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.).

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer.

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.

Seizure Rates in Enzalutamide-Treated Men With Metastatic Castration-Resistant Prostate Cancer and Risk of Seizure: The UPWARD Study.

Importance: The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure. Objective: To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC. Design, Setting, and Participants: The UPWARD study (A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer Patients Treated With Enzalutamide) is an international, multicenter (73 sites in 20 countries), single-arm, open-label safety study in institutional practice. Data were collected from September 25, 2013, to February 1, 2016. Patients had at least 1 risk factor for seizure at baseline, including medications that lower seizure threshold, history of stroke, or history of seizure. Exclusion criteria included seizure (assessed by neurologic examination and history) requiring antiseizure medication within the past 12 months. Intervention: Treatment with oral enzalutamide, 160 mg/d. Main Outcomes and Measures: The primary end point was the proportion of evaluable patients with 1 or more independently confirmed seizures during the 4-month study period; evaluable patients were defined as those who had 3 months or more of treatment or 1 or more confirmed seizures during this treatment period. Results: Of 423 patients with mCRPC receiving enzalutamide, 366 were evaluated. At baseline, risk factors for seizure included medications that lowered seizure threshold (242 of 423 patients [57.2%]), history of brain injury (112 [26.5%]), and history of cerebrovascular accident or transient ischemic attack (94 [22.2%]). Four of the 366 evaluable patients (1.1%) had at least 1 confirmed seizure within 4 months of enzalutamide initiation, and 3 (0.8%) additional patients experienced a seizure within 4 months following the 4-month study period. The incidence of confirmed seizure was 2.6 per 100 patient-years (7 seizures). Of the 423 patients receiving enzalutamide, 357 (84.4%) experienced at least 1 treatment-emergent adverse event (an adverse event temporally related to the study treatment); 141 (33.3%) had at least 1 serious treatment-emergent adverse event, and 29 (6.9%) had at least 1 drug-related serious adverse event. Thirty-eight deaths (9.0%) were reported during treatment or within 30 days of drug discontinuation; 4 were considered possibly drug related. Conclusions and Relevance: Incidence of seizure is similar in patients with mCRPC and similar seizure risk factors with or without enzalutamide exposure. The risk profile presented, along with the previously established efficacy of enzalutamide, suggests that enzalutamide can benefit patients with a history of seizures or other predisposing factors, but each patient should be closely monitored for the duration of treatment.

Efficacy and Safety of Enzalutamide vs Bicalutamide in Younger and Older Patients with Metastatic Castration Resistant Prostate Cancer in the TERRAIN Trial.

PURPOSE: Enzalutamide significantly prolonged median progression-free survival vs bicalutamide in chemotherapy naïve men with metastatic castration resistant prostate cancer in the TERRAIN (Enzalutamide versus Bicalutamide in Castrate Men with Metastatic Prostate Cancer) trial. In this post hoc analysis we investigated the influence of age on the efficacy and safety of enzalutamide vs bicalutamide in this population. MATERIALS AND METHODS: Patients were randomized 1:1 to enzalutamide 160 mg per day or bicalutamide 50 mg per day. Progression-free survival, time to prostate specific antigen progression and safety were analyzed post hoc in younger (age less than 75 years) and older (age 75 years or greater) subgroups. RESULTS: Enzalutamide significantly reduced the risk of disease progression or death vs bicalutamide in patients younger than 75 years (HR 0.38, 95% CI 0.27-0.52, p <0.0001) and 75 years old or older (HR 0.59, 95% CI 0.37-0.92, p = 0.018). Time to prostate specific antigen progression was also significantly prolonged with enzalutamide vs bicalutamide in each subgroup. The adverse event distribution between treatments was similar in each subgroup except for more (5% or greater difference between subgroups) atrial fibrillation, urinary tract infections, falls and decreased appetite as well as less extremity pain and hot flushing in enzalutamide treated patients 75 years old or older, and less back pain and hot flushing in bicalutamide treated patients 75 years old or older. Grade 3 or greater cardiac events were more frequent in enzalutamide treated and bicalutamide treated patients who were 75 years old or older vs younger than 75 years. Fatigue was more frequent in enzalutamide treated patients with a similar distribution in each age subgroup. CONCLUSIONS: Enzalutamide improved clinical outcomes vs bicalutamide irrespective of age. Increased falls and cardiac events suggest caution when prescribing to older patients (age 75 years or greater) with significant comorbidity.

Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial.

BACKGROUND: Improving health-related quality of life (HRQoL) is an important goal in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To examine the impact of enzalutamide versus bicalutamide on HRQoL in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: TERRAIN is a multinational, phase 2, randomised, double-blind study in asymptomatic/mildly symptomatic men with mCRPC (ClinicalTrials.gov, NCT01288911). Patients were randomised (1:1) via an interactive voice and web response system to enzalutamide 160mg/d (n=184) or bicalutamide 50mg/d (n=191), with androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), European Quality of Life 5-Domain Scale (EQ-5D), and Brief Pain Inventory, Short-form questionnaires every 12 wk. Primary and secondary analyses utilised mixed models for repeated measures and pattern mixture models, respectively. RESULTS AND LIMITATIONS: At 61 wk, 84 (46%) enzalutamide and 39 (20%) bicalutamide patients in the study were assessed. At 61 wk, changes from baseline favoured enzalutamide versus bicalutamide on three FACT-P domains in mixed models for repeated measures analyses and seven in pattern mixture models analyses. There were no differences in changes for EQ-5D index/visual analogue scale scores. Risk of first deterioration was lower with enzalutamide for FACT-P total (hazard ratio: 0.64, 95% confidence interval: 0.46-0.89, p=0.007), FACT-G total (hazard ratio: 0.70, 95% confidence interval: 0.50-0.98, p=0.04), PCS pain (hazard ratio: 0.74, 95% confidence interval: 0.54-1.00, p=0.048), and EQ-5D index (hazard ratio: 0.66, 95% confidence interval: 0.47-0.93, p=0.02) scores versus bicalutamide. Brief Pain Inventory, Short-form scores increased in both groups. There was no difference in time-to-pain progression. Study limitations include the exploratory nature of the HRQoL analyses, lack of multiple comparisons corrections, and unknown effects of anxiety/depression on HRQoL. CONCLUSIONS: In patients with asymptomatic/mildly symptomatic mCRPC, enzalutamide provides HRQoL benefit versus bicalutamide. PATIENT SUMMARY: Enzalutamide treatment was associated with better health-related quality of life in several domains versus bicalutamide in asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. This likely relates to previously reported lower rates of symptomatic disease progression.

Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial.

PURPOSE: Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC. PATIENTS AND METHODS: A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS). RESULTS: Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials. CONCLUSION: Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.

Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study.

BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that has been shown to improve survival in two placebo-controlled phase 3 trials, and is approved for patients with metastatic castration-resistant prostate cancer. The objective of the TERRAIN study was to compare the efficacy and safety of enzalutamide with bicalutamide in patients with metastatic castration-resistant prostate cancer. METHODS: TERRAIN was a double-blind, randomised phase 2 study, that recruited asymptomatic or minimally symptomatic men with prostate cancer progression on androgen-deprivation therapy (ADT) from academic, community, and private health-care provision sites across North America and Europe. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive enzalutamide 160 mg/day or bicalutamide 50 mg/day, both taken orally, in addition to ADT, until disease progression. Patients were stratified by a permutated block method (block size of four), by whether bilateral orchiectomy or receipt of luteinising hormone-releasing hormone agonist or antagonist therapy started before or after the diagnosis of metastases, and by study site. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was progression-free survival, analysed in all randomised patients. Safety outcomes were analysed in all patients who received at least one dose of study drug. The open-label period of the trial is in progress, wherein patients still on treatment at the end of the double-blind treatment period were offered open-label enzalutamide at the discretion of the patient and study investigator. This trial is registered with ClinicalTrials.gov, number NCT01288911. FINDINGS: Between March 22, 2011, and July 11, 2013, 375 patients were randomly assigned, 184 to enzalutamide and 191 to bicalutamide. 126 (68%) and 168 (88%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 20·0 months (IQR 15·0-25·6) in the enzalutamide group and 16·7 months (10·2-21·9) in the bicalutamide group. Patients in the enzalutamide group had significantly improved median progression-free survival (15·7 months [95% CI 11·5-19·4]) compared with patients in the bicalutamide group (5·8 months [4·8-8·1]; hazard ratio 0·44 [95% CI 0·34-0·57]; p<0·0001). Of the most common adverse events, those occurring more frequently with enzalutamide than with bicalutamide were fatigue (51 [28%] of 183 patients in the enzalutamide group vs 38 [20%] of 189 in the bicalutamide group), back pain (35 [19%] vs 34 [18%]), and hot flush (27 [15%] vs 21 [11%]); those occurring more frequently with bicalutamide were nausea (26 [14%] vs 33 [17%]), constipation (23 [13%] vs 25 [13%]), and arthralgia (18 [10%] vs 30 [16%]). The most common grade 3 or worse adverse events in the enzalutamide or bicalutamide treatment groups, respectively, were hypertension (13 [7%] vs eight [4%]), hydronephrosis (three [2%] vs seven [4%]), back pain (five [3%] vs three [2%]), pathological fracture (five [3%] vs two [1%]), dyspnoea (four [2%] vs one [1%]), bone pain (one [1%] vs four [2%]), congestive cardiac failure (four [2%] vs two [1%]), myocardial infarction (five [3%] vs none), and anaemia (four [2%] vs none]). Serious adverse events were reported by 57 (31%) of 183 patients and 44 (23%) of 189 patients in the enzalutamide and bicalutamide groups, respectively. One of the nine deaths in the enzalutamide group was thought to be possibly related to treatment (due to systemic inflammatory response syndrome) compared with none of the three deaths in the bicalutamide group. INTERPRETATION: The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma, Inc and Medivation, Inc.

Colonoscopic and histologic features of colonic Crohn's disease in Chinese patients.

OBJECTIVE: An attempt was made to provide a better insight into endoscopic and histological features and to enhance the understanding of the diagnostic value of colonoscopy combined with biopsy for colonic Crohn's disease. METHODS: As presented in our 27 cases of colonic Crohn's disease (Crohn's colitis), the endoscopic findings and histological changes of biopsy specimens were analyzed. As collated with correspondent results of biopsy and surgical specimens, the diagnostic accuracy of endoscopy was evaluated. RESULTS: Of these patients, 26 involvements of the colon (often combined with other sites of the bowel) were observed (96.3%). However, involvements limited to the colon alone were seen in only four cases (14.8%). Endoscopically, diverse patterns of multi-staged-segmental distributed and multi-sited inflammatory lesions, both destructive and proliferative/regenerative changes were observed in the bowel of the same patient. The diagnostic accuracy of colonoscopy, as confirmed by the histological examination of biopsy and resected specimens, was 66.7%. The major characteristic features of mucosal biopsy were the focal distribution of inflammatory infiltration and lymphoid aggregate. Otherwise, it may include edematous and widened submucosa, deep fissuring ulcers and hyperplasia, fibrosis and granulomas (detected in 30% of the group), among others. CONCLUSION: The colonic involvement of Crohn's disease was common. Colonoscopy may be valuable in establishing a diagnosis and in assessing the extent and severity of such colonic involvement. Biopsy is helpful to confirm a diagnosis conducted by colonoscopy. Colonoscopy combined with biopsy may replace radiology as the initial test of choice in many clinical situations.

Difficulty with diagnosis of malignant pancreatic neoplasms coexisting with chronic pancreatitis.

Chronic pancreatitis is a relatively common disease. We encountered two different cases of belatedly demonstrated pancreatic carcinoma featuring underlying chronic pancreatitis. The first case was one that was highly suspected as that of a malignancy based upon imaging study, but unfortunately, it could not be confirmed by intra-operative cytology at that time. Following this, the surgeon elected to perform only conservative bypass surgery for obstructive biliary complication. Peritoneal carcinomatosis was later noted and the patient finally died. The second case, a malignant mucinous neoplasm, was falsely diagnosed as a pseudocyst, based upon the lesion's sonographic appearance and associated elevated serum amylase levels. After suffering repeated hemoptysis, the patient was found to exhibit lung metastasis and peritoneal seeding. We reviewed some of the literature, including those studies discussing chronic pancreatitis predisposing to a malignant change. These two case analyses illustrate clearly that the diagnosis for such conditions, which is simply based upon imagery or pathological considerations may end up being one of a mistaken malignancy. Some of our suggestions for the treatment of such malignancies as revealed herein include, total pancreatomy for univocal mass lesion, and needle aspiration of lesion-contained tissue for amylase, CA199 and CEA levels for a suspicious cystic pancreatic mass.

Gene delivery of endothelial nitric oxide synthase into nucleus tractus solitarii induces biphasic response in cardiovascular functions of hypertensive rats.

BACKGROUND: Nitric oxide (NO) plays an important role in central control of blood pressure (BP). An intrinsic defect in NO availability in brain nucleus contributes to the elevated BP in the spontaneously hypertensive rats (SHR). This study was aimed to investigate the effect of endothelial NO synthase (eNOS) gene delivery in the nucleus tractus solitarii (NTS) on the cardiovascular functions of SHR. METHODS: Adenovirus vectors encoding either eNOS (Ad-eNOS) or green fluorescent protein (Ad-GFP) were used for gene transfer study. The cardiovascular functions in SHR received NTS gene delivery that were monitored by an oscillometric device. RESULTS: Infection of neuronal cells with Ad-eNOS increased the nitrite production but decreased the level of superoxide anion (O(2)(-)), indicating that eNOS gene delivery increased NO availability. After microinjection into NTS, adenovirus-mediated GFP or eNOS expression was confirmed by fluorescence microscopy and immunohistochemical analysis. On days 3 to 14 after injection, a significant decrease in mean BP (MBP and heart rate (HR) was observed in Ad-eNOS-treated SHR, but not in Ad-GFP- or saline-treated SHR. Within this period, microinjection of the soluble guanylate cyclase inhibitor significantly reversed the Ad-eNOS-mediated depressor effect. However, on days 24 to 40, the MBP of Ad-eNOS-treated animals escalated, then returned to the normal range after day 50. The mechanism underlying the rebound of BP in Ad-eNOS-injected SHR remains to be elucidated. CONCLUSIONS: Intra-NTS eNOS gene delivery causes a depressor response in SHR, but a transient increase in MBP was observed after the Ad-eNOS-induced hypotension disappeared.

Neurofibroma with increased uptake of [F-18]-fluoro-2 deoxy-D-glucose interpreted as a metastatic lesion.

We report a patient with a solitary spinal neurofibroma in the posterior mediastinum interpreted as a metastatic tumor. A 46-year-old female with rectal cancer who had undergone operation and subsequent adjuvant chemotherapy two years previously was referred to our department for a follow-up whole body FDG-PET study. PET scan revealed a mass with increased uptake of FDG (SUV = 4.6) in the posterior mediastinum. MRI examination showed a dumbbell neurogenic tumor originating from the intercostal nerve at T6 level. A subsequent CT-guided biopsy demonstrated a neurofibroma.

Intense uptake of [F-18]-fluoro-2 deoxy-D-glucose in active pulmonary tuberculosis.

FDG PET is well recognized for its utility in cancer workup. Nonetheless, the differentiation between malignant and benign pulmonary lesions by FDG PET is challenging. The authors report three proved cases of pulmonary tuberculosis in acute active and open stages. The activities and extents of infection were demonstrable in FDG PET, which could not be observed in either chest radiograph or computed tomography.

F-18 fluorodeoxyglucose positron emission tomography in pulmonary cryptococcoma.

Cryptococcosis is not uncommon. Potential interpretation pitfalls should be kept in mind when fluorodeoxyglucose (FDG) positron emission tomography (PET) is used for differentiating pulmonary nodules and for discriminating infection from malignancy, especially in areas where the prevalence of granulomatous infection is high and in immunocompromised patients. In this case, a nodular mass was shown on chest radiography and computed tomographic (CT) scanning. A consolidated infection or a bronchioloalveolar carcinoma was suspected because the CT scan showed air bronchograms within the mass and another perihilar infiltration. The FDG PET scan clearly delineated the lesion and had intermediately high glucose uptake (standard uptake value, 3.8-4.0), which led to the exclusion of the possibility of bronchioloalveolar carcinoma because most of these tumors had normal or mildly increased FDG accumulation. Cryptococcoma was finally diagnosed. Hence, the CT scan and FDG PET played complementary roles in the differential diagnosis of this nodular mass.