Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma.

BACKGROUND: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown. METHODS: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization. RESULTS: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing. CONCLUSIONS: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).

Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study.

BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator's choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy. INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed. FUNDING: F Hoffmann-La Roche.

Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study.

BACKGROUND: The primary analysis of IMvigor130 showed a significant progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial cancer. However, this finding did not translate into significant overall survival benefit for group A versus group C at the final analysis, precluding formal statistical testing of outcomes with atezolizumab monotherapy (group B) versus group C. Here we report the final overall survival results for group B versus group C; this report is descriptive and should be considered exploratory due to the study's statistical design. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) who had locally advanced or metastatic urothelial cancer previously untreated in the metastatic setting and Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), using a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin score, and investigator's choice of platinum-based chemotherapy, to receive either atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo in group A and group C; atezolizumab monotherapy in group B was open label. For groups B and C, atezolizumab (1200 mg) or placebo was administered intravenously every 3 weeks. Chemotherapy involved 21-day cycles of gemcitabine (1000 mg/m2 body surface area on day 1 and day 8 of each cycle) plus the investigator's choice of carboplatin (area under the curve 4·5 mg/mL per min or 5 mg/mL per min) or cisplatin (70 mg/m2 body surface area), administered intravenously. Co-primary endpoints were progression-free survival and overall survival in group A versus group C, and overall survival in group B versus group C, tested hierarchically, in the intention-to-treat (ITT) population, and then the populations with high PD-L1 tumour expression (immune cell [IC] expression score of IC2/3) if the results from group A versus group C were significant. Here, we report the co-primary endpoint of overall survival for group B versus group C in the ITT and IC2/3 populations. The ITT population for this analysis comprised concurrently enrolled patients in groups B and C who were randomly assigned to treatment. For the safety analysis, all patients enrolled in group B and group C who received any study treatment were included. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 362 patients were assigned to group B and 400 to group C, of whom 360 and 359, respectively, were enrolled concurrently (ITT population). 543 (76%) of 719 patients were male, 176 (24%) were female, and 534 (74%) were White. As of data cutoff (Aug 31, 2022), after a median follow-up of 13·4 months (IQR 6·2-30·8), median overall survival was 15·2 months (95% CI 13·1-17·7; 271 deaths) in group B and 13·3 months (11·9-15·6; 275 deaths) in group C (stratified hazard ratio 0·98 [95% CI 0·82-1·16]). The most common grade 3-4 treatment-related adverse events were anaemia (two [1%] in patients who received atezolizumab monotherapy vs 133 [34%] in those who received placebo plus chemotherapy), neutropenia (one [<1%] vs 115 [30%]), decreased neutrophil count (0 vs 95 [24%]), and decreased platelet count (one [<1%] vs 92 [24%]). Serious adverse events occurred in 163 (46%) patients versus 196 (50%). Treatment-related deaths occurred in three (1%; n=1 each, pneumonia, interstitial lung disease, large intestinal obstruction) patients who received atezolizumab monotherapy and four (1%; n=1 each, diarrhoea, febrile neutropenia, unexplained death, toxic hepatitis) who received placebo plus chemotherapy. INTERPRETATION: The final analysis from IMvigor130 did not show a significant improvement in overall survival with first-line atezolizumab monotherapy compared with platinum-based chemotherapy in the intention-to-treat population. The safety profile of atezolizumab monotherapy remained acceptable after extended follow-up, with no new safety signals. FUNDING: F Hoffmann-La Roche.

Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. METHODS: In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636. FINDINGS: Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1-17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5-8·3) in group A and 6·3 months (6·2-7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70-0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9-18·9) in group A and 13·4 months (12·0-15·2) in group C (0·83, 0·69-1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1-17·8) for group B and 13·1 months (11·7-15·1) for group C (1·02, 0·83-1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. INTERPRETATION: Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. FUNDING: F Hoffmann-La Roche and Genentech.

Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial.

BACKGROUND: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus. METHODS: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). RESULTS: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus. CONCLUSIONS: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC. LAY SUMMARY: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.

Use of Immunotherapy in Patients With Cancer During the COVID-19 Pandemic.

In an asymptomatic 77-yearold woman, former 55 packyears smoker, a routine X-ray showed a 45-mm superior left lobe lesion. A chest CT scan confirmed a 36-mm superior left lobe lesion and an aortic-pulmonary lymph node enlargement measuring 42 mm, suspicious for neoplasia. A PET-CT scan showed an elevated uptake in the primary lesion, in the aortic-pulmonary lymph node, and in the left hilar lymph node with a standardized uptake value - 40 and 4.3, respectively. CT-guided lung biopsy showed a lung squamous cell carcinoma. An endobronchial ultrasound-guided transbronchial needle aspiration for lymph-node staging was negative for lymph node spread. Brain MRI was negative. Final staging was determined to be a IIIA (T2bN2) squamous cell carcinoma of the lung.

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. METHODS: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. RESULTS: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). CONCLUSIONS: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

First Brazilian Consensus of Advanced Prostate Cancer: Recommendations for Clinical Practice.

INTRODUCTION: Prostate cancer still represents a major cause of morbidity, and still about 20% of men with the disease are diagnosed or will progress to the advanced stage without the possibility of curative treatment. Despite the recent advances in scientific and technological knowledge and the availability of new therapies, there is still considerable heterogeneity in the therapeutic approaches for metastatic prostate cancer. OBJECTIVES: This article presents a summary of the I Brazilian Consensus on Advanced Prostate Cancer, conducted by the Brazilian Society of Urology and Brazilian Society of Clinical Oncology. MATERIALS AND METHODS: Experts were selected by the medical societies involved. Forty issues regarding controversial issues in advanced disease were previously elaborated. The panel met for consensus, with a threshold established for 2/3 of the participants. RESULTS AND CONCLUSIONS: The treatment of advanced prostate cancer is complex, due to the existence of a large number of therapies, with different response profiles and toxicities. The panel addressed recommendations on preferred choice of therapies, indicators that would justify their change, and indicated some strategies for better sequencing of treatment in order to maximize the potential for disease control with the available therapeutic arsenal. The lack of consensus on some topics clearly indicates the absence of strong evidence for some decisions.

Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study.

BACKGROUND: Germline genetic polymorphisms might affect the risk of recurrence in patients with localised renal-cell carcinoma. We investigated the association between genetic polymorphisms and recurrence of renal-cell carcinoma. METHODS: We analysed germline DNA samples extracted from patients with localised renal-cell carcinoma treated at the Dana-Farber/Harvard Cancer Center (Boston, MA, USA). We selected a discovery cohort from a prospective database at the Dana-Farber/Harvard Cancer Center and selected a validation cohort from department records at the Brigham and Women's Hospital (Boston, MA, USA). We validated the findings from the discovery cohort in the validation cohort. We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms. We assessed the association between genotype and recurrence-free survival, adjusted for baseline characteristics, with the Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. We used a false discovery rate q value to adjust for multiple comparisons. FINDINGS: We included 554 patients (403 in the discovery cohort and 151 in the validation cohort). We successfully genotyped 290 single nucleotide polymorphisms in the discovery cohort, but excluded five because they did not have a variant group for comparison. The polymorphism rs11762213, which causes a synonymous aminoacid change in MET (144G→A, located in exon 2), was associated with recurrence-free survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio [HR] 1·86, 95% CI 1·17-2·95; p=0·0084) in multivariate analysis. Median recurrence-free survival for carriers of the risk allele was 19 months (95% CI 9-not reached) versus 50 months (95% CI 37-75) for patients without the risk allele. In the validation cohort the HR was 2·45 (95% CI 1·01-5·95; p=0·048). INTERPRETATION: Patients with localised renal-cell carcinoma and the MET polymorphism rs11762213 might have an increased risk of recurrence after nephrectomy. If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma. FUNDING: Conquer Cancer Foundation and American Society of Clinical Oncology (Career Development Award); The Trust Family Research Fund for Kidney Cancer; US National Institutes of Health, National Cancer Institute Kidney Cancer Specialized Program of Research Excellence.

Latin American Consensus for the Evaluation and Treatment of Patients With Metastatic/Locally Advanced Urothelial Carcinoma.

PURPOSE: Urothelial cancer accounts for approximately 3% of new cancer cases worldwide, with a high burden of disease in countries with medium and low human development indexes where its incidence and mortality are increasing. The purpose of this consensus is to develop statements on the evaluation and treatment of locally advanced and metastatic urothelial carcinoma that would further guide the clinical practice in Latin America. METHODS: A systematic review of the literature was conducted by an independent team of methodologists. Then, a modified Delphi method was developed with clinical specialists from different Latin American countries. RESULTS: Forty-two consensus statements, based on evidence, were developed to address the staging, the evaluation (suitability for chemotherapy, risk assessment, and biomarkers), and systemic treatment (first-line and subsequent therapies) of locally advanced or metastatic urothelial carcinoma. The statements made in this consensus are suggested practice recommendations in the Latin American context; however, the importance of a complete and individualized patient evaluation as a guide for therapeutic selection is highlighted. The availability and affordability of support tools for the evaluation of the disease, as well as specific therapies, may limit the application of the best practices suggested. RECOMMENDATIONS: Therapeutic decisions need to be tailored to the context-specific clinical setting and availability of resources. Local research is promoted to improve outcomes for patients with this challenging cancer in Latin America.

Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update.

PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.

Multicenter Database of Patients with Germ-Cell Tumors: A Latin American Cooperative Oncology Group Registry (LACOG 0515).

INTRODUCTION: Germ-cell tumors (GCTs) are the most common malignancy in young men. There is a paucity of data on GCTs in developing countries. LACOG 0515 study aimed to evaluate clinical characteristics and treatment outcomes in patients with GCTs from Brazilian cancer centers. MATERIALS AND METHODS: This is a retrospective cohort study evaluating male patients diagnosed with GCTs from 2000 to 2018 in 13 Brazilian hospitals. We described baseline characteristics, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 1232 patients were included, with a median age of 30 years. Histology was seminoma in 47.1% and non-seminoma GCT (NSGCT) in 52.9%. The primary tumor site was testis in 96.5%. At diagnosis, clinical stage I was present in 68.1% and 34.7% and clinical stages IS/II/III in 31.9% and 65.2% of patients with seminoma and NSCGT, respectively. Following orchiectomy, 55.2% of patients with clinical stage I were managed with surveillance. The 5-year disease-free survival rates among patients with stage I were 98.0% in seminoma and 92.3% in NSGCT, with 5-year OS of 99.6% and 97.6%, respectively. Among patients with advanced disease (IS, II, and III), the 5-year PFS were 88.7% in seminoma and 68.7% in NSGCT, with 5y-OS of 97.6% and 82.8%, respectively. CONCLUSION: This is the largest Brazilian cohort of GCTs. Our results show a high rate of adjuvant chemotherapy in patients with clinical stage I. Although our data demonstrate slightly inferior PFS compared with the International Germ Cell Cancer Collaborative Group and other contemporary series, the OS rates were similar.

Treatment Patterns Among Patients With Advanced Prostate Cancer in Brazil: An Analysis of a Private Healthcare System Database.

Background: With the ongoing expansion of life-prolonging therapies approved to treat advanced prostate cancer, there is currently an unmet need to better understand real-world treatment patterns and identify optimal treatment sequencing for men with metastatic castration-resistant prostate cancer (mCRPC). Methods: In this retrospective, observational cohort analysis, patients with confirmed mCRPC were identified in the Auditron claims database and used to describe mCRPC treatment patterns and trends in the Brazilian private healthcare system from 2014 to 2019. Demographics and clinical characteristics, prostate cancer stage at diagnosis, and type and number of treatment lines were evaluated. The primary endpoint was identification of the drugs used in first-line therapies in mCRPC, and the secondary endpoint included a description of sequential lines of therapy (second and third lines) in mCRPC. Results: A total of 168 electronic patient records were reviewed. Docetaxel was the most frequently used first-line treatment (35.7%), followed by abiraterone (33.3%) and enzalutamide (13.1%). Docetaxel, abiraterone, and enzalutamide also accounted for 34.6%, 28.0%, and 15.0%, respectively, of second-line therapies. In third-line therapies, cabazitaxel (26.1%), enzalutamide (23.9%), docetaxel (15.2%), and abiraterone (15.2%) were most commonly prescribed. Irrespective of stage at diagnosis, treatment patterns were similar once the disease progressed to the metastatic castration-resistance stage. Conclusions: Docetaxel was the most frequently utilized therapy for mCRPC treatment, followed by abiraterone and enzalutamide. Although the current analyses provide real-world insights into treatment patterns for patients with mCRPC in Brazil, additional real-world data are needed to further validate and expand on these findings.

Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials.

CONTEXT: Whether androgen deprivation therapy (ADT) causes excess cardiovascular deaths in men with prostate cancer is highly controversial and was the subject of a joint statement by multiple medical societies and a US Food and Drug Administration safety warning. OBJECTIVE: To perform a systematic review and meta-analysis of randomized trials to determine whether ADT is associated with cardiovascular mortality, prostate cancer-specific mortality (PCSM), and all-cause mortality in men with unfavorable-risk, nonmetastatic prostate cancer. DATA SOURCES: A search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases for relevant randomized controlled trials in English between January 1, 1966, and April 11, 2011. STUDY SELECTION: Inclusion required nonmetastatic disease, intervention group with gonadotropin-releasing hormone agonist-based ADT, control group with no immediate ADT, complete information on cardiovascular deaths, and median follow-up of more than 1 year. DATA EXTRACTION: Extraction was by 2 independent reviewers. Summary incidence, relative risk (RR), and CIs were calculated using random-effects or fixed-effects models. RESULTS: Among 4141 patients from 8 randomized trials, cardiovascular death in patients receiving ADT vs control was not significantly different (255/2200 vs 252/1941 events; incidence, 11.0%; 95% CI, 8.3%-14.5%; vs 11.2%; 95% CI, 8.3%-15.0%; RR, 0.93; 95% CI, 0.79-1.10; P = .41). ADT was not associated with excess cardiovascular death in trials of at least 3 years (long duration) of ADT (11.5%; 95% CI, 8.1%-16.0%; vs 11.5%; 95% CI, 7.5%-17.3%; RR, 0.91; 95% CI, 0.75-1.10; P = .34) or in trials of 6 months or less (short duration) of ADT (10.5%; 95% CI, 6.3%-17.0%; vs 10.3%; 95% CI, 8.2%-13.0%; RR, 1.00; 95% CI, 0.73-1.37; P = .99). Among 4805 patients from 11 trials with overall death data, ADT was associated with lower PCSM (443/2527 vs 552/2278 events; 13.5%; 95% CI, 8.8%-20.3%; vs 22.1%; 95% CI, 15.1%-31.1%; RR, 0.69; 95% CI, 0.56-0.84; P < .001) and lower all-cause mortality (1140/2527 vs 1213/2278 events; 37.7%; 95% CI, 27.3%-49.4%; vs 44.4%; 95% CI, 32.5%-57.0%; RR, 0.86; 95% CI, 0.80-0.93; P < .001). CONCLUSION: In a pooled analysis of randomized trials in unfavorable-risk prostate cancer, ADT use was not associated with an increased risk of cardiovascular death but was associated with a lower risk of PCSM and all-cause mortality.

Erdafitinib treatment in Brazilian patients with metastatic urothelial carcinoma (mUC): real-world evidence from an Expanded Access Program.

BACKGROUND: Erdafitinib is the first targeted therapy approved for the treatment of patients with metastatic urothelial carcinoma (mUC). Approval was based on a phase II single-arm trial that demonstrated significant activity of erdafitinib in patients with tumors harboring FGFR2/3 alterations. In Brazil, an Expanded Access Program (EAP) provided patients with early access to erdafitinib prior to market authorization. The current report describes characteristics and outcomes of patients with mUC on erdafitinib therapy. METHODS: Patients with mUC that failed first- and second-line systemic therapies were screened for FGFR2/3 alterations in primary or metastatic tumor tissues. Patients with FGFR2/3 alterations were selected to receive erdafitinib at the standard dosing schedule and were followed prospectively to evaluate the efficacy and safety outcomes. RESULTS: From 19 April 2019, through 13 March 2020, 47 patients with mUC from 10 Brazilian centers were tested for FGFR2/3 alterations. Alterations in FGFR2/3 were found in 12 patients (25.5%) and all of them were eligible for the EAP. Four patients (33%) had partial response, while two patients (17%) had stable disease. Progressive disease, the best response, was observed in five patients (42%). At a median follow-up of 16.2 months, the median time to treatment failure (TTF) was 2.8 months. When considering only patients with objective response, the median TTF was 5.3 months. Adverse events (AEs) were reported for any grade and grade 3 or higher in 10 patients (83%) and 5 patients (42%), respectively. The most common AE was hyperphosphatemia. CONCLUSION: This first real-world evidence report of heavily treated patients with mUC confirms the efficacy and safety of erdafitinib in a disease setting with a lack of treatment options.

A phase 2 randomized clinical trial of abiraterone plus ADT, apalutamide, or abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels (LACOG 0415).

BACKGROUND: Androgen deprivation therapy (ADT) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are the standard treatments for advanced castration-sensitive prostate cancer (CSPC). We investigated ADT-free alternatives for advanced CSPC. PATIENTS AND METHODS: LACOG 0415 is a phase 2, open-label, non-comparative, randomized trial. Patients with advanced CSPC were randomized (1:1:1) to receive goserelin plus abiraterone acetate and prednisone (ADT plus AAP arm), apalutamide (APA arm), or apalutamide plus abiraterone acetate and prednisone (APA plus AAP arm). The primary endpoint was the proportion of patients with PSA of ≤0.2 ng/mL at week 25 in the modified intention-to-treat population. Safety analyses were performed in all patients with at least one dose of the study drug. RESULTS: Of 128 randomized patients, 120 patients were evaluable for PSA response at week 25; 17.2% had a high-risk biochemical recurrence, 8.6% had locally advanced disease, and 74.2% had distant metastases. At week 25, PSA of ≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in ADT plus AAP, APA, and APA plus AAP arms, respectively. PSA decline of ≥80% was observed in 100%, 90.0%, and 97.4%, respectively. Grade 3-4 AEs were observed in 31.0%, 21.4% and 36.4%, respectively. Testosterone levels increased significantly in the APA arm and decreased significantly in ADT plus AAP and APA plus AAP arms. CONCLUSIONS: ADT-free alternatives provide a high PSA response in advanced CSPC, although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25. These results warrant further investigation of ADT-free treatments as alternatives in advanced CSPC. SOURCE STUDY REGISTRATION: ClinicalTrials.govNCT02867020.

Consensus for Treatment of Metastatic Castration-Sensitive Prostate Cancer: Report From the First Global Prostate Cancer Consensus Conference for Developing Countries (PCCCDC).

PURPOSE: International guideline recommendations may not always be extrapolated to developing countries where access to resources is limited. In metastatic castration-sensitive prostate cancer (mCSPC), there have been successful drug and imaging advancements that were addressed in the Prostate Cancer Consensus Conference for Developing Countries for best-practice and limited-resource scenarios. METHODS: A total of 24 out of 300 questions addressed staging, treatment, and follow-up for patients with mCSPC both in best-practice settings and resource-limited settings. Responses were compiled and presented in percentage of clinicians supporting each response. Questions had 4-8 options for response. RESULTS: Recommendations for staging in mCSPC were split but there was consensus that chest x-ray, abdominal and pelvic computed tomography, and bone scan should be used where resources are limited. In both de novo and relapsed low-volume mCSPC, orchiectomy alone in limited resources was favored and in relapsed high-volume disease, androgen deprivation therapy plus docetaxel in limited resources and androgen deprivation therapy plus abiraterone in high-resource settings were consensus. A 3-weekly regimen of docetaxel was consensus among voters. When using abiraterone, a regimen of 1,000 mg plus prednisone 5 mg/d is optimal, but in limited-resource settings, half the panel agreed that abiraterone 250 mg with fatty foods plus prednisone 5 mg/d is acceptable. The panel recommended against the use of osteoclast-targeted therapy to prevent osseous complications. There was consensus that monitoring of patients undergoing systemic treatment should only be conducted in case of prostate-specific antigen elevation or progression-suggestive symptoms. CONCLUSION: The treatment recommendations for most topics addressed differed between the best-practice setting and resource-limited setting, accentuating the need for high-quality evidence that contemplates the effect of limited resources on the management of mCSPC.

Consensus on Treatment and Follow-Up for Biochemical Recurrence in Castration-Sensitive Prostate Cancer: A Report From the First Global Prostate Cancer Consensus Conference for Developing Countries.

PURPOSE: To present a summary of the treatment and follow-up recommendations for the biochemical recurrence in castration-sensitive prostate cancer (PCa) acquired through a questionnaire administered to 99 PCa experts from developing countries during the Prostate Cancer Consensus Conference for Developing Countries. METHODS: A total of 27 questions were identified as related to this topic from more than 300 questions. The clinician's responses were tallied and presented in a percentage format. Topics included the use of imaging for staging biochemical recurrence, treatment recommendations for three different clinical scenarios, the field of radiation recommended, and follow-up. Each question had 5-7 relevant response options, including "abstain" and/or "unqualified to answer," and investigated not only recommendations but also if a limitation in resources would change the recommendation. RESULTS: For most questions, a clear majority (> 50%) of clinicians agreed on a recommended treatment for imaging, treatment scenarios, and follow-up, although only a few topics reached a consensus > 75%. Limited resources did affect several areas of treatment, although in many cases, they reinforced more stringent criteria for treatment such as prostate-specific antigen values > 0.2 ng/mL and STAMPEDE inclusion criteria as a basis for recommending treatment. CONCLUSION: A majority of clinicians working in developing countries with limited resources use similar cutoff points and selection criteria to manage patients treated for biochemically recurrent castration-sensitive PCa.

Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials.

BACKGROUND: Sunitinib and sorafenib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors used in various cancers. Bleeding has been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to calculate the incidence and relative risk associated with use of sunitinib and sorafenib. METHODS: We searched PubMed (from January, 1966, to April, 2009) and meeting proceedings of the American Society of Clinical Oncology and the European Society of Medical Oncology (2004-09) for relevant clinical trials. Eligible studies included phase 2 and 3 trials and expanded-access programmes. Statistical analyses were done to calculate summary incidences, relative risks, and 95% CI, using random-effects or fixed-effects models based on the heterogeneity of included studies. FINDINGS: 23 trials were selected for the meta-analysis, yielding a total of 6779 patients. The incidence of bleeding events (all grades) was 16.7% (95% CI 12.7-21.5), and that of high-grade events was 2.4% (1.6-3.9). The relative risk of all-grade bleeding events associated with sunitinib and sorafenib (for randomised controlled trials only) was 2.0 (1.14-3.49; p=0.015). Our analysis was also stratified by underlying malignant disease (renal-cell carcinoma vs non-renal-cell carcinoma) and agent used, but no differences were recorded. INTERPRETATION: Treatment with the VEGFR tyrosine-kinase inhibitors sunitinib and sorafenib is associated with a significant increase in risk of bleeding. FUNDING: None.

First-line Treatment of Metastatic Renal Cell Carcinoma in the Immuno-oncology Era: Systematic Review and Network Meta-analysis.

Combination treatments with immuno-oncology (IO) agents and IO agents plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) have been approved for first-line treatment of patients with metastatic renal cell carcinoma (mRCC). No direct comparisons have been performed among these treatment options. We performed a systematic review and network meta-analysis to compare and rank the available regimens for first-line treatment in terms of survival benefit and efficacy. In accordance with the Preferred Reporting Items for Systematic Review statement, a systematic search of reported studies was performed in MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE up to May 31, 2019. Network meta-analysis models were adjusted using the Bayesian method. Four randomized clinical trials, with a total of 3758 patients, met the inclusion criteria. Considering systemic therapy, 1880 patients had received sunitinib and 550, 432, 442, and 454 patients had received ipilimumab plus nivolumab (ipi + nivo), pembrolizumab plus axitinib (pembro + axi), avelumab plus axitinib (avelu + axi), and atezolizumab plus bevacizumab (atezo + bev). No difference was found in overall survival between ipi + nivo and pembro + axi for the intention to treat population (hazard ratio [HR], 1.34; 95% credible interval [CrI], 0.92-1.97). No difference was found in progression-free survival among the treatments. The overall response rate (ORR) was superior with pembro + axi and avelu + axi compared with the ORR with the other treatments (atezo + bev vs. pembro + axi: HR, 0.66; 95% CrI, 0.52-0.84; ipi + nivo vs. pembro + axi: HR, 0.73; 95% CrI, 0.59-0.90; atezo + bev vs. avelu + axi: HR, 0.55; 95% CrI, 0.43-0.71; avelu + axi vs. ipi + nivo: HR, 1.66; 95% CrI, 1.31-2.12), with no differences across them (HR, 1.21; 95% CrI, 0.95-1.53). In the present indirect comparison, for an intention to treat population, we found no survival differences between pembro + axi and ipi + nivo. All treatments showed better progression-free survival compared with sunitinib that was similar among them. The combination of an IO agent (pembrolizumab or avelumab) and axitinib seemed to be the most effective therapy for the ORR.