Background:
This study investigated whether the effectiveness of first-line tyrosine-kinase inhibitors was associated with sites of disease in patients with metastatic renal cell carcinoma (mRCC).
...Methods:
A retrospective cohort of consecutive mRCC patients receiving first-line sorafenib (SO) or sunitinib (SU) was analyzed.
Results:
In total, 203 patients received SO and 99 SU. In patients with liver metastasis, SU was associated with a 18% higher risk of time-to-treatment failure (TTF), and a 39% higher risk of death than SO: conversely, patients without liver metastases who received SU showed a 46% decreased risk of TTF and 62% decreased risk of death.
Conclusions:
mRCC patients with liver metastases treated with first-line SO showed a better outcome compared with SU, while mRCC patients without liver metastases treated with first-line SU showed a better outcome compared with SO.
TPS712
Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Neoadjuvant immunotherapy (I/O) ...demonstrated clinical safety and efficacy in various solid tumors including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for treatment of MIBC. Increasing evidence emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive role. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. The Neo-GDFather trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: Multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. Other inclusion criteria comprise an ECOG performance status 0-1 and a pure/predominant UC histology. No statistical assumptions were undertaken at this stage.Treatment consists of three 4-week cycles i.v., Q4Wk, and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations of EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., #2501 ASCO Annual Meeting 2023 Oral Abstract Session. Clinical trial information: Not yet available.
TPS723
Background: The therapeutic gold standard for muscle invasive bladder cancer (MIBC) is radical cystectomy (RC) preceded by neoadjuvant chemotherapy when appropriate. However, RC is a major ...surgery procedure with 13% rate of severe complication and a perioperative mortality rate of about 1.5 - 5 %. Trimodal therapy (TMT) is a “bladder sparing” option alternative to RC. TMT consists of complete transurethral bladder tumor resection (TURBT) followed by a combination of systemic chemotherapy and locoregional radiotherapy (RT), with the option of “salvage” cystectomy in case of local treatment failure. Immunotherapy with anti-PD1/PD-L1 monoclonal antibody significantly improves survival of metastatic BC patients, and it seems to potentiate the activity of RT without increased toxicity. Therefore, we investigate the role of a multimodal TMT strategy to increase the disease-free survival (DFS) and avoid or delay RC in non-metastatic MIBC pts. Methods: CNN-BC trial (NCT05203913) is a phase 2, open-label, mono-institutional study evaluating the activity and safety of TMT with cisplatin, nab-paclitaxel and nivolumab as systemic therapy in non-metastatic MIBC pts. Eligible pts should have undergone complete TURBT with diagnosis of T2-T3 N0M0 urothelial carcinoma, and no evidence of lymph nodes or metastatic disease at FDG-PET within 6 weeks from the start of treatments. TMT consists of nivolumab (480 mg IV every 4 weeks for a total of 13 doses), weekly nab-paclitaxel (60mg/m2) plus cisplatin (20mg/m2) administered concurrently with RT (60Gy in 25 fractions over 5 weeks on original bladder tumor, plus a concomitant boost of 50Gy in 25 fractions on whole bladder and pelvic nodes). The primary endpoint is the 1-year DFS rate, defined as the rate of survival free of recurrence in pelvic nodes or bladder, or appearance of distant metastases. Secondary endpoints include: the rate of pts who require salvage cystectomy, the rate of locoregional complete response (CR) and of locoregional DFS, median DFS, safety, and quality of life. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05203913 .
Highlights • The therapeutic landscape of renal cell carcinoma (RCC) has greatly expanded in the last decade. • Clinicians are used to classify RCC based on tumor histology, distinguishing the most ...frequent clear cell RCC type from the other RCC subtypes, which are simplistically grouped as non-clear cell RCC. • To date, the only validated systems for prognostically stratifying patients with metastatic renal cell carcinoma rely on the evaluation of clinical factors, since no molecular biomarkers with a prognostic or predictive value have been identified so far. • A Efforts are directed at delineating signaling pathways underlying clear cell and non-clear cell RCC carcinogenesis, possibly identifying driven-mutations as potential targets for therapy. • Novel molecular targets for therapy (such as MET, FGFR, PD-1/PD-L1) are under investigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•About 35% of localized RCC patients recur after nephrectomy.•A unique and universally accepted risk factor model is still missing.•VEGFR-TKIs failed in demonstrating a significant activity as ...adjuvant treatment.•Adjuvant pembrolizumab significantly prolongs the disease-free survival.•The efficacy of others ICIs is controversial in the adjuvant/peri-operative setting.•The management of resected oligo-metastatic RCC patients (M1NED) is evolving.
Standard treatment for localized non-metastatic renal cell carcinoma (RCC) is radical or partial nephrectomy. However, after radical surgery, patients with stage II-III have a substantial risk of relapse (around 35%). To date a unique standardized classification for the risk of disease recurrence still lack. Moreover, in the last years great attention has been focused in developing systemic therapies with the aim of improving the disease-free survival (DFS) of high-risk patients, with negative results from adjuvant VEGFR-TKIs. Therefore, there is still a need for developing effective treatments for radically resected RCC patients who are at intermediate/high risk of relapse. Recently, interesting results came from immune-checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, with a significant benefit in terms of disease-free survival from adjuvant pembrolizumab. However, the conflicting results of diverse clinical trials investigating different ICI-based regimens in the adjuvant setting, together with the still immature data on the overall survival advantage of immunotherapy, requires careful considerations. Furthermore, several questions remain unanswered, primarily regarding the selection of patients who could benefit the most from immunotherapy. In this review, we have summarized the main clinical trials investigating adjuvant therapy in RCC, with a particular focus on immunotherapy. Moreover, we have analyzed the crucial issue of patients’ stratification according to the risk of disease recurrence, and we have described the possible future prospective and novel agents under evaluation for perioperative and adjuvant therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The activity of chemotherapy as salvage therapy for recurrent bladder cancer has been well defined, although the optimum therapy combination is less clear. Since the early nineties several cisplatin ...based regimens have been compared but no one regimen has reported a superior benefit. Currently, regimens such as methotrexate, vinblastine, doxorubicin and cisplatin and gemcitabine-cisplatin should be considered two equal alternatives in patients eligible for cisplatin, but the differing toxicity profiles should be evaluated in the choice of treatment. The use of a triple combination with paclitaxel, gemcitabine and cisplatin should be avoided in clinical practice, although its use may be carefully considered in patients needing a rapid downsizing of disease and with primary bladder tumor. Despite this evidence, several questions remain, and there is a need for answers in the future.
Metabolic Phenotype of Bladder Cancer Massari, Francesco; Ciccarese, Chiara; Santoni, Matteo ...
Cancer treatment reviews,
04/2016, Volume:
45
Journal Article
Peer reviewed
Open access
Highlights • Metabolism of bladder cancer represents a key issue for cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis, representing therefore interesting ...targets for therapy. • Bladder cancer metabolism displays an increased expression of genes favoring the pentose phosphate pathway (glucose-6-phosphate dehydrogenase G6PD) and the fatty-acid synthesis (fatty acid synthase FASN), along with a decrease of AMP-activated protein kinase (AMPK) and Krebs cycle activities. Moreover, the PTEN/ PI3K/AKT/mTOR pathway, hyper-activated in bladder cancer, acts as central regulator of aerobic glycolysis, hence contributing to cancer metabolic switch and tumor cell proliferation. • Glycogen metabolism pathway plays a robust role in bladder cancer development. In particular, the overexpression of GLUT-1, the loss of the tumor suppressor glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), and the increased activity of the tumor promoter enzyme glycogen phosphorylase impair glycogen metabolism. An increase in glucose uptake, decrease in normal cellular glycogen storage, and overproduction of lactate are consequences of decreased oxidative phosphorylation and inability to reuse glucose into the pentose phosphate and de novo fatty acid synthesis pathways. • In this review we discuss the role of cancer metabolism in bladder cancer and the possible role for novel opportunities for targeted therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Purpose of Review
To discuss recent advances in the treatment of advanced urothelial carcinoma (UC) and how best to incorporate new therapies into clinical practice.
Recent Findings
There have been ...several recent practice-changing phase 2 and 3 trials of immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and targeted agents in advanced UC. Based on data from these trials, ICIs can be used as first-line maintenance therapy in patients who do not progress on platinum-based chemotherapy, second-line therapy for those with progression, and first-line therapy in cisplatin-ineligible patients with PD-L1 expression; ADCs and targeted agents provide later-line treatment options.
Summary
Despite substantial progress in the treatment of advanced UC, there are still many uncertainties, including the optimal treatment sequence for novel agents, and reliable predictive biomarkers to aid in treatment selection. There is also an unmet need for effective treatment options in patients unfit for any platinum-based chemotherapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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