A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer

BACKGROUND: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). RESULTS: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. CONCLUSION: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC

Patient-reported outcomes (PROs) with first-line (1L) cemiplimab in patients with locally advanced non-small cell lung cancer (laNSCLC): EMPOWER-Lung 1 subpopulation

In this post hoc analysis of patients with laNSCLC and PD-L1 ≥50%, cemiplimab resulted in significant favourable overall change from BL in GHS/QoL and important cancer-related and lung cancerespecific symptoms versus chemo. PRO results further support the favourable benefit-risk profile of 1L cemiplimab versus chemo in laNSCLC with PD-L1 ≥50%. Clinical trial identification: NCT03088540

phase i ii study of spartalizumab pdr001 an anti pd1 mab in patients with advanced melanoma or non small cell lung cancer

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Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study

PURPOSE: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318). MATERIALS AND METHODS: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue. RESULTS: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for "pain at its least in the last 24 hours" (28.7 vs 21.8 months, respectively; p=0.0146), "pain interfered with mood" (not estimable vs 22.4 months; p=0.0017), "pain interfered with walking ability" (28.7 vs 20.2 months; p=0.0027), "pain interfered with relations" (not estimable vs 23.0 months; p=0.0139) and "pain interfered with sleep" (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups. CONCLUSIONS: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo

Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study

Background: In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue. Methods: In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days −6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1–7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing. Findings: Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0–10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0–3·17) in the apalutamide group and 1·00 (0–2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0–3·29) in the apalutamide group and 1·43 (0·14–3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04–not reached) in the apalutamide group versus 11·99 months (8·28–18·46) in the placebo group (HR 0·89 [95% CI 0·75–1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58–not reached in the apalutamide group; not reached–not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55–11·96) in the apalutamide group and 6·24 months (4·63–7·43) in the placebo group (HR 0·90 [95% CI 0·73–1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70–11·10) in the apalutamide group and 9·23 months (7·39–12·91) in the placebo group (HR 1·02 [95% CI 0·85–1·22]; p=0·85). Interpretation: Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade. Funding: Janssen Research & Development

Role of the antiangiogenetic drug paclitaxel on healing of intestinal anastomosis: An experimental study

Background: The aim of intraperitoneal administration of antineoplastic agents is the prevention of the implantation of tumoral cells after surgical intervention or the treatment of peritoneal carcinomatosis. The efficiency of intraperitoneal administration of paclitaxel, which is also an antiangiogenetic agent, has been investigated recently. The aim of this experimental study was to evaluate, taking into consideration its antiangiogenetic properties, the effects of intraperitoneal paclitaxel on healing of end to end colonic anastomosis. Methods: 42 rats were allocated to 2 main groups (n=21 for each group) to be evaluated on postperative day 3 (group A) and postoperative day 7 (group B). Each of the two main groups was divided into 3 subgroups (7 rats each). These subgroups were determined as control and two treatment groups administered paclitaxel in a dose of 2.5 mg/kg and 3.5 mg/kg intraperitoneally. Anastomosed segments of colon were harvested on postoperative day 3 or 7 and evaluated to determine bursting pressure of anastomoses, hydroxyproline levels and neovascularization with CD-31. Results: In both groups, there were no significant differences between control and paclitaxel-treated groups with respect to bursting pressure. The level of hydroxyproline showed a significant decrease in all paclitaxel-treated groups compared with control groups (p=0.001). Neovascularization was found to be decreased significantly on day 3 in the doses of paclitaxel 2.5 mg/kg (6.4±1.63) and 3.5 mg/kg (5.89±1.01) compared with control (8.02±0.88) (p=0.029 and p=0.005, respectively). There were no significant differences in neovascularization in either groups on postoperative day 7. Conclusions: We suggest that intraperitoneal administration of paclitaxel during surgical procedure decreases the hydroxyproline content and neovessel formation that are necessary for healing of intestinal anastomosis

The Impact of Hybrid Capture-Based Comprehensive Genomic Profiling on Treatment Strategies in Patients with Solid Tumors

© 2022 by Turkish Society of Medical Oncology.Objective: The development of bioinformatics and comprehensive genomic profiling (CGP) has provided insights into the ap-plicability and functionality of the genomic alterations (GA). In this study, we evaluated the impact of CGP on the treatment plan and outcomes in a significant number of patients. Material and Methods: We carried out a retrospective case-control study on 164 adult patients with advanced solid tumors from 15 oncology centers in Türkiye. Results: In all cases, CGP was performed within 23.8 [standard deviation (SD)±32.1] months of initial diagnosis. Non-small cell lung carcinoma, breast cancer, unknown primary carcinoma, colorectal carcinoma, and sarcoma were among the most common tumor types, accounting for 61.5% of all cases. CGP was performed immediately after the diagnosis of advanced cancer in 13 patients (7.9%). In 158 patients (96.4%), at least one GA was found as per the CGP report. Also, in the reports, the average tumor mutational burden (TMB) and GAs were 7.3 (SD±8.7) mut/Mb and 3.5 (SD±2.0), respectively. According to CGP reports, 58 patients had 79 evidence-based drug suggestions for their particular tumor type, whereas 97 patients had 153 evidence-based drug suggestions for another tumor type. After the primary oncologist interpreted the CGP reports, significant changes were made to the treatment of 35 (21.3%) patients. Conclusion: We strongly believe that in the future, high-TMB or other tumor-agnostic biomarkers will become much more afford-able, and CGP will serve as one of the major decision-making tools for the treatment of patients along with pathological, radiological or lab-oratory tests

Paraneoplastic pemphigus associated with fludarabine use

Paraneoplastic pemphigus is a severe mucocutaneous disease associated with B-cell lymphoproliferative disorders. A 51-yr-old man presented to the oncology clinic with mucocutaneous skin lesions after six cycles of fludarabine for non-Hodgkin's lymphoma. A punch biopsy from the skin showed suprabasal acantholysis and blister formation in the epidermis and upper dermis. Direct immunofluorescence demonstrated intercellular IgG deposition in all epidermal layers and complement (C3) at the basement membrane. The indirect immunofluorescence on rat bladder showed intercellular binding of IgG. These findings were consistent with paraneoplastic pemphigus associated with fludarabine use. The temporal association between fludarabine use and paraneoplastic pemphigus suggests there is an etiopathological link between these two entities