Raphael Brandao Moreira

Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients

A meta-analysis of immune checkpoint therapies showed a small but significant increase in the risk of developing key immune-related adverse events of any grade, as well as selected high-grade gastrointestinal and liver toxicities. Immune-related adverse events (irAE) have been described with immune checkpoint inhibitors (ICI), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab, or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6,528 received an ICI (nivolumab, 1,534; pembrolizumab, 1,522; atezolizumab, 751; and ipilimumab, 2,721) and 4,926 had not. Compared with non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P < 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P < 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared with PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications. Cancer Immunol Res; 5(4); 312–8. ©2017 AACR.

Clinical Response to Sorafenib in a Patient with Metastatic Colorectal Cancer and FLT3 Amplification

Background A considerable number of patients with metastatic colorectal cancer progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with sorafenib treatment of a patient with FLT3 mutation in refractory metastatic colorectal cancer. Methods Treatment with sorafenib of a patient with metastatic colorectal cancer and FLT3 translocation who had previously been heavily treated. Results The patient with metastatic colorectal cancer, aged 51 years, showed significant symptomatic and laboratory improvement with sorafenib treatment (400 mg twice daily). Conclusion The presented case illustrates how an aggressive and refractory colorectal tumor may respond well to targeted therapy.

Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial-level meta-analysis: DFS as a Metric of Overall Survival in RCC

Overall survival (OS) is a critical endpoint in adjuvant trials but requires long durations to events and significant patient resources. In the current study, the authors assessed whether disease‐free survival (DFS) can be an early clinical surrogate for OS in the adjuvant setting for localized renal cell carcinoma (RCC).

Differential side effects profile in patients with mCRPC treated with abiraterone or enzalutamide: a meta-analysis of randomized controlled trials

Background Abiraterone and enzalutamide are currently approved for mCRPC patients. Both drugs have distinct mechanisms of action and may have different toxicity profile. There are limited data comparing the side effects of abiraterone and enzalutamide. We performed a meta-analysis of randomized controlled trials (RCT) to better characterize the risk of adverse events associated with both drugs. Methods We performed a literature search on MEDLINE for studies reporting abiraterone and enzalutamide side effects from January 1966 to July 31, 2015. Abstracts presented at ASCO meetings from 2004 to 2015 were selected manually. Phase III RCT were included in analysis. We assessed the risk of adverse events reported in RCT by performing two meta-analyses: abiraterone-prednisone vs. placebo-prednisone (2,283 pts) and enzalutamide vs. placebo (2,914 pts). Summary of incidence, relative-risks (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results Overall, enzalutamide was not associated with all-grade (RR 1.06 - 95% CI 0.67-1.65) or grade ≥3 (RR 0.81 - 95% CI 0.28-2.33) cardiovascular events, but was associated with increased risk of all-grade fatigue (RR 1.29 - 95% CI 1.15-1.44). On the other hand, abiraterone was associated with increased risk of all-grade (RR 1.28 - 95% CI 1.06-1.55) and grade ≥3 (RR 1.76 - 95% CI 1.12-2.75) cardiovascular events, but was not associated with all-grade (RR 0.85 - 95% CI 0.58-1.23) or grade ≥3 (RR 1.07 - 95% CI 0.97-1.19) fatigue. Conclusions In this meta-analysis, abiraterone was associated with an increased risk of cardiovascular events, while enzalutamide was associated with an increased risk of fatigue.

The management of immune-related adverse events associated with immune checkpoint blockade

ABSTRACT Immunotherapy has become an important component of modern oncology therapy. Recently methods of immune checkpoint blockade include; anti-CTLA-4, anti-PD-1/PD-L1, or a combination of both therapies and have been developed with the objective of restoring immune system T-cell responses against cancer. This strategy has demonstrated important clinical activity in different tumor types and is currently approved for the treatment of several malignancies worldwide. However, the experience gathered so far with this strategy has revealed emerging immune-related adverse events (irAEs) that deserve particular attention. irAEs can affect any organ or system and require adequate diagnosis, rapid recognition and appropriate management as they may have an impact on the outcome of patients receiving these therapies.

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

Micro‐Abstract In light of the emerging evidence of the antineoplastic potential of metformin, we investigated its effect on survival outcomes in metastatic renal cell carcinoma using a large clinical trial database. Although metformin did not affect survival in the overall cohort, it conferred a survival advantage in diabetic metastatic renal cell carcinoma patients treated with sunitinib. 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.

The Development of Brain Metastases in Patients with Renal Cell Carcinoma: Epidemiologic Trends, Survival, and Clinical Risk Factors Using a Population-based Cohort

BACKGROUND The incidence of brain metastases (BM) in patients with renal cell carcinoma (RCC) is hypothesized to have increased in the last 2 decades. OBJECTIVE To define incidence trends according to patient and clinical characteristics, to identify risk factors, and to describe outcomes of patients with BM for RCC. DESIGN, SETTING, AND PARTICIPANTS Patients diagnosed with RCC between the years 2010 and 2013 within the Surveillance, Epidemiology, and End Results database. An external validation was also considered using patients diagnosed with RCC between 2010 and 2012 within the National Cancer Database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Incidence proportions of BM were calculated. Risk factors correlated with BM at diagnosis were identified via a 1000-bootstrap corrected multivariable logistic regression model. A risk model was then developed and evaluated using measures of predictive accuracy. Overall survival was examined using Cox regression analyses. RESULTS AND LIMITATIONS The overall incidence proportions of BM at RCC diagnosis was 1.51% (95% confidence interval: 1.39-1.64%). White/other race, clear cell histology, and sarcomatoid differentiation, T2-4 disease, tumor dimension >10 cm, and N+ disease were significantly associated with BM at RCC diagnosis, and retained within the final prediction model. A risk score was created based on these variables (c-index: 0.803). BM at RCC diagnosis occurred in 0.5%, 3.6%, and 7.7% of patients categorized as low risk, intermediate risk, and high risk. Patients with BM were more likely to succumb to any death than those without BM at diagnosis (median overall survival: 6.4 mo vs not reached, respectively, adjusted hazard ratio: 1.87, 95% confidence interval: 1.67-2.08, p < 0.001). The real incidence of BM at RCC diagnosis is likely underestimated given that the observed rate likely reflects patients who presented with symptoms. CONCLUSIONS Patients with BM at RCC have poor oncological outcomes. We have characterized the epidemiology of BM at RCC diagnosis and developed a clinical risk model for the purpose of predicting the development of BMs in patients diagnosed with a cortical renal mass. PATIENT SUMMARY In this report we examined recent proportions of patients with brain metastases at kidney cancer diagnosis in a large community database originating from the US. We developed a model that may be used during routine clinical practice to predict brain metastases. The urologic-oncological community may consider baseline imaging for brain metastases in patients without any symptoms but at high risk of having brain metastases according to the risk model. However, the proposed model certainly needs further testing and validation in the clinical setting. Future studies on brain metastases survival and treatment options are also needed.

Abstract A18: Genomic and neoantigen evolution and resistance to immune checkpoint blockade in metastatic renal cell carcinoma

Blockade of the PD1/PD-L1 T cell immune checkpoint yields responses and survival benefits exceeding mTOR blockade alone in metastatic renal cell carcinoma (mRCC). However, predictors of response to anti-PD1/PD-L1 therapy are mostly unknown, and pathways of acquired resistance to immune checkpoint therapy are poorly understood. In this study, we undertook whole exome sequencing and neoantigen analysis of matched “trios” (primary tumor resection, immune-checkpoint-refractory metastasis, and germline tissue) from 3 patients treated with anti-PD1 or anti-PD-L1 therapy for mRCC. Patients RCC-001 and RC-002 received anti-PD1 therapy after VEGF-targeted therapy and patient RCC-003 received anti-PD-L1 first-line for mRCC. All 3 patients experienced tumor regression on immune checkpoint therapy, with treatment durations of 10 months, 2 years, and 3 months, respectively. Progressive disease samples were sequenced for analysis of genomic mechanisms of treatment resistance. Whole transcriptome sequencing was obtained on primary and metastatic tumors from RCC-003. Nonsynonymous mutation load was moderate in all samples (range: 33-46 primary, 36-67 resistant). Alterations in VHL were seen in RCC-001 and RCC-002 before and after treatment. RCC-003 had a frameshift deletion in the tumor suppressor NF2 and a nonsense mutation in the MHCI antigen-processing protein TAP1 in both primary and refractory tumors. Resistance-associated mutations in RCC-002 included a frameshift deletion in MR1, involved in MHC I antigen presentation, and missense mutations in TJP1, implicated in JAK/STAT signaling, and PIAS2, implicated in STAT2 and PTEN regulation. JAK2 amplifications have been found to upregulate PD-L1 expression (Green et al. 2010, Blood), and PTEN loss mediates resistance to T cell-mediated immmunotherapy in vitro (Peng et al. 2016, Cancer Discovery). None of the primary tumors harbored alterations in microsatellite-instability-associated genes, and loss of β2 microglobulin was not observed in any sample. Despite moderate mutational loads, each sample harbored a sizeable number of neoantigens (range: 24-76 primary, 50-104 resistant). Across the 6 samples, 28 to 69% of nonsynonymous mutations were predicted to yield at least one neoantigen, with one alteration yielding a maximum of 12 unique neoantigens. Up to 60% of neoantigens observed in the primary tumor were not seen in the resistant setting (range: 20.8-59.2%). Whole transcriptome sequencing in RCC-003 showed 18/24 predicted neoantigens were expressed in the primary tumor and 24/50 in the refractory sample. 13 neoantigens were shared between the two samples, while 5 were unique to the pre-treatment tumor. Integrated whole exome and whole transcriptome sequencing with matched germline profiling identified 5 neoantigens in RCC-003 that were found exclusively in the primary tumor (lost in the treatment-resistant tumor). This could represent immune evasion via deletion of immunogenic mutations, cytotoxic killing of immunogenic tumor clones, or intrinsic resistance to immune checkpoint therapy in heterogenous tumors. Ongoing in vitro analysis of reactivity of predicted neoantigens from all 3 samples with patient-derived T cells will further clarify the biological significance these putative tumor antigens. Citation Format: Diana Miao, Guillermo De Velasco, Dennis Adeegbe, Craig Norton, Dylan Martini, Stephanie Mullane, Raphael Moreira, Sabina Signoretti, Kwok-Kin Wong, Toni Choueiri, Eliezer Van Allen. Genomic and neoantigen evolution and resistance to immune checkpoint blockade in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A18.

Next-generation sequencing (NGS) in metastatic breast cancer (mBC) patients: Translation from sequence data into clinical practice.

133 Background: A considerable number of patients with mBC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mBC and its clinical utility. METHODS We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 315 genes and selective intronic sequencing from 28 genes for refractory mBC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. RESULTS Samples from 20 patients were tested. Histologic subtype consisted of triple negative (50%), HER 2 +, hormonal receptor [HR] - 15%, HR + and HER 2 - (35%). A targetable genomic alteration was identified in 14 (70%) patients, most frequently in TP53 (11 [55%]), PIK3CA (8 [40%]), FGFR1 (4 [20%]), CCND1 (3 [15%]), PTEN (3[15%]) and BRCA2 (2[10%]). Therapy could be personalized in 9 (45%) of 14 patients. Of the 9 patients who were received targeted therapy, 7 (77%) had an objective response and had stable disease for more than 3 months. CONCLUSIONS Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced breast cancer patients. The assay provided clinical benefit in 35% of the patients.

Impact of first-line fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with advanced gastroesophageal adenocarcinoma: A retrospective analysis.

216 Background: Despite a large number of randomized trials, there is no consensus as to the best regimen for advanced gastroesophageal cancer. Combination therapy with docetaxel, cisplatin, and 5-FU has shown increased response rates, progression-free survival (PFS) and overall survival (OS), but at the cost of significant toxicity. Based on a small phase II study, FLOT has been adopted by some groups given its better toxicity profile. We aim at reporting our experience with this regimen Methods: Patients with unresectable advanced gastroesophageal adenocarcinoma who received FLOT (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24h infusion in combination with docetaxel 50 mg/m2 on day 1 every 2 weeks) as first-line therapy at our institution were retrospectively evaluated. PFS and OS were estimated by the Kaplan-Meier method. Results: A total of 23 patients were reviewed, most of them with metastatic disease (60%). Median age was 56 years (range 26–76) and 74% were male. Me...