Cabozantinib in the Routine Management of Renal Cell Carcinoma: A Systematic Literature Review of Real-World Evidence.

Real-world cabozantinib use has increased since its approval to treat patients with advanced renal cell carcinoma (RCC) in 2016. We reviewed cabozantinib use in real-world clinical practice and compared outcomes with pivotal cabozantinib randomized control trials (RCTs). This PRISMA-standard systematic literature review evaluated real-world effectiveness and tolerability of cabozantinib in patients with RCC (PROSPERO registration: CRD42021245854). Systematic MEDLINE, Embase, and Cochrane database searches were conducted on November 2, 2022. Eligible publications included ≥ 20 patients with RCC receiving cabozantinib. After double-screening for eligibility, standardized data were abstracted, qualitatively summarized, and assessed for risk of bias using the Newcastle-Ottawa Scale. Of 353 screened publications, 41 were included, representing approximately 11,000 real-world patients. Most publications reported cabozantinib monotherapy cohort studies (40/41) of retrospective (39/41) and multicenter (32/41) design; most included patients from North America and/or Europe (30/41). Baseline characteristics were demographically similar between real-world and pivotal RCT populations, but real-world populations showed greater variation in prevalence of prior nephrectomy, multiple-site/brain metastasis, and nonclear-cell RCC histology. Cabozantinib activity was reported across real-world treatment lines and tumor types. Overall survival, progression-free survival, and objective response rate values from pivotal RCTs were within the ranges reported for equivalent outcomes across real-world studies. Common real-world grade ≥ 3 adverse events were consistent with those in pivotal RCTs (fatigue, palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension), but less frequent. No new tolerability concerns were identified. Real-world RCC survival outcomes for cabozantinib monotherapy were broadly consistent with pivotal RCTs, despite greater heterogeneity in real-world populations.

CaboCombo: a prospective, phase IV study of first-line cabozantinib + nivolumab for advanced renal cell carcinoma.

Cabozantinib plus nivolumab was approved as a first-line (1L) treatment for advanced renal cell carcinoma (aRCC) following the CheckMate 9ER trial. CaboCombo (ClinicalTrials.gov identifier: NCT05361434) is a non-interventional study designed to evaluate the effectiveness and tolerability of cabozantinib plus nivolumab in a real-world setting. Overall, 311 patients with clear-cell aRCC receiving 1L cabozantinib plus nivolumab will be recruited from at least 70 centers in seven countries worldwide. The primary end point is overall survival at 18 months. Secondary end points include progression-free survival, objective response rate, safety, patterns of treatment, subsequent anticancer therapies and quality of life. CaboCombo will provide real-world evidence on the characteristics, treatment sequences, and outcomes of patients with aRCC receiving 1L cabozantinib plus nivolumab.

Renal cell carcinomas (RCC) are cancers that grow in the kidneys. Clear-cell RCC is the most common type reported in almost three quarters of patients. RCC tumors become advanced if they grow and spread to other parts of the body. In a clinical trial called CheckMate 9ER, a combination of two drugs called cabozantinib and nivolumab improved survival compared with a drug called sunitinib in patients with advanced clear-cell RCC who had not received any previous treatments. In CheckMate 9ER, cabozantinib plus nivolumab also reduced the size and slowed the spread of tumors compared with sunitinib. However, clinical trials only allow certain patients to participate under strict treatment conditions and so do not provide information on how a treatment will work in all patients. Researchers therefore carry out additional studies to gather extra information from real-world clinical practice. CaboCombo is a study that will look at how well cabozantinib plus nivolumab stops tumors from growing and spreading, the side effects of the drugs, and also how the drugs are used by doctors. It is an observational study, which means that researchers will observe all patients and doctors using the treatment but they will not intervene. The aim of the study is to gather information that will help doctors make treatment decisions for their patients. This article describes how the CaboCombo study will be carried out and the information it will give the researchers. The results will help physicians make decisions on the best treatment option for patients. Clinical Trial Registration: NCT05361434 (ClinicalTrials.gov).

Meta-Analysis of Paediatric Patients with Central Precocious Puberty Treated with Intramuscular Triptorelin 11.25 mg 3-Month Prolonged-Release Formulation
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BACKGROUND/AIMS: A meta-analysis was undertaken to assess the effect of triptorelin 11.25 mg 3-month prolonged-release formulation in central precocious puberty (CPP). METHODS: All available clinical studies with triptorelin 11.25 mg were included. The primary outcome was the proportion of children with suppressed luteinising hormone (LH) response (peak LH ≤3 IU/L) to the gonadotrophin-releasing hormone (GnRH) test 3 months after triptorelin 11.25 mg injection. Secondary outcomes included: the proportion with suppressed peak LH response at 6 months and the proportion with suppressed peak follicle-stimulating hormone (FSH) response (≤3 IU/L), suppressed oestradiol (≤20 pmol/L) in girls or suppressed testosterone (≤30 ng/dL) in boys at 3 months. RESULTS: 153 children (13 boys, 140 girls) were included. The proportion with a suppressed peak LH response to the GnRH test was 87.6% (95% CI: 81.3-92.4, p < 0.0001, for a proportion >70%) and 92.8% (95% CI: 87.5-96.4, p < 0.0001, for a proportion >70%) at 3 and 6 months, respectively. FSH peak, oestradiol, and testosterone were suppressed in 86.7% (95% CI: 79.1-92.4), 97.1% (95% CI: 91.6-99.4), and 72.7% (95% CI: 39.0-94.0) of children at 3 months, respectively. CONCLUSION: Triptorelin 11.25 mg 3-month formulation is efficacious in suppressing LH peak and other gonadal hormones and in slowing the progression of CPP in children.
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Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards. METHODS: Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42-96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2-12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl. RESULTS: After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80-92%, from 83-93%, and from 65-97% with median (interquartile range) serum testosterone values of 2.9 (2.9-6.5), 5.0 (2.9-8.7), and 8.7 (5.8-14.1) ng/dl at study end, respectively. CONCLUSION: In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.

Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer.

OBJECTIVES: Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. METHODS: In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. RESULTS: Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2-99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6-99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0-95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). CONCLUSIONS: This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer.

Recombinant human growth hormone plus recombinant human insulin-like growth factor-1 coadministration therapy in short children with low insulin-like growth factor-1 and growth hormone sufficiency: results from a randomized, multicenter, open-label, parallel-group, active treatment-controlled trial.

BACKGROUND/AIMS: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) both contribute to growth. To determine if recombinant human (rh)GH + rhIGF-1 therapy is more effective than rhGH alone to treat short stature, we assessed the efficacy and safety of coadministered rhGH + rhIGF-1 in short children with GH sufficiency and low IGF-1. METHODS: In a 3-year, randomized, multicenter, open-label trial, patients with height SD score ≤-2.0 and IGF-1 SD score ≤-1.0 for age and sex, and with stimulated GH ≥10 ng/ml for age and sex, were randomized to receive (all doses in µg/kg/day): 45 rhGH alone (group A), 45 rhGH + 50 rhIGF-1 (group B), 45 rhGH + 100 rhIGF-1 (group C) or 45 rhGH + 150 rhIGF-1 (group D). Height velocity (HV) and Δ height SD score were measured. RESULTS: The first-year HV (modified intention-to-treat population) was 9.3 ± 1.7 cm/year (group A), 10.1 ± 1.3 cm/year (group B), 9.7 ± 2.5 cm/year (group C) and 11.2 ± 2.1 cm/year (group D) (p = 0.001 for groups A vs. D). This effect was sustained, resulting in a height SD score improvement during the second and third years. Most treatment-emergent adverse events were mild and transient. CONCLUSION: In children with short stature, GH sufficiency and low IGF-1, coadministration of rhGH/rhIGF-1 (45/150 µg/kg) significantly accelerated linear growth compared with rhGH alone, with a safety profile similar to the individual monotherapies.

Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study.

CONTEXT: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis. OBJECTIVE: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. DESIGN AND SETTING: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010). PARTICIPANTS: Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 µg/L) were recruited. METHODS: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. RESULTS: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10(-5), Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10(-10); case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P < 2.3 × 10(-6)) were associated with SS. At P < 10(-4), single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS. CONCLUSIONS: IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.