Frequency Of Treatment-related Adverse Events Research Articles

IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation

BackgroundContinuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high...

Abstract CT266: Chinese race and origin have no clinically meaningful effect on tiragolumab and atezolizumab pharmacokinetics and safety in patients with advanced solid tumors

Abstract Background: Tiragolumab is a fully human IgG1 monoclonal antibody targeting the immune checkpoint TIGIT and is under evaluation in combination with anti-PD-L1 (atezolizumab) therapy. Here we report PK, safety, and preliminary anti-tumor activity from a Phase I open-label study (YP42514, CTR20210219) evaluating tiragolumab + atezolizumab in Chinese patients (pts) with advanced or metastatic solid tumors. Methods: Pts ≥18 years of age with an ECOG performance status of 0 or 1, a life expectancy of ≥12 weeks, adequate hematologic and end organ function who were residents in mainland China were eligible. Pts received tiragolumab 600 mg + atezolizumab 1200 mg IV every 3 weeks. Serial PK sampling was obtained in the first dosing Cycle on Days 1, 2, 8, 15, and 21, followed by sparse peak and trough collection. PK parameters were assessed by noncompartmental analysis and summarized using descriptive statistics. The severity of adverse events (AEs) was assessed using NCI CTCAE v5. Confirmed overall response rate and duration of response (DOR) were determined by investigator. Data cutoff: Feb 10, 2022. To support the dosing approach, findings in the current study were compared with results of a global Phase I study GO30103 (NCT02794571) [Bendell JC, et al. Cancer Res 2020;80:(suppl 16; Abst CT302)] in pts from France, Korea, Spain, the United States, Canada, and Australia receiving the same combination and dosing regimen. Results: Twenty Chinese pts were enrolled and received a median of 5 doses of tiragolumab + atezolizumab. Pts had a median age of 57.5 (range 44-73) years, were mostly male (85%), had a median of ≥2 prior lines of therapy and 30% of pts received prior immunotherapy. Non-small cell lung cancer was the most common tumor type (55%). Exposures in Chinese pts were comparable to the global population, with a geometric mean ratio (GMR) of 1.07 for Cycle 1 tiragolumab area under the concentration-time curve from 0 to 21 days, and a GMR of 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. The frequency of treatment-related AEs, all-cause grade 3/4 AEs, grade 3/4 AEs of special interest, and AEs leading to withdrawal from study treatment were generally similar for pts in China (85.0%, 40%, 10%, and 5.0%) and those in the global GO30103 study (71.3%, 41.7%, 5.3%, and 5.6%). Treatment exposure was similar in the YP42514 study vs the respective global GO30103 cohort. Two Chinese pts (10%) had a partial response, their DORs were 3 and 6 months (censored), and seven pts (35%) had stable disease. Conclusions: Tiragolumab + atezolizumab was tolerable with preliminary anti-tumor activity. No meaningful differences in the PK or safety profile of tiragolumab + atezolizumab were seen between Chinese and global populations. Citation Format: Colby Shemesh, Yongsheng Wang, Andrew An, Hao Ding, Phyllis Chan, Qi Liu, Yih-Wen Chen, Benjamin Wu, Qiong Wu, Xian Wang. Chinese race and origin have no clinically meaningful effect on tiragolumab and atezolizumab pharmacokinetics and safety in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT266.

Characterization of long-term survivors in the TOPAZ-1 study of durvalumab or placebo plus gemcitabine and cisplatin in advanced biliary tract cancer.

531 Background: At the primary analysis of TOPAZ-1 (NCT03875235; data cut-off [DCO] Aug 11, 2021), durvalumab (D) + gemcitabine and cisplatin (GC) significantly improved overall survival (OS) vs placebo (PBO) + GC in participants (pts) with advanced biliary tract cancer (BTC), with OS curves that separated over time (Oh et al. NEJM Evid 2022), that persisted with further follow-up (DCO Feb 25, 2022; HR, 0.76 [95% CI, 0.64–0.91]; 18-month OS, 34.8% [D + GC] vs 24.1% [PBO + GC]; Oh et al. Ann Oncol 2022 Abs 56P). We characterized long-term survivors (LTS) in TOPAZ-1. Methods: Pts untreated for unresectable locally advanced, recurrent or metastatic BTC received D (1500 mg every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on days 1 and 8 Q3W, up to 8 cycles, followed by D (1500 mg Q4W) or PBO. Characteristics and outcomes of LTS (pts who survived ≥18 months after randomization; DCO Feb 25, 2022) were assessed. Results: There were more LTS with D + GC vs PBO + GC (Table). Characteristics of LTS were consistent with the full analysis set (FAS, all randomized pts) including age, sex, region, primary tumor location, disease classification (metastatic vs locally advanced) and PD-L1 expression. Recurrent disease was more common than initially unresectable disease in LTS vs FAS. Median exposure to study treatment was 11.3 months (mo; D), 9.7 mo (PBO) and 5.5 mo (GC, both arms) in LTS and 7.3 mo (D), 5.8 mo (PBO) and 5.1 mo (GC, both arms) in FAS. The objective response rate in LTS was greater with D + GC vs PBO + GC (44.3%, D + GC; 33.8%, PBO + GC), and greater for both groups vs FAS (26.7%, D + GC; 18.7%, PBO + GC). A higher proportion of LTS in the PBO + GC group received subsequent anticancer therapy, including immunotherapy, than LTS in the D + GC group. The frequency of treatment-related adverse events leading to discontinuation in LTS was consistent with FAS. Conclusions: In TOPAZ-1, characteristics of LTS were generally consistent with the FAS. Overall, LTS were more common with D + GC; LTS in the PBO + GC group appear to be associated with higher frequency of subsequent treatments, including immunotherapy. Clinical trial information: NCT03875235 . [Table: see text]

Inhibition of the CD47-SIRPα axis for cancer therapy: A systematic review and meta-analysis of emerging clinical data

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.

Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial

Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC. In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m2 plus doxorubicin 40·0 mg/m2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m2, doxorubicin 45·0 mg/m2, and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete. Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group). Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control. PharmaMar.

Efficacy and safety of immune checkpoint inhibitors in post-TKI NSCLC patients harboring EGFR mutations.

Immune checkpoint inhibitors (ICIs) have been validated in epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC) patients. However, there exists no evidence regarding NSCLC patients harboring EGFR mutations, experiencing EGFR-TKI (tyrosine kinase inhibitor) treatment failure. We collected clinical information from real world and conducted a time series-based meta-analysis to determine the efficacy and safety of ICIs in patients harboring EGFR mutations and experienced EGFR-TKIs resistance. Twenty-two NSCLC patients with EGFR mutations after TKI resistance were included from two hospitals. PubMed, Embase and Cochrane Library were searched for relevant literature published until December 31, 2021. Endpoint outcomes included mortality and progression-free survival (PFS) at different times of follow-up. In total, 22 patients showed that the median PFS was 5.6months (range 2.0-9.0months). According to treatment strategies, the median PFS was 2.4months (range 2.0-5.3months) in the ICI monotherapy group and 5.9months (range 2.8-9.0months) in the ICI combined Chemotherapy group. Additionally, sixteen studies, including 5 trials, 10 controlled cohorts and 1 real-world study, were assessed, involving a total of ICI-treated NSCLC patients with EGFR mutation after TKI failure. The 6-month survival and PFS rate were 0.82 (95% CI 0.36-0.97) and 0.55 (95% CI 0.34-0.74), respectively. ICI combined chemotherapy showed the best survival outcome among these groups, as demonstrated by the 12-month survival rate and PFS. No new safety signals were identified with the combination therapy. The frequency of treatment-related adverse events was similar to that in previously reported studies of chemotherapy combined with checkpoint inhibitors. The addition of ICIs plus chemotherapy may significantly improve progression-free survival among patients with locally advanced or metastatic non-squamous NSCLC who EGFR-TKIs resistance.

IMPemBra, a phase 2 study comparing pembrolizumab with intermittent/short‐term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation: Three-year survival data and translational analyses.

9552 Background: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-PD-(L)1 showed high response rates, but also high frequency of treatment-related adverse events (TRAE) in BRAFV600-mutated melanoma patients (pts). Short‐time MAPKi already induces T cell infiltration in pts and was synergistic with anti-PD‐1 in a pre-clinical model. This phase 2b trial aimed to identify the optimal duration of MAPKi with dabrafenib + trametinib (D+T) in combination with pembrolizumab (PEM). We have previously shown that no SUSARs were observed, toxicity was related to duration of D+T, and response rates increased after addition of D+T. Here we present 3-year PFS and OS data and results of translational analyses. Methods: In IMPemBra, pts with treatment-naïve BRAFV600E/K mutant advanced melanoma started with PEM 200mg Q3W. After 2 cycles, pts were randomized to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib 150 mg BID + trametinib 2mg QD for 2 x 1 week (cohort 2), 2 x 2 weeks (cohort 3) or continuous for 6 weeks (cohort 4). All cohorts continued PEM for up to 2 years. Primary endpoints were safety, treatment adherence and immune-activating capacity of the different regimens. Secondary endpoints were objective response rate (ORR) and PFS, OS was an exploratory endpoint. For survival analyses, pts that received D+T (cohort 2-4) were pooled. Results: Thirty-two pts were randomized, 56% were male, 53% had M1c disease and 88% had a LDH level &lt; ULN. No new grade 3-4 TRAE were observed; frequencies were 12%, 12%, 50% and 62% for pts in cohort 1, 2, 3 and 4, respectively. ORRs were 75% in cohort 1 and 2, and 88% in cohort 3 and 4. The frequency of PD1+CD8+ T cells in peripheral blood decreased slightly during treatment and there were no differences between cohorts. In cohort 1 and 2, an increase in IFNγ signature in tumor biopsies was already observed after 6 weeks of PEM, in cohort 3-4 an increase in IFNγ signature was observed in week 9, after addition of D+T. The same pattern was observed for CD8+ T cell infiltration and PD-L1 expression. After a median follow-up of 43.5 months, the median PFS of pts treated with PEM monotherapy was 10.6 months versus 32.3 months for pts treated with PEM plus D+T (p = 0.19). The 3-year PFS rates were 25.0% and 50.0% respectively. Median OS was 40.5 months in the PEM pts and not reached for pts treated with PEM plus D+T (p = 0.32); 3-year OS rates were 62.5% and 70.8% respectively. Conclusions: IMPemBra demonstrated that short-term addition of intermittent D+T to PEM seems a more feasible, tolerable and an effective alternative for the continuous triple combination. In addition, it gives the opportunity to treat with second line targeted therapy after disease progression. Therefore, this regimen should be considered for further investigation in a larger cohort. Clinical trial information: NCT02625337.

Co-Administration of Menstrual Blood-Derived Stem Cells and Remdesivir for the Treatment of Severe Coronavirus Disease 2019 (COVID-19) Induced Pneumonia: A Research Protocol

Introduction: Remdesivir (Veklury), a viral ribonucleic acid (RNA)-dependent RNA polymerase inhibitor designed by Gilead Sciences, has shown reductions in recovery time for coronavirus disease 2019 (COVID-19) patients, although its efficacy remains controversial. It has been proposed that combining remdesivir with immunomodulators may improve clinical efficacy. Mesenchymal stem cells (MSCs) exert immunomodulatory properties, which resolve COVID-19-induced pneumonia in early-phase trials. Menstrual blood-derived stem cells (MenSCs) present a novel MSC source, superior in availability, proliferative ability, and ethicality than traditional stem cell sources. This study aims to investigate the efficacy of remdesivir-MenSC combination therapy in resolving severe COVID-19-induced pneumonia. Methods: A randomized, double-blind, controlled study will be performed to assess two primary endpoints: time of recovery, defined as no longer requiring ongoing medical care, and normalization of the immune system, defined as the change in the concentration of key cytokines from baseline. Safety will also be measured as the frequency of treatment-related adverse events (AE). The study will aim to recruit 400 eligible subjects, aged 18 to 75, hospitalized with severe COVID-19, and they will be assigned to either receive intravenous (IV) infusions of MenSCs and remdesivir, or receive only remdesivir. A stratified log-rank test will be conducted to compare the time of recovery between study arms, with stratification by disease severity (baseline ordinal score). Two-way repeated measures ANOVA will be used to compare cytokine levels over time in the treatment group compared to the control group. Discussion: We expect remdesivir-MenSC combination therapy to surpass remdesivir in clinical efficacy and safety profile by improving clinical status, lowering duration of hospitalization, reducing mortality, and lowering the incidence of treatment-related AEs. Conclusion: Investigating this promising approach is an essential step in determining the feasibility of stem cell-based treatments in improving current COVID-19 therapeutics and patient outcomes. In particular, evaluating the clinical potential of MenSCs may provide insight into future therapeutic research as the literature has shown that MenSCs are superior to traditional MSC sources.

Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute Phase Peyronie's Disease: A Multi-institutional Analysis

To study, in a multi-institutional setting, the efficacy/safety outcomes in acute phase Peyronie's disease (PD) of multiple high-volume centers employing CCH to treat PD, which is defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis. It is a chronic condition that afflicts 3%-13% of the US male population. There is no current multi-institutional research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD. Retrospective data were collected for consecutive patients with PD who underwent treatment with CCH between April 2014 and March 2018 at 5 institutions. 918 patients were included. Patients with duration of PD no longer than 6 months at presentation qualified as being in the acute phase of PD. Main outcomes of interest include the change in curvature after receiving CCH therapy, and frequency of serious treatment-related adverse events. Successful improvement in curvature is defined as an at least 20% decrease in penile curvature from baseline after CCH therapy. A total of 918 patients were included in the analysis, of which 134 (14.6%) qualified as acute phase PD (group 1) and the remaining 784 (85.4%) qualified as stable phase (group 2). Mean duration of PD was 4.44 ± 1.68 months for group 1, and 40.8 ± 61.2 months for group 2. There was no significant difference in final change in curvature between acute and stable phase of PD (13.5° vs 15.6°, P = .09). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (16 patients, 11.9%) and the stable phase (77 patients, 9.8%; P=.44). In our multivariate analysis, only number of CCH cycles received was predictive of improvement of curvature. This large multi-institutional analysis confirms that CCH therapy is as safe and efficacious in acute phase PD as it is in stable phase PD.

Clinical outcomes of neoadjuvant chemotherapy for patients with breast cancer: Tri-weekly nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide: a retrospective observational study.

ABSTRACTNeoadjuvant chemotherapy (NAC) using the combination of anthracycline and taxanes is the standard regimen for patients with primary breast cancer. Among the taxanes, conventional paclitaxel (PTX) and docetaxel have usually been adopted in the neoadjuvant or adjuvant setting. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free formulation that can be delivered to cancer cells at higher doses than conventional PTX. This study is a retrospective observational study in a single institution. We evaluated the efficacy and safety of nab-PTX followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) in the neoadjuvant setting. In this study, 50 patients with primary breast cancer received nab-PTX (q3w, 260 mg/m2 ± trastuzumab 6 mg/kg) followed by FEC (q3w, 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) prior to surgery. The efficacy was evaluated using the clinical response rate (CRR), pathological complete response (pCR) rate, and Ki67 labeling index. Safety was evaluated using the frequency of treatment-related adverse events and relative dose intensity (RDI). All patients received at least one course of chemotherapy. The CRR and pCR rate were 88.0% and 40.0%, respectively. The mean Ki67 labeling index was significantly decreased from 47.7% to 24.6% after NAC. The safety profiles were comparable with previously reported regimens, and high RDIs were obtained (97.2% for nab-PTX and 95.5% for FEC). This study illustrated the efficacy and tolerability of a neoadjuvant regimen of nab-PTX followed by FEC.

Safety of Timothy Grass Sublingual Immunotherapy Tablet in Children: Pooled Analyses of Clinical Trials

Timothy grass sublingual immunotherapy (SLIT) tablets are indicated for children with allergic rhinitis with or without conjunctivitis. To use pooled analyses to assess the short- and long-term tolerability and safety of timothy grass SLIT-tablet in children. Data from 9 double-blinded, randomized European or North American trials that included children with allergic rhinitis with or without conjunctivitis treated up to 3 years with once-daily timothy grass SLIT-tablet or placebo were pooled. In all, 1818 (timothy grass SLIT-tablet, n= 923; placebo, n= 895) subjects were included in the analysis. The frequency of treatment-emergent adverse events (AEs) was 86% in the SLIT-tablet group and 83% in the placebo group, and the frequency of treatment-related AEs (TRAEs) was 59% and 23%, respectively. Most (98%) TRAEs were mild to moderate in severity. The 2 most common TRAEs with SLIT-tablet were oral pruritus (33%) and throat irritation (19%), which had a median onset of 1 day and recurrence of 14.5 and 5 days, respectively. In all, 8% of subjects in the SLIT-tablet group and 2% in the placebo group discontinued because of AEs. There were 7 serious AEs assessed as related to SLIT-tablet, 1 systemic allergic reaction (severe with a drop in blood pressure), 3 epinephrine administrations, no eosinophilic esophagitis events, and no serious airway obstructions. The safety profile was similar in subjects across geographic regions and with and without asthma. Pooled data indicate that short- and long-term timothy grass SLIT-tablet is well tolerated in children, regardless of geographic region. AEs were generally local, mild, and transient allergic reactions.

The Nobel Prize in Physiology or Medicine 2018 was awarded to Cancer Therapy by Inhibition of Negative Immune Regulation

On October 1, The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to Dr. James P. Allison and Dr. Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation.The Nobel Assembly at Karolinska Institute released the comments that Dr. Allison and Dr. Honjo showed how different strategies for inhibiting the brakes on the immune system could be used in the treatment of cancer [1-5]. The seminal discoveries by the two laureates constitute a landmark in our fight against cancer. https://www.nobelprize.org/prizes/medicine/2018/prize-announcement/I sincerely wish to congratulate two recipients, co-workers and many patients cooperated in clinical trials. In this journal, we have published several reviews and papers on immunity checkpoints so far. The reason is that the mission of this journal is in scientific awareness and dissemination of new immunotherapy.I herein introduce briefly my previous report with some modification [6]. Immune checkpoints inhibitors (ICIs) have opened promising avenues in the treatment of cancer. Various blocking antibodies targeting programmed cell death -1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for human use. They significantly improved disease outcome in a number of cancer patients by boosting anti-tumor immune responses. As Seidel, Otsuka and Kabashima described in their review article [7], mortality among advanced stage patients and the frequency of treatment-related adverse events remain high with current treatment. And, it is also noteworthy that unexpected immune related adverse effects (irAEs) appear, even when it becomes better to be administered to many cancer patients [8]. Unfortunately, the mechanisms of endocrine irAEs by ICIs, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. However, appropriate uses and index setting related to prognosis are being studied in many fields such as dermatology [9] and other organs [6,7].While solving such problems, we have to understand that the mechanisms of immunogenic cell death are now moving from concepts to the clinic. We will explain the mechanism behind ICD and how it will perhaps breathe a new life into chemotherapy use in cancer, not front and center but as a helpful hand to immunotherapy [10].For a long time many scientists or doctors attempted to engage the immune system in the fight against cancer. Many clinicians stared at cancer patients who were to be dying by their side, mourning their inability. However, cancer therapy by inhibition of negative immune regulation checkpoint therapy has fundamentally changed the way we view how cancer can be managed and many patients will receive much better care and cure.

Safety of incobotulinumtoxinA in the treatment of facial lines: Results from a pooled analysis of randomized, prospective, controlled clinical studies

BACKGROUND The safety and efficacy of incobotulinumtoxinA in aesthetics has been established in multiple studies. Although individual studies have been reported, a combined assessment of incobotulinumtoxinA safety across studies is not available. OBJECTIVE To assess the frequency of adverse events (AEs) across prospective incobotulinumtoxinA studies in aesthetics. MATERIALS AND METHODS Safety data were assessed from 9 placebo-controlled or active-controlled single-dose studies on glabellar frown lines (GFL), crow's feet (CF), and upper facial lines (UFL). Analyses by treatment cycle included 4 repeat-dose studies on GFL and UFL. RESULTS One thousand three hundred seventy-seven subjects received incobotulinumtoxinA (GFL, n = 1,189; CF, n = 83; UFL, n = 105) in single-dose studies (placebo-controlled studies: incobotulinumtoxinA, n = 866; placebo, n = 395). Over 1,000 subjects received incobotulinumtoxinA in repeat-dose studies (GFL, n = 880; UFL, n = 290). In placebo-controlled single-dose studies, incidences of treatment-related AEs ranged from 5.4% (GFL) to 22.9% (UFL). The most frequent treatment-related AE in single-dose studies was headache (GFL, 4.8%; UFL, 11.4%). In repeat-dose studies, incidence of AEs was highest during cycle 1 (GFL, 8.9%; UFL, 17.2%) and decreased across treatment cycles. No serious treatment-related AEs were observed. CONCLUSION Results confirm the favorable safety and tolerability of incobotulinumtoxinA. The frequency of treatment-related AEs was low and may decrease with subsequent treatments.

Image-guided adaptive radiotherapy in patients with locally advanced non-small cell lung cancer: the art of PET.

With a worldwide annual incidence of 1.8 million cases, lung cancer is the most diagnosed form of cancer in men and the third most diagnosed form of cancer in women. Histologically, 80-85% of all lung cancers can be categorized as non-small cell lung cancer (NSCLC). For patients with locally advanced NSCLC, standard of care is fractionated radiotherapy combined with chemotherapy. With the aim of improving clinical outcome of patients with locally advanced NSCLC, combined and intensified treatment approaches are increasingly being used. However, given the heterogeneity of this patient group with respect to tumor biology and subsequent treatment response, a personalized treatment approach is required to optimize therapeutic effect and minimize treatment induced toxicity. Medical imaging, in particular positron emission tomography (PET), before and during the course radiotherapy is increasingly being used to personalize radiotherapy. In this setting, PET imaging can be used to improve delineation of target volumes, employ molecularly-guided dose painting strategies, early response monitoring, prediction and monitoring of treatment-related toxicity. The concept of PET image-guided adaptive radiotherapy (IGART) is an interesting approach to personalize radiotherapy for patients with locally advanced NSCLC, which might ultimately contribute to improved clinical outcomes and reductions in frequency of treatment-related adverse events in this patient group. In this review, we provide a comprehensive overview of available clinical data supporting the use of PET imaging for IGART in patients with locally advanced NSCLC.

The Nobel Prize in Physiology or Medicine 2018 was awarded to Cancer Therapy by Inhibition of Negative Immune Regulation

On October 1, The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to Dr. James P. Allison and Dr. Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation.The Nobel Assembly at Karolinska Institute released the comments that Dr. Allison and Dr. Honjo showed how different strategies for inhibiting the brakes on the immune system could be used in the treatment of cancer [1-5]. The seminal discoveries by the two laureates constitute a landmark in our fight against cancer. https://www.nobelprize.org/prizes/medicine/2018/prize-announcement/I sincerely wish to congratulate two recipients, co-workers and many patients cooperated in clinical trials. In this journal, we have published several reviews and papers on immunity checkpoints so far. The reason is that the mission of this journal is in scientific awareness and dissemination of new immunotherapy.I herein introduce briefly my previous report with some modification [6]. Immune checkpoints inhibitors (ICIs) have opened promising avenues in the treatment of cancer. Various blocking antibodies targeting programmed cell death -1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for human use. They significantly improved disease outcome in a number of cancer patients by boosting anti-tumor immune responses. As Seidel, Otsuka and Kabashima described in their review article [7], mortality among advanced stage patients and the frequency of treatment-related adverse events remain high with current treatment. And, it is also noteworthy that unexpected immune related adverse effects (irAEs) appear, even when it becomes better to be administered to many cancer patients [8]. Unfortunately, the mechanisms of endocrine irAEs by ICIs, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. However, appropriate uses and index setting related to prognosis are being studied in many fields such as dermatology [9] and other organs [6,7].While solving such problems, we have to understand that the mechanisms of immunogenic cell death are now moving from concepts to the clinic. We will explain the mechanism behind ICD and how it will perhaps breathe a new life into chemotherapy use in cancer, not front and center but as a helpful hand to immunotherapy [10].For a long time many scientists or doctors attempted to engage the immune system in the fight against cancer. Many clinicians stared at cancer patients who were to be dying by their side, mourning their inability. However, cancer therapy by inhibition of negative immune regulation checkpoint therapy has fundamentally changed the way we view how cancer can be managed and many patients will receive much better care and cure.

Safety of IncobotulinumtoxinA in the Treatment of Facial Lines: Results From a Pooled Analysis of Randomized, Prospective, Controlled Clinical Studies.

The safety and efficacy of incobotulinumtoxinA in aesthetics has been established in multiple studies. Although individual studies have been reported, a combined assessment of incobotulinumtoxinA safety across studies is not available. To assess the frequency of adverse events (AEs) across prospective incobotulinumtoxinA studies in aesthetics. Safety data were assessed from 9 placebo-controlled or active-controlled single-dose studies on glabellar frown lines (GFL), crow's feet (CF), and upper facial lines (UFL). Analyses by treatment cycle included 4 repeat-dose studies on GFL and UFL. One thousand three hundred seventy-seven subjects received incobotulinumtoxinA (GFL, n = 1,189; CF, n = 83; UFL, n = 105) in single-dose studies (placebo-controlled studies: incobotulinumtoxinA, n = 866; placebo, n = 395). Over 1,000 subjects received incobotulinumtoxinA in repeat-dose studies (GFL, n = 880; UFL, n = 290). In placebo-controlled single-dose studies, incidences of treatment-related AEs ranged from 5.4% (GFL) to 22.9% (UFL). The most frequent treatment-related AE in single-dose studies was headache (GFL, 4.8%; UFL, 11.4%). In repeat-dose studies, incidence of AEs was highest during cycle 1 (GFL, 8.9%; UFL, 17.2%) and decreased across treatment cycles. No serious treatment-related AEs were observed. Results confirm the favorable safety and tolerability of incobotulinumtoxinA. The frequency of treatment-related AEs was low and may decrease with subsequent treatments.

Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute-Phase Peyronie’s Disease

BackgroundPeyronie’s disease (PD), defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis, is a chronic condition that afflicts 3% to 13% of the US male population; there is no current research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD. AimTo examine the efficacy and safety of CCH in the treatment of acute-phase PD. MethodsWe retrospectively reviewed the records for all patients treated with CCH for PD from April 2014 through April 2017. Patients who reported penile pain and duration of PD no longer than 12 months at presentation qualified as being in the acute phase of PD. The primary outcomes of interest were final changes in curvature after CCH treatment regardless of the number of CCH cycles received and frequency of treatment-related adverse events. OutcomesParameters of efficacy and safety were compared between acute- and stable-phase PD. ResultsA total of 162 patients were included in the study, of which 36 (22%) qualified as having acute-phase PD (group 1) and the remaining 126 (78%) qualified as having stable-phase PD (group 2). Median duration of PD was 8.5 months (range = 1–12) for group 1 and 18 months (range = 1–492) for group 2. There was no significant difference in final change in curvature between the acute and stable phases of PD (16.7° vs 15.6°; P = .654). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (4 patients, 11%) and the stable phase (12 patients, 10%; P = .778). Clinical ImplicationsCCH therapy is as safe and efficacious in acute-phase PD as it is in stable-phase PD. Strengths and LimitationsThis is the first report that assesses the safety and efficacy of CCH therapy focusing on acute-phase PD. This study was composed of a large cohort of patients receiving CCH therapy in acute- and stable-phase PD. Limitations include bias associated with retrospective studies, a small sample, and a single-center setting. ConclusionsAlthough CCH is not clearly indicated for treatment during the acute phase of PD, these results suggest that CCH use during this phase can be effective and safe. There was no statistically significant difference in final change in curvature or treatment-related adverse events after CCH therapy delivered between the acute and stable phases of PD.Nguyen HMT, Anaissie J, DeLay KJ, et al. Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute-Phase Peyronie’s Disease. J Sex Med 2017;14:1220–1225.

Racial variations in response to intralesional collagenase clostridium histolyticum in men with Peyronie's disease.

BackgroundAn examination of potential racial variations between Caucasian American (CA) and African American (AA) men in the efficacy and safety of collagenase clostridium histolyticum (CCH) in the treatment of Peyronie’s disease (PD).MethodsWe retrospectively reviewed the records for all patients treated with CCH for PD between 04/2014 and 05/2017. Patients were divided into two groups based on their self-reported race. The primary outcomes of interest were final change in curvature after CCH treatment regardless of number of CCH cycles received, and frequency of treatment-related adverse events (TRAEs).ResultsA total of 159 patients were included in the study, of which 146 (91.8%) were CA while 13 (8.2%) were AA. Mean duration of PD was 28.3 months for CA patients and 16.8 months for CA patients (P=0.436). There was no significant difference in final change in curvature CA and AA patients (15.9° vs. 13.1° respectively, P=0.445). There was no statistically significant difference in frequency of TRAEs between CA patients (17, 12%) and AA patients (0, 0%) (P=0.208).ConclusionsAlthough racial variations in efficacy and safety of CCH in patients with PD have not been addressed in the literature, preliminary results from our study suggest that CCH therapy may be equally efficacious and safe in both CA and AA men. There was no statistically significant difference in final change in curvature, International Index of Erectile Function (IIEF) scores, penile length, or TRAEs after CCH treatment between CA and AA patients.

Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial.

BackgroundThere is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.MethodsA multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.Results378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).ConclusionsDue to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.Trial registrationClinicalTrials.gov NCT01310738

MP56-02 SAFETY AND EFFICACY OF COLLAGENASE CLOSTRIDIUM HISTOLYTICUM IN THE TREATMENT OF ACTIVE PHASE PEYRONIE'S DISEASE

You have accessJournal of UrologySexual Function/Dysfunction: Peyronie’s Disease II1 Apr 2017MP56-02 SAFETY AND EFFICACY OF COLLAGENASE CLOSTRIDIUM HISTOLYTICUM IN THE TREATMENT OF ACTIVE PHASE PEYRONIE'S DISEASE James Anaissie, Kenneth DeLay, Nora Haney, Faysal Yafi, and Wayne Hellstrom James AnaissieJames Anaissie More articles by this author , Kenneth DeLayKenneth DeLay More articles by this author , Nora HaneyNora Haney More articles by this author , Faysal YafiFaysal Yafi More articles by this author , and Wayne HellstromWayne Hellstrom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1755AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To examine the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase Peyronie's Disease (PD). METHODS We conducted a retrospective review of the records for all patients treated with CCH for PD between 04/2014 and 03/2016. Patients qualified as being in the acute phase of PD if they reported penile pain and duration of PD < 12 months at presentation. The primary outcomes of interest were final change in curvature after CCH treatment regardless of number of CCH cycles received, and frequency of treatment-related adverse events (TRAE). Paired t-Test and Chi-squared tests were performed to determine statistical significance (P<0.05). RESULTS A total of 77 patients were included in the study, of which 21 (27%) qualified as acute phase PD and the remaining 56 (73%) as stable phase. Median duration of PD was 8 months for acute phase patients, and 21 months for stable phase (p=0.033). There was no significant difference in final change in curvature between the acute and stable phase of PD (16.2° vs. 14.9°, p=0.702). There was a significant difference in change in curvature reported after the first cycle of treatment between the acute and stable phase (21.7° vs. 12.5°, p=0.037). There was no statistically significant difference in frequency of TRAEs between the acute phase (3, 14%) and the stable phase (4, 7%) (p=0.332). CONCLUSIONS Although CCH is currently contraindicated during the acute phase of PD, preliminary results suggest that CCH use during this setting may be both effective and safe. There was no statistically significant difference in final change in curvature or TRAEs after CCH therapy between the acute and stable phase of PD. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e755 Advertisement Copyright & Permissions© 2017MetricsAuthor Information James Anaissie More articles by this author Kenneth DeLay More articles by this author Nora Haney More articles by this author Faysal Yafi More articles by this author Wayne Hellstrom More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...