Cyclin-dependent kinases (CDK) 4/6 inhibitors, namely abemaciclib, palbociclib, and ribociclib, interfere with cell cycle progression, induce cell senescence and might promote cancer cell disruption by a cytotoxic T cells-mediated effect. Phase III randomized clinical trials have proven that CDK4/6 inhibitors (CDK4/6i) in combination with several endocrine agents improve treatment efficacy over endocrine agents alone for hormone receptor positive (HR+) HER2 negative (HER2–) metastatic breast cancer (MBC). Based on such results, these combinations have been approved for clinical use. Preclinical studies in cell cultures and mouse models proved that CDK4/6i are active against a broad spectrum of solid tumors other than breast cancer, including liposarcoma, rhabdomyosarcoma, non-small cell lung cancer, glioblastoma multiforme, esophageal cancer, and melanoma. The role of CDK4/6i in monotherapy in several solid tumors is currently under evaluation in phase I, II, and III trials. Nowadays, abemaciclib is the only of the three inhibitors that has received approval as single agent therapy for pretreated HR+ HER2– MBC. Here we review biological, preclinical and clinical data on the role of CDK4/6 inhibitors as single agents in advanced solid tumors.

Background Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches. Methods We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as firstline or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR. Findings We identified 2689 published results and 140 studies (comprising 50 029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0•42; 95% credible interval [CrI] 0•25-0•70), ribociclib plus letrozole (0•43; 0•24-0•77), abemaciclib plus anastrozole or letrozole (0•42; 0•23-0•76), palbociclib plus fulvestrant (0•37; 0•23-0•59), ribociclib plus fulvestrant (0•48; 0•31-0•74), abemaciclib plus fulvestrant (0•44; 0•28-0•70), everolimus plus exemestane (0•42; 0•28-0•67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0•39; 0•22-0•66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8•95; 95% CrI 1•03-76•92). Interpretation In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free surv...

Background CDK4/6-inhibitors (CDK4/6i)+endocrine therapy (ET) prolonged progression-free survival as first/second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) prognosis. Given the recent publication of overall survival (OS) data for the three CDK4/6i, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups. Methods We conducted a systematic literature search to select all available phase II/III randomized clinical trials of CDK4/6i+ET reporting OS data in first/second-line therapy of HR+/HER2-negative pre/postmenopausal MBC. A random effect model was applied for the analyses. Heterogeneity was assessed with I2 statistic. Subgroup analysis were performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP). Results Six studies were included in our analyses (3,421 patients). A clear OS benefit was observed in patients without (HR:0.68, 95%CI:0.54–0.85, I2=0.0%) and with visceral involvement (HR:0.76, 95%CI:0.65–0.89, I2=0.0%), with ≥3 metastatic sites (HR:0.75, 95%CI:0.60–0.94, I2=11.6%), in endocrine resistant (HR:0.79, 95%CI:0.67-0.93, I2=14.4%). and sensitive subset (HR:0.73, 95%CI:0.61-0.88, I2=0.0%), for age <65 (HR:0.80, 95%CI:0.67-0.95, I2=0.0%) and ≥65 years (HR:0.71, 95%CI:0.53-0.95, I2=44.4%), in postmenopausal (HR:0.75, 95%CI:0.66-0.86, I2=0.0%) and pre/perimenopausal setting (HR:0.76, 95%CI:0.60-0.96, I2=0.0%), as well as in CT-naïve patients (HR:0.72, 95%CI:0.55–0.93, I2=0.0%). Conclusions CDK4/6i+ET combinations compared to ET alone improve OS independent of age, menopausal status, endocrine sensitiveness and visceral involvement, and should be preferred as upfront therapy instead of endocrine monotherapy.

Background Basophils, eosinophils and monocytes may be involved in BCG-induced immune responses and be associated with outcomes of bladder cancer patients receiving intravesical BCG. Our objective was to explore the association of baseline counts of basophils, eosinophils and monocytes with outcomes of patients with high-grade T1 bladder cancer receiving a standard course of intravesical BCG. Methods We retrospectively reviewed medical records of patients with primary T1 HG/G3 bladder cancer. After re-TURBT, patients were treated with a 6-week course of intravesical BCG induction followed by intravesical BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months from initiation of therapy The analysis of potential risk factors for recurrence, muscle invasion and cancer-specific and overall survival was performed using univariable Cox regression models. Those factors that presented, at univariate analysis, an association with the event at a liberal p < 0.1, have been selected for the development of a multivariable model. Results A total of 1045 patients with primary T1 HG/G3 were included. A total of 678 (64.9%) recurrences, 303 (29.0%) progressions and 150 (14.3%) deaths were observed during follow-up. Multivariate analysis showed that logarithmic transformation of basophils count was associated with a 30% increment in the hazard of recurrence per unit increase of logarithmic basophils count (HR 1.30; 95% confidence interval 1.09-1.54; p = 0.0026). Basophil count modeled by quartiles was also significantly associated with time to recurrence [second vs. lower quartile HR 1.42 (1.12-1.79); p = 0.003, third vs. lower quartile HR 1.26 (1.01-1.57); p = 0.041; upper vs. lower quartile HR 1.36 (1.1-1.68); p = 0.005]. The limitations of a retrospective study are applicable. Conclusion Baseline basophil count may predict recurrence in BCG-treated HG/G3 T1 bladder cancer patients. External validation is warranted.

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.