formation of anti-tumor immunity and can be one of the markers of treatment efficacy and prognosis. Studies evaluating TILs in ER+ BC have mixed results. Materials and methods. The aim of the study was to assess the rate of RCB 0-I of 4xddAC (doxorubicine/cyclophosphamide)–T (4xdocetaxel once every 3 weeks or 12xpaclitaxel weekly) NA chemo compared to standart regimen and to study the subpopulation composition of the lymphoid infiltrate and its effect on achieving RCB 0-I. RCB 0-I as a primary end point was chosen due comparable long-term results in ER+HER2- BC as per meta-analisys. Results: The study included pts with stage II-III ER+(ER≥10%) HER2- BC who received NA A-T chemo in a single center from Jan 2017 to Aug 2022. The majority of patients (85,2%) had stage III disease. Statistical hypothesis: NA ddAC–T chemo would increase the rate of RCB 0-1 to 32% from 22% with ACq3w (once every 3 weeks)-T, with a study power of 80%, ά = 0.05, 138 patients should be included in the study. A total of 315 patients were included, 147 received ddAC-T and 168 - ACq3w-T. After propensity matching analysis 138 patients in each group were included in the final analysis. TILs were studied in core-biopsy samples before NA chemo in 79 patients by flow cytometry. The following 8 subpopulations of lymphocytes were assessed as percentage in the cell pool: CD3+, CD3+CD4+, CD3+CD8+, CD4+CD127+CD25+, CD3-CD19+, CD3-CD16+CD56+, CD3+CD16+CD5+, CD8+CD279+(PD-1). The results are presented in medians (Me) due to abnormal distribution. The RCB 0 rate was 18.8% in the ddAC-T group vs 14.5% in the ACq3w-T group (p=0.379), RCB 0-1 - 33.3% vs 21.7% respectively (p=0.04). According to subgroup analysis, significant benefit of ddAC regimen found in patients ≤ 50 y.o., cN0, with PR ≥20%. For the following populations of TILs significant differences in Me for RCB0-I vs RCB II-III were observed: CD3+CD8+, CD3–CD19+, CD3–CD19+, CD8+CD279+. In multivariative analisys CD8+CD279+(PD-1)≤Me proved to be an independent predictive factor for RCB 0-I (p=0,048). Immunological signature CD8+CD279+ ≤ Me, CD3+CD8+ ≤ Me, CD4+CD25+ &amp;gt; Me, CD3-CD19+ &amp;gt; Me was associated with the rate of 66,7% of RCB 0-I vs 0% with the signature with the opposite values. Conclusion: ddAC-T NA chemo compared to standart regimen in ER+HER2- BC increases RCB0-1 rate. CD8+CD279+(PD-1)≤Me is an independent predictive factor for RCB 0-I. Citation Format: Elena Kovalenko, Elena Artamonova, Yaroslav Zhulikov, Maxim Khoroshilov, Alexander Petrovskiy, Igor Vorotnikov, Tatiana Zabotina, Zaira Kadagidze. Efficacy of neoadjuvant dose-dense versus standard chemotherapy regimens in ER+ HER2-negative breast cancer: a single-center matched-cohort study. Exploratory analysis of immune markers [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 PO4-01-12.

Abstract PO1-01-02: Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study

Abstract Background: The optimal neoadjuvant treatment regimen for HER2-positive breast cancer remains unclear, especially regarding the use of anthracycline. We conducted a prospective phase II study to evaluate sequential neoadjuvant chemotherapy with pegylated liposomal doxorubicin (PLD)/cyclophosphamide followed by taxanes in the presence of full-course trastuzumab/pertuzumab in HER2-positive early breast cancer patients. Methods: In this single-arm, open-label, multicenter, phase II study, eligible patients with confirmed HER2-positive early breast cancer were recruited from four independent hospitals. Patients received four cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (ypT0/is ypN0, tpCR). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, the proportion of patients requiring breast-conserving surgery, and safety. For biomarkers analysis, tumor tissues were collected at baseline and evaluated for Topoisomerase 2 Alpha (TOP2A) expression assessed prospectively with immunohistochemistry (IHC) assay by independent pathologists. Results: Between May 27, 2020 and May 11, 2022, 78 eligible patients were treated and underwent surgery, of whom 42 (53.8%) patients underwent breast-conserving surgery. After neoadjuvant therapy, 47 (60.3%, 95% CI, 48.5%-71.2%) patients achieved a tpCR in the breast and axilla. The bpCR was observed in 49 (62.8%) patients. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. All (100%) patients achieved disease control since the end of the first cycle. No correlations between clinicopathological variables and pathological response were observed. Grade 3 or worse AEs occurred in 35 (44.9%) patients. Nine (11.5%) patients experienced asymptomatic LVEF reduction (≥10% from baseline), but all with a minimum value of &amp;gt;55%. No treatment-related surgical delay or death occurred. For biomarkers analysis, the status of TOP2A was not found to be associated with pCR or 4th-cycle ORR. Conclusions: This dual HER2-blockade plus polychemotherapy as sequential neoadjuvant regimen demonstrates promising anti-tumor activity and acceptable tolerability for patients with HER2-positive breast cancer. Citation Format: Yaping Yang, Liang Jin, Yudong li, Fengxia Gan, Nanyan Rao, Jun Zhang, Ruifa Feng, Zhenzhen Liu, Qiang Liu. Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study [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 PO1-01-02.

Abstract LB272: Sequential inhibition of PARP and BET as a rational therapeutic strategy for glioblastoma multiforme

Abstract Glioblastoma multiforme (GBM), characterized as one of the most aggressive brain cancers, presents significant treatment challenges due to its rapid growth, heterogeneity, and robust defensive mechanisms. Despite advancements in neuro-oncology, GBM's prognosis remains grim, with the median survival of approximately 15 months, underscoring the urgent need for innovative therapeutic strategies. Facing these challenges, PARP inhibitors (PARPi) hold substantial promise in treating GBM, evidenced by over 20 ongoing clinical trials. However, their application has been limited by side effects such as nausea, fatigue, and particularly anemia, as well as a narrow therapeutic spectrum focusing mainly on patients with homologous recombination deficiency (HRDness). Through unbiased transcriptomic and proteomic sequencing, and employing Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA), and Transcriptome-Proteome Correlation Analysis, we discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, extending beyond the previously known impact of BET inhibition on homologous recombination repair. In vitro experiments using GBM cell lines and patient-derived primary GBM cells demonstrated that concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, we observed that DNA damage persists after the discontinuation of PARPi monotherapy. Leveraging these residual effects of PARPi, subsequent BETi administration elevated replication stress levels, leading to the inactivation of GBM cell cycle checkpoints, with efficacy comparable to concurrent treatment. The treatment-induced prolonged stalling of replication forks resulted in their collapse and the formation of double-ended double-strand breaks (DSBs). In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, while protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. In vivo orthotopic transplantation tumor experiments in zebrafish and nude mice demonstrated consistent effects, indicating that sequential administration of PARPi followed by BETi maintained anti-tumor efficacy, similar to concurrent treatment, while reducing toxicity, as evident by the reduced impact on hemoglobin levels. Our findings provide a broader and deeper understanding of the synergistic interaction between BETi and PARPi than previously recognized. This study offers compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy. Citation Format: Xin Peng, Xin Huang, Shaolu Zhang, Naixin Zhang, Shengfan Huang, Yingying Wang, Zhenxing Zhong, Shan Zhu, Haiwang Gao, Zixiang Yu, Xiaotong Yan, Zhennan Tao, Yuxiang Dai, Zhe Zhang, Xi Chen, Feng Wang, Francois X. Claret, Ning Ji, Yuxu Zhong, Dexin Kong. Sequential inhibition of PARP and BET as a rational therapeutic strategy for glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB272.

A scoping review of vasculitis as an immune-related adverse event from checkpoint inhibitor therapy of cancer: Unraveling the complexities at the intersection of immunology and vascular pathology

Background/purposeVasculitis as an immune-related adverse event (irAE) from checkpoint inhibitor therapy (ICI) to treat cancer is a rare clinical event, and little is known regarding its nosology, clinical manifestations, or response to treatment and outcomes. MethodsTo address these gaps, we used the Preferred Reporting Items for Systemic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) framework to further define this complication. Two independent PUBMED searches in September and November of 2022 revealed 127 publications with 37 excluded from title by relevance, 43 excluded by article type, and 23 excluded due to lack of biopsy results, or biopsy negative for vasculitis. Twenty-nine documented cases from 24 publications were included for final analysis. Basic demographics, ICI details, timing of onset of vasculitis symptoms, irAE treatment and outcomes were collected. The vasculitides were classified using 2022 ACR/EULAR Vasculitis Classification Criteria as well as 2012 Revised Chapel-Hill Nomenclature. Adaptations from Naidoo et al. 2023 [1] consensus definitions for irAEs were used and efforts were made to classify steroid-responsive versus unresponsive irAEs. ResultsOf the 29 cases reviewed, the average age of patients was 62.1 ± 11.0, composed of 58.6 % (n = 17) male and 41.3 % (n = 12) female. Prominent cancer types were lung cancer (41.4 %; n = 12), melanoma (41.4 %; n = 12), and renal cancer (10.3 %; n = 3), with majority being stage 4 (75.9 %, n = 22) and stage 3 (10.3 %, n = 3). Only 8 cases met the ACR/EULAR criteria, and by Chapel-Hill Nomenclature, approximately a third were small-vessel vasculitis (31.0 %; n = 9) with n = 4 positive for ANCA. Most biopsies were taken from the skin (37.9 %, n = 11) and kidney (24.1 %, n = 7). Patients were either treated with single (65.5 %, n = 19), dual (17.2 %; n = 5), or sequential (17.2 %; n = 5) ICI regimen which included anti-PD-1 therapy in all but one case, with mean of 8.7 ± 10.5 cycles received. Mean time to onset of symptoms from start of ICI was 7.2 ± 7.8 months, with 55.2 % occurring >3 months since the initial immunotherapy. Vasculitis treatment included glucocorticoids in 96 % of cases and immunotherapy was often discontinued (44.8 %; n = 13). Clinical improvement of irAE was documented in 86.2 % (n = 25). Data were missing in terms of fate of ICI (34.5 %; n = 10) and tumor outcomes (41.4 %; n = 12). Cancer progressed in 20.7 % (n = 6), stable in 34.5 % (n = 10) cases, and 6 patients died of all-causes. ConclusionVasculitis as an irAE appears clinically heterogeneous and rare. Among reported cases with adequate documentation, vasculitis is of delayed onset following the initiation of immunotherapy. Outcomes of ICI-vasculitis were generally favorable, responding to glucocorticoids and immunotherapy withdrawal. There is an urgent need for more standardized reporting of rare irAEs such as vasculitis to clarify clinical risks, classification, relationship to immunotherapy and outcomes.

Abstract 7374: Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma

Abstract Background: Resistance of cancer cells to monotherapies has led to the development of sequential or combination therapy regimens. However, dosing and scheduling of these therapies is challenging due to the numerous dosing and scheduling combinations that can be given. Mathematical models are thus critical tools for addressing this challenge as multiple therapy combinations can be tested in silico to finalize a patient-specific therapeutic regimen in vivo. Here we develop a mathematical framework for combining targeted radiation therapy (TRT) with Chimeric Antigen Receptor (CAR)-T cell immunotherapy and demonstrate the use of in silico techniques to schedule these therapies for maximizing survival. Methods: In the mathematical framework tumor growth is assumed to be exponential and the effect of radiation on both tumor cells and CAR-T cells is modeled using the linear-quadratic model of cell survival to radiation. A predator-prey model is used to characterize the dynamics of tumor and CAR-T cells. Using a preclinical disseminated mouse model of multiple myeloma (MM1S), we evaluate tumor response to 200 nCi of 225Ac-DOTA-Daratumumab (TRT) and 1 million cells of CS1 CAR-T cell therapy both as monotherapies as well as in combination. Tumor burden tracked using bioluminescence imaging from six groups of mice is used to calibrate model parameters: (a) No treatment. (b) Day 7 TRT. (c) Day 7 CAR-T cell therapy. (d) Day 7 TRT + Day 18 CAR-T cell therapy. (e) Day 7 TRT + Day 25 CAR-T cell therapy. (f) Day 7 TRT + Day 32 CAR-T cell therapy. Response to therapy is evaluated using progression-free survival (PFS), overall survival (OS) and time to minimum tumor burden (tmin), all of which are calculated using the predicted in silico tumor burden dynamics and the tumor burden at the start of first therapy. We evaluate these response metrics for various dosing and scheduling regimens. Results: Therapy intervals that were too short or too long are shown to be detrimental for therapeutic efficacy. TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing, while the interval being too long results in tumor regrowth, negatively impacting tumor control and survival. If a single dose is split into multiple doses, the splitting is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Based on the model parameters we estimate the minimum required TRT activity and CAR-T cell dose to demonstrate an improvement in PFS. Conclusions: The proposed model demonstrates the impact of different dosing and scheduling regimens of TRT and CAR-T therapy on survival metrics. It is a potent tool for translating preclinical results to the clinic and eventually tailor therapy regimens for patients. Citation Format: Vikram Adhikarla, Dennis Awuah, Enrico Caserta, Megan Minnix, Maxim Kuznetsov, Amrita Krishnan, Jeffrey Y. Wong, John E. Shively, Xiuli Wang, Flavia Pichiorri, Russell C. Rockne. Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma [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 7374.

Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after atezolizumab/bevacizumab failure: A real-world study.

Atezolizumab plus bevacizumab (ATE+BEV) therapy has become the recommended first-line therapy for patients with unresectable hepatocellular carcinoma (HCC) because of favorable treatment responses. However, there is a lack of data on sequential regimens after ATE+BEV treatment failure. We aimed to investigate the clinical outcomes of patients with advanced HCC who received subsequent systemic therapy for disease progression after ATE+BEV. This multicenter, retrospective study included patients who started second-line systemic treatment with sorafenib or lenvatinib after HCC progressed on ATE+BEV between August 2019 and December 2022. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). Clinical features of the two groups were balanced through propensity score (PS) matching. This study enrolled 126 patients, 40 (31.7%) in the lenvatinib group, and 86 (68.3%) in the sorafenib group. The median age was 63 years, and males were predominant (88.1%). In PS-matched cohorts (36 patients in each group), the objective response rate was similar between the lenvatinib- and sorafenib-treated groups (5.6% vs. 8.3%; P=0.643), but the disease control rate was superior in the lenvatinib group (66.7% vs. 22.2%; P<0.001). Despite the superior progression- free survival (PFS) in the lenvatinib group (3.5 vs. 1.8 months, P=0.001), the overall survival (OS, 10.3 vs. 7.5 months, P=0.353) did not differ between the two PS-matched treatment groups. In second-line therapy for unresectable HCC after ATE+BEV failure, lenvatinib showed better PFS and comparable OS to sorafenib in a real-world setting. Future studies with larger sample sizes and longer follow-ups are needed to optimize second-line treatment.

Sequential therapy with topical clobetasol for 14 days followed by hydroquinone versus hydroquinone alone in facial melasma treatment: a randomized, double-blind, controlled clinical trial.

Clobetasol has demonstrated remarkable results in treating melasma within a short time frame; however, its use is limited because of the risk of local side effects. To date, there is no controlled trial on sequential clobetasol/hydroquinone for melasma. This study aimed to investigate the tolerability and efficacy of 0.05% clobetasol followed by 4% hydroquinone (CLOB-HQ) in comparison to the isolated use of 4% hydroquinone (HQ). A double-blinded, randomized clinical trial involving 50 women with facial melasma was performed. They were directed to apply 0.05% clobetasol every night for 14 days, followed by 4% hydroquinone for 46 days (CLOB-HQ group), or the use of hydroquinone for 60 days (HQ group). Evaluations were carried out at inclusion, andafter 14 and 60 days of treatment, measuring modified Melasma Area and Severity Index (mMASI), Melasma Quality of Life scale (MELASQoL), and colorimetry. The Global Aesthetic Improvement Scale (GAIS) was assessed by a blinded evaluator. There was no difference in the main outcomes at D14 and D60 (P > 0.1). For CLOB-HQ, the mean (CI 95%) reduction in mMASI was 13.2% (5.1-21.3%) and 43.1% (32.2-54.0%) at D14 and D60, and for HQ, they were 10.6% (5.9-27.5%) and 44.8% (33.2-52.3%). The MELASQoL, colorimetric luminosity, and GAIS showed a progressive improvement for both groups despite no difference between them. No severe side effects were identified. No cases of telangiectasias, atrophy, or perioral dermatitis were associated with the use of CLOB. The sequential CLOB-HQ regimen was safe and well tolerated, even though its efficacy was not different from HQ after 14 or 60 days of treatment. Based on these findings, the use of clobetasol 14 days before hydroquinone is not advisable for the treatment of melasma.

Mechanical alloying of AlCoCrFe and AlCoCrFeNi: Design and experimental evaluation of medium- and high-entropy alloy particles for cold spraying

The manufacturability of equiatomic high-entropy alloy (HEA) particles with single- and dual-phase crystal structures using the high-energy mechanical alloying (HE-MA) method was explored in this study. Following a material design-of-experiment (DoE) curriculum, particles were synthesized in a planetary mill. Milling times varied while operating under two distinct HE-MA manufacturing regimes: the conventional approach (simultaneous milling of constituent elements) and the sequential method (progressive milling with the introduction of elements in a specific order). Within the conventional regime, equiatomic AlCoCrFe and AlCoCrFeNi blends were milled, focusing on the influence of incorporating nickel (Ni) as a transient element into the base composition. This led to an equivalent particle size distribution ranging from 5 to 100 μm. Notably, the presence of Ni resulted in an increased fraction of the face-centered cubic (FCC) phase, coupled with a simultaneous reduction in grain and crystallite sizes, thereby enhancing the overall material strength. This knowledge was applied to the design and synthesis of a target equiatomic FeNiCoCrAl HEA system. In this context, individual elements were added to the starting/milled Fe + Ni alloy at four-hour intervals, in line with the sequential milling regimen. The results showed an interesting evolution: the conventionally milled AlCoCrFeNi particles exhibited a dual-phase body-centered cubic (BCC) and FCC structure, with a composition of 55% BCC and 45% FCC phase fractions, while the sequentially milled FeNiCoCrAl particles demonstrated a single-phase BCC structure after 24 h of milling.