First-line Therapy For Patients Research Articles

Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel in first-line patients with advanced pancreatic cancer (ACCENT trial): Interim analysis.

e16337 Background: Narmafotinib (AMP945) is a highly potent and selective, orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK is a non-receptor tyrosine kinase over-expressed in pancreatic cancer, where it contributes to cell survival, proliferation, migration and chemoresistance and thus plays a key role in tumor growth, FAK also contributes to multiple mechanisms underlying fibrosis and immunosuppression in the tumor microenvironment. Narmafotinib has successfully completed a Phase 1 study in healthy volunteers where the drug was safe and well tolerated with pharmacokinetics consistent with once-a-day dosing. A Phase 1b/2a trial of narmafotinib, in combination with gemcitabine and Abraxane, in advanced pancreatic cancer patients – the ACCENT trial – is currently underway in Australia and South Korea. Methods: The ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and tolerability, and efficacy of narmafotinibin combination with gemcitabine and Abraxane (nab-paclitaxel) standard of care as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. In Part A, patients were enrolled in a 3+3 design to determine the narmafotinib recommended Phase 2 dose (RP2D), with narmafotinibdose-escalation (100, 200 and 400 mg). Safety and tolerability were assessed according to incidence and severity of adverse events. Narmafotinibplasma PK samples were collected on Days -8, -7, 1, 3, 8, and 10 of Run-In/Cycle 1. Imaging was conducted every 2 months. Part B of the trial is a Simon’s two stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1.1. Results: Preliminary analysis across all doses (14 patients) showed narmafotinib to be generally safe and well-tolerated and showed promising signs of efficacy. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib and 9/14 patients have remained on trial for 5 months or more. There have been 6 confirmed PRs (4 in 400 mg cohort; 2 in 200 mg cohort) as best response. A single DLT was reported: uncontrolled grade 3 nausea (400 mg cohort). Fatigue, grade 3 or below related to narmafotinib occurred in more than one participant. The PK for narmafotinib is dose-proportional across the dose range tested, and the chemotherapy regimen used in this study did not impact narmafotinib PK. Safety, tolerability and efficacy data continues to be collected and will be presented. Conclusions: Based on this promising Phase 1b data, 400 mg of narmafotinib has been selected for the RP2D and Part B of the trial is now underway and recruiting patients in Australia and South Korea. The trial will enrol up to 50 patients as part of the Phase 2 expansion cohort. Clinical trial information: NCT05355298 .

Economic evaluation of camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma in the United States and China.

Camrelizumab combined with rivoceranib has been proven effective for treating unresectable hepatocellular carcinoma (uHCC). However, their higher prices than sorafenib could impose a substantial economic burden on patients. This study aimed to evaluate the relative cost-effectiveness of the combination of camrelizumab and rivoceranib versus sorafenib as first-line therapy for patients with uHCC from the perspective of the US and Chinese payers. Using data from the CARES-310 trial, a partitioned survival model (PSM) was developed, considering the perspectives of the US and Chinese payers. The model employed a 15-year time horizon and a biweekly cycle. Direct medical costs and utility data were collected from previous studies and open-access databases. Primary outcomes included quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Price simulations, sensitivity analyses, and subgroup analyses were conducted. The ICER for the US and China was $122,388.62/QALY and $30,410.56/QALY, respectively, falling below the willingness-to-pay (WTP) thresholds of $150,000/QALY for the US and $35,898.87/QALY for China. Price simulations indicated the cost-effectiveness of camrelizumab plus rivoceranib when the price of camrelizumab (200mg) remained below $6275.19 in the US and $558.09 in China. The primary determinant of cost-effectiveness in both regions was the cost of camrelizumab. The combination of camrelizumab and rivoceranib is a cost-effective first-line therapy for uHCC in both the US and China. Lowering their prices could significantly influence their cost-effectiveness and accessibility to patients. These findings will guide clinicians in treating uHCC and help decision-makers formulate value-based drug pricing strategies.

Cardioneuroablation for vasovagal syncope. Results from an EHRA Survey

Abstract Background Cardioneuroablation (CNA) is a recently introduced catheter-based therapy for vasovagal syncope (VVS), involving the modulation of the cardiac autonomic nervous system. Over the past decade, the body of evidence supporting CNA has consistently grown, sparking increased interest, and leading to broader adoption of this novel therapy for VVS treatment. However, several knowledge gaps persist, particularly concerning clinical indications, methodology, and long-term outcomes. Purpose The aim of this survey is to provide a comprehensive overview of the daily utilization of CNA in Europe. Methods and Results Among 204 participants, half reported that they are already performing CNA in their centres. The survey indicated CNA as an emerging therapy, with most centres initiating this treatment within the last two years. A significant majority of those who responded (71%) adopted a systematic approach by targeting ganglionated plexuses (GPs) in both the right atrium (RA) and left atrium (LA) as their first-line approach. The second most common approach (16%) involved performing ablation LA GPs only in the cases where there is no response following RA ablation. Figure 1 shows the GPs usually targeted for ablation. The most frequent procedural endpoint was the increase in the heart rate. Ninety percent of respondents relied on an anatomical approach for GP localization, while 59% also guided the procedure using electrogram analysis. Less frequently used approaches included pre-procedural imaging (20%), high-frequency stimulation (17%), and spectral analysis (10%). Only 11% of physicians discharged patients who underwent CNA without anticoagulation or antiplatelet therapy. In most cases (58%), respondents discharged their patients with anticoagulation, while 28% on single antiplatelet therapy. Overall, CNA is considered an effective procedure (80% of responders rating its effectiveness at or above 70%) and a safe procedure (with an estimated 1% rate of procedure-related complications, with symptomatic sinus tachycardia being the most frequently reported). Conclusions This survey confirmed high expectations for the future of this therapy, as most responders anticipate that CNA will be indicated as a first-line therapy for patients with recurrent cardioinhibitory VVS. Future efforts are necessary to standardize the procedural flow and peri-procedural patient management.

#1649 Obinutuzumab is effective for the treatment of rituximab-resistant membranous nephropathy

Abstract Background and Aims Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in nondiabetic adults. Rituximab has become the first-line therapy for patients with MN after the recognition of MN as an autoimmune disease. However, 40% of patients with MN do not respond to rituximab. Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody that has superior in vitro B-cell cytotoxicity compared with rituximab which might provide an attractive option for rituximab-resistant MN. We presented our single-center experience of treating MN with obinutuzumab. Method Fourteen patients with rituximab-resistant PLA2R-associated MN who received obinutuzumab at the First affiliated hospital of Xi'an Jiaotong university between January 2022 and June 2023 were included in this retrospective study. Resistance to rituximab was defined as the failure to achieve complete (urinary protein excretion <0.3 g/d along with normal serum albumin concentration and stable renal function) or partial (urinary protein excretion <3.5 g/d or with ≥50% reduction vs baseline, accompanied by improvement or normalization of serum albumin concentration and stable GFR) remission of NS in 3-6 months after 2 doses of rituximab administration. Clinical and laboratory parameters were evaluated at presentation, before and after obinutuzumab administration. Results Of all patients with an average age of 50.0 ± 13.6 years, 10 (71.4%) patients were men, 8 (57.1%) patients had hypertension and 4 (28.6%) patients had diabetes. The median disease duration was 1.3 (1.0, 4.8) years. At presentation, the proteinuria and albumin levels were 7.94 ± 4.23 g/d and 21.5 ± 3.6 g/L, respectively. The mean serum creatinine level was 70.5 ± 10.7 µmol/L and the patients had a median baseline anti-PLA2R level of 193.5 (104.5,299.2) RU/mL. Six patients had been previously exposed to steroids, alkylating agents, calcineurin inhibitors in different combinations in addition to rituximab. Both patients received 1 g of obinutuzumab on day 0 and day 15. At obinutuzumab administration, the proteinuria and albumin levels were 8.43 ± 3.36 g/d and 22.4 ± 4.0 g/L, respectively. The mean serum creatinine level was 85.1 ± 28.5 µmol/L and median anti-PLA2R level decreased to 32.7 (10.7,178.) RU/mL compared with that at presentation. After a median follow-up of 5.4 (4.0, 9.7) months after obinutuzumab therapy, complete remission was achieved in 4 (28.6%) and partial remission was achieved in 8 (57.1%) of patients. Of the remaining two patients who did not achieve complete or partial remission, 1 patient had a follow-up of 4 months and had a 33% decline in proteinuria accompanied by improvement in serum albumin. The other patient had an anti-PLA2R level higher than 1500 RU/mL (exceeding detection upper limit) at obinutuzumab administration and an inadequate follow-up of 3 months without proteinuria decline. Whereas, anti-PLA2R level decreased to 18.17 RU/ml accompanied by B-lymphocyte depletion (absolute CD19 count <5 cells/ml) at that time. Of the 12 patients who achieved complete or partial remission, the median time from treatment to remission was 4.7 ± 2.3 months. Two patients with longer follow-up maintained complete remission at 1 year. At first complete or partial remission, the proteinuria and albumin levels were 3.47 ± 1.99 g/d and 32.5 ± 3.3 g/L, respectively. The mean serum creatinine level was 74.8 ± 24.1 µmol/L and anti-PLA2R levels of 11 patients had a decline in the titer to <2 RU/ml (negative result for our immunology laboratory). B-lymphocyte depletion was achieved in all these patients. Conclusion Obinutuzumab may represent an attractive alternative therapy in patients with resistance to rituximab. Larger prospective studies are needed to validate these findings.

Imatinib-induced ulcerative colitis.

Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for patients with KIT mutation in gastrointestinal stromal tumor (GIST). Nausea, vomiting, diarrhea, dyspepsia and abdominal pain are common gastrointestinal adverse reactions of imatinib, but imatinib-induced ulcerative colitis (UC) is rarely reported. We presented a case of UC induced by imatinib in a 56-year-old male patient who experienced this adverse event after 5 years of imatinib 400 mg/d treatment following GIST resection. The patient's diarrhea and bloody stools showed significant improvement following the discontinuation of imatinib therapy and administration of antidiarrheal medications. Then, imatinib was restarted at a daily dosage of 400 mg. UC is a rare adverse event associated with imatinib. Physicians should consider the possibility of UC induced by imatinib when patients present with diarrhea and bloody stool after receiving imatinib treatment. This case offered objective evidence of UC induced by imatinib.

Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF/VEGFR2/p38 pathway by targeting HIF-1a in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PurposeTo evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. MethodsCCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. ResultsPPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 μM). Significantly, treatment with PPI at 1.0 μM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. ConclusionsWe present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.

Clinico-biological factors predicting the benefit of the LV5FU2 maintenance strategy as a first-line therapy in patients with metastatic pancreatic cancer

Abstract Introduction Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy. Patients and Methods We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated. Results Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant. Conclusion Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337).

Obstructive Sleep Apnea Treatment and the Evaluation of Clinical Effectiveness of Uniquely Designed Oral Appliance Therapy Device.

Continuous positive airway pressure (CPAP) has been considered first-line therapy for patients with obstructive sleep apnea (OSA); however, adherence to the therapy is suboptimal. Oral appliance therapy (OAT) is an alternative to CPAP that may lend to better patient adherence, quality of life, and overall patients' effectiveness of therapy. This was a prospective, single-site, non-randomized study to evaluate the clinical effectiveness of a uniquely designed OAT device with an embedded adherence tracking chip in the treatment of mild and moderate OSA patients over three months. The effectiveness of OAT therapy was defined as the numerical product of efficacy and adherence. The efficacy of the device was defined as the change from baseline in the apnea-hypopnea index (AHI). Adherence was based on usage for a minimum of 4 hours/night of use, for at least five out of seven nights a week. 45 participants fitted with the OAT device completed at least one follow-up visit and had recordable objective data. Average patient wearing time was 7 hours/night and a reduction of the AHI from 16.4 events/hour to 5.7 events/hour after three months of use.Mean disease alleviation (MDA), which serves as a measure of the overall therapeutic effectiveness, was 62% when looking at 4 hours/night of usage. As the comfort of the device is related to wearing time, subjective data indicated the optimum first-time fit of the device. The study OAT device was well tolerated throughout the study. When both efficacyand adherence are considered, OAT can be a clinically effective tool to treat OSA.

Abstract PO2-06-09: A prospective phase 2 study on efficacy and safety of AK105, anlotinib combined with nab-paclitaxel (nab-P) as a first-line therapy in patients(pts) with advanced triple-negative breast cancer(TNBC)

Abstract Background: PD-1/PD-L1 inhibitor plus chemotherapy have shown tolerability and significant clinical benefits in pts with advanced TNBC. Antiangiogenic agent could remodel tumor blood vessels and increase the response to immune-checkpoint inhibitors (ICIs). AK105, an anti-PD-1 antibody, can effectively prevents PD-1 from binding to PD-L1 and PD-L2, and avoid immune evasion of tumor cells. Anlotinib is a novel antiangiogenic, multi-target tyrosine kinase inhibitor which inhibits VEGFR, FGFR, PDGFR, c-KIT, c-RET and MET. This investigator initiated trial (IIT) (NCT05244993) aims to investigate the efficacy and safety of AK105, anlotinib combined with nab-P as a first-line therapy in pts with advanced TNBC. Methods: In this multicenter, prospective, single arm, phase 2 study, eligible pts were female aged 18-75 years, with ECOG PS 0-1, who had locally advanced or recurrent/metastatic triple-negative (estrogen receptor-, progesterone receptor- and HER2-) breast cancer. Eligible pts were treated with intravenous AK105 (200 mg on day 1), oral anlotinib (12 mg once daily on days 1-14) and intravenous nab-P (125 mg/m2 on days 1 and 8) . The triplet combination regimen repeated every 21 days until disease progression, death or intolerable toxicity. The primary endpoint is overall response rate (ORR), and the secondary endpoints are disease control rate (DCR), progression-free survival (PFS), overall survival (OS)and safety. Results: From July 2022 to July 2023, 19 patients were enrolled in this study. Median follow-up was 6.18 months (95% CI 1.29-11.06). Of all the patients whose efficacy could be evaluated (16/19), no patient achieved complete response (CR); 9(56.25%), 6(37.5%) and 1(6.25%) patients got partial response (PR), stable disease (SD) and progression disease (PD), respectively. ORR was 56.25 % (95% CI 30.55-79.25) and DCR was 93.75% (95% CI 67.71-99.67). mPFS and OS have not reached. The most common adverse events (AEs) were grade 1 or 2. The grade 3 AEs were neutropenia (15.79%), Leukopenia (10.52%), elevated ALT (5.26%), elevated AST (5.26%) and hypercholesteremia (5.26%). There were one case of grade 4 neutropenia and one case of grade 4 hypertriglyceridemia. No treatment-related death was observed. Conclusion: The combination of AK105, anlotinib and nab-P showed better treatment response and tolerable toxicity in the treatment of first-line patients with TNBC. Further studies enrolling more patients are still needed. Citation Format: Liang Zhang, Tao Sun. A prospective phase 2 study on efficacy and safety of AK105, anlotinib combined with nab-paclitaxel (nab-P) as a first-line therapy in patients(pts) with advanced triple-negative breast cancer(TNBC) [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 PO2-06-09.

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [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 PO2-04-07.

Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, > 9 responders were need in stage 1 (n=18) for the study to continue, and >19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [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 PO1-06-12.

Abstract PO5-10-02: Neighborhood deprivation index and time to initiation in patients with metastatic breast cancer

Abstract Background Cyclin-dependent kinase 4 and 6 inhibitors (CDKi) are first-line therapy for patients with estrogen-positive (ER+) metastatic breast cancer (MBC). The accessibility, usability, and outcomes according to demographic factors have not been well studied in real world practice. Methods Retrospective review of patients with ER+ MBC prescribed first line CDKi therapy at a large NCI-designated cancer center from January 2015 through December 2022. Patient records were abstracted for outcomes including 1) time from CDKi prescription to drug initiation (TTI), 3) time from CDKi initiation to progression, and 3) time from CDKi initiation to death/or 6/30/2022. Patient variables collected were: patient age (continuous), race (patient self-report – Black, White, Other), partner status (Married, Not married), Insurance type (Medicare, Medicaid, Private); Mean BMI; Number of comorbidities (5 categories). Neighborhood deprivation index (NDI) was determined from the patient’s address with higher scores indicating more deprivation. Descriptive, comparative, and correlational statistics were used. Results A total of 173 patients were included in the analysis. Mean age – 63.1, (SD 12.7, range 24-94); race – White n=157, Black n=16; marital status – Married n=102, Not married n=71; mean NDI – 61.0 (SD 23.7, range 6-100); mean BMI – 28.9 (SD 6.9, range 16-48); number of comorbidities – 0 n=35, 1-2 n= 35, 3-4 n = 55, 5-6 n = 20, 7+ n = 28; insurance type – Medicare n = 115, Medicaid n = 21, Private n = 37. TTI: the median TTI was 14 days. There were no statistically significant differences in TTI based on age, race, NDI, or other demographic variables. Time to progression: in the multivariate model, younger age at diagnosis and Medicaid insurance were associated with shorter time to progression. Overall survival: not married, younger age at diagnosis, and Medicaid insurance were associated with shorter overall survival. Discussion Demographic factors are associated with diverse outcomes of MBC therapy, not attributed to delay in CDKi treatment initiation. Personalization of support during MBC illness according to risk factors for worse outcomes may help to equalize incomes. Citation Format: Sneha Rajendran, Dianxu Ren, Marina Petruzzi, Margaret Rosenzweig. Neighborhood deprivation index and time to initiation in patients with metastatic breast cancer [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 PO5-10-02.

Targeted and immunotherapy for the management of advanced urothelial carcinoma of the bladder.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed. Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy. Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

BackgroundLenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC.MethodsIn this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy.ResultsSixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients.ConclusionsTislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC.Trial registrationClinicalTrials.gov (NCT 04401800).

A randomized clinical trial of catheter ablation and antiarrhythmic drug therapy for suppression of ventricular tachycardia in ischemic cardiomyopathy: The VANISH2 trial

Recurrent ventricular tachycardia (VT) in patients with prior myocardial infarction is associated with adverse quality of life and clinical outcomes, despite the presence of implanted defibrillators (ICDs). Suppression of recurrent VT can be accomplished with antiarrhythmic drug therapy or catheter ablation. The Ventricular Tachycardia Antiarrhythmics or Ablation In Structural Heart Disease 2 (VANISH2) trial is designed to determine whether ablation is superior to antiarrhythmic drug therapy as first line therapy for patients with ischemic cardiomyopathy and VT.The VANISH2 trial enrolls patients with prior myocardial infarction and VT (with one of: ≥1 ICD shock; ≥3 episodes treated with antitachycardia pacing (ATP) and symptoms; ≥5 episodes treated with ATP regardless of symptoms; ≥3 episodes within 24 hours; or sustained VT treated with electrical cardioversion or pharmacologic conversion). Enrolled patients are classified as either sotalol-eligible, or amiodarone-eligible, and then are randomized to either catheter ablation or to that antiarrhythmic drug therapy, with randomization stratified by drug-eligibility group. Drug therapy, catheter ablation procedures and ICD programming are standardized.All patients will be followed until two years after randomization. The primary endpoint is a composite of mortality at any time, appropriate ICD shock after 14 days, VT storm after 14 days, and treated sustained VT below detection of the ICD after 14 days. The outcomes will be analyzed according to the intention-to-treat principle using survival analysis techniques.The results of the VANISH2 trial are intended to provide data to support clinical decisions on how to suppress VT for patients with prior myocardial infarction.Clinicaltrials.gov registration NCT02830360

Short-duration aerobic high-intensity intervals versus moderate exercise training intensity in patients with peripheral artery disease: study protocol for a randomised controlled trial (the Angiof-HIIT Study)

IntroductionSupervised exercise training is among the first-line therapies for patients with peripheral artery disease (PAD). Current recommendations for exercise include guidance focusing on claudication pain, programme and session duration, and...

Abstract CT220: Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer (ACCENT trial): interim analysis

Abstract Background: Narmafotinib (AMP945) is a selective and orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK plays a key role in tumour growth, particularly in immunosuppression, cancer cell invasion and metastasis, and contributes to multiple mechanisms underlying fibrosis. In the Phase 1 study (healthy volunteers) narmafotinib was safe and well tolerated across single ascending dose (15 to 125 mg) and multiple ascending doses for 7 days (25 to 100 mg), with PK/PD data demonstrating wide tissue distribution and target engagement. Methods: ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and efficacy of narmafotinib in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. In Part A, patients were enrolled in a 3+3 design to determine the narmafotinib recommended Phase 2 dose (RP2D), with narmafotinib dose-escalation (100, 200 and 400 mg). Part B is a Simon’s two stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1.1 (centrally by independent reviewers). Narmafotinib plasma PK samples were collected on Days -8, -7, 1, 3, 8, and 10 of Run-In/Cycle 1. Safety and tolerability were assessed according to incidence and severity of adverse events. Imaging was conducted every 2 months. Results: Preliminary analysis across all doses (14 patients) showed narmafotinib to be generally safe and well-tolerated and showed promising signs of efficacy. At first on study imaging (Day 56), 86% of patients had stable disease and 12% had a partial response (PR). Subsequent RECIST assessments conducted locally at sites showed PR in 47% of patients. A single DLT was reported: uncontrolled grade 3 nausea (400 mg cohort). Fatigue, grade 3 or below was related to narmafotinib occurred in more than one participant. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib, with 7 patients receiving narmafotinib in combination with chemotherapy for 5 months or more. The PK for narmafotinib is dose-proportional across the dose range tested, and the half-life supports once a day dosing. The chemotherapy regimen used in this study did not impact narmafotinib PK. Conclusions: Based on this promising Phase 1b data, 400 mg of narmafotinib has been selected for RP2D and the trial will proceed through Simon’s Two Stage design and enrol up to 50 patients as part of the Phase 2 expansion cohort. Citation Format: Terrie-Anne Cock, Anthony Bishop, Nicole Kruger, Sarah McCormack, Marion Harris, Sumitra Ananda, Lara Lipton, Adnan Nagrial, Nick Pavlakis, Warren Joubert, Laura Donato, Jason Lickliter, Christopher Burns. Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer (ACCENT trial): interim analysis [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 CT220.

Abstract CT032: Promotive clinical effects of pembrolizumab with necitumumab in patients having advanced non-small cell lung cancer with PD-L1 expression of 50% or higher in a phase II study (K-TAIL-202)

Abstract Background: Pembrolizumab is the standard of care for advanced non-small cell lung cancer (NSCLC) with high programmed death-1 ligand 1 (PD-L1) expression. However, combination therapies comprising pembrolizumab and ipilimumab, tiragolumab, or lenvatinib have not demonstrated superior efficacy in this patient group. This study explored the effectiveness of the novel combination of pembrolizumab and necitumumab as first-line therapy in patients having advanced NSCLC with PD-L1 expression of 50% or higher. Methods: Patients with untreated advanced NSCLC with PD-L1 expression of 50% or higher received pembrolizumab and necitumumab every 3 weeks up to 35 cycles. The primary endpoint was investigator-assessed objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. The sample size was calculated using 80% power with a one-sided alpha error of 10%, a threshold ORR of 39.0%, and an expected ORR of 54.8%. Results: From December 2020 to March 2023, 50 patients were enrolled. Patient characteristics were as follows: male/female patients: 38/12; median age: 72 years (range: 51-90 years); histology, adenocarcinoma/squamous cell carcinoma/other: 35/15/5; and PS, 0/1: 20/30. At the time of the primary analysis, the ORR was 76.0% (95% CI: 61.9%-86.9%), with 2.0%, 74.0%, 10.0%, and 8.0% of the patients showing complete response, partial response, stable disease, and progressive disease, respectively. The median PFS was 15.7 months (95% CI, 10.3 to not reached) and the median OS was not reached. Common toxicities included rash (86%) and hypomagnesemia (60%). Grade 3 interstitial lung disease was noted in 5 patients (10%) and grade 5 cardiac arrest in 1 patient (2%). Conclusion: Combination therapy comprising pembrolizumab and necitumumab demonstrated a 76.0% ORR, meeting the primary endpoint, with manageable toxicities. The regimen showed promising clinical activity in patients with NSCLC and high PD-L1 expression, warranting further investigation. Clinical trial ID: jRCT2031200248. Citation Format: Atsushi Horiike, Hiroshi Wakui, Shunichi Sugawara, Yuji Minegishi, Sadatomo Tasaka, Sojiro Kusumoto, Toshio Sakatani, Hiroyuki Suzuki, Yukio Hosomi, Yuichi Tambo, Tsuneo Shimokawa, Hiroo Ishida, Eisaku Miyauchi, Katsuhiko Naoki, Tatsuro Fukuhara, Emiko Mura, Toshiaki Tsurui, Risako Suzuki, Nana Iriguchi, Tomoyuki Ishiguro, Yuya Hirasawa, Ryo Manabe, Masahiro Shimokawa, Ryotaro Ohkuma, Hirotsugu Ariizumi, Yutaro Kubota, Kazuyuki Hamada, Sachiko Takenoshita, Kakei Ryu, Takehiko Sambe, Eisuke Inoue, Satoshi Wada, Kiyoshi Yoshimura, Hironori Sagara, Shinichi Kobayashi, Takuya Tsunoda. Promotive clinical effects of pembrolizumab with necitumumab in patients having advanced non-small cell lung cancer with PD-L1 expression of 50% or higher in a phase II study (K-TAIL-202) [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 CT032.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6–18.0) for the immunotherapy group compared with 9.9 months (8.0–11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40–0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3–32.8) for the control group (HR, 0.57 [95% CI, 0.33–0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Atrial Fibrillation Management During Surgical vs Transcatheter Aortic Valve Replacement

BackgroundSocietal guidelines support atrial fibrillation (AF) treatment during surgical aortic valve replacement (SAVR). Recently, many patients with AF at low to intermediate risk are managed by transcatheter aortic valve replacement (TAVR). Therefore, we evaluated longitudinal outcomes in these populations. MethodsThe United States Centers for Medicare and Medicaid Services inpatient claims database was evaluated for all beneficiaries with AF undergoing TAVR or SAVR with/without AF treatment (2018-2020). Treatment of AF included concomitant left atrial appendage obliteration, with/without surgical ablation, or endovascular appendage occlusion and/or catheter ablation at any time. Diagnosis-related group and International Classification of Diseases, 10th Revision, codes defined procedures with doubly robust risk adjustment across each group. ResultsA total of 24,902 patients were evaluated (17,453 TAVR; 7,449 SAVR). Of patients undergoing SAVR, 3176 (42.6%) underwent AF treatment (SAVR+AF). Only 656 TAVR patients (4.5%) received AF treatment. Comparing well-balanced SAVR+AF vs SAVR vs TAVR, there were no differences in the in-hospital incidence of renal failure, bleeding, or stroke, but increased pacemaker requirement (odds ratio [OR], 3.45; P < .0001) and vascular injury (OR, 9.09; P < .0001) were noted in TAVR and higher hospital mortality (OR, 4.02; P < .0001) in SAVR+AF. SAVR+AF was associated with lower readmission for stroke compared with SAVR alone (hazard ratio [HR], 0.87; P = .029) and TAVR (HR, 0.68; P < .0001) and with improved survival vs TAVR (HR, 0.79; P = .019). ConclusionsIn Medicare beneficiaries with AF requiring aortic valve replacement, SAVR+AF was associated with improved longitudinal survival and freedom from stroke compared with TAVR. SAVR+AF treatment should be considered first-line therapy for patients with AF requiring aortic valve replacement.