Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial.

PURPOSE: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. PATIENTS AND METHODS: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. RESULTS: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores. CONCLUSIONS: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.

Monoinstitutional real world experience in management of Vinflunine as second line therapy for transitional cell carcinoma of the urothelium.

Vinflunine is the only cytotoxic agent tested as a second line therapy in transitional cell carcinoma of the urothelium in a phase III trial. It is not largely employed in clinical practice because of the high incidence of grade 3-4 toxicity. We evaluated efficacy and safety of Vinflunine at the dose of 280 mg/m2 every 3 weeks associated with primary prophylaxis with granulocyte growth factors and laxatives for patients progressed after platinum + Gemcitabine. Overall survival was 8.5 months, progression-free survival 4.33 months and response rate 25%, with disease control rate 57.2%. Grade III-IV neutropenia occurred in 10.7% of the patients, grade III-IV anemia and grade III thrombocytopenia in 10.7% and 7.2%, respectively. Among non haematological toxicity, grade I-II constipation was reported in 14.2% of the patients, without grade III-IV adverse events. No discontinuation for toxicity was observed. This study underlines that Vinfluinine at a dose of 280 mg/m2 associated with primary prophylaxis for neutropenia and constipation is effective and with a favorable toxicity profile.

Neoadjuvant Chemotherapy for Patients with Muscle-invasive Urothelial Bladder Cancer Candidates for Curative Surgery: A Prospective Clinical Trial Based on Cisplatin Feasibility.

BACKGROUND: Neoadjuvant chemotherapy demonstrated a survival benefit versus cystectomy alone in muscle-invasive urothelial bladder cancer. Despite this advantage, preoperative chemotherapy is not widely employed. When patients are unfit for cisplatin-based regimen, they are often candidates for immediate surgery. In our study, patients with muscle-invasive bladder cancer were treated with neoadjuvant chemotherapy. The principal objective was the rate of complete pathological response (pCR). Secondary end-points were disease-free survival (DFS), overall survival (OS) and toxicity. PATIENTS AND METHODS: Patients (n=72) with Eastern Cooperative Oncology Group (ECOG) performance status 0-1, clinical stage cT3-4, and/or N+ muscle-invasive bladder cancer were enrolled. The chemotherapy regimen was established according to the cisplatin feasibility. Thirty patients were treated with cisplatin/gemcitabine (Gem) and 42 with carboplatin/Gem. RESULTS: The rate of pCR was 29.2%, 36% with cisplatin-based treatment and 23.8% with carboplatin (p=0.3574). DFS and OS were longer in pCR patients, while no difference was reported between cisplatin/Gem and Carboplatin/Gem groups. CONCLUSION: Our results confirm the prognostic value of pCR in neoadjuvant chemotherapy for muscle-invasive bladder cancer. When the patients are not fit for cisplatin, a carboplatin/Gem regimen represents a valid option because of comparable long-term outcome. When cisplatin is not feasible, the exclusion of a preoperative treatment is not justified.

Treatment Options for EGFR T790M-Negative EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer.

The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients' prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR. The remaining 50% of patients with acquired resistance (AR) to EGFR-TKIs do not harbour the T790M mutation. In these cases, other mechanisms are involved in the development of AR such as perturbations of downstream pathways (e.g. K-RAS mutations), activation of alternative bypassing pathways (including c-Met, AXL, PIK3CA, BRAF), or histologic transformation. This review summarizes the main treatment strategies for this particular and heterogeneous group of "T790M-negative" patients.

Cardiac metastasis from renal cell carcinoma successfully treated with pazopanib: impact of TKIs' antiangiogenic activity.

Cardiac metastasis from renal cell carcinoma, especially without neoplastic thrombosis of the vena cava, is extremely rare. The prognosis of patients with metastatic renal cell carcinoma has been radically influenced by the introduction of tyrosine kinase inhibitors, but very few reports in the literature have described their activity in heart metastasis. We report the case of a woman with a left ventricle metastasis from kidney cancer without renal vein involvement, who was treated with pazopanib. The patient achieved a prolonged partial response, with clear signs of metastasis devascularization and a favorable toxicity profile.