Second-line Treatment Option Research Articles

Efficacy of Second-line Nivolumab Versus Tyrosine Kinase Inhibitors for Renal Cell Carcinoma With Bone Metastases.

Combination therapy with immune checkpoint inhibitors has become the standard first-line treatment for metastatic renal cell carcinoma (mRCC), leading to changes in second-line treatment options, such as nivolumab or tyrosine kinase inhibitors (TKIs). However, very few studies have compared the efficacy of these drugs in patients with mRCC, particularly those with bone metastases (BM), which are associated with a poor prognosis. This study compared the efficacy of nivolumab and TKIs as second-line treatments for mRCC patients with BM and examined the microenvironments of primary tumors and BM lesions. This multi-institutional retrospective study included 87 mRCC patients with BM who received either nivolumab or TKIs as second-line treatments. We analyzed tumor-infiltrating immune cells expressing CD8 and CD20, along with PD-L1, HIF2α, c-MET, VEGFR2, and AXL, in primary tumors and BM sites using immunohistochemistry. This analysis indicated that poor-risk classification, as per the International Metastatic RCC Database Consortium criteria (p<0.01), and elevated serum alkaline phosphatase levels (p=0.031) were significantly associated with poor prognosis. No significant difference in overall survival was observed between patients receiving nivolumab and those receiving TKIs. However, the objective response rate of patients with BM lesions was significantly higher when receiving TKIs than when receiving nivolumab (p=0.014). Immunohistochemistry revealed significantly higher VEGFR2 expression in BM lesions than primary tumors. TKIs could be a promising second-line treatment option for mRCC patients with bone-limited metastases.

Beamion BCGC-1: A phase Ib/II trial of the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (BI 1810631) + trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) for patients with metastatic breast cancer (mBC) and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC).

TPS509 Background: Approximately 15% of mGEAC tumors overexpress HER2. Currently, the HER2-targeted antibody-drug conjugate (ADC), T-DXd, is approved in mGEAC as a second-line or later-line treatment option following the failure of prior trastuzumab-containing therapy. Zongertinib (BI 1810631) is a novel, orally administered HER2-selective TKI that spares EGFR. In a Phase I trial (NCT04886804), zongertinib showed encouraging tolerability and efficacy in patients with HER2 aberration-positive advanced solid tumors, including mGEAC. Beamion BCGC-1 (NCT06324357) is a Phase Ib/II dose escalation/optimization trial investigating zongertinib plus T-DXd or T-DM1 in patients with HER2+ mGEAC or mBC. Here we focus on the mGEAC cohorts, in which patients will receive zongertinib in combination with T-DXd. Methods: Across the whole trial, approximately 240 patients will be enrolled from approximately 48 sites in 6 countries. In the mGEAC cohorts, approximately 80 patients with histologically/cytologically confirmed locally advanced/metastatic, unresectable, HER2-positive, pre-treated mGEAC will be enrolled. All patients must have investigator-assessed progression and documented HER2-positive disease (overexpressed and/or amplified; confirmed by immunohistochemistry and in situ hybridization). In Phase Ib, approximately 20 patients will receive escalating doses of zongertinib plus a fixed approved dose of T-DXd (6.4 mg/kg, once every 21 days). Dose escalation will be guided by a Bayesian Logistic Regression Model, with overdose control. In Phase Ib, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (first 21-day cycle); secondary endpoints include objective response (RECIST v1.1), DLTs during the on-treatment period and pharmacokinetics. In Phase II, up to 60 patients with mGEAC will be randomized 1:1 to receive one of two zongertinib dose levels (dose levels informed by Phase Ib), plus a fixed approved dose of T-DXd. In Phase II, the primary endpoint is objective response; secondary endpoints include progression-free survival, disease control, treatment-emergent adverse events leading to dose reduction, pharmacokinetics and patient-reported outcomes. Patients will remain on treatment until disease progression, undue toxicity or any other protocol-defined stopping criterion. Enrollment is ongoing. Clinical trial information: NCT06324357 .

Results of a phase 2 trial of ramucirumab plus docetaxel as second-line treatment for patients with advanced gastric cancer (HGCSG 1903).

447 Background: Ramucirumab (RAM) has shown efficacy in combination with paclitaxel (PTX) or irinotecan in the second-line treatment of advanced gastric cancer (AGC). However, the efficacy and safety regarding the combination therapy of RAM and docetaxel (DTX) have not been reported. We hypothesized that RAM plus DTX for patients with AGC could be as effective as RAM plus PTX and could reduce the incidence of neuropathy. Methods: HGCSG 1903 was a non-randomized, single arm, phase 2 trial carried out at 20 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM (8 mg/kg on day1 and 15) plus DTX (60 mg/m 2 on day1) combination therapy administered in 28-day cycle were continued until disease progression or emergence of adverse events requiring discontinuation. The primary endpoint was response rate (RR) with threshold value of 10.7% and an expected value of 27.9%. A total of 35 cases are planned for registration. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011200010. Results: Between Nov 2020 and Dec 2023, 36 patients were enrolled. Median age was 70 (range, 36–82); female/male were 7/29; ECOG PS 0/1, 16/20, respectively. One patient did not initiate study treatment at the onset of bowel obstruction after enrollment. In the efficacy and safety analysis set of 35 patients, RR was 25.7% (95%C.I., 12.5–43.3%) and disease control rate was 74.3% (95%C.I., 56.7–87.5%). Median OS and PFS were 11.9 months (95%C.I., 3.0–20.7) and 3.1 months (95%C.I., 2.1–4.2), respectively. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (68.6%), leucopenia (57.1%), febrile neutropenia (17.1%), hypertension (14.3%), anorexia (11.4%), anemia (8.6%), and fatigue (5.7%). Grade 4 neutropenia occurred in 60.0% of patients. The protocol was amended to allow primary G-CSF prophylaxis during study period. The number of patients who received primary G-CSF prophylaxis after the amendment was 7/13 (53.8%). Neuropathy occurred in 65.7% of all grades, with no incidence of grade 3 or higher. No death and new safety signals with a causal relation to study treatment were observed. Conclusions: The primary endpoint of response rate was met in HGCSG 1903. Although neutropenia and febrile neutropenia may be more frequent, they were manageable. RAM plus DTX might be considered as an option for second-line treatment of patients with AGC. Clinical trial information: jRCTs011200010.

A phase two trial evaluating FOLFIRI plus aflibercept after failure of FOLFOXIRI plus bevacizumab in patients with unresectable metastatic colorectal cancer.

FOLFOXIRI plus bevacizumab (BEV) is an option for first-line treatment of metastatic colorectal cancer (mCRC). However, there is no consensus on the optimal treatment strategy when disease progresses. The EFFORT open-label, multicenter, single-arm phase II study investigated whether FOLFIRI plus aflibercept retains activity after progression of FOLFOXIRI plus BEV treatment. The patients with unresectable mCRC who failed first-line FOLFOXIRI plus BEV received FOLFIRI plus aflibercept. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). Angiogenic biomarkers were measured before treatment initiation. From April 2019 to May 2021, 35 patients were enrolled and 34 were analysed in the FAS population (men, 18; median age, 63years [range: 32-78]). The primary tumor was left-sided in most cases (23/34), 23 patients were RAS mutant, 3 patients had BRAF V600E mutation and 27 patients had liver metastases. The primary end-point was met with a median PFS of 4.3months [80% confidence interval [CI] 3.7-5.1]. Median overall survival was 15.2months [95% CI 8.9-22.7]. Per RECIST, there were 1 complete response, 4 partial responses, 21 stable diseases and 8 disease progressions. Overall response rate was 14.7% [95% CI 5.0-31.1], and disease control rate was 76.5% [95% CI 58.8-89.3]. Responses were more common in patients with high VEGF-C, low VEGF-D and low PlGF levels before treatment. FOLFIRI plus aflibercept, administered after failure of FOLFOXIRI plus BEV, is effective and has a manageable safety profile. This regimen may be a useful second-line treatment option for these patients.

Liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab as second-line therapy in metastatic colorectal cancer (IRIS): A multi-center, single-arm, prospective, phase II study.

195 Background: In patients with advanced colorectal cancer (CRC), the recommended second-line treatment following first-line therapy with oxaliplatin-based regimens is irinotecan-based therapy. Liposomal irinotecan, a novel formulation of traditional irinotecan, has demonstrated potential to enhance efficacy while minimizing toxicity. This study aims to investigate the efficacy and safety of liposomal irinotecan in combination with 5-FU/LV and bevacizumab as a second-line treatment option for metastatic CRC. Methods: This is a multi-center, single-arm, prospective, phase II study. Patients with metastatic CRC who received oxaliplatin-based chemotherapy as first-line treatment were enrolled to receive liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab regimen until disease progression and/or unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 50 patients were enrolled from Jan 2024 to Jul 2024 across 6 sites in China. The median age was 56.5 years (range: 30.0-76.0), with 58.0% male and 36.0% ECOG 0. Among the patients, 38.0% had left-sided colon cancer, 24.0% had right-sided colon cancer, and 38.0% had rectal cancer. As of Sept 14, 2024, 39 patients had at least one tumor assessment and 19 patients were still on treatment. ORR and DCR were 20.5% (8/39, 95% CI: 9.3%-36.5%) and 84.6% (33/39, 95% CI: 69.5%-94.1%), respectively. Eleven patients had disease progression and 5 patients died, and the median PFS and OS were not reached. The relative dose intensity of liposomal irinotecan and 5-fluorouracil were 92.8% (range: 23.6%-109.6%) and 89.5% (range: 13.3%-116.8%), respectively. During treatment, 43 (86.0%) patients had at least one adverse event (AE) and 24 (48.0%) had grade 3-4 AE. Most common (≥ 10%) grade 3-4 AEs were neutropenia (20.0%), leukocytopenia (16.0%) and diarrhea (10.0%). No unexpected toxicities observed in this study. Conclusions: These preliminary results reveled that liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab after oxaliplatin-based treatment for metastatic CRC was well tolerated with encouraging clinical activity, which warrants further follow up. Clinical trial information: NCT06184698 .

Paclitaxel oral solution versus paclitaxel injection as a second-line therapy in advanced gastric cancer: A randomized, open-label, non-inferiority phase 3 trial.

442 Background: Paclitaxel injection (paclitaxel IV) is category 1 preferred regimen in the second-line therapy of gastric cancer, while it has shortcomings including vehicle-led safety risk, long time injection, premedication or frequent hospital visit. Paclitaxel oral solution (Liporaxel), the world's first successfully developed oral formulation, is an alternative. This study aimed to establish non-inferiority in efficacy and comparable safety profile of paclitaxel oral solution versus paclitaxel IV, as a second-line monotherapy in gastric cancer. Methods: This is a randomized, open-label, non-inferiority phase 3 trial conducted at 53 centers in China. Patients with unresectable or recurrent or metastatic gastric cancer progressed after fluoropyrimidine- or fluoropyrimidine plus platinum-based first-line therapy were randomly assigned at 1:1 ratio (stratified by gastrectomy, ECOG PS and prior chemotherapy) to receive paclitaxel oral solution (200mg/m 2 twice daily on days 1, 8, 15 of a 28-day cycle) or paclitaxel IV (175mg/m 2 on day 1 of a 21-day cycle). Co-primary endpoints were progression-free survival (PFS) assessed by blind independent review committee (BIRC) and overall survival (OS), with non-inferiority margin of hazard ratio (HR) of 1.18 for PFS and 1.16 for OS. Results: From April 22, 2019, to January 31, 2022 (data cut-off), 536 patients were randomized to receive either paclitaxel oral solution (n=268) or paclitaxel IV (n=268), with a median follow-up of 13.4 vs. 12.6 months. PFS met non-inferiority criteria, with BIRC-assessed median PFS of 3.02 months (95% confidence interval [CI]: 2.69, 3.71) in the oral group vs. 2.89 months (95% CI: 2.53, 3.48) in the IV group (HR=0.894, 95% CI: 0.719, 1.112, p =0.311). OS (cut-off on February 15, 2023, for OS primary analysis) demonstrated superiority for paclitaxel oral solution, with median OS of 9.13 months (95% CI: 7.72, 10.97) vs. 6.54 months (95% CI: 5.75, 7.26), showing 2.59-month improvement (HR=0.770, 95.5% CI: 0.635, 0.934, p =0.006). For the treatment-related adverse events (TRAEs), the oral group showed lower incidences of neuropathy (22.3% vs. 38.7% all grade), alopecia, fatigue, musculoskeletal and connective tissue disorders, and no hypersensitivity occurred without premedication. The most common ≥Grade 3 TRAEs were neutrophil count decreased (47.9% in oral vs. 54.5% in IV), white blood cell count decreased (41.5% vs. 35.3%) and anemia (16.6% vs. 10.9%). Grade 5 TRAEs were rare with comparable rates across two groups (four [1.5%] vs. three [1.1%]). Conclusions: Paclitaxel oral solution demonstrated non-inferiority in PFS and superiority in OS compared to paclitaxel IV, with clinically manageable and favorable safety profile, supporting paclitaxel oral solution as a second-line treatment option for gastric cancer. Clinical trial information: CTR20190050.

Treatment effect of head extension by cervical collar on moderate obstructive sleep apnea-A randomized controlled trial.

As available treatments in obstructive sleep apnea are all associated with side-effects or adherence problems, there is a need for alternative treatment options. In this randomized, open, parallel-group intervention study, the effect of head extension by cervical collar was evaluated in patients with moderate obstructive sleep apnea. One-hundred patients with moderate obstructive sleep apnea (apneas and hypopneas per estimated hours asleep = respiratory events index: 15-30) were randomized to either lifestyle intervention, or cervical collar in combination with lifestyle intervention. Both groups received lifestyle advice. In addition, the treatment group was treated with a cervical collar, which allows adjustment of head extension, during sleep. Assessment with questionnaires and polygraphy were performed at baseline and after 6 ± 2 weeks. A linear regression model was used to assess a total effect on respiratory events index, which was the primary endpoint. In the intention-to-treat analysis, the cervical collar in combination with lifestyle intervention group decreased their respiratory events index (p = 0.008) and oxygen desaturation index (p = 0.008) more than the lifestyle intervention group, with a mean difference of -4.5 and -4.3, respectively. In the sub-analysis, there was a clear effect on respiratory events index in the supine position (mean difference between the groups -9.1, p = 0.018) but not on non-supine apnea-hypopnea index (-2.3, p = 0.17). We conclude that head extension by cervical collar during sleep resulted in improved respiratory events index and oxygen desaturation index values in patients with moderate obstructive sleep apnea. Cervical collar can be a second-line treatment option in this group, especially in positional obstructive sleep apnea.

The effectiveness of sequential afatinib and furmonertinib in an advanced lung adenocarcinoma with rare compound EGFR mutation (L833V/H835L).

Uncommon atypical mutations account for 10-15% of all epidermal growth factor receptor (EGFR) activating mutations in nonsmall-cell lung cancer (NSCLC). Tumors harboring rare EGFR mutations show highly heterogeneous responses to EGFR tyrosine kinase inhibitors (TKIs). There is insufficient clinical evidence for uncommon types of EGFR mutations, especially those with compound EGFR mutations. In addition, for those with uncommon compound EGFR mutations, few studies have focused on acquired resistance mechanisms and subsequent treatment strategies after disease progression on EGFR-TKIs. Here, a 66-year-old smoking male was diagnosed with lung adenocarcinoma accompanied by pleural metastasis. A rare L833V/H835L compound mutation in exon 21 of EGFR was detected in tumor biopsy by next-generation sequencing. Afatinib was used as first-line therapy and showed favorable efficacy. The patient continued afatinib treatment for a duration of 24 months. A new T790M mutation was detected with a rebiopsy after progression on afatinib. Then the patient received cryoablation therapy and a third-generation EGFR-TKI, furmonertinib. Our case suggests that a comprehensive screening for EGFR mutations should be conducted before and during treatment in clinical practice, and afatinib and furmonertinib could be first- and second-line treatment options in NSCLC patients harboring EGFR L833V/H835L mutations.

Second-Line Treatment Options for Patients with Metastatic Triple-Negative Breast Cancer: A Review of the Clinical Evidence.

Metastatic triple-negative breast cancer has a poor prognosis and poses significant therapeutic challenges. Until recently, limited therapeutic options have been available for patients with advanced disease after failure of first-line chemotherapy. The aim of this review is to assess the current evidence supporting second-line treatment options in patients with metastatic triple-negative breast cancer. Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. The benefit of treatment was evaluated using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale. Based on the evidence review, sacituzumab govitecan was identified as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer, supported by clinical evidence and consensus across international clinical guidelines. Olaparib and talazoparib are of use in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and germline BRCA1/2 mutations. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

Clinical Guidelines for Canine Transmissible Venereal Tumour Treatment: Systematic Review and Meta-Analysis.

The treatment of canine transmissible venereal tumour (CTVT) has evolved since its initial description in 1810. Initially considered untreatable in the early 20th century, extensive research over time has significantly advanced our understanding of its aetiopathogenesis. This led to successful chemotherapy treatments, which have shown superior outcomes compared to surgical interventions. Vincristine, in particular, has proven effective in treating CTVT. However, the development of chemoresistance underscores the need to explore alternative therapeutic options. This systematic review provides a comprehensive analysis of CTVT treatment practices from 1950 to 2023, aiming to establish a gold standard and enhance clinical decision-making. Initially, 3633 studies were identified, with 42 meeting the eligibility criteria. Our findings suggest that vincristine sulphate monotherapy is the recommended first-line treatment for CTVT. Administering vincristine intravenously at a dosage of 0.5-0.75 mg/m2 weekly for 4-6 sessions resulted in a 93.1% (67.4%-100%) complete response rate in dogs. Extending the treatment to eight sessions increased the complete response rate to 98.9% (83.3%-100%). Radiation therapy, lomustine and doxorubicin are viable second-line treatment options; however, extensive cohort studies are required to confirm their efficacy in achieving remission in vincristine-resistant cases. Additionally, no clear criteria could be established for initiating treatment with drugs other than vincristine in previously untreated dogs. Surgery is considered a third-line option. Notably, complete remission is anticipated following recommended systemic and local therapies in nearly all cases. Despite concerns about chemoresistance, current guidelines indicate a favourable response to suggested treatments even in resistant cases.

Paclitaxel for second-line treatment of squamous cell carcinoma of the head and neck: A multicenter retrospective Italian study

BACKGROUND Squamous cell carcinoma of the head and neck (SCCHN) accounts for 3% of all malignant tumors in Italy. Immune checkpoint inhibitors combined with chemotherapy is first-line treatment for SCCHN; however, second-line treatment options are limited. Taxanes are widely used for combination therapy of SCCHN, as clinical trials have shown their efficacy in patients with this disease, particularly in patients with prior therapy. AIM To perform a multicenter retrospective study on the efficacy and safety of weekly paclitaxel for SCCHN. METHODS All patients were previously treated with at least one systemic therapy regimen, which included platinum-based therapy in the vast majority. No patient received prior immunotherapy. RESULTS Median progression-free survival (mPFS) was 3.4 months and median overall survival (mOS) was 6.5 months. Subgroup analysis was performed according to three principal prognostic factors: Smoking, alcohol consumption, and body mass index. Analysis demonstrated reduced survival, both mOS and mPFS, in the unfavorable prognostic groups, with the biggest deltas observed in mOS. CONCLUSION Weekly paclitaxel provided favorable survival and disease control rates, with low severe adverse events. Paclitaxel is a safe and valid therapeutic option for patients with SCCHN who received prior therapy.

Experience of Metronidazole Triple Therapy After Clarithromycin Triple Therapy Failure for Helicobacter pylori Eradication in Korea.

Background/Objectives: Bismuth quadruple therapy (BQT) is recommended as the best second-line regimen after failure of first-line clarithromycin triple therapy (CTT) for Helicobacter pylori eradication. However, there are some limitations to this approach, including the lack of an appropriate sequel regimen after failure of BQT and complicated administration. Metronidazole triple therapy (MTT) is simple to administer, but it is not widely recommended. This study was conducted to determine the efficacy of MTT as second-line regimen for H. pylori eradication after failure of CTT. Methods: We retrospectively reviewed the medical records of the Korean patients with H. pylori infection who underwent second-line treatment after failure of first-line CTT from October 2013 to October 2019. The efficacy of MTT and BQT for H. pylori eradication was compared. Results: The eradication rate in the BQT group tended to be higher than that in the MTT group; however, the difference was not statistically significant (208/233, 89.3% versus 244/284, 85.9%, p = 0.287). Among 40 patients with second-line MTT eradication failure, 21 received the third-line BQT, and 15 showed successful eradication (15/21, 71.4%). In the men 70 years or older, the eradication rate of MTT was lower than that of BQT without statistical significance (75.8% versus 94.1%, p = 0.141). Conclusions: These findings suggested that MTT could be a second-line treatment option, reserving BQT for Helicobacter pylori eradication after first line CTT failure, except in elderly men 70 years or older.

Superior survival benefits of triple combination immunotherapy compared to standard chemotherapy as second-line treatment for advanced biliary tract cancer: a retrospective analysis.

Advanced biliary tract cancer (BTC) is associated with a poor prognosis and limited options for second-line treatment. The TOPAZ-1 and KEYNOTE-966 trials have demonstrated the benefits of combining immune checkpoint inhibitors (ICIs) with chemotherapy in treating BTC. However, the efficacy of FOLFOX as a second-line therapy is limited, highlighting the need for more effective treatment approaches. This retrospective study compared a triple regimen-comprising ICIs, tyrosine kinase inhibitors, and chemotherapy-to standard chemotherapy in patients with metastatic BTC who had progressed on first-line gemcitabine-based therapy. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Of the 121 patients, 86 received the triple regimen and 35 received standard chemotherapy. The triple regimen showed a significantly higher ORR (37.2% vs. 2.8%, p < 0.0001) and DCR (89.5% vs. 71.4%). The median PFS was 6 months for the triple regimen compared to 2.0 months for standard chemotherapy (HR 0.29, p < 0.0001). The median OS was 16.0 months for the triple regimen versus 6.0 months for standard chemotherapy (HR 0.35, p < 0.0001). Treatment-related adverse events were comparable between the groups. The triple combination of immunotherapy offers superior survival benefits compared to standard chemotherapy as a second-line treatment for advanced BTC, warranting further investigation for potential clinical adoption.

The application of immunotherapy combined with taxanes in second‑line treatment of advanced HER2 negative gastric cancer.

Human epidermal growth factor receptor-2 (HER2) negative advanced gastric cancer (GC) has a high global incidence and mortality rate with limited options for second-line treatment. Monotherapy is not effective and the combination of chemotherapy and immunotherapy has not yet been included in the guidelines. The present study aimed to explore a new treatment approach by conducting a single-center, retrospective, observational real-world study. A total of 21 patients with advanced HER2-negative GC, who had progressed after receiving standard first-line regimens [tegafur, gimeracil and oteracil potassium capsules (S-1) or capecitabine plus oxaliplatin], were selected. The application of programmed cell death-1 (PD-1) inhibitor combined with taxanes was selected as the second-line treatment. The primary outcomes measured were progression-free survival (PFS), pathological complete response, objective response rate (ORR), disease control rate (DCR) and adverse reactions in the present patient cohort. The median (m)PFS in the overall population was 7.1 months, with a 95% confidence interval (CI) of 6.0-8.2 months and the median overall survival (mOS) was 11.3 months, with a 95% CI of 4.5-18.2 months. The ORR was 9.5% and the DCR was 90.5%. Univariate and multivariate analyses indicated that Ki67 <70% and tumor marker-positive status [one or two increases among carcinoembryogenic antigen (CEA), cancer antigen (CA) 199 and CA125] were independent prognostic factors for PFS and overall survival (OS) in second-line treatment. Significant statistical differences were noted in PFS (mPFS=5.3 months, 95% CI: 3.1-7.5 months vs. mPFS=9.1 months, 95% CI: 6.2-12.0 months; P=0.002) and OS (mOS=8.8 months, 95% CI: 7.0-10.7 months vs. mOS=17.2 months, 95% CI: 16.0-18.5 months; P=0.013) between the Ki67-high group (Ki67 ≥70%) and the Ki67-low group (Ki67 <70%). Significant statistical differences were noted in OS between tumor marker-negative status (CEA, CA199 and CA125 within normal range) and tumor marker-positive status (one or two increases among CEA, CA199 and CA125; mOS=17.2 months, 95% CI: 16.0-18.4 months vs. mOS=8.8 months, 95% CI: 5.3-12.4 months; P=0.018); however, no significant differences were noted in PFS between these two groups. The present study retrospectively analyzed the new second-line approach of PD-1 inhibitor combined with taxanes for HER2 negative GC which effectively improved patient PFS and OS compared with single-agent chemotherapy. The expression levels of Ki67 and the tumor marker-negative status possess potential clinical value in monitoring prognosis and guiding future individualized use of chemotherapy combined with immunotherapy.

Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.

Long-term survival following anti-PD-(L)1 monotherapy in advanced urothelial cancer and an assessment of potential prognostic clinical factors: a multicentre observational study

BackgroundAnti-PD-(L)1 agent are approved as first- and second-line treatment options in advanced urothelial cancer (UC), but information about long-term survival is scarce. There is a need for prognostic factors, as these may help in the decision-making concerning anti-PD-(L)1 in patients with UC. Here, we examined long-term survival following anti-PD-(L)1 in advanced UC and assessed clinical factors for their correlation with survival.MethodsWe collected data from patients with advanced UC treated with anti-PD-(L)1 between 2013 and 2023. Overall- and progression-free survival (OS, PFS) were determined using the Kaplan-Meier method. Independent variables were analysed by uni- and multivariate Cox regression for their association with OS and PFS.ResultsSurvival analyses included 552 patients. Patient characteristics in our cohort were consistent with those of a typical advanced UC population. After median follow-up of 49 months, five-year OS and PFS rates were 16.0% and 6.9% respectively. The absence of visceral and/or bone metastases and elevated C-reactive protein level, gamma-glutamyltransferase level and neutrophil-to-lymphocyte ratio were identified as favourable prognostic factors for OS.ConclusionsA selected subset of patients with advanced UC may experience long-term clinical benefit from anti-PD-(L)1 treatment. We identified prognostic factors that might be used for risk assessment and clinical trial stratification.

Esophageal cancer: new developments in prevention and therapy

Esophageal carcinomas comprise 2 entities, squamous cell carcinoma and adenocarcinoma, which differ in pathogenesis and treatment. Elimination of inflammatory influences and risk factors, such as obesity and gastroesophageal reflux that contribute to a rising incidence of adenocarcinoma, is crucial for tumor prevention. In Germany, general endoscopic screening for upper GI tumors is not recommended, whereas endoscopic surveillance is applied in the presence of Barrett's metaplasia. In the future, better prediction models will be needed to identify patients at risk who will benefit from endoscopic surveillance. Precancerous lesions and early tumor stages can be removed endoscopically using modern resection methods. In recent years, therapeutic strategies for advanced esophageal tumors have undergone significant changes. In the multimodal treatment of locally advanced stages, radiochemotherapy remains to play a key role for squamous cell carcinoma, whereas new evidence highlights the importance of perioperative chemotherapy for the optimal management of adenocarcinoma. Systemic treatment options for both tumor entities have been significantly expanded due to the successful use of immune checkpoint inhibitors in adjuvant and palliative treatment regimen. Determination of PD-L1 and MSI status has therefore become decisive for the choice of therapy. In metastatic stages of adenocarcinoma, chemotherapy can now be supplemented by multiple antibodies directed against Her2, PD1, or claudin 18.2, and the antibody-drug conjugate trastuzumab deruxtecan has become a Her2-targeted option in second line treatment.

Systemic treatments for radioiodine-refractory thyroid cancers.

Differentiated thyroid cancers (DTCs) constitute the primary histological subtype within thyroid cancer. Due to DTCs' distinctive radioiodine (RAI) uptake mechanism, standard treatment involving surgery, with or without adjunctive therapy using RAI and levothyroxine inhibition, typically yields favorable prognoses for the majority of patients with DTCs. However, this favorable outcome does not extend to individuals with decreased RAI uptake, termed radioiodine-refractory thyroid cancers (RAI-RTCs). Recent research has revealed that the genetic mutations and gene rearrangements affecting sites such as RTKs, RAS, BRAF and TERTp lead to structural and functional abnormalities in encoded proteins. These abnormalities aberrantly activate signaling pathways like the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-hydroxykinase (PI3K) signaling pathways, resulting in thyroid cells dedifferentiation, sodium/iodide symporter (NIS) dysfunction, and consequent the RAI-refractory nature of DTCs. Targeted therapy tailored to mutations presents a promising avenue for the treatment of RAI-RTCs. Lenvatinib and sorafenib, multi-kinase inhibitors, represent the standard first-line systemic treatment options, while cabozantinib is the standard second-line treatment option, for this purpose. Furthermore, ongoing clinical trials are exploring selective kinase inhibitors, immune checkpoint inhibitors, and combination therapies. Notably, numerous clinical trials have demonstrated that selective kinase inhibitors like BRAF, MEK and mTOR inhibitors can restore RAI uptake in tumor cells. However, further validation through multicenter, large-sample, double-blinded randomized controlled trials are essential. Enhanced treatment strategies and innovative therapies are expected to benefit a broader spectrum of patients as these advancements progress.

8679 Case: The Sexual, Physical and Psychological Effects of Post-Finasteride Syndrome

Abstract Disclosure: E.M. Lonergan: None. S.M. Maher: None. I. Yaseen: None. D.B. O'Shea: None. Post-finasteride syndrome (PFS) is an increasingly recognised disorder with a myriad of physical and neuropsychiatric symptoms persisting for greater than three months in a small proportion of patients treated with Finasteride. We present the case of a 45-year-old male who was taking oral Finasteride for hair loss. He first presented to endocrinology services having stopped Finasteride after twenty years reporting new onset reduced libido, penile shrinkage, fatigue, new food intolerances and agitated depression which was the predominant symptom in this case. He described the emergence of gynaecomastia, which was evident on examination, as well as muscle atrophy. Biochemistry was unremarkable including testosterone 24.6 nmol/L (8.6-29.0), oestradiol 100 pmol/L (50 – 159), LH 7.1 IU/L (1.7-8.6), FSH 16.8 IU/L (1.5-12.4), urinary free cortisol 177 nmol/24h (12-486) and urinary steroid profile. The patient was offered a trial of IM testosterone for 3 months followed by a course of hCG which he declined after discussing with patients online via a PFS patient forum citing anecdotal pseudo immune downregulation in this cohort. GLP-1 receptor agonist therapy was considered as a second-line treatment option. The patient expressed a preference for hydrocortisone treatment after conducting online research which has not been commenced due to a lack of evidence. The inhibition of 5-alpha-reductase in Finasteride-treated patients has been documented to cause reversible sexual dysfunction. However, with increasing case reports of PFS, it was included in the list of Rare and Genetic Diseases of the NIH in 2015. The syndrome encompasses symptoms and signs seen in our case, as well as erectile dysfunction, decreased ejaculatory volume, infertility, Peyronie’s disease, testicular pain, dry skin, memory problems and insomnia. Suicidal ideation was included in the product label as per FDA mandate in 2022. The literature is largely inconclusive regarding the underlying aetiology, duration, and severity of the disorder. A large retrospective study revealed 0.8% of patients developed sexual dysfunction with persistence in 33% of these cases after drug suspension, the main independent risk factor being drug treatment for longer than 7 months. Neuropsychiatric symptoms are likely related to the presence of 5-alpha-reductase isoforms in the brain with resulting alterations in CSF and plasma neuroactive steroid levels and metabolites. Evidence-based treatment options for PFS are limited. PFS is a rare but debilitating syndrome to which a subset of patients appears to be predisposed, but of which the pathophysiology is poorly understood. Further studies in this regard, as well as an exploration of effective treatment options are required. Presentation: 6/1/2024

A Case of Multidrug-Resistant Tuberculosis in a Young Patient With Rheumatoid Arthritis

Multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) represent a critical global health challenge. MDR TB is characterized by resistance to isoniazid and rifampin, two key first-line anti-TB drugs [1]. XDR TB is characterized by its resistance to isoniazid, rifampin, any fluoroquinolone, and at least one injectable drug, rendering it impervious to most first- and second-line treatment options [1]. Below, we present a case of a patient with a history of rheumatoid arthritis (RA) who was diagnosed with pulmonary TB and was found to have MDR TB.