Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

A Phase II Study Evaluating Orteronel, an Inhibitor of Androgen Biosynthesis, in Patients With Androgen Receptor (AR)-Expressing Metastatic Breast Cancer (MBC).

BACKGROUND: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC). METHODS: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint. RESULTS: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%). CONCLUSIONS: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.

Disorders in bone-mineral parameters and the risk of death in persons with chronic kidney disease stages 4 and 5: the PECERA study.

BACKGROUND: Abnormalities of bone mineral parameters are associated with increased mortality in patients on dialysis, but their effects and the optimal range of these biomarkers are less well characterized in non-dialysis chronic kidney disease (CKD). METHODS: PECERA (Collaborative Study Project in Patients with Advanced CKD) is a 3-year, prospective multicenter, open-cohort study of 966 adult patients with non-dialyzed CKD stages 4-5 enrolled from 12 centers in Spain. Associations between levels of serum calcium (Ca) (corrected for albumin), phosphate (P), and intact parathyroid hormone (iPTH) with all-cause mortality (primary outcome) and cardiovascular mortality (secondary outcome) were examined using time-dependent Cox proportional hazards models and penalized splines analysis adjusted by demographics and comorbidities, treatments and biochemical values collected every 6 months for 3 years. RESULTS: After a median follow-up of 29 months (IQR: 13-36 months) there were 181 deaths (19%). The association of calcium with all-cause mortality was J-shaped, with an increased risk for all-cause mortality at levels > 10.5 mg/dL. For phosphate and iPTH levels, the association was U-shaped. The serum values associated with the minimum risk of mortality were 3.8 mg/dL for phosphate and 70 pg/mL for iPTH, being the lowest risk ranges between 2.8 and 5.0 mg/dL, and between 38 and 112 pg/mL for phosphate and iPTH, respectively. CONCLUSIONS: Our study provides evidence on the non-linear association of serum calcium, phosphate and iPTH levels with mortality in stage 4 and 5 CKD patients, and suggests potential survival benefits for controlling bone mineral parameters in this population, as previously reported for dialysis patients.

Cohort study with patients older than 80 years with stage 5 chronic kidney failure on hemodialysis vs conservative treatment: Survival outcomes and use of healthcare resources.

Renal replacement treatment has not been generalized to the elderly for different reasons. The main objective of the present cohort study is to compare survival in patients older than 80 years with chronic kidney disease stage 5 on renal replacement treatment with those on conservative treatment. The use of healthcare resources is compared too. A Cox proportional hazards regression analysis was run with the outcome variable death during the follow-up period. The independent variables were treatment type, age, gender, smoking habit, serum albumin, hemoglobin, Charlson Index, diabetes mellitus, arterial hypertension, ischemic cardiopathy, and neoplasm. For outcome variable "death," renal replacement treatment obtained a hazard ratio of 0.273 (P .006, CI95% 0.108-0.686) vs conservative treatment. In conclusion, patients older than 80 years with chronic kidney disease stage 5 on renal replacement treatment presented a lower mortality risk than those receiving conservative treatment. Comorbidity and age are both associated with mortality, but do not cancel out the survival advantage. In healthcare resources, the renal replacement treatment group made greater use of tests, medical visits and consumption of hospital dispensing drugs, but there were no differences with respect to the days of hospital admission or assistance in home hospitalization.