Second-line Treatment In Patients Research Articles

Abstract RF02-03: Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is approved in over 40 countries for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (a score of 1+ on immunohistochemistry [IHC] analysis or an IHC score of 2+ and negative results on in-situ hybridization) breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. DESTINY-Breast08 (DB-08) was designed to establish the safety, tolerability, and preliminary activity of T-DXd in combination with widely used standard of care therapies in HER2-low hormone receptor (HR)+ metastatic breast cancer (mBC). Results reported here are from the dose-expansion stage of the Phase 1b, multicenter, open-label, parallel-assignment DB-08 study arms investigating T-DXd–endocrine therapy (ET) combinations [NCT04556773]. Methods: Eligible patients had centrally confirmed HER2-low advanced/mBC with measurable disease per RECIST 1.1 and were documented as HR+. Among patients with mBC, ≤1 prior line of ET ± a targeted therapy was allowed, and prior chemotherapy in the mBC setting was exclusionary. Patients received T-DXd 5.4 mg/kg intravenously (IV) every three weeks (Q3W) + anastrozole 1 mg orally daily (T-DXd + ANA) or T-DXd 5.4 mg/kg IV Q3W + fulvestrant 500 mg intramuscularly Q4W, with a 500 mg loading dose on Cycle 1 Day 15 (T-DXd + FUL). Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival, duration of response (all evaluated by investigator per RECIST 1.1), and overall survival (OS). Data cutoff (DCO) was ~24 weeks after the last patient in each arm had received study treatment. Results: As of February 20, 2023, 21 patients in the T-DXd + ANA arm and 20 patients in the T-DXd + FUL arm had received study treatment. Median age was 55 and 66 years, 67% and 75% of patients received a prior line of ET ± a targeted therapy for mBC, 33% and 25% had no prior line of treatment for mBC, and median follow up in censored patients was 12.1 months (range 4.0, 17.3) and 8.5 months (range 1.3, 15.1) in the T-DXd + ANA and T-DXd + FUL arms, respectively. Adverse events (AEs) occurred in 95.2% (20/21) of patients in the T-DXd + ANA arm and 100% (20/20) of patients in the T-DXd + FUL arm, with AEs ≥Grade 3 occurring in 47.6% (10/21) and 55.0% (11/20) of patients in each arm, respectively. The most common any-grade AEs, occurring in ≥30% of patients in either arm, are reported in the Table. Three (15%) adjudicated drug-related interstitial lung disease/pneumonitis events were reported in the T-DXd + FUL arm (all Grade 2; at DCO, one case had resolved, one was resolving, and one was not resolved); none were reported in the T-DXd + ANA arm. AEs were manageable by drug interruption and dose reduction. Confirmed ORR was 71.4% (15/21; 95% confidence interval [CI] 47.8, 88.7) in the T-DXd + ANA arm, and 40.0% (8/20; 95% CI 19.1, 64.0) in the T-DXd + FUL arm (Table). OS data were not mature at this DCO. Conclusions: Safety profiles for T-DXd-ET combinations were generally comparable to T-DXd monotherapy and manageable with dose modification and routine clinical practice. T-DXd in combination with anastrozole or fulvestrant was active in first- or second-line treatment of patients with HER2-low HR+ mBC. Citation Format: Komal Jhaveri, Fabrice André, Erika Hamilton, Peter Schmid, Carey Anders, Laura Testa, Inna Ganshina, Yen-Shen Lu, Seock-Ah Im, Robyn Young, Magdalena Wrona, Caron Lloyd, Yiwen Zhang, Sherene Loi. Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-03.

Efficacy of upadacitinib in the achievement of clinical and endoscopic remission in hospitalized patients with ulcerative colitis.

Janus kinase (JAK) inhibitors have been developed and are clinically available for management of active UC patients although most studies have been conducted for the outpatients and few studies have demonstrated its efficacy in endoscopic and histological remission of hospitalized patients with UC. The aim of the present study was to investigate the efficacy of upadacitinib, which is a novel selective JAK1 inhibitor, in the treatment of ulcerative colitis. We present the cases of three hospitalized patients with ulcerative colitis who achieved clinical remission after significant and rapid improvement with upadacitinib. While upadacitinib was used as the second-line treatment for patients with insufficient treatment effects for corticosteroids or ustekinumab, a patient received it just after admission because they were steroid dependent and previously used advanced therapy before hospitalization. All patients demonstrated rapid clinical responses within 7days and the partial Mayo scores were 0 at week 8. All patients achieved confirmed endoscopic and histological remissions. We conclude that upadacitinib is a potential treatment option for hospitalized patients with an inadequate response to other biologics and JAK inhibitors.

Varlitinib and Paclitaxel for EGFR/HER2 Co-Expressing Advanced Gastric Cancer: a Multicenter Phase Ib/II Study (K-MASTER-13).

Varlitinib is a pan-human epidermal growth (HER) inhibitor targeting epidermal growth factor receptor (EGFR), HER2, and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (IHC) (≥1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median PFS and overall survival (OS) were 3.3 months and 7.9 months, respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), AST/ALT elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer

BackgroundCombining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting...

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

Real-World Effectiveness and Safety of Ramucirumab as a Second-Line Treatment for Patients with Unresectable Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma in Japan and South Korea: A Systematic Literature Review.

Gastric cancer has the highest incidence and mortality in Eastern Asia. The efficacy and safety of ramucirumab (RAM) monotherapy or in combination with paclitaxel (PTX) for patients with unresectable advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEA) have been established in clinical trials. To assess the effectiveness and safety of RAM or RAM-based therapy as a second-line treatment in real-world clinical practice in Eastern Asia and to pave the way for future research, a systematic literature review (SLR) was conducted. Studies published between January 2014 and December 2021 were identified in PubMed, Embase, Cochrane Library, CNKI, Wanfang, and CBM databases. This SLR included 23 studies from Japan and South Korea, of which 22 were retrospective and 11 were full-text articles. Most studies investigated RAM + PTX (range of median overall survival [mOS] 7.4-12.2months; median progression-free survival [mPFS] 3.35-7.0months). Data were limited for RAM, RAM + albumin-bound paclitaxel, and RAM + taxane. RAM + PTX was associated with longer survival (mOS 9.3-12.2months vs. 5.2-9.7months; mPFS 4.1-5.1months vs. 3.0-4.1months) than PTX. Patients with prior anti-programmed cell death1 (anti-PD-1) exposure experienced longer mPFS (4.8 vs. 3.4months) from RAM + taxane than those without prior anti-PD-1 exposure. Few patients (3.3-6.3%) discontinued RAM or RAM-based therapy because of adverse events (AEs). Hematological toxicities were most frequently occurring AEs and no new safety signals were identified compared to clinical trials. RAM + PTX as a second-line treatment is effective and associated with an acceptable toxicity profile in patients with advanced or metastatic G/GEA in real-world settings of Japan and South Korea. More studies are recommended to further evaluate effectiveness and safety of RAM or RAM-based therapy, especially after anti-PD-1 therapy, in a wider Eastern Asian population. INPLASY registration number INPLASY2022120023.

Evaluating photodynamic therapy versus brolucizumab as a second-line treatment for polypoidal choroidal vasculopathy.

To compare the one-year outcomes between intravitreal brolucizumab (IVBr) monotherapy and photodynamic therapy (PDT) as a second-line treatment in patients with polypoidal choroidal vasculopathy (PCV) who did not respond to first-line therapy. This case-control study included eyes with PCV that do not respond to aflibercept or ranibizumab. The patients were retrospectively registered. We compared outcomes, including best-corrected visual acuity (BCVA), anatomical results, and the need for additional treatments, between IVBr and a combination therapy using PDT as second-line treatments for refractory PCV, after adjusting for potential confounders. We analyzed E-values to evaluate the robustness of the results against unmeasured confounders. Twenty-two eyes received IVBr, and twenty-four underwent PDT. No apparent differences were observed in BCVA and central macular thickness (CMT) changes from baseline between the groups (IVBr vs. PDT: BCVA, 0.01 ± 0.47 logMAR vs. 0.04 ± 0.18 logMAR, P-value = 0.756; CMT: -36.3 ± 99.4μm vs. -114.7 ± 181.4μm, P-value = 0.146). Only in the PDT group, five eyes (20.8%) did not require additional treatment after the second-line treatment, the adjusted odds ratio indicating no further treatment needed was 11.98 (95% confidence interval: 1.42-2070.07, P-value = 0.019). The E-value for the adjusted odds ratio was 23.44. Both second-line treatments for PCV exhibited similar visual and anatomical outcomes. Only in the PDT-treated eyes were there some patients who did not require further treatment after second-line therapy.

Comparison of Cabozantinib and Axitinib as Second-line Therapy After Nivolumab Plus Ipilimumab in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Comparative Analysis of Retrospective Real-world Data

BackgroundTo date, no studies have compared the treatment outcomes of second-line therapies in patients with metastatic clear cell renal cell carcinoma (ccRCC). This study retrospectively evaluated the efficacy of cabozantinib and axitinib as second-line treatments in patients with metastatic ccRCC who previously received immune-oncology combination therapy. Patients and MethodsPatients with metastatic ccRCC treated with cabozantinib and axitinib as second-line therapy after nivolumab-ipilimumab treatment were identified among 243 patients with RCC treated between August 1, 2018 and January 31, 2022 at 34 institutions belonging to the Japanese Urological Oncology Group. Patients were assessed for treatment outcomes, including progression-free survival (PFS), overall survival, objective response rate (ORR), and incidence rate of treatment-related adverse events (AEs). ResultsForty-eight patients treated with cabozantinib and 60 treated with axitinib as second-line therapy after nivolumab-ipilimumab treatment for metastatic ccRCC were identified. The median PFS (95% confidence interval) was 11.0 months (9.0–16.0) with cabozantinib and 9.5 months (6.0–13.0) with axitinib. The ORRs were 37.5% (cabozantinib) and 38.3% (axitinib). The rates of any-grade AEs and grade ≥3 AEs were 79.2% (cabozantinib) versus 63.3% (axitinib; P=0.091) and 35.4% (cabozantinib) versus 23.3% (axitinib; P=0.202), respectively. In the poor-risk group, PFS was longer in the cabozantinib group than in the axitinib group (P=0.033). ConclusionThe efficacy and safety of cabozantinib and axitinib were comparable. In the poor-risk group, cabozantinib was more effective than axitinib. These findings provide valuable insights into the selection of second-line treatment options after nivolumab-ipilimumab treatment in patients with metastatic ccRCC. MicroAbstractThe treatment outcomes of the second-line therapies, cabozantinib and axitinib, following nivolumab and ipilimumab in 108 patients with metastatic clear cell renal cell carcinoma (ccRCC) were retrospectively compared. Comparable efficacy and safety were observed. In the poor-risk group, cabozantinib demonstrated superior progression-free survival over axitinib, offering valuable insights for second-line therapy selection after nivolumab-ipilimumab in patients with metastatic ccRCC.

Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy.

FOLFOX plus nivolumab represents a standard of care for first-line therapy of advanced gastroesophageal cancer (aGEC) with positive PD-L1 expression. The efficacy of second-line VEGFR-2 inhibition with ramucirumab (RAM) plus chemotherapy after progression to immunochemotherapy remains unclear. Medical records of patients with aGEC enrolled in the randomized phase II AIO-STO-0417 trial after treatment failure to first-line FOLFOX plus nivolumab and ipilimumab were retrospectively analyzed. Patients were divided into two groups based on second-line therapy: RAM plus chemotherapy (RAM group) or treatment without RAM (control group). Eighty three patients were included. In the overall population, progression-free survival (PFS) in the RAM group was superior to the control (4.5 vs 2.9 months). Responders (CR/PR) to first-line immunochemotherapy receiving RAM containing second-line therapy had prolonged OS from start of first-line therapy (28.9 vs 16.5 months), as well as second-line OS (9.6 vs 7.5 months), PFS (5.6 vs 2.9 months) and DCR (53% vs 29%) compared to the control. PD-L1 CPS ≥1 was 42% and 44% for the RAM and the control, respectively. Patients with CPS ≥1 in the RAM group showed better tumor control (ORR 25% vs 10%) and improved survival (total OS 11.5 vs 8.0 months; second-line OS 6.5 vs 3.9 months; PFS 4.5 vs 1.6 months) compared to the control. Prior exposure to first-line FOLFOX plus dual checkpoint inhibition followed by RAM plus chemotherapy shows favorable response and survival rates especially in patients with initial response and positive PD-L1 expression and has the potential to advance the treatment paradigm in aGEC.

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer

BackgroundBintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell...

Real-world experience with fluocinolone acetonide intravitreal implant in patients with diabetic macular edema.

to evaluate long-term effectiveness and safety of fluocinolone acetonide (FAc) implant used as second-line treatment in patients with persistent diabetic macular edema (DME). retrospective data chart review of 241 pseudophakic eyes of 178 patients treated with FAc from July 2017 to December 2021 in 10 medical retinal units in Italy. The primary endpoint was the change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 2 years. A Student's paired t-test was used. Additional therapies for DME and intraocular pressure (IOP)-related events were also evaluated. efficacy of FAc was assessed in a subset of 111 eyes with at least 24 months of follow-up. Mean BCVA increased at 2 years by 5.1 ETDRS letters (95%CI = 2.6-7.5; p < 0.001) while mean CMT decreased by 189 µm (95% CI 151-227; p < 0.001). Thirty-eight of these eyes (34.2%) needed additional intravitreal treatments, mainly anti-VEGF. Safety was evaluated on the entire cohort of 241 eyes treated with FAc. Overall, 66 eyes (27.4%) required emergent IOP-lowering medications (typically within the first-year post FAc) while 14 eyes (5.8%) underwent trabeculectomy, mostly during the second year of follow-up. FAc implant provides a substantial long-term functional and anatomical benefit when used as second-line treatment in eyes with DME. IOP rise can be adequately managed with topical agents although some eyes may require IOP-lowering surgery.

PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study

SummaryBackgroundImmune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC).MethodsThis was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients’ requirements) in combination with albumin paclitaxel (125 mg/m2, intravenously, days 1 and 8, or 250 mg/m2, intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1–21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs).ResultsFrom July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9–9.3), and the median OS was 10.1 months (95% CI, 7.5–14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3–4 immune-related liver damage.ConclusionSecond-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC.Trial registrationClinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724

Identifying optimal ALK inhibitors in first- and second-line treatment of patients with advanced ALK-positive non-small-cell lung cancer: a systematic review and network meta-analysis

ObjectivesTo compare the efficacy, safety and effects on quality of life of different ALK-inhibitors for global and Asian patients with advanced ALK-positive non-small-cell lung cancer (NSCLC).MethodsThe included RCTs were identified through a systematic search of PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and major cancer conferences. The assessment of progression-free survival (PFS), intracranial PFS, overall survival (OS), and patient-reported outcomes (PROs) was carried out using restricted mean survival time (RMST) model, fractional polynomial model and Royston-Parmar model. Time-invariant hazard ratio (HR) models were also used to validate and supplement the primary analysis. Objective response rate (ORR) and adverse events with any grade, grade 3–5 were assessed through a Bayesian network meta-analysis. The primary measures for OS, PFS, and PROs were HR and RMST. The odds ratio was the metric for evaluating safety, ORR, 12-month PFS rate, 24-month OS rate, and the 12-month non-deterioration rate of PROs. Subgroup analyses based on patient characteristics were performed.ResultsA total of fourteen studies (ten for first-line, four for second-line) consisting of nine treatments (chemotherapy, crizotinib, alectinib [600mg BID], low-dose alectinib [300mg BID], brigatinib, ceritinib, ensartinib, envonalkib, and lorlatinib) were included. In the first-line setting, alectinib showed a significant advantage over crizotinib and had the longest OS among all ALK-inhibitors. Compared to crizotinib, lorlatinib had the best efficacy regarding PFS for global patients, followed closely by alectinib and brigatinib. For Asian patients, alectinib significantly improved PFS compared to other treatments. In second-line, alectinib had the highest PFS for patients pretreated with crizotinib, followed by brigatinib, ceritinib and chemotherapy. Alectinib, irrespective of the dose, was the safest first-line option, whereas lorlatinib, brigatinib, and ceritinib showed poorer safety profiles. Alectinib was also the safest ALK-inhibitor for crizotinib-resistant patients. Brigatinib had the best performance in terms of PROs.ConclusionsConsidering both efficacy and safety, alectinib appears to be the preferable treatment in first-line and second-line, particularly for Asian patients.

Lurbinectedin in prostatic small cell and neuroendocrine carcinoma.

164 Background: Lurbinectedin (L) is a novel inhibitor of oncogenic transcription that was granted accelerated approval by the Food and Drug Administration in June 2020 for the treatment of metastatic small cell lung cancer (SCLC) following disease progression on or after platinum-based chemotherapy (PBC). Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) is a high-grade, invasive malignancy that accounts for &lt; 1% of all prostate cancers. SC/NEPC is distinct from prostatic adenocarcinoma and behaves similar to SCLC. NCCN guidelines for SC/NEPC recommend following the SCLC treatment guidelines. Using these guidelines, L may be used as a second-line treatment in patients (pts) with SC/NEPC who progress on or after PBC. We aimed to characterize the baseline characteristics, clinical course and therapeutic outcomes of pts treated with L for SC/NEPC. Methods: After IRB approval, 18 cases were gathered from 4 academic oncology centers. Baseline patient data, prior treatments and L treatment outcomes, including best radiographic and serologic responses, overall survival (OS), progression-free survival (PFS) and treatment toxicity were assessed. The Kaplan-Meier method was used to calculate OS and PFS from the L start date. Clinical benefit rate (CBR) included pts with complete response (CR), partial response (PR) and stable disease (SD) on imaging. Results: At the time of first L dose, all had metastatic disease with 2-6 distinct sites of metastases, most commonly bone (14/18, 77.8%), lymph nodes (14/18, 77.8%) and liver (13/18, 72.2%); median age was 63.5 (Range: 53-84); 11 pts (61.1%) had an ECOG 0-1; 4 pts (22.2%) had an ECOG of 2-3. The median total number of systemic therapies administered prior to L was 4 (Range: 2-7). All pts received PBC prior to L. The most common dose of L prescribed was 3.2 mg/m2 every 21 days (15/18, 83.3%). Androgen deprivation therapy was administered in conjunction with L in 9 pts (50%). The median number of cycles of L was 5 (Range: 1-10). L was discontinued due to toxicity in 1 patient (5.6%), disease progression in 10 pts (55.6%), transition to hospice in 2 pts (11.1%), 3 pts (16.7%) died while receiving treatment (not due to L toxicity), and 2 pts (11.1%) remained on L at the time of data reporting. The median OS and PFS from date of first L dose was 6.01 months (0.23 – 16.69) and 3.35 months (0.16 – 7.79), respectively. CBR was 9/16 (56.3%) with partial response in 5 pts (31.3%), stable disease in 4 pts (25%), and progressive disease in 7 pts (43.8%). Two pts did not have post-treatment imaging available to assess response. There were no hospitalizations for L treatment related adverse events (tRAE). The most common tRAE were grade I and II fatigue and anemia; 9 pts (50%) experienced no tRAE. The only grade IV toxicity was neutropenia in 3 pts (16.7%). Conclusions: L is a well-tolerated and active treatment option for patients with SC/NEPC. Prospective studies are needed to determine the role of L in the treatment of SC/NEPC.

Comparison of Study Designs for Primary Phase III Trials for Omalizumab Versus Dupilumab for Patients With Chronic Spontaneous Urticaria

Introduction&#x0D; Omalizumab is currently the only biologic approved and recommended as second-line treatment for patients with chronic spontaneous urticaria (CSU). However, clinical trial programs are underway for other biologic treatments such as dupilumab. Given head-to-head trials will not be conducted, consideration of study design may be important.&#x0D; Methods&#x0D; Comparison of participants, interventions, outcomes, and results for phase III primary efficacy clinical trials for omalizumab versus dupilumab for patients with CSU. The omalizumab trials were ASTERIA I/II (NCT01287117 and NCT01292473) and the dupilumab trial was LIBERTY-CSU CUPID (NCT04180488) that consisted of Study A, B, and C.&#x0D; Results&#x0D; Participants in ASTERIA I/II were 12 to 75 years with a diagnosis of CSU refractory to H1 antihistamines. Participants in LIBERTY-CSU CUPID were 6 to 80 years (Study A and C) or 12 to 80 years (Study B) with a diagnosis of CSU refractory to H1 antihistamines, and Urticaria Activity Score (UAS)7≥16 and Itch Severity Score (ISS)7≥8 during the 7 days before randomization; Study A and C included participants who were omalizumab naïve and Study B included intolerant or incomplete responders to omalizumab. For ASTERIA I and II, the interventions were placebo or omalizumab (75mg, 150mg, 300mg) every 4 weeks for 24 and 12 weeks, respectively. For LIBERY-CSU CUPID, the interventions were placebo or dupilumab (200mg or 300mg, weight based) every 2 weeks for 24 weeks. The primary efficacy outcome for ASTERIA I/II was change from baseline in ISS7 at Week 12. The primary efficacy outcome for LIBERTY-CSU CUPID was change from baseline in ISS7 at Week 24. For the ASTERIA I primary outcome, the change from baseline in ISS7 at Week 12 was -3.6 for placebo and -6.5, -6.7, and ‑9.4 for omalizumab 75mg, 150mg, and 300mg, respectively. For the ASTERIA II primary outcome, the change from baseline in ISS7 at Week 12 was -5.1 for placebo and ‑5.9, ‑8.1, and ‑9.8 for omalizumab 75mg, 150mg, and 300mg, respectively. For the LIBERTY-CSU CUPID Study A primary outcome, the change from baseline in ISS7 at Week 24 was ‑6.0 for placebo and -10.2 for dupilumab. The LIBERTY-CSU CUPID Study B was stopped due to futility based on a pre-specified interim analysis.&#x0D; Conclusion&#x0D; Comparing study designs for primary clinical trials for omalizumab and dupilumab for patients with CSU will aid in the comparative analysis and clinical evaluation of final trial results.&#x0D; Funding: ASTERIA I/II were funded by Genentech Inc. and Novartis Pharma AG.

Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced biliary tract cancer, pancreatic ductal adenocarcinoma or other solid tumors.

Mouse double minute 2 homolog (MDM2) is a key negative regulator of the tumor suppressor p53. Blocking the MDM2-p53 interaction, and restoring p53 function, is therefore a potential therapeutic strategy in MDM2-amplified, TP53 wild-type tumors. MDM2 is amplified in several tumor types, including biliary tract cancer (BTC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinomaand bladder cancer, all of which have limited treatment options and poor patient outcomes. Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.

Is There Room for Liposomal Irinotecan in Biliary Tract Cancer? A Meta-analysis of Randomised Trials

AimsThe combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. Materials and methodsWe systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. ResultsThe combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50–0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. ConclusionOur meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration.

Glucocorticosteroid-induced complications in patients with idiopathic thrombocytopenic purpura

Glucocorticosteroids (GCS) are the first-line treatment for idiopathic thrombocytopenic purpura (ITP). Despite their high efficacy in patients with newly diagnosed ITP, an adequate level of platelets remains after GCS withdrawal in only less than 20 % of patients. Additionally, GCS use is associated with an increased risk of different adverse reactions, including serious and life-threatening ones. Thrombopoietin receptor agonists represent a relatively new class of drugs for treating ITP as a second-line therapy. This paper reviews the risks of GCS pharmacotherapy, as well as the evidence supporting the use of thrombopoietin receptor agonists as both first-line and second-line treatment for patients with ITP.

Efficacy and safety of regorafenib as second-line treatment for patients with hepatocellular carcinoma and macrovascular invasion and(or) extrahepatic metastasis.

Macrovascular invasion and(or) extrahepatic metastasis are the main clinical characteristics of Chinese patients with hepatocellular carcinoma (HCC) after entering the second-line treatment. The aim of this study was to explore the efficacy and safety of regorafenib as a second-line treatment for these patients with HCC. We selected 253 patients with primary liver cancer who were treated in Henan Cancer Hospital from June 2017 to September 2020. According to the inclusion and exclusion criteria, 63 patients with HCC with macrovascular invasion and/or extrahepatic metastasis were finally included. The clinical data of patients were obtained by consulting the electronic medical record system and through telephone follow-up. The median overall survival (mOS), duration of drug use, and disease control rate (DCR) of patients were evaluated, and the Cox regression model was used to analyze the risk factors of prognosis. The mOS of 63 patients with HCC administered regorafenib as second-line treatment was 9.6 months, the duration of drug use was 3.8 months, and the DCR was 59% (37/63). Cox multivariate analysis showed that overall survival (OS) was closely related to the level of alpha-fetoprotein (AFP) and treatment method but not to the type of first-line drug. The mOS of patients with AFP ≥400 ng/mL was 7.4 months, which was significantly lower than that of those with AFP <400 ng/mL (12.5 months) (P=0.0052). The mOS of patients treated with regorafenib alone was 6.8 months, which was significantly lower than that of those treated with regorafenib combined with immunotherapy (24.3 months) and intervention therapy (17.5 months) (P<0.0001). The mOS of patients using regorafenib as second-line treatment in the first-line sorafenib group and first-line nonsorafenib group were 9.5 and 9.6 months, respectively (P=0.9766). The grade ≥3 adverse events (AEs) with an incidence of more than 10% included hand-foot syndrome, increased bilirubin, decreased albumin, and elevated transaminase, with incidences of 22%, 14%, 11%, and 10%, respectively. As second-line treatment for patients with HCC with macrovascular invasion and(or) extrahepatic metastasis, regorafenib has definite efficacy and tolerable adverse reactions. It is the preferred drug for the second-line treatment of patients with advanced HCC.

Long-Term Treatment with Fostamatinib in Japanese Patients with Primary Immune Thrombocytopenia: An Open-Label Extension Study Following a Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group Study

Background Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic immune thrombocytopenia (ITP) in adults in the US, Canada, Europe, Israel, and Japan. We evaluated the long-term efficacy and safety of fostamatinib treatment and the off-therapy platelet count in Japanese patients with primary ITP in a phase 3 clinical trial with a 24-week double-blind period, a 28-week open-label extension period, and a pre-defined washout period. Methods The trial enrolled Japanese patients who had failed to respond or did not tolerate ≥1 prior ITP treatment, who had a mean platelet count &amp;lt;30,000/μL (based on 3 screening and baseline platelet measurements), and had a platelet count at each visit &amp;lt;35,000/μL. Dosing was at 100 mg bid for 4 weeks and then 150 mg bid if needed and tolerated. One concomitant treatment was allowed (corticosteroids, azathioprine or danazol). The dosage of the concomitant treatment was to remain the same during the 24-week double-blind period but could be reduced or discontinued during the open-label period. Efficacy endpoints were platelet response rate (i.e., the percentage of patients who achieved a platelet count of ≥ 50 × 10 3/μL at 2 consecutive visits at least 28 days apart). The platelet count of the responders during the study period were evaluated. Results A total of 33 patients who were either treated with fostamatinib in the 24-week double-blind period (Fostamatinib-Fostamatinib group, n=22) or treated with placebo in the double-blind period and then treated with fostamatinib in the 28-week open-label extension period (Placebo-Fostamatinib group, n=11) were analyzed. Of those, 79% (26/33) were women, the median age was 62, the median baseline platelet count was 19 x 10 3/μL, and 58% (19/33) had two or more previous treatments. The platelet response rate was 36% (8/22) in the Fostamatinib-Fostamatinib group and 27% (3/11) in the Placebo-Fostamatinib group. The platelet count of the responders in the Fostamatinib-Fostamatinib group increased to ≥50 × 10 3/μL shortly after initiating fostamatinib and remained around 100 × 10 3/μL between Week 14 and Week 52, whereas the platelet count of the responders in the Placebo-Fostamatinib group remained low while receiving placebo but increased after receiving fostamatinib ( Figure 1). Among 14 patients with concomitant glucocorticoids treatments at the beginning of the open-label period, 43% (6/14) reduced or discontinued glucocorticoids while receiving fostamatinib without disease relapse. In the washout period of up to 4 weeks, all 12 patients experienced a mild decrease in platelet count, but none developed bleeding events ( Figure 2). Three of four patients who completed the 4-week washout period had a slight increase in platelet counts from Week 2 to Week 4. In the double-blind and open-label periods, adverse events were reported in 96% (21/22) of the Fostamatinib-Fostamatinib group and 100% (11/11) of the Placebo-Fostamatinib group, and treatment-related adverse events in 77% (17/22) and 46% (5/11), respectively. In the washout period, adverse events were reported in 50% (6/12) of patients, and treatment-related adverse events in 0% (0/12). We found no new safety risk or late-onset adverse events specific to Japanese patients. Conclusions The long-term efficacy and safety of fostamatinib were observed in Japanese patients with primary ITP, along with the feasibility of glucocorticoid reduction/discontinuation during fostamatinib treatment, and a lack of bleeding events after abrupt discontinuation of fostamatinib. The findings obtained from this study will help position fostamatinib as a second-line treatment in patients with primary ITP.