Reasons For Discontinuation Research Articles

Olokizumab in patients with inflammatory phenotype of osteoarthritis, treatment experience

Objective: to investigate the efficacy and safety of olokizumab (OKZ) in patients with knee osteoarthritis (OA) with synovitis, persistent pain and ineffectiveness of previous conservative therapy. Material and methods. The study included 15 patients with stage II–III knee OA who fulfilled the ACR criteria and had pain ≥50 mm on a visual analogue scale (VAS), synovitis and treatment failure. The age of patients ranged from 54 to 75 years; the duration of the disease was from 1 to 23 years. The duration of the study was 12 weeks, during which the patients received 3 subcutaneous injections of OKZ at a dose of 64 mg. The effectiveness of the treatment was assessed by the dynamics of pain intensity according to VAS, WOMAC and KOOS indices, the values of the DN4 questionnaire and the quality of life according to EQ-5D. In addition, the general assessment of the patient's health (GHA) according to VAS, the assessment of treatment efficacy by doctor and patient and the need for non-steroidal anti-inflammatory drugs (NSAIDs) were considered. All patients underwent laboratory testing. Results and discussion. During treatment, there was a significant decrease in pain intensity according to VAS, a statistically significant improvement in the KOOS and WOMAC indices (p<0.05), quality of life according to the EQ-5D questionnaire and GHA. Patients and doctors rated the treatment results very positively: an improvement or significant improvement was observed in 92.3% of cases. Adverse events were identified in 4 patients, which in 2 cases served as the reason for discontinuation of OKZ treatment and termination of participation in the study. During treatment with OKZ, a statistically significant decrease in CRP and ESR values, an increase in the concentration of interleukin 6 (p = 0.003), COMP (p = 0.03) and PIINP (p = 0.01) were observed. Conclusion. The results obtained suggest a significant symptomatic and anti-inflammatory effect of OKZ in patients with the inflammatory phenotype of OA.

The cenobamate KORK study-A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add-on lacosamide, perampanel, and brivaracetam.

In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal-onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real-world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult-to-treat epilepsies. Our aim was to investigate the efficacy of add-on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add-on lacosamide, perampanel, and brivaracetam therapy. Patients were enrolled from the CENKORK study, which is a prospective, non-interventional, open-label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure-free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow-up, leaving 150 cases for the 1-year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6-month and 1-year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6-month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). Add-on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. This observational study was carried out in 172 adult patients with difficult-to-treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

Multicentre service evaluation of injectable cabotegravir and rilpivirine delivery and outcomes across 12 UK clinics (SHARE LAI-net).

Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics. Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia. In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV. In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure.

Patient Adherence to a Real-World Digital, Asynchronous Weight Loss Program in Australia That Combines Behavioural and GLP-1 RA Therapy: A Mixed Methods Study.

Increasingly large numbers of people are using digital weight loss services (DWLSs) to treat being overweight and obesity. Although it is widely agreed that digital modalities improve access to care in general, obesity stakeholders remain concerned that many DWLSs are not comprehensive or sustainable enough to deliver meaningful health outcomes. This study adopted a mixed methods approach to assess why and after how long patients tend to discontinue Australia's largest DWLS, a program that combines behavioural and pharmacological therapy under the guidance of a multidisciplinary care team. We found that in a cohort of patients who commenced the Eucalyptus DWLS between January and June 2022 (n = 5604), the mean program adherence was 171.2 (±158.2) days. Inadequate supplying of a patient's desired glucose-like peptide-1 receptor agonist medication was the most common reason for discontinuation (43.7%), followed by program cost (26.2%), result dissatisfaction (9.9%), and service dissatisfaction (7.2%). Statistical tests revealed that ethnicity and age both had a significant effect on patient adherence. These findings suggest that DWLSs have the potential to improve access to comprehensive, continuous obesity care, but care models need to improve upon the one observed in the Eucalyptus Australia DWLS to mitigate common real-world program attrition factors.

Sodium phenylbutyrate-taurursodiol access, adherence and adverse event in patients with amyotrophic lateral sclerosis: Experience at one center in the United States.

Sodium phenylbutyrate-taurursodiol (PB-TURSO) was recently approved for treating amyotrophic lateral sclerosis (ALS). Third-party payors' coverage policies are evolving, and adverse events are just being fully assessed. The goals of this study were to evaluate patients' experiences in obtaining and continuing PB-TURSO and assess adverse events and medication adherence. Medical records of 109 ALS patients who were considered PB-TURSO candidates by the treating physician at a tertiary ALS clinic from October 2022 to May 2023 were reviewed. Data was recorded for demographics, clinical, and insurance information. A survey was e-mailed to patients asking about out-of-pocket expenses for PB-TURSO, financial assistance, medication start and (if applicable) stop dates, and reasons for discontinuation. Insurance information was available for 91 patients [57 males (62%); mean age 64.8 years (range 25.7-88)]. Of 79 who applied for insurance approval, 71 (90%) were approved; however, 19 required 1-3 appeals. Among 73 patients with available data about medication status, 54 started PB-TURSO and 19 did not, most commonly due to personal choice or out-of-pocket expenses. About 44% of patients (24/54) stopped taking PB-TURSO, primarily due to adverse events. Monthly out-of-pocket expenses varied from $0 to $3500 and 36 patients qualified for financial assistance. Administrative and nursing staff devoted 7.2 hours/week to the insurance authorization process. Most patients received insurance approval for PB-TURSO, but one-fourth required appeals. Some out-of-pocket costs were very high. Investment of staff time was substantial. These findings have implications for insurance coverage of, and adherence to, future ALS treatments.

Efficacy of post-lenvatinib treatments in patients (pts) with advanced renal cell carcinoma (aRCC).

4538 Background: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of post-lenvatinib therapies in pts with aRCC. Methods: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Pts having received treatment post lenvatinib exposure were eligible and divided into two cohort: pts post-1st line lenvatinib (2nd line cohort) and pts post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results: Overall, 84 pts received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. All pts received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 9.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most pts were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed pts (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. Most pts received 2nd line everolimus + lenvatinib (97%) (ORR 39%, median TTF 5.9 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most pts were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for pts progressing on lenvatinib-based therapies.

Real world experience of trastuzumab deruxtecan for the treatment of metastatic breast cancer in the UK.

1024 Background: Trastuzumab deruxtecan (TDXd), an antibody drug conjugate, was first approved in the UK for the treatment of human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) in 2021. We aimed to review the efficacy and tolerability of TDXd in a real-world UK setting. Methods: We collected clinical and demographic data from medical records on HER2+ mBC patients treated with TDXd in the UK from Jan 2021 to Dec 2023 inclusive. This included: radiological response, the frequency of dose reductions and treatment delays, and reasons for discontinuation. Clinical trial patients were excluded. Descriptive statistical techniques were applied. Results: Data was collected from 26 UK cancer centres on 280 patients. The median age at TDXd initiation was 56 years (range 29-85). Median treatment duration was 9 cycles (range 1-40). 239 patients (85%) had visceral disease. 257 and 196 patients (92% and 70%, respectively) had received prior Trastuzumab and Pertuzumab, respectively. 233 patients (83%) had received prior TDM1. The median number of lines of treatment prior to TDXd was 3 (range 1 to 9). 20 patients (7%) were initiated on a reduced dose and 115 further patients (41%) required at least one dose reduction. 151 patients (54%) had at least one dose interruption due to: infection or neutropenia (n=61), other toxicity (n=85), interstitial lung disease (ILD) investigation (n=39), patient request (n=81), other concurrent illness (n=10), and cardiac investigation (n=6). Of these, 55 patients had more than one treatment break. 157 patients (56%) had discontinued TDXd treatment due to: disease progression or death (n=100), drug toxicity (n=39) of which 22 were due to ILD, and patient choice (n=8). 123 patients remained treatment at the time of analysis. The overall response rate of TDXd was 63% overall: stable disease 23%, partial response 56%, complete response 7%. Conclusions: The real-world data set is not directly comparable to either the DB02 or DB03 trials, as it included patients who had received TDXd in both the second line and later line settings. However, the majority (80%) of these patients were treated in the third line and beyond. The rates of drug interruption and reduction were higher in the real-world data set than in DB02, which may impact on efficacy in the real-world setting. Overall response rate is similar between trial data and our real-world data, although the latter was not measured by RECIST. Data collection is ongoing, including an analysis of real-world progression free survival. [Table: see text]

OSIRAM-1/TORG1833: Overall survival results of a randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer.

8613 Background: Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram). We have previously shown the result of progression free survival (PFS) as a primary endpoint, the median PFS was 20.0 months for Osi+Ram and 24.0 months for Osi, hazard ratio of 1.054 (95% CI 0.674-1.648). In further analyses, we aimed to examine the effects of this combination therapy on overall survival (OS). Methods: Previously untreated EGFR mutation-positive advanced non-squamous NSCLC patients with a performance status of 0 or 1 were eligible. Asymptomatic and/or treated brain metastases were included. Eligible patients were randomized at a 1:1 ratio to receive Osi (80mg) every day either without or with Ram (10mg/kg) every 2 weeks until disease progression or unacceptable toxicity, stratified according to gender and the type of EGFR mutation (exon 19 deletion, L858R). The primary endpoint was PFS assessed by the independent blinded radiologic reviewer. Secondary endpoints included PFS assessed locally, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), OS and safety. Results: Between November 2018 and April 2020, 122 patients (Osi+Ram: 59, Osi: 63) were enrolled. The patients' characteristics were well balanced. 59% were females, and 61% had an exon 19 deletion. Median age was 70 years old (range, 29-86). With a median follow up of 36.0 months, the median OS was 43.4 months (95% CI 36.5-N.R.) for Osi+Ram and N.R. (95% CI 41.3-N.R.) for Osi, resulting in a hazard ratio of 1.159 (95% CI 0.645-2.083, p = 0.62). Median treatment duration for Ram was 140 (14-1239) days. Ram was discontinued in 45 patients (76%) by the treatment related adverse effects. Common reasons for Ram discontinuation were platelet count decreased (n=14), proteinuria (n=12), neutrophil count decreased (n=11), pneumonitis (n=3), bleeding (n=3) and infection (n=3). Pneumonitis was observed in 16% in Osi, 9% in Osi+Ram, with grade 3 observed in 2% of both arms. Conclusions: Both treatment arms demonstrated sustained OS over 43 months. However, this study did not show an advantage of biweekly Ram administration with Osi in terms of PFS and OS. Notably, there was surpassed increase of early discontinuation of Ram due to higher adverse events. Clinical trial information: 2080224085 .

Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC).

9592 Background: MCC and cSCC have limited treatment options when refractory to immune checkpoint inhibitor (ICI) therapy. IFx-Hu2.0 (IFx) is a plasmid DNA encoding for an immunogenic bacterial protein, Emm55, formulated with a transfection agent for direct intra-tumoral (IT) injection. In this Phase 1b study, we evaluated the safety and efficacy of different schedules of IT IFx in patients (pts) with advanced MCC or cSCC. Methods: In the first trial stage (n=9), IT IFx was administered in up to 3 lesions on 3 schedules following a 3+3 exposure escalation schema; weekly x 1, 2, or 3. In the second trial expansion stage (n=11), IT IFx was administered weekly x 3. The primary objective of the study was to establish safety and feasibility of repeated IT administrations of the investigational agent. ≥80% completion of planned study therapy was predefined as a successful feasibility outcome. Given the proposed potential for immune priming effects of IFx, we performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate response to ICI rechallenge. Results: We treated 22 pts (MCC, 13; cSCC, 9). All pts had received prior anti-PD(L)1 based treatment with disease progression being the reason for ICI discontinuation in all patients but one. Two pts did not complete planned study therapy due to rapid clinical progression and were replaced but included in the safety analysis. IT IFx was well tolerated at all dose schedules evaluated with 1 high-grade toxicity deemed possibly treatment related (G3 hepatitis in a patient recently treated with ICI). The study therefore met predefined study endpoints for safety and efficacy. After protocol specified IT therapy, 11 MCC pts and 6 cSCC pts were treated with anti-PD(L)1 based therapy as the immediate post-protocol treatment. Five of 9 (56%) evaluable MCC patients and 1 of 7 (14%) cSCC patients experienced an objective response to this ICI rechallenge, with duration of response ongoing in 4 patients (6+, 19+, 21+, 23+ months) and the two other responses lasting 23 and 33 months. The two remaining MCC patients were not evaluable for response from IO rechallenge due to radiation administered to the only measurable disease site(s), but both remain progression free at 11+ and 13+ months with previously progressive disease. Conclusions: IT IFx-Hu2.0 is safe and feasible to administer at weekly dosing repeated up to 3 weeks. An unplanned exploratory analysis revealed frequent (56%) and durable responses in advanced MCC to ICI re-challenge despite prior resistance to this class of drug, suggesting that IFx induced an immune priming effect. Preliminary biomarker analyses to investigate this phenomenon are ongoing and will be presented. Clinical trial information: NCT04160065 .

Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .

An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma.

TPS7098 Background: Targeting Bruton’s tyrosine kinase (BTK) has demonstrated impressive efficacy in relapsed or refractory mantle cell lymphoma (R/R MCL). Covalent BTK inhibitors (cBTKi) have produced extended disease remission and durable responses in R/R MCL. However, patients with continuous cBTKi treatment tend to develop selection or outgrowth of resistant clones, which triggers disease relapse. Non-covalent binding BTKi has become a treatment option for patients who progressed on cBTKi. LP-168 is a highly selective next-generation inhibitor of BTK that can bind wild-type BTK covalently and C481-mutated BTK non-covalently (reversibly) Here, we propose to evaluate the safety and efficacy of LP-168 monotherapy in patients with R/R MCL. Methods: NCT05716087 is an open-label, multicenter, single-arm, phase II study to assess the efficacy, safety, tolerability, and pharmacokinetics of LP-168 in Chinese patients with R/R MCL who have failed prior cBTKi treatment. Responses were evaluated using Lugano 2014 criteria. Eligible patients with R/R MCL must show evidence of disease progression or intolerance to at least a prior cBTKi. Patients are also required to have adequate bone marrow, liver function, kidney function, and heart function, and an ECOG performance status of 0-2. Moreover, patients must have at least one measurable lesion. Key exclusion criteria include previous non-covalent BTKi or BTK proteolysis-targeting chimeras (PROTAC) treatment, uncontrolled systemic disease, active infection, central nervous system (CNS) involvement, prior history of other malignancies within two years, and current pregnancy or breastfeeding. Concomitant use of strong or moderate CYP3A4 inducers and inhibitors or OATP1B1/OATP1B3 sensitive substrates is prohibited. LP-168 is orally administered at 150mg once daily in 28-day/cycle until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, or other reasons for treatment discontinuation. In this study, the primary endpoint was ORR according to an independent review committee (IRC) assessment based on the best overall response (BOR) of PR or better per Lugano 2014 criteria. Secondary endpoints include safety evaluation, quality of life assessment, PK parameters, ORR by investigator’s assessment, and other efficacy parameters, such as complete response ratio (CRR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and time to response (TTR). First patient was enrolled on May 12, 2023. Currently 41 study sites across China are actively enrolling patients. ClinicalTrials.gov Identifier: NCT05716087. Clinical trial information: NCT05716087 .

Prevention of sacituzumab govitecan (SG)-related neutropenia and diarrhea in patients (pts) with triple-negative or HR+/HER2- advanced breast cancer (ABC; PRIMED): A phase 2 trial.

1101 Background: SG is a Trop-2 directed antibody-drug conjugate approved for pts with advanced, pretreated, triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer. The most common SG-related adverse events (AEs) are neutropenia and diarrhea which can lead to treatment modifications. Granulocyte colony-stimulating factor (G-CSF) and loperamide (L) are frequently used for managing these AEs. PRIMED is assessing if primary prophylaxis with G-CSF and L can improve the tolerability of SG. Methods: PRIMED (NCT05520723) is an open-label, single-arm, phase II trial. Pts had received between 1-2 previous chemotherapy regimens for ABC, including a taxane in any setting, unless contraindicated. HR+/HER2- pts had to be endocrine-resistant. Pts received SG (10 mg/kg IV, d 1 and 8, every 21 d) until disease progression (PD) or unacceptable toxicity. G-CSF (0.5 MU/kg/day SC, d 3, 4, 10, and 11) and L (2 mg orally, twice a day or 4 mg QD, d 2, 3, 4, 9, 10, and 11) were given during the first two cycles. The primary endpoints were incidence of ≥ grade (G) 3 neutropenia (H0: ≥40%; H1: ≤22%) or ≥ G 2 diarrhea (H0: ≥25%; H1: ≤10%) after two cycles. Results: A total of 50 pts were enrolled between February 2023 and September 2023 (TNBC, n = 32 [64%]). At data cut-off on October 18, 2023 (median follow-up, 4.3 months), 31 pts remained on treatment. The main reason for treatment discontinuation was PD, which was reported for 16 pts. After the first two cycles, incidence of any G neutropenia and diarrhea were 28% and 34%, respectively. Eight pts (16%) had ≥ G 3 neutropenia, meeting this primary endpoint (p=0.0002). Eight pts (16%) had ≥ G 2 diarrhea (4% G 3), showing numerical benefit of prophylactic L (p=0.084). No pts developed febrile neutropenia. The overall rate of AEs associated with dose reductions and treatment interruptions was 18% and 44%, respectively. No treatment discontinuations due to AEs were reported. Conclusions: Prophylactic administration of G-CSF and L resulted in a clinically relevant reduction of the incidence and severity of SG-related neutropenia and diarrhea and limited AE related dose reductions/interruptions and treatment discontinuations. Clinical trial information: NCT05520723 .

Current status of PD-(L)1 inhibitor usage in advanced or metastatic non-small cell lung cancer: A national survey of oncologists in China.

e20559 Background: The aim of the present study conducted by Chinese Society of Clinical Oncology Expert Committee on Immunotherapy was to obtain real-world information on the use of PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC) in different regions of China via a national questionnaire survey for oncologists. Methods: This survey was distributed online to cancer-related medical departments in 202 first-tier to fourth-tier cities of China between March to April 2023. The national survey consisted of four sections regarding oncologists’ concerns about immunotherapy as follows: treatment choice, response assessment, treatment duration, and management of immune-related adverse events (irAEs). Results: A total of 2,018 oncologists completed this survey. For advanced squamous (SQ) and non-squamous (NSQ) NSCLC without targetable genetic alterations, PD-(L)1 inhibitor-based regimens were the most widely used first-line treatment regimen (SQ: 52%, NSQ: 46%), followed by chemotherapy alone (SQ: 37%, NSQ: 37%) and other regimens (SQ: 11%, NSQ: 17%). The average treatment duration of 1L PD-(L)1 inhibitor-based regimens in SQ NSCLC and NSQ NSCLC were 6.4 and 6.2 cycles, respectively. 67% of oncologists may discontinue immunotherapy or change regimens when the first radiographic tumor assessment was SD per RECIST 1.1. Other reasons for early discontinuation of PD-(L)1 inhibitors before PD or unacceptable toxicity included economic reasons (78%) and patients’ low willingness to continue immunotherapy even they reached CR/PR (62%). Oncologists in the second-tier cities and below were more likely to discontinue immunotherapy when the tumors were stable, with shorter treatment duration of 5.7 cycles versus 7.1 cycles in the first-tier cities. The most common irAEs included dermatologic, endocrine, pulmonary, gastrointestinal, and hepatic toxicities. Conclusions: PD-(L)1 inhibitor-based regimens have become the priority choice for advanced NSCLC in China, however, the status of standardized continuous use of immunotherapy is obviously insufficient. There is a gap between clinical practice and clinical trials regarding PD-(L)1 inhibitor usage, which need more attention. [Table: see text]

Study update of the oral CDK9 inhibitor KB-0742 in relapsed or refractory transcriptionally addicted advanced solid tumors.

3102 Background: KB-0742 is a potent, and selective, oral inhibitor of CDK9 being evaluated in a phase I/II study in patients with transcriptionally addicted advanced solid tumors (NCT04718675). Interim data from the first 4 dose levels were presented previously noting manageable safety (MTD not reached), a 24-hour plasma half-life, linear PK, CDK9 target engagement in peripheral blood mononuclear cells (PBMCs), and anti-tumor activity in patients with transcription factor fusion (TFF) driven sarcomas. Here we present updated KB-0742 safety, pharmacokinetics (PK), pharmacodynamic data (PD) and anti-tumor activity for patients from the ongoing dose escalation through 5 dose levels and 60 mg expansion. Methods: Study objectives include evaluation of safety, tolerability, PK, PD, and identification of KB-0742 MTD and RP2D. KB-0742 is administered orally once daily for 3 consecutive days followed by 4 days off, weekly in 28-day cycles, until unacceptable toxicity or disease progression. Eligible patients were enrolled in 5 escalation cohorts (10, 20, 40, 60 and 80 mg) or 60 mg dose expansion. Eligibility criteria include age &gt;18 years, relapsed or refractory solid tumors, and ECOG PS &lt; 2. PD is assessed in (PBMCs) and tumor tissue from pre- and on-treatment biopsy samples. Results: As of January 4, 2024, 112 patients were enrolled, 42 in dose escalation and 70 in expansion. Patients received a median of 3 lines of prior therapy. The most common tumor types enrolled were soft tissue sarcoma (STS) (n=36; 18 TFF positive) and adenoid cystic carcinoma (ACC) (n=18). Treatment-emergent adverse events occurring in &gt;15% of patients include nausea, vomiting, anemia, fatigue, diarrhea, and constipation; none assessed as grade 4 or 5. The most common reason for treatment discontinuation was disease progression (54.5%). Across 5 dose levels, PK remains linear with a terminal half-life of 24 hours. At 60 mg, evidence of target engagement was observed in post-treatment paired tumor tissue biopsies. Within STS, TFF positive patients displayed a trend towards improved outcomes vs. those without a TFF with a disease control rate (DCR) of 42.8% vs. 29.4%, and one partial response was observed in a patient with TFF positive myxoid liposarcoma at 60mg. The best observed response was durable stable disease (SD) yielding a DCR of 53.8% in ACC (n=18), and 83% in NSCLC (n=6). Two patients (MYCL1+ ovarian, NSCLC) with prolonged SD (&gt;140 days) continue treatment on 60mg. Conclusions: KB-0742 treatment at 60 and 80 mg was well tolerated, with manageable toxicity. Achievement of long-term SD and some preliminary anti-tumor efficacy in highly pretreated patients motivates continued enrollment of patients with transcriptionally addicted tumors. Dose escalation and expansion in transcriptionally addicted ( MYC amplification/overexpression) or TFF driven tumors continues. Clinical trial information: NCT04718675 .

Testosterone replacement therapy (TRT) in patients with locoregional prostate cancer (LPC) treated with prior androgen deprivation therapy (ADT): A single center review.

e24045 Background: In LPC, ADT may be combined with radiation therapy (RT) for 4-24 months. Post-ADT, a significant proportion of men experience prolonged hypogonadism. TRT can alleviate symptoms and improve metabolic outcomes. Contrary to longstanding concerns, there is no substantial evidence of increased prostate cancer recurrence in patients (pts) treated with single modalities (surgery or RT). However, sparse data ( &lt; 100 cases published to our knowledge) exist regarding recurrence risk of LPC with TRT after prior ADT, where baseline T levels may fall below the androgen receptor saturation point. Methods: We retrospectively abstracted clinical data from hospital records of men with stage I – IVA PC, treated with prior concurrent ADT and RT and subsequently received TRT between January 2014 and September 2023. Extracted data included demographics, cancer diagnosis/staging, ADT/TRT treatment details and PSA and clinical outcomes. The co-primary endpoints were change in PSA and incidence of PC recurrence. Results: 21 pts met criteria. Median age was 77. ISUP Grade Groups (GG) included: GG1: 2, GG2: 2, GG3: 8, GG4: 2, and GG5: 7. AJCC 8th ed. stages were: I: 2, II: 7, III: 7, IV-A: 5. The median duration of prior ADT was 8 months (IQR 5 – 17) and the median interval from RT to TRT was 19 months (IQR: 12 – 44). Prior to TRT, the median testosterone level was 30.5 ng/dL (IQR: 17-76). TRT formulations included: injection: 6, oral: 4, topical: 13. The median follow-up period from the start of TRT was 13 months, and the median duration on TRT was 10 months (IQR: 5-22). TRT was ongoing in 15 (71.4%) pts and discontinued in 6 (28.6%). Reasons for discontinuation included testosterone recovery (1), hospice (not PC related) (2), no perceived benefit (2), MD concern for PSA rise (1). After TRT, the median testosterone level was 336 ng/dL (IQR: 207-462). Median PSA pre- and post-TRT were undetectable and 0.08 ng/dL, respectively. None of the subjects experienced PC recurrence or PC-specific mortality. One pt showed PSA bounce without recurrence. Median BMI was unchanged before (28.3 kg/m2) and after (27.7 kg/m2) TRT (p = 0.48). Due to the nature of the study, quality of life measures and metabolic parameters could not be systematically abstracted. Conclusions: In men with LPC who remained hypogonadal long-term after prior ADT and RT, we found that TRT was not associated with a significant rise in median PSA and no cases of PC recurrence were documented. This included many with a history of very high-risk cancers (eg. GG ≥ 4, Stage ≥ III). This study adds to the sparse existing literature in this clinical setting and together they support the case for a prospective trial utilizing TRT in patients who remain hypogonadal after ADT and radiation.

A phase Ia, dose-escalation study of IMB071703 injection in patients (pts) with recurrent or metastatic, advanced solid tumors.

e14502 Background: IMB071703(XFab-α4-1BB/CD40L), a 4-1BB Fab and triCD40L fusion protein that activates dendritic cell and primes tumor-reactive T cells, mediates immune response, and further inhibits tumor development. We confirmed the expansion of antigen-specific T cells in various mouse models and potent tumor regression administrated by IMB071703 alone or in combination with gemcitabine in vivo, concomitant with improved tumor-reactive T-cell infiltration. IMB071703 showed no signs of liver toxicity at the dose levels up to 51 mg/kg in a repeated-dose study in non-human primates. Here, we describe initial data from a phase Ia study (CTR20230326). Methods: Eligible patients with recurrent or metastatic, advanced solid tumors were enrolled in this study. IMB071703 was administrated at escalating doses of 0.05, 0.15, 0.5,1.0 and 1.5 mg/kg intratumorally Q1W in Cycle 1 (C1:21days), and Q2W from Cycle 2 and subsequent cycles (Cn+1:28 days). Enrolled pts would first undergo DLT observative assessment (21 days). After pts were assessed safely during DLT observation, they would continue the scheduled dosage of IMB071703 until disease progression, intolerable toxicity or other reasons specified in the clinical protocol. The study objectives included the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary efficacy. Results: 7 pts with recurrent or metastatic, advanced solid tumors (median age 60 years, range 42-71; 4 male, 3 female; prior lines of therapy with range 1-6) were treated. Three dose levels, 0.05 mg/kg(n=1), 0.15 mg/kg(n=3), and 0.5mg/kg(n=3), had been evaluated. 1.0mg/kg dose escalation is ongoing. On cutoff date of 18 Dec. 2023, 1 pt is on the study and 6 pts had discontinued treatment. The reasons for discontinuation included confirmed disease progression (n=5) and other reason(n=1). 7 pts (100%) experienced treatment-emergent adverse events (TEAEs). 5 pts (71%) experienced treatment-related adverse events (TRAEs≥10%): Injection reaction (pain, fever, chill) (28%), fatigue (11%). All TRAEs were ≤grade 2. No DLT was observed. One death due to disease progression, as only a SAE, was identified to be unrelated. No objective response was observed in 6 evaluable pts. 1 pt was SD and 5 pts were PD. Pharmacodynamic data showed CD40 was occupied ≥50% in the 0.5 mg/kg level. The percentage of CTL (CD3+CD8+) in peripheral blood was increased (0.15mg/kg and 0.5mg/kg) Pharmacokinetic analysis also showed the mean half-life of IMB071703 was 2.45 hours in three dose levels. Biomarker analysis indicated 4-1BB up-regulation and PD-1 down-regulation was associated with the favorable response. Conclusions: IMB071703 Showed a good safety profile at the dose levels of 0.05 mg/kg, 0.15 mg/kg, and 0.5mg/kg. Both favorable tolerability and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: CTR20230326 .

Safety assessments and clinical features of PARP inhibitors from real-world data of Japanese patients with ovarian cancer

Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.

Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.

Phase II randomized study of maintenance therapy with regorafenib (REGO) versus placebo after first-line platinum and fluoropyrimidines-based chemotherapy in HER2 negative locally advanced/metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer: Results of a-MANTRA study (GOIRC-05-2016).

4056 Background: REGO is an oral multi-targeted TKI that showed promising activity in advanced HER2-neg gastric cancer pts. The a-MANTRA study aimed to evaluate the efficacy and safety of REGO as maintenance after first-line (1L) therapy in advanced GC/GEJ tumors. Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase-II study in which HER2 neg advanced GC/GEJ pts with disease control after 1L platinum and fluoropyrimidines-based therapy, were randomized (1:1 ratio) to receive maintenance placebo (ARM A) or REGO (ARM B) starting at 80 mg with an escalation up to 160 mg (once daily on d1-21 q28 days), until intolerance or PD. The primary endpoint was Progression Free Survival 1 (PFS1). Two-sided 80% CIs were calculated to detect HR of 0.57, using a one-sided α=0.10 to have 90% power, translating to 3 months of improvement in mPFS. 118 subjects were required to observe 88 events. The interim analysis (IA) was planned after 44 events. Results: 67 pts were randomized in 18 Italian Cancer Centers; 64 pts (33 in ARM A and 31 in ARM B) received treatment. Most of the pts were male (64.1%), Caucasian (96.8%), ECOG PS 0 (81.2%), and median age 66 (40-80) yrs; the main primary tumor side was proximal (64.1%) with intestinal subtype (54.7%). Peritoneum metastases were present in 42.2%. IA showed a 98% probability of achieving a positive and statistically significant result for mPFS1. The study was stopped early due to the introduction of ICIs as 1L in PD-L1-positive pts. The objective responses to 1L chemotherapy were RP (50.0%), SD (42.2%), and CR (7.8%). At a median follow-up of 31 months (IQR 19.1-33-8), 28 (84.8%) and 26 (83.8%) events for each arm were reported. The main reason for discontinuation was PD (66.7% and 35.5%). The mPFS was 3.91 (80% CI, 2.27-5.98) and 5.19 months (80% CI, 4.0-7.26) with HR= 0.736 (80%CI, 0.51-1.04; p=0.1318). The mOS was 11.25 and 16.97 months (80%CI, HR=0.596 [0.318-1.103], p=0.1003). The most common G3-4 toxicities in ARM A and B were fatigue (3.0 vs 6.4%), thrombocytopenia (3.0 vs 3.2%), hand-foot syndrome (0 vs 12.9%), diarrhea and skin rash (0 vs 3,2%, respectively). Conclusions: Despite the promising trend, considering the sample was not sized for the statistical study hypothesis, REGO maintenance therapy after 1L chemotherapy did not reach statistically significant results in mPFS1. No significant safety concerns were raised. New study designs following the REGO with ICIs are currently underway. Clinical trial information: NCT03627728 .

Sorafenib treatment duration in desmoid tumors.

11585 Background: Desmoid tumors are soft-tissue neoplasms, which, although unable to metastasize, can cause significant morbidity due to local invasion. Currently, the first-line approach is active surveillance. For tumors that progress during surveillance, systemic therapies can be used, including nirogacestat, sorafenib, pazopanib, and cytotoxic chemotherapy. However, their optimal duration is unknown. Here, we aim to assess the risk of treatment failure after discontinuing sorafenib before one year. Methods: We analyzed all patients with desmoid tumors treated with sorafenib at three academic centers from 01/01/2000-12/01/2021. We included patients who discontinued sorafenib not due to radiological or clinical progression and had documented no intention to start the next line of therapy at the time of discontinuation. The primary endpoint was 2-year treatment-free survival between patients who stopped sorafenib before and after 1 year. The secondary endpoint was the rate of toxic effects recorded according to the Common Terminology Criteria for Adverse Events during treatment. We calculated treatment-free survival using the Kaplan-Meier method with the Log-Rank Test to estimate the 95% confidence interval. All patients were censored at the 2-year mark. Fischer’s Exact T-test was performed to assess between-group differences. Results: 40 patients received sorafenib and discontinued it with no intention to start a next line of therapy. The main reasons for discontinuation were side effects (n=21, 52%) and physician-patient preference (n=10, 25%). 27 (67%)were women, and median age at diagnosis was 36.Regarding race and ethnicity,27 (47%)were White, 8 (20%)were Black, and 16 (40%) were Latino. The tumor was in the lower extremity in 10 (25%) cases, trunk in 3 (7%) cases, abdominal wall in 10 (25%), intra-abdominal in 5 (12%), upper extremity in 5 (12%) head-neck in 1 and breast in 1. 20 patients stopped treatment before one year and 20 after one year, with 7 and 3 patients requiring a next line of therapy in each group, respectively. The 2-year treatment-free survival was 60% (95% confidence interval [CI], 0.35 to 0.85) in the prior to 1-year group and 87.5% (95% CI, 0.71 to 1.0) in the post-1-year group (P = 0.046). The most frequently reported adverse events while on sorafenib were grade 1 or 2 events of palmar-plantar erythrodysesthesia (40%) and diarrhea (40%), with no difference between groups on therapy discontinuation due to side effects (p=0.1). Conclusions: Discontinuing sorafenib prior to 1 year was associated with a higher risk of requiring further therapy within the following two years. Still, most patients did not require additional therapy. This finding underscores the complexity of determining the optimal duration for sorafenib therapy, and multiple features should be considered, including side effects, symptom improvement, fertility planning, tumor cellularity (evaluated by T2 MRI signal), and physician-patient shared decision.