Javlor (vinflunine)

P3, N=608, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Aug 2024 --> Feb 2025

P3, N=696, Active, not recruiting, Gilead Sciences | Trial completion date: Oct 2024 --> Jul 2025 | Trial primary completion date: Oct 2024 --> Jul 2025

An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician's choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

These novel combinations are revolutionizing the treatment standard for metastatic urothelial carcinoma and necessitate a new approach to managing side effects.

In the Japanese subgroup, erdafitinib showed improved survival and response compared to chemotherapy, with no new safety concerns. These results support erdafitinib as a treatment option for Japanese mUC patients with FGFR alterations, and early FGFR testing after diagnosis of mUC should be considered.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2024 --> Nov 2026

THOR-1 trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs chemotherapy (taxane or vinflunine) in patients with advanced urothelial carcinoma of the bladder (UCB) or upper tract urothelial carcinoma (UTUC). Although histologically similar, the genomic landscape of FGFR3mut+ RPUC and UUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation, inherent selection biases, and the retrospective nature of this work. Findings may impact clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Feb 2024 --> Sep 2024

P3, N=608, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Feb 2024 --> Aug 2024

THOR trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs (taxane or vinflunine) in patients (pts) with advanced UCB or UTUC. Although histologically similar, the genomic landscape of FGFR3mut+ UTUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation. The findings may impact of clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).

Methods Patients in cohort 1 were randomised to erdafitinib (8 mg once daily) or chemotherapy (vinflunine or docetaxel once every 3 weeks). Grade 3/4 treatment-related adverse events (AEs) and discontinuations due to treatment-related AEs occurred in 41% and 3% of patients on erdafitinib and 58% and 12% of those on chemotherapy, respectively. Conclusions In the Asian subgroup, erdafitinib showed improved survival and response vs chemotherapy, with no new safety concerns, consistent with the overall THOR population.

P3, N=629, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting | Trial completion date: Oct 2033 --> Apr 2024

Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG performance status 0-2, adequate organ function, progression on/after prior systemic therapy (tx) that included an anti-PD-(L)1 agent, and ≤2 prior lines of tx were randomized 1:1 to receive erda (8 mg with pharmacodynamically guided uptitration to 9 mg on day 14) QD or investigator’s choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Methods Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG PS 0-2, adequate organ function, progression on/after 1-2 prior lines of systemic tx that included anti-PD-(L)1 were randomized 1:1 to erda (8 mg with pharmacodynamically guided uptitration to 9 mg) QD or investigator's choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. No new safety signals were observed. These results support the role of erda to treat pts with FGFRalt mUC after anti-PD-(L)1 tx.

P3, N=631, Recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2024 --> Oct 2033

Alongside, we considered possible intervention with the chemotherapeutics gemcitabine, cisplatin and vinflunine. Co-inhibitory connections are shown by lines and co-stimulatory connections by dotted lines. The inducible or suppressive actions of the drugs (underlined) on the respective targets are indicated.

In a real-world setting, CHT showed clinically meaningful response rates and survival in mUC patients after progression with pembrolizumab. Clinical benefit may primarily be achieved in patients with favorable ECOG PS, in patients treated with > 6 cycles pembrolizumab as well as in patients without presence of liver metastases.

P3, N=631, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Mar 2023 --> Oct 2023

Vinca alkaloids including vincristine, vinblastine, vindesine, and vinflunine are chemotherapeutic compounds commonly used to treat various cancers. This review covers the significant aspects of these vital drugs, from their discovery to the present day, in a concise manner. In addition, we emphasize the major hurdles that must be overcome in the coming years to improve vinca alkaloid's effectiveness.

Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG performance status 0-2, adequate organ function, progression on/after prior systemic therapy (tx) that included an anti-PD-(L)1 agent, and ≤2 prior lines of tx were randomized 1:1 to receive erda (8 mg with pharmacodynamically guided uptitration to 9 mg on day 14) QD or investigator’s choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. In pts with FGFRalt advanced/mUC after prior treatment with PD-(L)1, erda significantly improved OS, PFS, and ORR vs investigator’s choice of chemo. Erda toxicity was consistent with the known safety profile. These results support the role of erda to treat pts with FGFRalt mUC after PD-(L)1 tx.

To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/3 mRNA overexpression may be better predictors of rogaratinib response.

In this exploratory study, we investigated protein profiles in sequential plasma-isolated extracellular vesicles (EVs) from a subset of mUC patients treated within a Phase I trial with vinflunine combined with sorafenib. Several of the markers in the PFS or best treatment response signatures were also identified by a machine learning classification algorithm. In conclusion, protein profiling of EVs isolated from plasma of mUC patients shows a potential to identify protein signatures that may associate to PFS and/or treatment response.

Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC and potential clinical utility of these biomarkers may be context-dependent.

Cisplatin-gemcitabine is considered the standard first line for metastatic tumors. Carboplatin should replace cisplatin in cisplatin-ineligible patients. According to the EMA label, pembrolizumab or atezolizumab could be an option in cisplatin-ineligible patients with high PD-L1 expression...Pembrolizumab also increases survival versus vinflunine or taxanes in patients with progression after chemotherapy who have not received avelumab, as well as enfortumab vedotin in those progressing to first-line chemotherapy followed by an antiPDL1/PD1. Erdafitinib may be considered in this setting in patients with FGFR alterations. An early onset of supportive and palliative care is always strongly recommended.

Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine...Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease.

In EV-301, a phase 3 trial of patients (pts) with previously treated la/m UC, EV significantly prolonged overall survival (OS) vs chemotherapy (docetaxel, paclitaxel, vinflunine). As of Jun 29, 2021, 150 pts are enrolled (HR+/HER2- BC, n=20; TNBC, n=11). Recruitment is ongoing at ~50 sites in North America and Japan.

The therapeutic landscape of metastatic urothelial carcinoma (mUC) becomes increasingly dense: standard therapy remains cisplatin-based chemotherapy, followed by immunotherapy with checkpoint inhibitors as maintenance or second-line. New directions include erdafitinib, a fibroblast-growth factor receptor (FGFR) inhibitor in patients with corresponding mutations in FGFR2/3 receptor...It received FDA approval based on phase I/II data recently and thus represents an alternative to established third-line chemotherapies with vinflunine, paclitaxel or docetaxel...Enfortumab vedotin has shown encouraging efficacy and a good tolerability in phase I/II trials, especially in heavily pretreated patients and patients with liver metastases. It appears to outperform third-line chemotherapies; ongoing studies will show the future potential of EV in treatment sequence.

Vinflunine has been the only approved treatment in Europe for this indication...The last couple of years, three immune-checkpoint inhibitors have been approved in Europe (pembrolizumab, atezolizumab and nivolumab) and five in USA (pembrolizumab, atezolizumab, nivolumab, durvalumaband avelumab), showing improved overall survival (OS), response rate (ORR) and tolerance...Erdafitinib, the first anti-FGFR treatment in patients with mutations/fusions in FGFR2/3 showed an ORR of 40% and an OS of 13,8 months. Likewise, enfortumab-vedotin, an antibody conjugates, was approved by the FDA based on the phase II trial results...As a result, the landscape of urothelial canceris rapidly evolving. However, the challenge of individualizing and sequencing treatments remains.

P3, N=542, Completed, Merck Sharp & Dohme Corp. | Active, not recruiting --> Completed

Cohort 1 (n ~ 280): pts with prior chemo and PD-L1 inhibitor (prior PD- [L] 1 inhibitor -as monotherapy or combo; no more than 2 lines of prior allowed for cisplatin-ineligible pts) in combination or in maintenance setting will receive 8 mg / d continuous ERDA vs chemo (1: 1) with docetaxel or vinflunine. PD-L1 expression level per immunohistochemistry and UC subtype per RNA sequencing or other methods as exploratory end points. For additional information on specific sites / countries refer clinicaltrials.gov (NCT03390504).

P3, N=542, Active, not recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Mar 2020 --> Oct 2020

The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician's choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.

Cohort 1 (n ~280): pts with prior chemo and PD-L1 inhibitor (prior PD-[L]1 inhibitor -as monotherapy or combo; no more than 2 lines of prior allowed for cisplatin-ineligible pts) in combination or in maintenance setting will receive 8 mg/d continuous ERDA vs chemo (1:1) with docetaxel or vinflunine. Pts are being enrolled at sites in 25 countries. For additional information on specific sites/ countries refer clinicaltrials.gov (NCT03390504).

Pts were randomized 1:1 to 800 mg rogaratinib p.o. BID continuously or CT Q3W (i.v., docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2), and stratified by PIK3CA/RAS-activating mutations, prior immunotherapy, and modified 4-factor Bellmunt risk score. In pts with FGFR1/3 tumor mRNA-positive UC, rogaratinib had efficacy comparable with standard CT and an acceptable safety profile. Subgroup analysis suggests rogaratinib may be more active in pts with an FGFR3 DNA alteration. Sensitivity analysis of biomarker subgroups is ongoing.

Pts were randomized 1:1 to 800 mg rogaratinib p.o. BID continuously or CT Q3W (i.v., docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2), and stratified by PIK3CA/RAS-activating mutations, prior immunotherapy, and modified 4-factor Bellmunt risk score. In pts with FGFR1/3 tumor mRNA-positive UC, rogaratinib had efficacy comparable with standard CT and an acceptable safety profile. Subgroup analysis suggests rogaratinib may be more active in pts with an FGFR3 DNA alteration. Sensitivity analysis of biomarker subgroups is ongoing.

P3; N=631; Recruiting; Sponsor: Janssen Research & Development, LLC; Not yet recruiting --> Recruiting