Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma

Molins, Joaquim Bellmunt; Torres-Jiménez, Javier; Valderrama, Begoña P.; Echaburu, Juan Antonio Virizuela; Hernando-Polo, Susana; Durán, Miguel Ángel Climent; Villa-Guzmán, José Carlos; Arija, José Ángel Arranz; Ostiategui, Mar Llorente; Milagro, Nuria Laínez; González-del-Alba, Aranzazu; González, B. Mellado; Díaz, Enrique; Gauna, D. Castellano; Santasusana, Montserrat Domènech; Herranz, Urbano Anido; Soláns, Xavier; Pérez-Gracia, José Luis; Vázquez, Javier Puente; Morales-Bárrera, Rafael; Pous, Albert Font

doi:10.1016/j.clgc.2020.05.004

Cited by 12 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients were randomized to receive second-line vinflunine (every 21 days as a 20-min intravenous infusion at 320 mg/m 2 or at 280 mg/m 2 ) plus best supportive care or best supportive care alone. One patient was lost immediately to follow-up and nine discontinued treatment due to toxicity or patient decision [ 12 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…Maintenance therapy can be a useful treatment strategy to delay disease progression, improve quality of life, and increase overall survival both in patients with metastatic disease who are not eligible for second-line treatment but who might still expect some clinical benefit and in those who are eligible for second-line treatment but at risk of rapid disease progression [ 15 , 16 ]. In a previous randomized, controlled, open-label, phase II trial of aUCC patients with controlled disease after first-line cisplatin and gemcitabine, we demonstrated that maintenance therapy with vinflunine plus best supportive care resulted in significantly longer progression-free survival than best supportive care alone, with no unexpected long-term adverse effects [ 12 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…In order to identify potential mechanisms of resistance to vinflunine, we have conducted a differential gene expression analysis and a pathway analysis using GSEA including epithelial-to-mesenchymal transition (EMT) and the IL-6/JAK/STAT3 pathway, between patients with good and poor outcome included in our vinflunine maintenance trial [ 12 , 17 ]. The overarching aim was to develop new therapeutic approaches to overcome vinflunine resistance through an adequate understanding of the mechanisms underlying this resistance.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

Font

Porras

Valderrama

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

In the phase II MAJA trial, maintenance therapy with vinflunine resulted in longer progression-free survival compared to best supportive care in advanced urothelial cell carcinoma (aUCC) patients who did not progress after first-line platinum-based chemotherapy. However, despite an initial benefit observed in some patients, unequivocal resistance appears which underlying mechanisms are presently unknown. We have performed gene expression and functional enrichment analyses to shed light on the discovery of these underlying resistance mechanisms. Differential gene expression profile of eight patients with poor outcome and nine with good outcome to vinflunine administered in the MAJA trial were analyzed. RNA was isolated from tumor tissue and gene expression was assessed by microarray. Differential expression was determined with linear models for microarray data. Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the genes. In vitro functional studies were performed using UCC cell lines. Hierarchical clustering showed a differential gene expression pattern between patients with good and poor outcome to vinflunine treatment. GSEA identified epithelial-to-mesenchymal transition (EMT) as the top negatively enriched hallmark in patients with good outcome. In vitro analyses showed that the polyphenol curcumin downregulated EMT markers and sensitized UCC cells to vinflunine. We conclude that EMT mediates resistance to vinflunine and suggest that the reversion of this process could enhance the effect of vinflunine in aUCC patients.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

Font

Porras

Valderrama

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…62,63 However, phase 3 trials of non-ICI maintenance treatments in advanced UC were negative (lapatinib or sunitinib) or resulted in a PFS benefit but not an OS improvement (vinflunine). [64][65][66][67] A randomized phase 2 trial performed in the United States assessed pembrolizumab maintenance versus placebo in 108 patients with advanced UC that had not progressed after 1L platinum-containing chemotherapy. Pembrolizumab maintenance significantly prolonged PFS compared with placebo, which was the primary endpoint of the trial.…”

Section: Javelin Bladder 100: Avelumab 1l Maintenance Treatmentmentioning

confidence: 99%

Clinical evidence and insights supporting the use of avelumab first‐line maintenance treatment in patients with advanced urothelial carcinoma in the Asia‐Pacific region

Eto

Lee

Chang

et al. 2022

Asia-Pac J Clncl Oncology

View full text Add to dashboard Cite

Until recently, international and Asia‐specific guidelines for advanced urothelial carcinoma (UC) recommended first‐line (1L) platinum‐based chemotherapy, followed by second‐line (2L) anti‐PD‐1 or anti‐PD‐L1 immune checkpoint inhibitor (ICI) therapy where possible, or 1L ICI therapy in cisplatin‐ineligible patients with PD‐L1+ tumors. However, long‐term outcomes remain poor and only a minority of patients receive 2L therapy. The JAVELIN Bladder 100 trial—which assessed avelumab (anti‐PD‐L1 antibody) as 1L maintenance therapy plus best supportive care (BSC) versus BSC alone in patients with advanced UC that had not progressed with 1L platinum‐based chemotherapy—is the only phase 3 trial of ICI‐based treatment in the 1L setting to show significantly improved overall survival, and this treatment approach is now recommended in updated treatment guidelines. Available data from the trial suggest that efficacy and safety in patients enrolled in the Asia‐Pacific region were similar to findings in the overall population. In this review, we discuss the treatment of advanced UC, with a specific focus on studies in the Asia‐Pacific region, and summarize key findings supporting the use of avelumab 1L maintenance as a standard of care in this setting both in cisplatin‐eligible and cisplatin‐ineligible patients and irrespective of PD‐L1 status.

show abstract

“…Maintenance therapy following platinum-containing chemotherapy is an established treatment strategy in other tumor types, including pemetrexed in advanced non-small cell lung cancer (NSCLC) and poly(ADPribose) polymerase inhibitors in ovarian cancer [58][59][60][61][62]. Previous trials of switch-maintenance therapy in advanced UC using nonimmunotherapy approaches (ie, lapatinib, sunitinib, and vinflunine) did not show significantly improved OS, with only vinflunine showing a PFS benefit [63][64][65][66]. Administering an ICI in sequence via a 1L maintenance approach may provide treatment benefits that cannot be achieved with combination therapy.…”

Section: Exploiting the Complementary Effects Of Chemotherapy And Icis In Advanced Ucmentioning

confidence: 99%

Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice

Grivas

Agarwal

Pal

et al. 2021

Cancer Treatment Reviews

View full text Add to dashboard Cite

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switchmaintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 [95% CI, 0.56-0.86]; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin-or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1− tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.

show abstract

Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma

Cited by 12 publications

References 21 publications

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

Clinical evidence and insights supporting the use of avelumab first‐line maintenance treatment in patients with advanced urothelial carcinoma in the Asia‐Pacific region

Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice

Contact Info

Product

Resources

About