Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).

BACKGROUND: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations. METHODS: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity. RESULTS: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related). CONCLUSIONS: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib. CLINICAL TRIAL REGISTRATION: NCT02780687.

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Predicting Chemotherapy Toxicity in Older Patients with Cancer: A Multicenter Prospective Study.

BACKGROUND: Standard oncology tools are inadequate to distinguish which older patients are at higher risk of developing chemotherapy-related complications. MATERIALS AND METHODS: Patients over 70 years of age starting new chemotherapy regimens were prospectively included in a multicenter study. A prechemotherapy assessment that included sociodemographics, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and the development of grade 3-5 toxicity was examined by using logistic regression. RESULTS: A total of 551 patients were accrued. Chemotherapy doses (odds ratio [OR] 1.834; 95% confidence interval [CI] 1.237-2.719) and creatinine clearance (OR 0.989; 95% CI 0.981-0.997) were the only factors independently associated with toxicity. Only 19% of patients who received reduced doses of chemotherapy and had a creatinine clearance ≥40 mL/minute had grade 3-4 toxicity, compared with 38% of those who received standard doses or had a creatinine clearance <40 mL/minute (p < .0001). However, no satisfactory multivariate model was obtained using different selection approaches. CONCLUSION: Chemotherapy doses and renal function were identified as the major risk factors for developing severe toxicity in the older patient. These factors should be considered when planning to initiate a new chemotherapy regimen and should also lead to a closer follow-up in these patients. IMPLICATIONS FOR PRACTICE: Older patients are more vulnerable to chemotherapy toxicity. However, standard tools are inadequate to identify who is at higher risk of developing chemotherapy-related complications. Chemotherapy doses (standard vs. reduced) and renal function were identified as the major risk factors for developing severe toxicity in the elderly. These factors should be considered when planning to initiate a new chemotherapy regimen and should also lead to a closer follow-up.

Biological molecular layer classification of muscle-invasive bladder cancer opens new treatment opportunities.

BACKGROUND: Muscle-invasive bladder tumors are associated with a high risk of relapse and metastasis even after neoadjuvant chemotherapy and radical cystectomy. Therefore, further therapeutic options are needed and molecular characterization of the disease may help to identify new targets. The aim of this study was to characterize muscle-invasive bladder tumors at the molecular level using computational analyses. METHODS: The TCGA cohort of muscle-invasive bladder cancer patients was used to describe these tumors. Probabilistic graphical models, layer analyses based on sparse k-means coupled with Consensus Cluster, and Flux Balance Analysis were applied to characterize muscle-invasive bladder tumors at a functional level. RESULTS: Luminal and Basal groups were identified, and an immune molecular layer with independent value was also described. Luminal tumors showed decreased activity in the nodes of epidermis development and extracellular matrix, and increased activity in the node of steroid metabolism leading to a higher expression of the androgen receptor. This fact points to the androgen receptor as a therapeutic target in this group. Basal tumors were highly proliferative according to Flux Balance Analysis, which makes these tumors good candidates for neoadjuvant chemotherapy. The Immune-high group showed a higher degree of expression of immune biomarkers, suggesting that this group may benefit from immune therapy. CONCLUSIONS: Our approach, based on layer analyses, established a Luminal group candidate for therapy with androgen receptor inhibitors, a proliferative Basal group which seems to be a good candidate for chemotherapy, and an immune-high group candidate for immunotherapy.

Efficacy and safety of abiraterone acetate plus prednisone vs. cabazitaxel as a subsequent treatment after first-line docetaxel in metastatic castration-resistant prostate cancer: results from a prospective observational study (CAPRO).

BACKGROUND: To describe the patterns of second-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel treatment in a Spanish population, to identify the factors associated with those patterns, and to compare the efficacy and safety of the treatments most frequently administered. METHODS: Observational, prospective study conducted in patients with histologically or cytologically confirmed prostate adenocarcinoma; documented metastatic castration-resistant disease; progression after first-line, docetaxel-based chemotherapy with or without other agents. RESULTS: Of the 150 patients recruited into the study, 100 patients were prescribed abiraterone acetate plus prednisone (AAP), 44 patients received cabazitaxel plus prednisone (CP), and 6 patients received other treatments. Age (odds ratio [OR] 1.06, 95% [confidence interval] CI 1.01 to 1.11) and not elevated lactate dehydrogenase (LDH) levels (OR 0.33, 95% CI 0.14 to 0.76) were independently associated with the administration of AAP. Treatment with AAP was associated with significantly longer clinical/radiographic progression-free survival (hazard ratio [HR] 0.57, 95% CI 0.38 to 0.85) and overall survival (OS; HR 0.40, 95% CI 0.21 to 0.76) compared to CP, while no significant differences between the treatments were found regarding biochemical progression-free survival (PFS; HR 0.78 [95% CI 0.49 to 1.24]). However, in a post-hoc Cox regression analysis adjusted for potential confounders there were not differences between AAP and CP in any of the time-to-event outcomes, including overall survival. We observed no new safety signals related to either regimen. CONCLUSION: Second-line AAP for patients with mCRPC is the most common treatment strategy after progression with a docetaxel-based regimen. When controlling for potential confounders, patients receiving this treatment showed no differences in PFS and OS in comparison to those receiving CP, although these latter results should be confirmed in randomized controlled trials.

Radium-223 international early access program: results from the Spanish subset.

AIM: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). PATIENTS & METHODS: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. RESULTS: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with ≥50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). CONCLUSION: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.

Potential role of transmembrane 9 superfamily member 1 as a biomarker in urothelial cancer.

Bladder cancer is a urological tumor with high rates of recurrence despite recent advances in novel therapies. Many proteins involved in the molecular mechanisms are currently an enigma, especially the transmembrane 9 superfamily member 1 which has an unclear function. Wei et al published the function and mechanism of this protein, and showed that it could participate in the proliferation, migration and invasion of tumor cells in bladder cancer, therefore treatments directed against this protein may be beneficial in avoiding this condition.

A Review of Recent Advances in the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aß) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aß plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.

Different outcomes among patients with intermediate-risk metastastic renal cell carcinoma treated with first-line tyrosine-kinase inhibitors.

INTRODUCTION: Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. MATERIAL AND METHODS: All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. RESULTS: A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. CONCLUSION: In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria. These could help select patients that may benefit from first-line treatment with a TKI, particularly in settings with difficult access to novel therapies, such as immunotherapy-based combinations.

Real-world treatment patterns, survival outcomes, and health care resource utilization for locally advanced or metastatic urothelial carcinoma in Spain.

PURPOSE: Real-world evidence on locally advanced or metastatic urothelial carcinoma (la/mUC) management in Spain is limited. This study describes patient characteristics, treatment patterns, survival, and health care resource utilization (HCRU) in this population. METHODS/PATIENTS: This retrospective observational study included all adults with a first diagnosis/record of la/mUC (index date) from January 2015 to June 2020 at nine university hospitals in Spain. Data were collected up to December 31, 2020 (end of study), death, or loss to follow-up. Patient characteristics, treatment patterns, median overall survival (OS) and progression-free survival (PFS) from index date (Kaplan-Meier estimates), and disease-specific HCRU were described. RESULTS: Among 829 patients, median age at diagnosis was 71 years; 70.2% had ≥ 1 comorbidity, and 52.5% were eligible for cisplatin. Median follow-up was 12.7 months. Most (84.7%) patients received first-line systemic treatment; of these, 46.9% (n = 329) received second-line and 16.6% (n = 116) received third-line therapy. Chemotherapy was the most common treatment in all lines of therapy, followed by programmed cell death protein 1/ligand 1 inhibitors. Median (95% confidence interval) OS and PFS were 18.8 (17.5-21.5) and 9.9 (8.9-10.5) months, respectively. Most patients required ≥ 1 outpatient visit (71.8%), inpatient admission (56.6%), or emergency department visit (56.5%). CONCLUSIONS: Therapeutic patterns were consistent with Spanish guideline recommendations. Chemotherapy had a role in first-line treatment of la/mUC in Spain during the study period. However, the disease burden remains high, and new first-line treatments recommended in the latest European guidelines should be made available to patients in Spain.

Case-control study assessing the impact of COVID19 in advanced kidney cancer patients treated with antiangiogenics or immunotherapy: the COVID-REN study.

BACKGROUND: Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management. METHODS: We designed a retrospective case-control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment. RESULTS: 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19. CONCLUSIONS: Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy.

Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

BACKGROUND AND PURPOSE: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. PATIENTS AND METHODS: We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. RESULTS: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. CONCLUSIONS: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study).

BACKGROUND: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. OBJECTIVE: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. METHODS: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). CONCLUSIONS: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

Radiotherapy plus pembrolizumab for advanced urothelial carcinoma: results from the ARON-2 real-world study.

The addition of metastasis-directed radiotherapy (MDRT) to immunotherapy in patients with advanced urothelial carcinoma (aUC) has shown promising results. We report the real-world data from the ARON-2 study (NCT05290038) on the impact of conventional (CRT) or stereotactic body radiotherapy (SBRT) on the outcome of aUC patients receiving pembrolizumab after platinum-based-chemotherapy. Medical records of 837 patients were reviewed from 60 institutions in 20 countries. Two hundred and sixty-two patients (31%) received radiotherapy (cohort A), of whom 193 (23%) received CRT and 69 (8%) received SBRT. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. With a median follow-up of 22.7 months, the median OS was 10.2 months, 6.8 months and 16.0 months in no RT, CRT and SBRT subgroups (p = 0.005), with an 1y-OS rates of 47%, 34% and 61%, respectively (p < 0.001). The 1y-OS rate in the SBRT subgroup were significantly higher for both lower (63%) and upper tract UC (68%), for pure urothelial histology (63%) and variant histologies (58%), and for patients with bone (40%) and lymph-node metastases (61%). Median PFS was 4.8 months, 9.6 months and 5.8 months in the CRT, SBRT and no RT subgroups, respectively (p = 0.060). The 1y-PFS rate was significantly higher (48%) in the SBRT population and was confirmed in all patient subsets. The difference in terms of ORR was in favour of SBRT. Our real-world analysis showed that the use of SBRT/pembrolizumab combination may play a role in a subset of aUC patients to increase disease control and possibly overall survival.

Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?

BACKGROUND: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. OBJECTIVE: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. CONCLUSIONS: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. PATIENT SUMMARY: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.

Enfortumab Vedotin Following Platinum Chemotherapy and Avelumab Maintenance in Patients with Metastatic Urothelial Carcinoma: A Retrospective Data from the ARON-2EV Study.

BACKGROUND: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. OBJECTIVE: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. PATIENTS AND METHODS: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. CONCLUSIONS: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia.

As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin γ(2) overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirus-related 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin γ(2) was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.

Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma.

OBJECTIVE: To evaluate the effect of margin status and radiation dose in patients treated with radiation therapy (RT) for vulvar cancer. Clinical outcomes included vulvar recurrence (VR), relapse-free survival (RFS) and overall survival (OS). METHODS: We retrospectively reviewed the records of 300 patients with Stage I-IVA vulvar cancer treated between 1988 and 2009. Slides were reviewed and margin status was scored as negative (≥ 1 cm), close (<1cm) or positive after formalin fixation. Cox proportional hazards models were constructed to determine significant prognostic factors for vulvar relapse. RESULTS: Of 205 eligible patients, 69 (34%) had negative surgical margins, 116 (56%) had close margins and 20 (10%) had positive margins. Median follow-up time was 49 months. The 4-year RFS rate was 53% and OS was 73%. Of 78 recurrences, 62 had the vulva as the first site of recurrence. The 4-year rates of freedom from vulvar recurrence were 82%, 63% and 37% for those with negative, close and positive margins, respectively (p for trend=0.005). On multivariate analysis, close margins (HR=3.03, 95% CI 1.46-6.26) and positive margins (HR=7.02, 95% CI 2.66-18.54) were associated with a significantly increased risk of vulvar relapse. Those who received a dose ≥ 56 Gy had a lower risk of relapse than those who received ≤ 50.4 Gy (p<0.05). Though recurrences were noted with margins up to 9 mm, the highest risk of vulvar recurrence was associated with margins ≤ 5 mm (p=0.002). CONCLUSIONS: Close or positive margins were associated with a significantly increased risk of vulvar recurrence. Radiation with a dose ≥ 56 Gy may decrease the risk of vulvar recurrence.

Long-term Clinical Outcomes of a Spanish Cohort of Metastatic Renal Cell Carcinoma Patients with a Complete Response to Sunitinib.

INTRODUCTION: The long-term clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) and a complete response (CR) to the tyrosine kinase inhibitor (TKI) sunitinib are poorly known. The characteristics of these patients could reveal previously undetected associations with clinical variables. PATIENTS AND METHODS: This observational, retrospective study (ATILA) used data from a registry of patients with mRCC who had received first-line sunitinib and had achieved CR from 2007 to 2018 in Spain. RESULTS: Sixty-two patients with CR were included; 48 patients (77.4%) received sunitinib in monotherapy and 14 (22.6%) combined with or followed by local treatment. Median age was 58.5 years (range, 32-81). Most patients (79.0%) had clear cell histology and had undergone previous nephrectomy (90.3%). The majority (70.2%) had an intermediate IMDC prognosis, 23% favorable and 7.0% poor. The median time on treatment with sunitinib was 28.2 months (IQR, 16.7-41.0) and the median time to CR was 10.9 months (IQR, 7.2-19.3). After a median follow-up of 8 years (range, 3-13 years), the median PFS was not reached. The overall median duration of complete response was 64.1 months (IQR, 32.2-99.4). The tolerance and safety profile of sunitinib was consistent with previous reports. CONCLUSION: Durable CR to sunitinib was observed in patients regardless the prognosis group, metastasis site or histology type, with 75% of patients remaining in CR after 10 years. CLINICALTRIALS: gov: NCT03916458.

Global Real-World Outcomes of Patients Receiving Immuno-Oncology Combinations for Advanced Renal Cell Carcinoma: The ARON-1 Study.

BACKGROUND: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC). OBJECTIVE: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients. PATIENTS AND METHODS: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB). RESULTS: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001). CONCLUSIONS: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations. CLINICAL TRIAL REGISTRATION: NCT05287464.