Background: Drug repurposing has emerged as an effective strategy to accelerate drug discovery. Using the pipeline established from a large collaborative drug repurposing project focused on high-grade serous ovarian cancer (HGSOC), we identified ivacaftor, an FDA-approved cystic fibrosis medication, as a drug candidate predicted to interact with the receptor tyrosine kinase-like orphan receptor 1 (ROR1) which we have previously demonstrated as a therapeutic target in ovarian cancer.
Objectives: This study aimed to provide preclinical evidence supporting the potential repurposing of ivacaftor for HGSOC treatment.
Design: Ivacaftor was tested in 2D and 3D preclinical models as well as patient-derived organoid models in vitro.
Methods: Dose-response analysis was undertaken in ROR1 expressing HGSOC cell lines OVCAR4, KURAMOCHI, COV362 and COV318 in both 2D adherent and 3D bioprinted formats. Real-time live/dead and apoptosis cell staining were performed over a 72 h period using the IncuCyte live cell imaging platform. Flow cytometry was used to assess apoptosis, DNA damage and cell proliferation following treatment with either 15 µM ivacaftor or 30 µM carboplatin at 24, 48 and 72 h. Additionally, ROR1-expressing HGSOC patient-derived organoids (OC029, OC043 and OC058) underwent ivacaftor dose-response analysis. Cell apoptosis following 15 µM ivacaftor treatment was measured in real-time using an Annexin V assay in two additional organoid models (OC062 and OC075). Finally, the mechanisms associated with response to ivacaftor were explored in HGSOC cell lines through Western blotting.
Results: The IC50 for ivacaftor ranged from 6.5 to 13.2 µM in 2D cultures and 11.6 to 18.2 µM in 3D cultures. Treatment with 10 and 15 µM ivacaftor resulted in significantly increased cell death and reduced live cell counts compared to the vehicle control over 72 h. Organoids displayed IC50 values between 11.2 and 14.1 µM. Ivacaftor treatment induced apoptosis in organoids, with no significant impact on DNA damage or cell cycle in HGSOC cells. ROR1 signalling associated oncogenic pathways including the BMI-1 and the PI3K/AKT pathways were modulated following ivacaftor treatment.
Conclusion: In summary, ivacaftor demonstrated significant anti-tumour potential in preclinical HGSOC models, supporting its further investigation as a repurposed therapy for ovarian cancer.
Background: The efficacy and safety of poly (ADP-ribose) polymerase inhibitors (PARPis) in the Chinese real-world setting have not been well characterized.
Design: This is a retrospective analysis of PARPis efficacy in metastatic breast cancer (MBC) patients with homologous recombination repair (HRR) gene pathogenic variants (PVs).
Objectives: We aimed to evaluate the efficacy and toxicities of PARPis in real-world MBC patients.
Methods: Patients who received PARPi for MBC at the National Cancer Center and two other centers between January 1, 2019, and December 31, 2024, were consecutively included. The primary endpoint was progression-free survival (PFS). Univariable and multivariable Cox proportional hazard models were used to evaluate the predictive impact of clinicopathologic characteristics on PFS.
Results: In total, 62 MBC patients treated with olaparib (N = 55), talazoparib (N = 4), pamiparib (N = 2), and fluzoparib (N = 1) were enrolled. The median PFS (mPFS) in all patients was 6.0 months (95% confidence interval: 4.1-7.9). mPFS in the germline BRCA1 (gBRCA1; N = 19), gBRCA2 (N = 30), gBRCA (N = 4), somatic BRCA2 (sBRCA2; N = 1), gPALB2 (N = 4), and other HRR gene (N = 4) PVs carriers were 3.7, 8.0, 2.8, 2.7, 5.3, and 7.1 months, respectively (p = 0.334). In multivariate analysis, ⩽40 years old (hazard ratio (HR): 2.281, p = 0.008), third-line or later therapy (HR: 2.429, p = 0.019), and prior platinum-based treatment (HR: 2.172, p = 0.014) were independently associated with shorter PFS. The incidence of adverse events (AEs) of all grades was 62.5% (35/56). The most common AEs in all grades were anemia (30.4%), nausea (21.4%), and leukopenia (17.9%). Hematologic toxicity was the most common grade ⩾3 AEs.
Conclusion: PARPis showed promising PFS and tolerable toxicity in the real-world treatment of Chinese MBC patients with HRR-related gene mutations.
Background: In non-metastatic pancreatic adenocarcinoma (PDAC), the appropriate evaluation of tumor response to neoadjuvant treatment (NAT) has a substantial prognostic impact, but the tools used to assess it are imperfect and sometimes discordant.
Objectives: We aimed to explore the prognostic impact of morphological and pathological evaluations of tumor response to NAT.
Design: Single-center retrospective observational study.
Methods: We retrospectively studied all patients with borderline or locally advanced PDAC who underwent surgery after neoadjuvant chemotherapy (NAC) with FOLFIRINOX, ±additional chemoradiation (NACR) between 2016 and 2022 in a tertiary center. Morphological response was evaluated according to RECIST 1.1, and pathological response was assessed according to the CAP score and proportion of viable tumor cells (VTC). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS). Factors associated with the risk of recurrence were analyzed using ROC curves and multivariable Cox proportional hazard models.
Results: We included 91 patients (52% male, median age 66, 83% with borderline PDAC) who underwent surgery following NAC with additional NACR in 85% of patients. Overall, 38% of patients had an objective morphological response according to RECIST 1.1, which was not associated with prolonged RFS HR 1.16, 95% CI (0.62-2.10), p = 0.64). Conversely, poor pathological response was associated with shorter RFS on multivariable analysis, notably VTC ⩾ 30% (HR 2.28, 95% CI [1.08-5.13], p = 0.037). Median OS was 62.2 months with VTC ⩾ 30% versus 45.1 months with VTC < 30% (p = 0.025). Identifying PDAC with VTC < or ⩾30% had a strong reproducibility (kappa 0.86).
Conclusion: Morphological response per RECIST should not be the aim of NAT in patients with PDAC. Conversely, the proportion of VTC could be a reproducible, simple, and effective prognostic tool. Should this marker be further confirmed as valuable, it may help inform the adaptation of adjuvant treatment and follow-up in this setting.
The treatment landscape for patients with advanced gastric or gastroesophageal junction adenocarcinoma is evolving, driven by a deeper understanding of molecular profiling and the introduction of novel anticancer drugs. Systemic chemotherapy has improved survival compared to supportive care; however, overall survival worldwide remained limited to approximately 1 year. Recently, the introduction of upfront immune checkpoint inhibitors (ICIs) and/or targeted agents in biomarker-enriched populations has led to clinically meaningful survival improvements. The expansion of treatment options for metastatic disease, combined with the identification of biomarker-selected populations, underscores the importance of tailoring first-line, maintenance, and sequential therapies across multiple lines. In this context, the delivery of an effective first-line treatment is crucial, as less than half of patients retain fitness for additional anti-cancer therapies due to the morbidity associated with disease progression to the initial regimen even within modern clinical trials regardless of the use of targeted therapy or immunotherapy combined with chemotherapy. On the other hand, the expanding therapeutic armamentarium including ICIs, antibody-drug conjugates, and targeted therapies for molecularly selected subgroups, will enable the development of sequential treatment strategies across multiple lines of therapy. This review summarizes the current knowledge about maintenance strategies and subsequent lines of treatment in either biomarker selected and unselected populations.
Background: Patients with epithelial ovarian cancer (EOC) receiving neoadjuvant platinum-based chemotherapy (NACT) who remain ineligible for complete interval cytoreductive surgery (ICS) due to poor chemosensitivity (CA-125 KELIM™ score <1.0) have a poor prognosis (~20% 5-year survival). A weekly dose-dense carboplatin-paclitaxel regimen may improve outcomes in this high-risk subgroup.
Objectives: To demonstrate the superiority of a salvage weekly dose-dense carboplatin-paclitaxel regimen over continuation of the standard 3-weekly regimen in poor-prognosis EOC patients after 3-4 cycles of standard NACT.
Design: SALVOVAR is a pragmatic, open-label, multicenter, international, randomized phase III trial.
Methods and analysis: Patients with stages III-IV high-grade EOC are eligible if they present (1) an unfavorable standardized KELIM score <1.0, and (2) a disease not amenable to complete ICS after 3-4 cycles of standard 3-weekly carboplatin-paclitaxel. Patients are randomized (1:1) to either the experimental arm (dose-dense carboplatin AUC5 day 1 plus paclitaxel 80 mg/m2 on days 1, 8, and 15, every 3 weeks) or the control arm (continuation of the standard regimen) for 3 cycles. Bevacizumab use is allowed at investigator discretion. Stratification factors include planned bevacizumab administration, BRCA mutation status, and KELIM strata. The two co-primary endpoints are (1) improvement in late complete cytoreduction rates (from 5% in the control arm to 20% in the experimental arm), and (2) overall survival (target hazard-ratio, 0.61). Total 250 patients will be randomized. Secondary endpoints include objective response rate, progression-free survival, and safety. Additional planned analyses include quality-of-life, cost-effectiveness, surgical standardization, human sciences, and biology studies.
Ethics: The protocol was approved by the national ethics committee and health authorities.
Discussion: SALVOVAR will evaluate whether chemotherapy densification improves outcomes in poorly chemosensitive advanced EOC. If positive, this pragmatic strategy could be implemented in large-scale studies, independent of resource setting.
Trial registration: ClinicalTrials.gov NCT06476184 (June-2024). Available at: https://clinicaltrials.gov/study/NCT06476184.
Background: Immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents have become a standard strategy for advanced hepatocellular carcinoma (HCC). There remains an urgent need for effective biomarkers to guide treatment, with C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) scores and cytokine levels representing promising candidates.
Objectives: We aimed to assess the efficacy, safety, and potential biomarkers of anlotinib plus TQB2450 in patients with advanced HCC.
Design: This study was a single-arm, phase Ib trial. Twenty-five patients with advanced HCC were enrolled.
Methods: Patients received an intravenous infusion of TQB2450 (1200 mg, on Day 1) and oral administration of anlotinib (initiated at 10 mg, once a day, from Day 1 to Day 14), which was repeated every 3 weeks. Blood was collected at baseline for serum cytokine analysis.
Results: After a median follow-up of 41.80 months, the median progression-free survival (mPFS) was 5.49 months, and the median overall survival (mOS) was 8.94 months. Treatment-related adverse events (TRAEs) occurred in 22 patients, with grade ⩾3 TRAEs observed in 12 patients. Patients who achieved clinical benefit (CB) had higher baseline serum brain-derived neurotrophic factor (BDNF) levels than non-CB patients (median, 227.97 vs 129.26 pg/ml, p = 0.036). High serum BDNF concentrations (⩾153.59 pg/ml) were associated with longer mPFS (9.64 vs 3.52 months, p < 0.001) and mOS (18.14 vs 5.55 months, p = 0.010). A CRAFITY score combining BDNF and Eastern Cooperative Oncology Group (ECOG) score showed superior prognostic performance in patients receiving anlotinib plus TQB2450, which was confirmed in a validation cohort of 36 advanced HCC patients treated with ICIs and antiangiogenic agents.
Conclusion: Anlotinib plus TQB2450 demonstrated promising efficacy with manageable safety in advanced HCC. Elevated serum BDNF levels might serve as a potential positive prognostic marker and, together with ECOG score, may help complement the CRAFITY score in identifying subgroups that could benefit from ICIs and antiangiogenic therapy.
Trial registration: This study was registered on ClinicalTrials.gov (NCT03825705, registered January 31, 2019).
Background: Osimertinib is the preferred treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) in several settings; however, disease progression is common, and treatment options after progression are limited. Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 (TROP 2) monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a plasma-stable linker, has demonstrated efficacy in advanced NSCLC, including previously treated EGFR-mutated advanced NSCLC. Combining osimertinib and Dato-DXd may overcome heterogeneous osimertinib resistance mechanisms and limit tumor progression.
Objectives: TROPION-Lung15 is an ongoing, phase III, open-label, sponsor-blind, multicenter, randomized trial evaluating Dato-DXd ± osimertinib versus chemotherapy in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib.
Methods and design: Approximately 630 patients with histologically/cytologically confirmed non-squamous NSCLC, documented epidermal growth factor receptor tyrosine kinase inhibitor-sensitive mutations, and radiologic progression on prior osimertinib monotherapy will be enrolled. Patients will be randomized 1:1:1 to Dato-DXd (6 mg/kg intravenously every 3 weeks), osimertinib (80 mg orally once daily) plus Dato-DXd, or platinum-doublet chemotherapy, stratified by the history/presence of brain metastases (yes vs no), prior osimertinib therapy (adjuvant vs post-chemoradiotherapy/first-line vs second-line), and race. Treatment will continue until radiological progression (per Response Evaluation Criteria in Solid Tumors version 1.1), unacceptable toxicity, or another discontinuation criterion is met. The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) for osimertinib + Dato-DXd and PFS by BICR for Dato-DXd alone versus chemotherapy. Secondary endpoints include overall survival, central nervous system PFS by BICR, and safety/tolerability.
Ethics: The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide written informed consent.
Discussion: TROPION-Lung15 will assess Dato-DXd ± osimertinib in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib. Data from this study could lead to a new treatment option in this setting.
Trial registration: ClinicalTrials.gov identifier: NCT06417814 (date of registration: May 13, 2024).
Background: Prompt identification of actionable genomic alterations (AGAs) is essential in guiding treatment decisions in newly diagnosed advanced non-small-cell lung cancer (NSCLC).
Objectives: We aimed to determine the optimal testing strategy in terms of proportion of AGAs detected, time-to-treatment decision (TTTD) and average costs/patient in Singapore, a high-frequency AGA population.
Design: A model was constructed to evaluate AGA testing strategies, comparing the cost-effectiveness and budget impact of each strategy.
Methods: The 24 strategies studies included (1) upfront tissue/plasma next-generation sequencing (NGS) alone (small/medium/large panel), (2) exclusionary tissue single-gene testing (EGFR, ALK and ROS1) followed by tissue/plasma NGS, (3) exclusionary plasma EGFR followed by tissue or plasma NGS, (4) sequential single-gene testing followed by tissue/plasma NGS, (5) exclusionary or sequential testing without NGS and (6) small panel tissue NGS with fluorescence in situ hybridization (FISH) for ALK, ROS1, RET and MET. Literature review was performed to determine the incidence of NSCLC and the prevalence of each AGA in the population; costs, gene coverage and turnaround times were sourced through market research.
Results: AGAs and EGFR mutations occurred in 76.7% and 56.0% of patients, respectively. Upfront medium panel tissue NGS detected all AGAs at USD1813/patient, with a TTTD of 7 days-no benefit was seen from using large panel tissue NGS at a higher cost. Exclusionary tissue testing followed by medium panel tissue NGS detected 98.9% of AGAs at USD1506/patient, with a TTTD of 14.9 days. Exclusionary plasma EGFR testing followed by medium panel tissue NGS detected 98.3% of AGAs at USD1047/patient, with a TTTD of 8.4 days. Upfront small panel tissue NGS with FISH also detected 98.3% of AGAs at a cost of USD798/patient, with a TTTD of 14 days.
Conclusion: In our high EGFR-mutation prevalence population, exclusionary plasma EGFR followed by medium panel tissue NGS was cost-effective. Our analysis provides insight on NGS testing strategies of different gene panel sizes and sample types.
Background: The clinical validity of tumor-infiltrating lymphocytes (TILs) has been investigated extensively in triple-negative breast cancer (TNBC). However, inconsistent cutoff values across studies limit its clinical application.
Objective: To determine the optimal TILs cutoff predicting pathological complete response (pCR) and event-free survival (EFS) in Vietnamese TNBC patients undergoing neoadjuvant chemotherapy (NACT).
Design: A single-center, retrospective cohort study of 106 stage II-III TNBC patients treated with NACT at Ho Chi Minh City Oncology Hospital between January 2022 and May 2023.
Methods: Stromal TILs (sTILs) were evaluated on pre-treatment biopsy specimens using the International TILs Working Group guideline. The optimal cutoff was determined using receiver operating characteristic curve analysis. Logistic regression and Cox proportional hazards models were used to analyze potentially predictive and prognostic factors.
Results: An optimal 20% TILs cutoff stratified the cohort into high- and low-TIL groups, with significantly different pCR rates (50.9% vs 9.8%, p < 0.001). High TILs (odds ratio (OR) = 8.22, p < 0.001) and lower clinical tumor status (OR = 3.64, p = 0.033) independently predicted pCR. TILs (hazard ratio (HR) = 0.38, p = 0.017) and pCR status (HR = 0.08, p = 0.017) were independent prognostic factors for EFS.
Conclusion: A sTIL cutoff of 20% effectively predicts chemotherapy response and survival outcome in Vietnamese TNBC patients, supporting its use in clinical decision-making.
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