Projected Impact of Omidubicel-onlv on Racial/Ethnic Disparities in Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Outcomes in Hematologic Malignancies.

INTRODUCTION: In a phase III clinical trial (NCT02730299), omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy, showed rapid hematopoietic and immune recovery compared with standard umbilical cord blood (UCB) transplant across all racial/ethnic groups. METHODS: A decision-tree model was used to project the effect of omidubicel-onlv availability on addressing health disparities in allogeneic hematopoietic cell transplantation (allo-HCT) access and outcomes for patients with hematologic malignancies. The model used a hypothetical population of 10,000 allo-HCT-eligible US adults, for whom matched related donors were not available. Patients received matched or mismatched unrelated donor, haploidentical, UCB transplant, or no transplant. Scenarios with omidubicel-onlv use of 0% (status quo), 10%, 15%, 20%, and 30% were modeled on the basis of proportional reductions in other allo-HCT sources or no transplant by racial/ethnic group. RESULTS: Increased omidubicel-onlv use was associated with a higher proportion of patients undergoing allo-HCT, decreased time to allo-HCT, decreased 1-year non-relapse mortality, and increased 1-year overall survival, particularly among racial minorities. In the scenario modeling 20% omidubicel-onlv use, the proportion of Black patients receiving allo-HCT increased by 129%; increases were also observed in Asian (64%), Hispanic (45%), and other (42%) patient groups. Modeled time to allo-HCT improved among transplanted patients (23%) from 11.4 weeks to 8.8 weeks. One-year OS in the overall population increased by 3%, with improvements ranging from 3% for White patients to 5% for Black patients. CONCLUSION: This study demonstrates that broad access to omidubicel-onlv could increase access to allo-HCT and improve outcomes for patients, with the greatest benefits seen among racial/ethnic minority groups.

Health care costs among patients with hematologic malignancies receiving allogeneic transplants: a US payer perspective.

ABSTRACT: Patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant (allo-HCT) require extensive care. Using the Merative MarketScan Commercial Claims and Encounters database (2016 Q1-2020 Q2), we quantified the costs of care and assessed real-world complication rates among commercially insured US patients diagnosed with a hematologic malignancy and aged between 12 and 64 years undergoing inpatient allo-HCT. Health care resource use and costs were assessed from 100 days before HCT to 100 days after HCT. Primary hospitalization was defined as the time from HCT until first discharge date. Incidence of complications was assessed using medical billing codes from HCT date to 100 days after HCT. Among the 1082 patients analyzed, allo-HCT grafts included peripheral blood (79%), bone marrow (11%), and umbilical cord blood (3%). In the 100 days after HCT, 52% of the patients experienced acute graft-versus-host disease; 21% had cytomegalovirus infection. The median primary hospitalization length of stay (LOS) was 28 days; 31% required readmission in first 100 days after HCT. Across the transplant period (14 days pretransplant to 100 days posttransplant), 44% of patients were admitted to the intensive care unit with a median LOS of 29 days. Among those with noncapitated health plans (n = 937), median cost of all-cause health care per patient during the transplant period was $331 827, which was driven by primary hospitalization and readmission. Additionally, the predicted median incremental costs per additional day in an inpatient setting increased with longer LOS (eg, $3381-$4071, 10th-20th day.) Thus, decreasing length of primary hospitalization and avoiding readmissions should significantly reduce the allo-HCT cost of care.

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells.

Natural killer (NK) cells are a vital component of cancer immune surveillance. They provide a rapid and potent immune response, including direct cytotoxicity and mobilization of the immune system, without the need for antigen processing and presentation. NK cells may also be better tolerated than T cell therapy approaches and are susceptible to various gene manipulations. Therefore, NK cells have become the focus of extensive translational research. Gamida Cell's nicotinamide (NAM) platform for cultured NK cells provides an opportunity to enhance the therapeutic potential of NK cells. CD38 is an ectoenzyme ubiquitously expressed on the surface of various hematologic cells, including multiple myeloma (MM). It has been selected as a lead target for numerous monoclonal therapeutic antibodies against MM. Monoclonal antibodies target CD38, resulting in the lysis of MM plasma cells through various antibody-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, significantly improving the outcomes of patients with relapsed or refractory MM. However, this therapeutic strategy has inherent limitations, such as the anti-CD38-induced depletion of CD38-expressing NK cells, thus hindering ADCC. We have developed genetically engineered NK cells tailored to treat MM, in which CD38 was knocked-out using CRISPR-Cas9 technology and an enhanced chimeric antigen receptor (CAR) targeting CD38 was introduced using mRNA electroporation. This combined genetic approach allows for an improved cytotoxic activity directed against CD38-expressing MM cells without self-inflicted NK-cell-mediated fratricide. Preliminary results show near-complete abolition of fratricide with a 24-fold reduction in self-lysis from 19% in mock-transfected and untreated NK cells to 0.8% of self-lysis in CD38 knock-out CAR NK cells. Furthermore, we have observed significant enhancements in CD38-mediated activity in vitro, resulting in increased lysis of MM target cell lines. CD38 knock-out CAR NK cells also demonstrated significantly higher levels of NK activation markers in co-cultures with both untreated and αCD38-treated MM cell lines. These NAM-cultured NK cells with the combined genetic approach of CD38 knockout and addition of CD38 CAR represent a promising immunotherapeutic tool to target MM.

Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma.

Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of l-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.

Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials.

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.

The Impact of Age and Gender on Outcomes of Patients With Advanced Renal Cell Carcinoma Treated With Targeted Therapy.

BACKGROUND: A growing body of evidence suggests that age and gender play a role in cancer outcomes. The objective of this study was to investigate the effect of age and gender on survival of patients with metastatic renal cell carcinoma (RCC). METHODS: We conducted a pooled analysis of patients with metastatic RCC treated on phase II and III clinical trials. Patients were stratified by age (young [<50 years], intermediate [50-70 years], versus elderly [>70 years]) and gender. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 4736 patients with metastatic RCC. Overall, there was no difference in overall survival (OS) when stratified by age (21.0 vs. 17.3 months for elderly vs. intermediate age groups, P = .382; 20.0 vs. 17.3 months for young vs. intermediate age groups, P = .155) or gender (19.8 vs. 19.0 for male vs. female, P = .510). Progression-free survival (PFS) was shorter in younger individuals compared with the intermediate age patients (6.0 vs. 7.1 months, P < .001), but similar across gender groups. Although all grade adverse events were more common in elderly patients (fatigue, diarrhea, decreased appetite, and weight), serious adverse events were similar between groups. CONCLUSIONS: Although OS was similar between age groups, younger individuals had a shorter PFS. Gender was not an independent determinant of survival. Elderly patients experienced more adverse events than their younger counterparts. These findings are important to guide clinicians when counseling patients about expectations and toxicity associated with therapy.

Outcomes in Black and White Patients With Metastatic Renal Cell Carcinoma Treated With First-Line Tyrosine Kinase Inhibitors: Insights From Two Large Cohorts.

PURPOSE: To investigate whether black race is an independent predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC). METHODS: We performed a retrospective 2-cohort (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] and trial-database) study of patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Unmatched (UM) and matched (M) analyses accounting for imbalances in region, year of treatment, age, and sex between races were performed. Cox models adjusting for histology, number of metastatic sites, nephrectomy, and IMDC risk compared time to treatment failure (TTF; IMDC cohort), progression-free survival (PFS; trial-database cohort), and OS. RESULTS: The IMDC cohort included 73 black versus 3,381 (UM) and 1,236 (M) white patients. The trial-database cohort included 21 black versus 1,040 (UM) and 431 (M) white patients. Median OS for black versus white patients was 18.5 versus 25.8 months in the IMDC group and 21.0 versus 25.6 months in the trial-database group. Differences in OS were not significant in multivariable analysis in the IMDC group (hazard ratio [HR]M, 1.0; 95% CI, 0.7 to 1.5; HRUM, 1.1; 95% CI, 0.8 to 1.4) and trial-database (HRM, 1.5; 95% CI, 0.8 to 2.7; HRUM, 1.4; 95% CI, 0.8 to 2.6) cohorts. TTF for black patients was shorter in the UM IMDC cohort (HRUM, 1.4; 95% CI, 1.1 to 1.8; P = .003), but not in the M analysis. PFS was shorter for black patients in both analyses in the trial-database cohort (HRM, 2.3; 95% CI, 1.4 to 3.9; P = .002; HRUM, 2.3; 95% CI, 1.4 to 3.9; P = .002). CONCLUSION: Black patients had more IMDC risk factors and worse outcomes with TKIs versus white patients. Race was not an independent predictor of OS. Strategies to understand biologic determinants of outcomes for minority patients are needed to optimize care.

Effect of Antibiotic Use on Outcomes with Systemic Therapies in Metastatic Renal Cell Carcinoma.

BACKGROUND: Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis. OBJECTIVE: To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents. DESIGN, SETTING, AND PARTICIPANTS: We analyzed two cohorts: an institutional cohort (n=146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n=4144) receiving interferon-α (n=510), mammalian target of rapamycin (mTOR) inhibitors (n=660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n=2974) on phase II/III clinical trials. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors. RESULTS AND LIMITATIONS: Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n=31, 21%) had a lower ORR (12.9% vs 34.8%, p=0.026) and shorter PFS (adjusted hazard ratio [HR]=1.96, 95% confidence interval [CI] 1.20-3.20, p=0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n=709, 17%) adversely impacted OS in patients treated with interferon (HR=1.62, 95% CI 1.13-2.31, p=0.008) or with VEGF-TT and prior cytokines (HR=1.65, 95% CI 1.04-2.62, p=0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration. CONCLUSIONS: Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs. PATIENT SUMMARY: We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use.

The Effect of Weight Change During Treatment With Targeted Therapy in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: The relationship between weight change during treatment and survival remains poorly characterized in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In this retrospective analysis we included 3311 patients with mRCC treated in phase II/III first-line or second-line targeted therapy clinical trials and assessed the effect of weight change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) at 6 and 12 weeks from treatment initiation. Weight change was defined as weight loss (≥5% reduction), weight gain (≥2% increase), or stable weight from baseline. Survival analyses were performed using the Kaplan-Meier method and adjusted for known prognostic factors using Cox regression multivariable analysis. RESULTS: Overall, 1916 (58%) had stable weight, 936 (28%) had weight loss, and 459 (14%) had weight gain at 12 weeks. Patients with weight loss at 12 weeks had inferior OS compared with those with stable weight (hazard ratio [HR], 1.494; 95% confidence interval [CI], 1.322-1.688; P < .0001; median OS 18.7 vs. 26.9 months), and shorter PFS (HR, 1.315; 95% CI, 1.189-1.455; P < .0001; median PFS, 7.2 vs. 10.1 months). The ORRs for patients with weight loss, stable weight, and weight gain at 12 weeks were 23.4% (n = 219/936), 32.1% (n = 615/1916), and 35.9% (n = 165/459), respectively (adjusted odds ratio, 0.715; P = .03). Findings were consistent at 6 weeks. Adverse events were similar between groups. CONCLUSION: We showed that mRCC patients who experience weight loss during treatment have worse outcomes compared with patients with stable weight at 6 and 12 weeks of treatment. Weight loss at 6 weeks from treatment initiation might be an early clinical biomarker of worse survival and might provide prognostic utility.

Response of Primary Renal Cell Carcinoma to Systemic Therapy.

BACKGROUND: Upfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials. OBJECTIVE: We investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox's models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses. RESULTS AND LIMITATIONS: In total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16-23) in patients treated with first-line therapy (any type), 28% (22-33) in those treated with first-line VEGF-targeted therapy, and 23% (19-28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5-13) and 20% (15-27) in IMDC poor- and intermediate-risk patients, respectively. CONCLUSIONS: Systemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics. PATIENT SUMMARY: Antiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.

Impact of Geographic Regions on Overall Survival in Patients With Metastatic Renal Cell Carcinoma: Results From an International Clinical Trials Database.

PURPOSE: Health determinants vary according to geographic region and may affect the outcomes of patients with metastatic renal cell carcinoma (mRCC) treated during clinical trials of targeted therapy. Here, we investigate the overall survival (OS) of patients with mRCC treated in the era of targeted therapy by geographic region. METHODS: We conducted a pooled analysis of patients with mRCC who were treated during phase II or III clinical trials. Clinical characteristics and survival data were collected. Statistical analyses were performed with the Kaplan-Meier method and log-rank test in univariable analysis. RESULTS: Overall, 4,736 patients were included in the analysis. Patient characteristics differed according to geographic region. No statistically significant differences in OS were observed when the United States/Canada (USC) was compared with the following other regions: Latin America, Asia/Oceania/Africa, and Eastern Europe. In a univariable analysis, OS differed among patients enrolled in trials in USC compared with Western Europe (20.3 v 17.4 months; hazard ratio, 1.15; 95% CI, 1.03 to 1.3; P = .015), but it did not differ in a multivariable analysis. All-grade treatment-related adverse events (AEs) were observed more frequently in USC. There were no significant differences in grade 3 to 5 AEs among groups. CONCLUSION: Despite different baseline characteristics, OS was similar among patients enrolled in clinical trials across different geographic regions. Access to clinical trials as well as disease biology, AE reporting, and quality of care may contribute to potential differences in outcomes.

The Clinical Presentation, Survival Outcomes, and Management of Patients With Renal Cell Carcinoma and Cardiac Metastasis Without Inferior Vena Cava Involvement: Results From a Pooled Clinical Trial Database and Systematic Review of Reported Cases.

BACKGROUND: Cardiac metastases from renal cell carcinoma (RCC) are uncommon and there are limited data regarding the presentation and outcomes of this population. The objective of this study was to evaluate the characteristics and outcomes of patients with RCC with cardiac metastasis without inferior vena cava (IVC) involvement. MATERIALS AND METHODS: We conducted a pooled retrospective analysis of metastatic RCC patients treated in 4 clinical trials. Additionally, we conducted a systematic review of cases reported in the literature from 1973 to 2015. Patients with cardiac metastases from RCC without IVC involvement were included. Patient and disease characteristics were described. Additionally, treatments, response to therapy, and survival outcomes were summarized. RESULTS: Of 1765 metastatic RCC patients in the clinical trials database, 10 had cardiac metastases without IVC involvement. All patients received treatment with targeted therapy. There was 1 observed partial response (10%) and 6 patients showed stable disease (60%). The median progression-free survival was 6.9 months. The systematic review of reported clinical cases included 39 patients. In these patients, the most common cardiac site of involvement was the right ventricle (51%; n = 20). Patients were treated with medical (28%; n = 11) and/or surgical treatment (49%; n = 19) depending on whether disease was isolated (n = 13) or multifocal (n = 26). CONCLUSION: To our knowledge, this is the first series to report on the presentation and outcomes of patients with cardiac metastasis without IVC involvement in RCC. We highlight that although the frequency of patients with cardiac metastases without IVC involvement is low, these patients have a unique clinical presentation and warrant special multidisciplinary management.

Characterization of Patients With Poor-Risk Metastatic Renal-Cell Carcinoma: Results From a Pooled Clinical Trials Database.

BACKGROUND: Poor-risk patients with metastatic renal-cell carcinoma remain poorly characterized in prospective clinical trials. Therefore, we sought to provide a comprehensive analysis of this patient population, defined by 3 widely used prognostic models, treated with targeted therapy. PATIENTS AND METHODS: We conducted a pooled retrospective analysis of 4736 metastatic renal-cell carcinoma patients treated on phase 2 and 3 clinical trials. Poor-risk patients were defined according to the Memorial Sloan Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), and Hudes risk models. Baseline characteristics, overall survival, progression-free survival, objective response rate, and adverse events were reported in poor-risk patients defined by each of the 3 models. The concordance (C)-index was used to assess the prognostic performance of the models. A subset of poor-risk patients who continued to receive treatment for > 12 months was characterized. RESULTS: Overall, we identified 1145 (24%), 904 (19%), and 1901 (40%) poor-risk patients by the IMDC, MSKCC, and Hudes models, respectively. Median overall survival was 8.5 months, 7.5 months, and 10.6 months; and median progression-free survival was 3.7 months, 3.5 months, and 4.2 months in the IMDC, MSKCC, and Hudes models, respectively. The objective response rate ranged between 10% and 14%. Additionally, 9% to 14% of poor-risk patients continued to receive treatment for > 12 months. Most importantly, the C-index was 0.826, 0.830, and 0.825 in the IMDC, MSKCC, and Hudes risk models, respectively. CONCLUSION: We demonstrate that poor-risk patients continue to have dismal outcomes and warrant alternative treatment strategies to help improve outcomes. A subset of patients experienced prolonged clinical benefit and should be further explored.

Proton Pump Inhibitors and Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma.

INTRODUCTION: Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and can affect the optimal absorption of concomitant oral medications, such as vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs). The purpose of this study was to investigate the effect of PPI use on survival in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. MATERIALS AND METHODS: We conducted a pooled analysis of mRCC patients treated in phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 2188 patients treated with sunitinib (n = 952), axitinib (n = 626) or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users showed similar overall survival compared with non-PPI users (hazard ratio [HR], 1.051; 95% confidence interval [CI], 0.769-1.438; P = .754; median, 24.1 vs. 21.3 months). Similarly, progression-free survival (HR, 1.016; 95% CI, 0.793-1.301; P = .902; median, 5.5 vs. 8.0 months) and objective response rates (23.3% vs. 27.4%; P = .344) were not different between PPI users and nonusers. These findings were consistent across International mRCC Database Consortium risk groups and according to line of therapy. Adverse events were similar between PPI users and nonusers. CONCLUSION: We showed that PPI use does not appear to negatively affect the efficacy and safety of select VEGF-TKIs in patients with mRCC. Documentation of concomitant medications and patient education on potential drug interactions are critical for optimizing the use of oral cancer-targeting therapy.

Design and Rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: A Prospective Academic and Community-Based Study of Patients With Metastatic Renal Cell Cancer.

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.

Comprehensive Analysis of Survival Outcomes in Non-Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials.

BACKGROUND: Clinical data from patients with non-clear cell renal cell carcinoma (nccRCC) receiving targeted therapy are limited, and many clinical trials have excluded these patients from study entry. We sought to investigate the outcomes of patients with nccRCC treated in clinical trials in the modern era compared with the outcomes of patients with clear cell RCC (ccRCC). PATIENTS AND METHODS: We conducted a retrospective study of patients with metastatic RCC who had received targeted therapy in Pfizer-sponsored phase II and III clinical trials from 2003 to 2013. Associations between the histologic type and treatment outcome (overall survival [OS] and progression-free survival [PFS]) were assessed using the log-rank test on univariate analysis or the Wald χ2 test from Cox regression on multivariable analysis, adjusted for baseline characteristics, including age, sex, Eastern Cooperative Oncology Group performance status, body mass index, International Metastatic RCC Database Consortium risk factors, previous nephrectomy, previous therapy, metastatic sites, angiotensin system inhibitor use, and statin use. RESULTS: We identified 4527 patients with metastatic RCC: 4235 with ccRCC and 337 with nccRCC. Overall, the median OS was shorter for those with nccRCC than for those with ccRCC (15.7 vs. 20.2 months; hazard ratio [HR], 1.41; 95% confidence interval 1.22-1.63; P < .001). When stratified by the International Metastatic RCC Database Consortium risk group, the median OS was inferior for the intermediate- and poor-risk patients with nccRCC than for those with ccRCC. However, no differences were found in the favorable risk group for nccRCC versus ccRCC. The patients with nccRCC who had received vascular endothelial growth factor-targeted therapy had shorter PFS compared with that of ccRCC patients (median, 6.1 vs. 8.5 months; HR, 1.49; P < .001) but similar PFS when treated with mammalian target of rapamycin inhibitors (median, 4.3 vs. 4.4 months; HR, 0.92; P = .63). CONCLUSION: Our findings have confirmed that patients with nccRCC are underrepresented in clinical trials and highlight the need for further prospective studies exploring current and novel agents for this patient population.

Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma.

INTRODUCTION: Observational studies have suggested that metformin use is associated with favorable outcomes in several cancers. For renal cell carcinoma (RCC), data have been limited. Therefore, we investigated the effect of metformin on survival in metastatic RCC (mRCC) using a large clinical trial database. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with mRCC in phase II and III clinical trials. The overall survival (OS) in metformin users was compared with that of users of other antidiabetic agents and those not using antidiabetic agents. Progression-free survival, objective response rate, and adverse events were secondary endpoints. Subgroup analyses were conducted after stratifying by class of therapy, type of vascular endothelial growth factor tyrosine kinase inhibitors, and International Metastatic RCC Database Consortium (IMDC) risk groups. RESULTS: We identified 4736 patients with mRCC, including 486 with diabetes, of whom 218 (4.6%) were taking metformin. Metformin use did not affect OS when compared with users of other antidiabetic agents or those without diabetes. Furthermore, metformin use did not confer an OS advantage when stratified by class of therapy and IMDC risk group. However, in diabetic patients receiving sunitinib (n = 128), metformin use was associated with an improvement in OS compared with users of other antidiabetic agents (29.3 vs. 20.9 months, respectively; hazard ratio, 0.051; 95% confidence interval, 0.009-0.292; P = .0008). CONCLUSION: In the present study, we found a survival benefit for metformin use in mRCC patients treated with sunitinib. Clinical and preclinical studies are warranted to validate our results and guide the use of metformin in the clinic.

Estimation of tumour regression and growth rates during treatment in patients with advanced prostate cancer: a retrospective analysis.

BACKGROUND: We applied mathematical models to clinical trial data available at Project Data Sphere LLC (Cary, NC, USA), a non-profit universal access data-sharing warehouse. Our aim was to assess the rates of cancer growth and regression using the comparator groups of eight randomised clinical trials that enrolled patients with metastatic castration-resistant prostate cancer. METHODS: In this retrospective analysis, we used data from eight randomised clinical trials with metastatic castration-resistant prostate cancer to estimate the growth (g) and regression (d) rates of disease burden over time. Rates were obtained by applying mathematical models to prostate-specific antigen levels as the representation of tumour quantity. Rates were compared between study interventions (prednisone, mitoxantrone, and docetaxel) and off-treatment data when on-study treatment had been discontinued to understand disease behaviour during treatment and after discontinuation. Growth (g) was examined for association with a traditional endpoint (overall survival) and for its potential use as an endpoint to reduce sample size in clinical trials. FINDINGS: Estimates for g, d, or both were obtained in 2353 (88%) of 2678 patients with data available for analysis; g differentiated docetaxel (a US Food and Drug Administration-approved therapy) from prednisone and mitoxantrone and was predictive of overall survival in a landmark analysis at 8 months. A simulated sample size analysis, in which g was used as the endpoint, compared docetaxel data with mitoxantrone data and showed that small sample sizes were sufficient to achieve 80% power (16, 47, and 25 patients, respectively, in the three docetaxel comparator groups). Similar results were found when the mitoxantrone data were compared with the prednisone data (41, 39, and 41 patients in the three mitoxantrone comparator groups). Finally, after discontinuation of docetaxel therapy, median tumour growth (g) increased by nearly five times. INTERPRETATION: The application of mathematical models to existing clinical data allowed estimation of rates of growth and regression that provided new insights in metastatic castration-resistant prostate cancer. The availability of clinical data through initiatives such as Project Data Sphere, when combined with innovative modelling techniques, could greatly enhance our understanding of how cancer responds to treatment, and accelerate the productivity of clinical development programmes. FUNDING: None.

Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.

BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models categorize patients with 1 or 2 risk factors as intermediate prognosis (INTMP). This category encompasses 15 and 19 permutations of the MSKCC and IMDC risk factors, respectively. The purpose of the present retrospective analysis of data from INTMP patients in 6 clinical trials was to determine whether this heterogeneity influences the response to sunitinib. PATIENTS AND METHODS: Patients with INTMP metastatic renal cell carcinoma (mRCC) were identified using the MSKCC and IMDC classifications. The statistical data were analyzed using Cox regression analysis, Kaplan-Meier methods, and Pearson χ2 tests. RESULTS: The patient characteristics and risk factors were similar in the MSKCC (n = 548) and IMDC (n = 517) groups. Overall, 59% had 1 risk factor and 41% had 2 risk factors. The most common was low hemoglobin alone or with an interval of < 1 year since diagnosis. In both groups, patients with 1 risk factor had longer overall survival (OS) and progression-free survival (PFS) than did those with 2 risk factors (P < .001 for both outcomes). Patients in the IMDC group with 1 risk factor had a greater objective response rate (ORR; P = .023). In both groups, OS was longer for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 than for those with ECOG PS 1 or 2 (P < .001). An ECOG PS of 0 was also associated with superior PFS and ORR in the MSKCC group (P < .05). CONCLUSION: INTMP comprises a heterogeneous group of mRCC patients in whom the number of risk factors and ECOG PS might predict the outcome with sunitinib.

Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations.

PURPOSE: Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC. METHODS: The impact of BMI (high BMI: ≥ 25 kg/m2 v low BMI: < 25 kg/m2) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors. RESULTS: In the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015). CONCLUSION: High BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.