Median Treatment Duration Research Articles

Polymyalgia rheumatica is a risk factor for more recalcitrant disease in giant cell arteritis: A retrospective cohort study

ObjectivesTo evaluate differences in presentation and outcome of giant cell arteritis (GCA) patients with and without polymyalgia rheumatica (PMR) symptoms. MethodsConsecutive patients diagnosed with GCA between 2000 and 2020 and followed for ≥12 months at the University Hospitals Leuven (Belgium), were included retrospectively. ResultsWe included 398 GCA patients, of which 181 (45%) with PMR symptoms. Patients with PMR symptoms had a longer symptom duration (11 vs 6 weeks, p < 0.001). They less frequently reported fever (19% vs 28%, p = 0.030) and fatigue (52% vs 64%, p = 0.015) and tended to have less permanent vision loss (12% vs 19%, p = 0.052). There was no difference in the cumulative oral GC dose at 2 years (4.4 vs 4.3 g methylprednisolone, p = 0.571). However, those with PMR symptoms were treated with higher GC doses during subsequent follow-up (p < 0.05 from 38 months after diagnosis) and had a lower probability of stopping GC (62% vs 71%, HR 0.74 [95%CI 0.58–0.94], p = 0.018) with a longer median duration of GC treatment (29 vs 23 months, p = 0.021). In addition, presence of PMR symptoms was associated with an increased risk of relapse (64% vs 51%, HR 1.38 [95%CI 1.06–1.79], p = 0.017) with a higher number of relapses (1.47 [95%CI 1.30–1.65] vs 1.16 relapses [95%CI 1.02–1.31], p = 0.007). Patients with PMR symptoms less frequently developed thoracic aortic aneurysms during follow-up (3% vs 11%, p = 0.005). ConclusionGCA patients with PMR symptoms had more recalcitrant disease with a higher risk of relapse and longer duration of GC treatment with need for higher GC doses.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study

IntroductionPrevious results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. MethodsAdult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. ResultsAt the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. ConclusionsWith four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Evaluating the safety of high-intensity focused ultrasound treatment for rectal endometriosis: results from a French prospective multicentre study including 60 patients.

Is increasing the intensity of high-intensity focused ultrasound (HIFU) by 30% in the treatment of rectal endometriosis a safe procedure? This study demonstrates the safety of a 30% increase in the intensity of HIFU in the treatment of rectal endometriosis, with no Clavien-Dindo Grade III complications overall, and namely no rectovaginal fistulae. A feasibility study including 20 patients with rectal endometriosis demonstrated, with no severe complications, a significant improvement in digestive disorders, dysmenorrhoea, dyspareunia, and health status, although the volume of the endometriosis nodule did not appear to be reduced. A prospective multicentre cohort study was conducted between 2020 and 2022 with 60 patients with symptomatic rectal endometriosis. Following the failure of medical treatment, HIFU treatment was offered as an alternative to surgery. As the main objective of this study was to examine safety, all adverse events observed during the 6 months of follow-up were analysed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and Clavien-Dindo classifications. Secondary objectives included evaluating the evolution of symptoms using validated questionnaires: gynaecological and digestive pain symptoms with a visual analogue scale, health status with the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire, average post-operative daily pain level, and analgesic medication required in the 10 days following treatment. MRI was also performed at Day 1 to detect early complications. Finally, we performed a blinded MRI review of the evolution of the nodule at 6 months post-treatment. The procedure was performed under spinal anaesthesia for 30% of the patients. The median duration of treatment was 32 min. Fifty-five patients left the hospital on Day 1. MRI scans performed on Day 1 did not highlight any early-onset post-operative complication. Using the Clavien-Dindo classification, we listed 56.7% Grade I events, 3.4% Grade II events, and no events Grade III or higher. At 1, 3, and 6 months, all gynaecologic, digestive and general symptoms, as well as health status, had significantly improved. The evolution of the nodule was also significant (P < 0.001) with a 28% decrease in volume. The main objective was safety and not effectiveness. The study was not randomized and there was no control group. HIFU treatment for rectal endometriosis results in an improvement of symptoms with low morbidity; as such, for selected patients, it could be a valuable alternative to surgical approaches following the failure of medical treatment. The study was funded by the company EDAP TMS. Professors Dubernard and Rousset are consultants for EDAP TMS. Dubernard received travel support from EDAP-TMS. Dr F. Chavrier received industrial grants from EDAP-TMS. He has developed a device for generating focused ultrasonic waves with reduced treatment time. This device has been patented by EDAP-TMS. Dr Lafon received industrial grants from EDAP-TMS; he declares that EDAP-TMS provided funding directly to INSERM to support a young researcher chair in therapeutic ultrasound, which is unrelated to the current study. ClinicalTrials.gov identifier NCT04494568.

Impact of the IDEA Collaboration Study on Real-World Practice Patterns of Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Population-Based Study.

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration showed no significant clinical difference in outcomes in patients with stage III colon cancer (CC) treated with 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy (O-ACT). We aimed to assess change in real-world practice patterns before and after publication of the IDEA study. This retrospective cohort study included patients age ≥18 years with stage III CC diagnosed between January 1, 2012, and December 31, 2020. Eligible patients received >1 dose of ACT between March 20, 2012, and May 10, 2021 inclusive. They were categorized into pre-IDEA (diagnosed before March 31, 2018) and post-IDEA (diagnosed on or after April 1, 2018) groups. The primary outcome was the median duration and type of ACT and factors associated with a shorter duration. Secondary outcomes were 2-year overall survival (OS) and cancer-specific survival (CSS). In total, 740 patients were included (median age, 64 years, range, 27-90; 52.7% male). 48.8% had pT4 and/or pN2 disease. 77% received O-ACT. In the post-IDEA era, capecitabine plus oxaliplatin (CAPOX) ACT use increased (22.8%-50.7%, P < .001), and median duration of treatment was significantly shorter (2.7 v 4.8 months, P < .001). Factors associated with shorter O-ACT duration included diagnosis in the post-IDEA era (odds ratio, 2.08, P = .002), absence of pT4 and/or pN2 disease (hazard ratio [HR], 1.71, P = .01), and receipt of CAPOX (HR, 2.58, P < .001). Two-year OS and CSS were comparable between pre- and post-IDEA eras (OS 95% v 94%; CSS 96% v 96%). Our study shows that the results of the IDEA trial have been largely adopted in clinical practice with shorter duration of ACT in low-risk stage III CC.

Trastuzumab deruxtecan versus treatment of physician’s choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study

BackgroundIn the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody–drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician’s choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1–2 prior lines of chemotherapy.MethodsThis subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66).ResultsMedian PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1–2.ConclusionsT-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals.Clinical trial registration numberClinicalTrials.gov, NCT03734029.

Neurobrucellosis Presenting with Motor Damage or Hearing Loss, and Use of Steroids are Associated with a Higher Risk of Sequelae or Relapse: A Systematic Review of Individual Participant Data

BackgroundNeurobrucellosis presents diverse clinical challenges and risks of long-term complications.ObjectiveWe aimed to assess the relationship between the duration of antibiotic therapy, clinical factors, and the outcome of neurobrucellosis with a case report combined with a systematic review of the literature.MethodsWe present a case of a 31 years-old man successfully treated at our Institution. We then searched Ovid MEDLINE, Embase and Scopus for articles that encompassed neurobrucellosis cases, duration of treatment, and outcome. The primary outcome was to assess an association between the duration of treatment and the risk of sequelae or relapses. Univariate, multivariate and sensitivity analysis were carried out to define which variables affect​ed​ the clinical outcome. Quality assessment was performed using a dedicated tool.ResultsA total of 123 studies were included, totaling 221 patients. Median duration of treatment was 4 months (IQR 3 – 6), 69% patients recovered without sequelae, 27% had sequelae. Additionally, five patients had a relapse, and 4 patients died. Multivariate analysis found that the duration of treatment, age, and the use of ceftriaxone were not associated with a higher risk of sequelae or relapses. A significant association was found for corticosteroids use (OR 0.39, 95% IC 0.16 – 0.96, p = 0.038), motor impairment (OR 0.29, 95% IC 0.14 – 0.62, p = 0.002), and hearing loss (OR 0.037, 95% IC 0.01 – 0.11, p < 0.001).ConclusionsThis study highlights the variability in clinical presentations and treatment approaches for neurobrucellosis. Patients with factors indicating higher sequelae risk require meticulous follow-up.

Safety and anti-tumor activity of BAY 2927088 in patients with HER2-mutant NSCLC: Results from an expansion cohort of the SOHO-01 phase I/II study.

LBA8598 Background: HER2 ( ERBB2) mutations have been reported in approximately 2-4% of patients (pts) with NSCLC, with exon 20 insertions being the most common. BAY 2927088 is an oral, reversible tyrosine kinase inhibitor that potently inhibits mutant HER2 and mutant EGFR in preclinical models. Encouraging objective responses were observed in pts with NSCLC harboring a HER2-activating mutation and treated with BAY 2927088 in the dose-escalation/backfill part of the Phase I/II SOHO-01 trial (NCT05099172). More recently the FDA has granted Breakthrough Therapy designation for BAY 2927088 for previously treated pts with advanced NSCLC and activating HER2 mutations. Here we report the safety, anti-tumor activity, and longitudinal circulating tumor DNA (ctDNA) data in a cohort of pts treated with BAY 2927088 from the expansion part of this trial. Methods: Pts with advanced NSCLC harboring a HER2-activating mutation and who experienced disease progression after at least 1 systemic therapy, but naïve to HER2-targeted therapy, were enrolled and received BAY 2927088 at 20 mg twice daily. Plasma samples were collected at baseline and several on-treatment time points for longitudinal ctDNA profiling using next-generation sequencing (NGS; Oncomine Precision Assay). Results: As of February 19, 2024, 34 pts were treated with BAY 2927088, with a median follow-up of 8 months. Median age was 62 years, 68% were female, 74% had never smoked, and 53% had received ≥2 lines of systemic anti-cancer therapy. Median duration of treatment with BAY 2927088 was 7.1 months (range 0.2-9.2). Treatment was ongoing in 17 pts (50%). Ten pts had a dose reduction, 8 had dose interruptions, and 3 discontinued study treatment due to a drug-related adverse event. The most common adverse events were diarrhea (85%; mainly grade 1-2) and rash (47%; grade 1-2). In 33 pts evaluable for efficacy, responses were observed in 23 (objective response rate 70%; 95% CI 51.3, 84.4) and 5 (15%) had stable disease for a disease control rate of 82% (95% CI 64.5, 93.0). Responses were rapid (median time to response 5.7 weeks) and durable (median duration of response not reached). Median progression-free survival was 8.1 months (95% CI 4.4, not evaluable). In a subset of 20 pts with successful paired (baseline, on-treatment) blood NGS and detectable HER2 ctDNA at baseline, 19/20 (95%) had a decrease in ctDNA and 1 pt with progressive disease had an increase in ctDNA; 15/20 (75%) had no detectable ctDNA after 6 weeks of treatment (including 3/4 pts with stable disease). Conclusions: BAY 2927088 led to rapid, substantial, and durable responses in pts with pretreated HER2-mutant NSCLC. The safety profile was consistent with previously reported data. These data support the further clinical development of BAY 2927088 in pts with HER2-mutant NSCLC. Clinical trial information: NCT05099172 .

Palbociclib plus exemestane with GnRH agonist vs capecitabine in premenopausal patients with HR+/HER2- metastatic breast cancer: Updated survival results of the randomized phase 2 study Young-PEARL.

LBA1002 Background: The Young-PEARL study demonstrated improved progression free survival (PFS) (mPFS: 20.1 vs. 14.4 mo.) of exemestane plus palbociclib with ovarian function suppression (OFS) compared to capecitabine in premenopausal patients with HR+/HER2- metastatic breast cancer (mBC). Here we report updated survival outcomes with median follow-up of 54.8 months (data cutoff, November 30, 2023). Methods: Premenopausal women aged 19 years or older with HR+/HER2- BC who had relapsed or progressed during previous tamoxifen therapy were enrolled. One line of previous chemotherapy for mBC was allowed. The primary endpoint was PFS, which was defined as the time from C1D1 to disease progression or death. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR) and toxicities. Results: 184 patients were randomly assigned to exemestane plus palbociclib with OFS (n=92) or capecitabine (n=92). Median age was 44.0 years (range, 28-58). Key efficacy and safety are shown in Table. Final analysis was conducted for 174 patients. The updated mPFS was 19.5 mo. (90% CI, 14.3-22.3) for exemestane + palbociclib + OFS compared with 14.0 mo. (90% CI, 11.7-18.7) for capecitabine (HR 0.75, P=0.04). mOS was 54.8 mo. (95% CI, 48.9-77.1) for palbociclib arm and 57.8 mo. (95% CI, 46.3-N/A) for capecitabine arm (HR 1.06, P=0.77). mPFS2 (from the date of 1st PD to 2nd PD) was significantly shorter in palbociclib arm than those of capecitabine arm (7.5 vs. 11.7 mo. P=0.02). Confirmed ORR based on the investigator assessments was 33.3% (95% CI, 23.6-43.1) for palbociclib and 33.7% (95% CI, 23.6-43.9) for capecitabine. Median treatment duration was 18.9 mo. (range 1.6-88.4) in palbociclib and 13.5 mo. (range 0.1-70.8) in capecitabine. In palbociclib arm, 86 (93.5%) experienced grade 3 or more TEAEs, mainly asymptomatic neutropenia (64.1%), compared to 41 (48.2%) patients with grade ≥3 TEAEs in the capecitabine arm, mainly Hand-Foot syndrome and neutropenia (18.8% for each). Conclusions: Young-PEARL study showed exemestane + palbociclib with OFS improves efficacy compared with capecitabine in terms of PFS, which did not lead to an OS benefit for patients with premenopausal HR+/HER2- mBC (median follow-up duration: 54.8 months). The overall safety profile of palbociclib and capecitabine continues to be manageable with longer follow-up. Clinical trial information: NCT02592746 . [Table: see text]

Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06).

LBA1000 Background: T-DXd is approved for HER2-low (IHC 1+ or 2+/ISH-negative) mBC after ≥1 line of chemotherapy (CT). DB-06 (NCT04494425) evaluated T-DXd in pts with HER2-low or -ultralow (IHC 0 with membrane staining), HR+ mBC after disease progression (PD) on endocrine-based therapy and no prior CT for mBC. Methods: Pts with HER2-low or -ultralow, HR+ mBC were randomized 1:1 to T-DXd 5.4 mg/kg or TPC. Pts had no prior CT for mBC, with ≥2 lines of ET for mBC, or 1 line of ET for mBC if PD occurred ≤24 months (mo) of adjuvant ET or ≤6 mo of ET+CDK4/6i for mBC. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in HER2-low. Key secondary endpoints were PFS in intent-to-treat (ITT = HER2-low and -ultralow) and overall survival (OS). Other endpoints included objective response rate (ORR) and safety. Results: As of Mar 18, 2024, 866 pts (HER2-low, n=713; HER2-ultralow, n=153) were randomized; 90.4% had prior CDK4/6i. TPC group pts were selected for capecitabine (59.8%), nab-paclitaxel (24.4%) or paclitaxel (15.8%). T-DXd significantly improved PFS vs TPC in HER2-low (HR, 0.62 [95% CI 0.51, 0.74], P&lt;0.0001; median, 13.2 vs 8.1 mo). ITT and HER2-ultralow results were consistent with HER2-low (Table). Median treatment duration was 11.0 mo (T-DXd) vs 5.6 mo (TPC). OS was immature at first interim analysis (HER2-low HR, 0.83 [95% CI 0.66, 1.05], P=0.1181; median follow up, 18.6 mo). Grade (Gr) ≥3 drug-related adverse events occurred in 40.6% (T-DXd) vs 31.4% (TPC). Adjudicated interstitial lung disease / pneumonitis occurred in 49 (11.3%; 0.7% Gr 3/4, 0.7% Gr 5) vs 1 (0.2% Gr 2) pts receiving T-DXd vs TPC. Conclusions: T-DXd showed a statistically significant and clinically meaningful PFS benefit vs TPC (CT) in HER2-low mBC. HER2-ultralow results were consistent with HER2-low. Safety was in line with known profiles. DB-06 establishes T-DXd as a standard of care following ≥1 endocrine-based therapy for pts with HER2-low and -ultralow, HR+ mBC. Clinical trial information: NCT04494425 .[Table: see text]

Dosing and treatment duration of suppressive antimicrobial therapy in orthopedic implant infections: a cohort study.

Introduction: Limited data inform about the optimal dosing and duration of suppressive antimicrobial therapy (SAT) for orthopedic implant infection (OII). We aimed to compare the effectiveness of low-dosage with standard-dosage SAT and evaluate the safety of stopping SAT. Methods: All patients with OII treated with SAT from 2011 to 2022 were retrospectively included. Data were extracted from electronic patient files. Low-dosage SAT was defined as antimicrobial therapy dosed lower than the standard dosage recommended for OII. The association of dosing strategy and other factors with failure-free survival were assessed by Kaplan-Meier and Cox proportional hazard models. Results: One-hundred-and-eight patients were included. The median follow-up time after SAT initiation was 21months (interquartile range (IQR) 10-42 months). SAT was successful in 74 patients (69 %). Low-dosage SAT ( ) was not associated with failure in univariate (hazard ratio (HR) 1.23, 95 % confidence interval (CI) 0.53-2.83) and multivariate analyses (HR 1.24, 95 % CI 0.54-2.90). In 25 patients (23 %), SAT was stopped after a median treatment duration of 26 months. In this group, one patient (4 %) developed a relapse. Conclusions: In this study, low-dosage SAT was as effective as standard dosage SAT. Moreover, stopping SAT after 2 to 3years may be justified in patients with a good clinical course. These findings warrant further research on optimal dosing and duration of SAT and on the durability of in vivo biofilms.

The Effect of Age and Other Patient Characteristics on Outcomes Among Nontransplanted Patients Who Were Treated With First-Line Lenalidomide, Bortezomib, and Dexamethasone: Results From the ConnectⓇ MM Registry

BackgroundLenalidomide (R), bortezomib (V), and dexamethasone (d) is a standard-of-care regimen in newly diagnosed multiple myeloma (NDMM); however, characteristics and outcomes for nontransplanted patients receiving frontline RVd are not well understood. PatientsThe ConnectⓇ MM Registry is a large, US, multicenter, prospective observational cohort study of NDMM patients. MethodsThis analysis investigated characteristics and outcomes of patients who received RVd alone or followed by Rd or R (RVd ± Rd/R) who did not undergo frontline autologous stem cell transplantation. ResultsAs of August 2021, 314 of 1979 nontransplanted patients received RVd ± Rd/R as initial therapy. Of these, 135 were aged ≤ 65 years and 179 were > 65 years. 108 patients had time to relapse (TTR) of ≤ 12 months and 182 had TTR > 12 months. Baseline characteristics were comparable regardless of TTR and age group except renal function, which was more commonly impaired in older patients. Among patients aged ≤ 65 and > 65 years, median duration of first-line treatment was 6.3 and 9.0 months, median time to next line for those who received second-line therapy was 15.5 and 15.2 months, median progression-free survival (PFS) was 19.3 and 23.0 months, and median overall survival was 60.0 and 59.1 months, respectively. High-risk disease (per IMWG criteria) and high serum calcium were associated with higher hazard of progression or death; the adjusted PFS hazard ratio with respect to age (≤ 65 vs. > 65 years) based on multivariable analysis was 1.18 (0.89-1.57; P = .25). ConclusionThese results indicate RVd is active across age groups and provide a better understanding of outcomes with RVd in NDMM.

Simulated Target Attainment of Multidose Regimens of Dalbavancin for Prolonged Durations of Therapy

Abstract Background Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use. Methods An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens. The primary endpoint evaluated was days of median 24-hour free area under the curve over the minimum inhibitory concentration (AUC/MIC) &amp;gt;27.1, the established PK target. Results A dosing regimen of 1500 mg on day 0 and day 7 resulted in median AUC/breakpoint value above the target for 57 days (lower 95% confidence interval [CI], 37 days). A modified regimen of 1500 mg on day 0 and day 21 resulted in an additional 11 days of median AUC/breakpoint target attainment. The other standard dosing regimen modeled was 1000 mg on day 0, then 500 mg weekly for 5 doses. This regimen achieved the AUC/breakpoint target for 76 days (lower 95% CI, 59 days). This regimen was modified to 1000 mg on day 0, then 500 mg on days 14 and 28, which shortened the median effective treatment duration by 14 days but required 3 fewer doses. Conclusions These simulated results, when combined with the favorable observational data, support the use of commonly reported dalbavancin regimens for prolonged therapy durations. In addition, these pharmacokinetic/pharmacodynamic data support extending the dosing interval beyond the frequently reported weekly regimens, which should be investigated further with a clinical trial.

Efficacy and biomarker analysis of phase 2 (P2) and window-of-opportunity (WoO) cohorts of patients with recurrent glioblastoma (rGBM) treated with ST101, an inhibitor of the transcription factor C/EBPβ.

2011 Background: CCAAT/enhancer-binding protein β (C/EBPβ) is an important transcription factor in GBM cell maintenance and is associated with worse outcomes and resistance to chemotherapy through transcription of genes associated with cell cycle and DNA repair. C/EBPβ is also required for maintenance of immunosuppressive tumor-associated macrophages. ST101 is a first-in-class antagonist of C/EBPβ that promotes selective GBM cell death without impacting normal cell viability (Darvishi, 2022), and repolarization of macrophages toward an immunostimulatory program. In an all comers P1 study, ST101 was well-tolerated, showed significant tumor uptake, ~40 hr plasma half-life, and signal of efficacy (1PR +8SD). With strong rationale targeting C/EBPβ in GBM and evidence that ST101 crosses the BBB in preclinical biodistribution studies, cohorts in rGBM were explored. Methods: Pts with ≤2 recurrences of GBM were enrolled in a P2 cohort (n=30) and treated with 500mg QW. A WoO cohort of 6 pts with rGBM received 2-4 doses of ST101 500mg QW prior to surgery and resumed ST101 after surgery until progression (NCT04478279). Endpoints for the two cohorts included response, PFS and OS while the WoO cohort also included tissue analyses (GBM subtypes, tumor microenvironment (TME) characterization, ST101 tumor penetration, and C/EBPβ target engagement). Clinical data is available for both cohorts and tissue analysis is available for the WoO cohort. Results: Data is a snapshot as of February 1, 2024. ST101 was safe and well-tolerated in both cohorts with no discontinuations due to AEs. Pts in the P2 study show 30% DCR (1PR + 8SD), 20% 6-mo PFS and 37% OS at 1 year. Median duration of treatment is 3.4 mos with 2 pts stable and still on study for 10+ and 16+ mos. In the WoO study, efficacy from post-surgery MRI showed 67% DCR (2 PR + 2 SD) and ~50% 6-mo PFS. Median OS cannot be assessed at this early stage. The median duration of treatment is 6.02 mos with 2 pts still on study for 7+ and 10+ mos. Tissue compared before and after ST101 exposure shows ST101 uptake and C/EBPβ target engagement by IHC, and pathologic evidence of treatment effect, such as geographic necrosis, in 5/6 pts. Evaluation of tumor and TME characteristics in post-ST101 treatment tissue will be presented. Conclusions: Monotherapy ST101 in pts with rGBM has an excellent safety profile and results in comparable outcomes to current 2nd line treatments. ST101 crosses the BBB, engages its target, and potentially induces treatment-related necrosis. These encouraging clinical activity, safety, and tissue findings, as well as preclinical data showing additive activity in combination with lomustine, support advancing ST101 to a randomized, placebo-controlled study comparing ST101 + lomustine vs. lomustine + placebo in rGBM. We aim to initiate this study in Q3 2024. Clinical trial information: NCT04478279 .

Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study.

3038 Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. TRAEs occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%), which were all grade 1-2. Only 1 pt experienced ILD/pneumonia (7.3mg/kg, grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg. Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved PR per RECIST 1.1 by investigator. Thus, ORR and DCR was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2-positive and HER2-low breast cancer, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .

A real-world, patient-reported outcomes study in patients with platinum-sensitive recurrent ovarian cancer receiving long-term maintenance therapy with niraparib.

e23164 Background: Niraparib has been approved for the maintenance treatment of newly diagnosed advanced and platinum-sensitive recurrent ovarian cancer (PSR OC). The phase 3 PRIMA and NOVA studies showed that maintenance niraparib did not worsen quality of life (QoL) compared with placebo. However, no QoL data have been reported for Asian OC patients treated with niraparib. Here, we report patient-reported outcomes (PROs) for PSR OC patients who received niraparib as maintenance therapy for more than two years in a real-world setting. Methods: This prospective, real-world study included OC patients participating in the Niraparib Patient Assistance Program (PAP) in China (NCT06037213). Eligible patients had histologically confirmed PSR epithelial OC, fallopian tube, or primary peritoneal cancer, had been maintained on niraparib for more than two years without disease progression and were still receiving niraparib within 28 days. PROs were assessed every 4-6 weeks for three times using the EQ-5D-5L questionnaire and the FOSI. In addition, a 6-question niraparib medication questionnaire including starting dose, adaptive dose, dose adjustments and reasons, missed doses, concomitant medications was administered at baseline. Results: The PAP enrolled 3154 PSR OC patients, 1151 had been on niraparib for more than two years and could be followed up. From August 2023 to January 2024, 604 eligible patients were recruited and completed at least one assessment. The median age was 58 years (range, 27-82 years). The median duration of treatment with niraparib was 34.8 months (range, 30.5-46.7 months). Among 445 patients with BRCAm status, 104 were BRCAm (23.4%) and 341 were BRCAwt (76.6%). A total of 491 patients (81.3%) received niraparib 200 mg as a starting dose, while 107 (17.7%) required dose adjustments in clinical practice. Presently, 503 (83.3%) were on 200mg. 523 (86.6%) were compliant with the daily oral dose of niraparib, without missing any doses in the previous 6 months. 193 patients (32.0%) had common chronic disease, and 176 (29.1%) were taking concomitant medications during maintenance. The EQ-5D-5L HUI and VAS scores remained stable across the three assessments. The baseline mean EQ-5D-5L HUI and VAS scores were 0.98 (SD 0.05) and 84.31 (SD 10.50), respectively, and the least squares (LS) mean changes from baseline to the third assessment were -0.004 (SE 0.001) and -0.609 (SE 0.248), respectively. A similar situation was observed for the FOSI score. The baseline mean FOSI score was 31.13 (SD 1.37), and the LS mean change from baseline to the third assessment was -0.359 (SE 0.033). Conclusions: In the real world, patients with PSR OC who underwent long-term maintenance treatment with niraparib exhibited a consistently stable QoL. This finding highlights the significant clinical value of niraparib in maintaining QoL in these populations.

Tumor treating fields for newly diagnosed high-grade glioma based on the criteria of 2021 WHO CNS5: A retrospective analysis of Chinese patients in a single center.

High-grade glioma (HGG) is known to be characterized by a high degree of malignancy and a worse prognosis. The classical treatment is safe resection supplemented by radiotherapy and chemotherapy. Tumor treating fields (TTFields), an emerging physiotherapeutic modality that targets malignant solid tumors using medium-frequency, low-intensity, alternating electric fields to interfere with cell division, have been used for the treatment of new diagnosis of glioblastoma, however, their administration in HGG requires further clinical evidence. The efficacy and safety of TTFields in Chinese patients with HGG were retrospectively evaluated by us in a single center. We enrolled and analyzed 52 patients with newly diagnosed HGG undergoing surgery and standard chemoradiotherapy regimens from December 2019 to June 2022, and followed them until June 2023. Based on whether they used TTFields, they were divided into a TTFields group and a non-TTFields group. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. There were 26 cases in the TTFields group and 26 cases in the non-TTFields group. In the TTFields group, the median PFS was 14.2 months (95% CI: 9.50-18.90), the median OS was 19.7 months (95% CI: 14.95-24.25) , the median interval from surgery to the start of treatment with TTFields was 2.47 months (95% CI: 1.47-4.13), and the median duration of treatment with TTFields was 10.6 months (95% CI: 9.57-11.63). 15 (57.69%) patients experienced an adverse event and no serious adverse event was reported. In the non-TTFields group, the median PFS was 9.57 months (95% CI: 6.23-12.91) and the median OS was 16.07 months (95% CI: 12.90-19.24). There was a statistically significant difference in PFS (p = 0.005) and OS (p = 0.007) between the two groups. In this retrospective analysis, TTFields were observed to improve newly diagnosed HGG patients' median PFS and OS. Compliance was much higher than reported in clinical trials and safety remained good.

Evaluation of the safety, pharmacokinetics, and efficacy of JSKN003 in patients with advanced solid tumors: A phase I/II clinical study.

3031 Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability, that may lead to a broader therapeutic window. Methods: JSKN003-102 (NCT05744427) is a phase I (dose escalation and dose expansion) and phase II (cohort expansion) study in Chinese patients (pts) with advanced solid tumors. Pts (ECOG PS 0-1) with HER2-expressing (IHC ≥ 1+) or HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, MTD or RP2D, pharmacokinetics, and preliminary antitumor activity. Here the results from phase I were reported. Results: As of 5th Jan 2024, 46 pts (25 breast cancers, 11 gastric cancers, 8 colorectal cancers, 1 lung cancer, and 1 ovarian cancer) were enrolled and received JSKN003 across 6 dose levels, including 2.1 (n=1), 4.2 (n=10), 5.2 (n=14), 6.3 (n=15), 7.3 (n=3), and 8.4 mg/kg (n=3), Q3W, in phase I period. Among the 46 pts, 18 were IHC 3+, 21 were IHC 2+, and 7 were IHC 1+. Most pts (73.9%) received ≥ 3 prior lines of therapy, including 60.9% and 45.6% of pts received prior anti-HER2 and anti-HER2 ADC therapy, respectively. The median duration of treatment was 13.1 (range, 2.1 - 42.4) weeks, and 37 pts (80.4%) remained on treatment. Treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%), and the common, mostly grade 1 and 2, were diarrhea (37.0%) and nausea (32.6%). Only 6 pts (13.0%) experienced grade ≥3 TRAEs, and the common were lymphopenia (4.3%) and neutropenia(4.3%). 1 pt (2.2%) had treatment related SAE (nausea, grade 3). No pts experienced DLT or interstitial lung disease, and no TRAE led to death or discontinuation. Following a single dose, exposures (Cmax and AUC) of JSKN003 increased proportionally over a dose range of 4.2 mg/kg to 6.3mg/kg. T1/2 of JSKN003 is approximately 3-5 days. No significant accumulation was observed after 4 cycles treatment. The exposure of released payload was very low, demonstrating the stability of the JSKN003 in circulation. 37 pts had at least one post-baseline tumor assessment. The ORR and DCR was 51.4% (95%CI: 34.4, 68.1) and 91.9% (95%CI: 78.1, 98.3), respectively. The ORR in pts with HER2 IHC 1+, 2+ and 3+ was 20.0% (95% CI: 0.5, 71.6), 33.3% (95% CI: 11.8, 61.6), and 76.5% (95% CI: 50.1, 93.2), respectively. For pts who received prior anti-HER2 ADC, the ORR was 57.9% (95% CI: 33.5, 79.7). For HER2 positive breast cancer and gastric cancer, the ORR was 66.7% (95% CI: 38.4, 88.2) in 15 pts and 100% (95% CI: 39.8, 100) in 4 pts, respectively. Conclusions: MTD of JSKN003 was not reached yet. And safety of JSKN003 was extremely excellent with encouraging preliminary antitumor activity in heavily pretreated pts with advanced solid tumors. Clinical trial information: NCT05744427 .

Interchangeability of anti-PD1 antibodies in patients (pts) with metastatic NSCLC.

e20553 Background: PD-(L)1 inhibitors are approved immunotherapy agents in treatment for mNSCLC, however, limited data exists about switching between different anti-PD1 antibodies. Our study aimed to evaluate the safety and efficacy of the interchangeability of nivolumab, pembrolizumab, and atezolizumab in patients (pts) with mNSCLC in the 2nd and 3rd line. Methods: We retrospectively evaluated data of pts with mNSCLC treated in four oncology centers in Moscow and SaintPetersburg (Russia). Inclusion criteria were as follows: histologically confirmed mNSCLC with no driver mutations, performance status ECOG 0-2, monotherapy of anti-PD(L)1 antibody, and switching to another PD(L)1 inhibitor for any reason except progression disease or toxicity after initiating of immunotherapy. The primary end-point was progression-free survival (PFS), and secondary end-points were the rate of all grades and grade 3-4 adverse events (CTC AE 5.0). A sample size of 83 achieves 80% power to detect an equivalence difference of 15% in 3-months PFS after the change of anti-PD1 antibody with a one-sided significance level of 0,05. Results: A total of 103 patients (27% female) were included with a mean age of 66 years (33-93). 0-1, 2, and ≥3 organs with metastases have 70 (68%), 17 (17%), and 16 (16%) pts, respectively. Performance status ECOG 0, 1, and 2 was in 16 (16%), 70 (68%), and 17 (17%) pts, respectively. 50 (48%) patients received pembrolizumab, 40 (39%) pts received nivolumab, and 13 (13%) pts – atezolizumab. 48 (47%) pts were switched to atezolizumab, 28 (27%) pts were switched to nivolumab, 26 (25%) pts – to pembrolizumab. The median duration of treatment with the first anti-PD(L)1 antibody was 6 months (1-53 months), with the second PD(L)1-inhibitor was 3 months (1-41 months). Within 3 months after 1 replacement of the drug, there were 77 (74,7%) pts without progression. With the median follow-up of 8 months (1-41), the estimated 3-month PFS was 79,3%. The efficacy of switching was not associated with the agent (HR 0,97, 95CI 0,68-1,38, p = 0,9). There were 2 cases of AEs of 3-4 grades when switching to the second drug. Conclusions: Switching from one anti-PD(L)1 antibody to another in pts with mNSCLC is possible in case of limited access to PD(L)1 inhibitors.

Correlation between metastatic site and immunotherapy efficacy in patients with advanced dMMR/MSI colorectal cancer: Real-World Italian multicentric retrospective study (Colon-MSI).

e15544 Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The Colon-MSI study aimed to describe a cohort of MSI mCRC pts treated with ICIs before Italian pembrolizumab approval and to evaluate the efficacy, safety, and possible predictive factors of response in a real-world setting. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs before June 30, 2023, in 16 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. We explored the correlation between clinicopathological factors, survival outcomes, and treatment response. Results: Between January 2021 and June 2023, we reported 83 consecutive pts with data available. Among all, the median age was 61 years (23-86), 42 (51%) were female, and 45 (54%) had a ECOG PS 0; 35 (42%) pts were at stage IV at diagnosis, and 61 (74%) had right colon tumor site. The most common metastatic sites were liver (35%), lymph nodes (43%), peritoneum (31%), and lung (15%); 48 (58%) pts had a single metastatic site. 33 (39%) pts had a mucinous adenocarcinoma, 32 (39%) BRAF mutated, 32 (39%) RAS mutated, and 26% presented a Lynch syndrome. The majority of pts (69%) were pre-treated, and 26 pts (31%) received ICIs in first line. Nivolumab alone or plus Ipilimumab, and Pembrolizumab, were administered in 23 (28%), 3 (4%), and 57 (68%) pts, respectively. The median follow-up was 23 (1-65) months (m) and the median duration of treatment was 23 m (0-65) with 27 pts still ongoing. Treatment-related severe toxicities (G3 or G4) were observed only in 5.6% of pts. The median OS and PFS were not reached; the mean OS was 45.6 m (IC 95% 39.6-51.6) and the mean PFS was 38.8 m (IC 95% 32.5-45.1). Complete response (CR) was observed in 20 pts (24%), partial response (PR) in 28 (34%), stable disease (SD) in 19 (23%) and progression disease (PD) in 16 (19%). Overall response (ORR) was observed in 48 pts (57.8%; 95 %IC 0.31- 0.53), and disease control rate in 67 pts (80.7%; 95% IC 0.11– 0.29). Lung metastatic site was associated with poorer outcome in terms of OS (p = 0.001, HR 3.88 IC 95% 1.7-8.9), PFS (p = 0.045 HR = 2.31 IC95% 1-5.2), and ORR (p = 0.015 OR = 6.19 IC95% 1.4-26.9). Significantly worse PFS was also observed in pts with liver metastasis (p = 0.009 HR = 2.5 IC 95% 1.3-4.9). Conclusions: Our data confirm that ICIs are effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest an unfavorable correlation between lung and liver metastasis and the ICI response. Further biomolecular analysis will be provided in the future.