Median Number Of Doses Research Articles

Mental health related adverse events of cytisine and varenicline in smokers with and without mental health disorders: Secondary analysis of a randomized controlled trial

IntroductionLittle is known about the adverse events (AEs) of cytisine versus varenicline among individuals with mental health disorders (MHDs), highlighting the necessity for further exploration to inform clinical practice. This secondary analysis of clinical trial data aimed to investigate the effect of varenicline vs. cytisine regarding mental-health-related AEs (MH-related AEs) on smokers with and without MHDs. MethodsAustralian daily smokers interested in quitting were randomised to varenicline (84 days) or cytisine (25 days) and categorised by self-reported MHD diagnosis or treatment in the past year (MHD or non-MHD groups). Treatment adherence was assessed by self-reported number of doses taken during the active treatment phase via two check-in calls (at one month), while AEs were evaluated through four phone interviews: two check-in calls (one month) and follow-up calls at four and seven months. Logistic regression analysis compared MH-related AEs between groups, including only participants taking at least one dose. ResultsOf 1452 smokers 246 reported MHDs, 725 received cytisine and 727 received varenicline. Median number of doses taken was comparable between MHD (34 cytisine and 12 varenicline) and non-MHD (33 cytisine and 13 varenicline) groups. MH-related AEs were: 14.1 % (n = 30) in MHD (12.5 % in cytisine and 15.4 % in varenicline), and 11.8 % (n = 126) in non-MHD group (10.9 % in cytisine and 13.7 % in varenicline). No significant difference in MH-related AE occurrence was identified between medication groups (aOR=0.96, 95 % CI 0.4 to 2.2, p-value = 0.94). ConclusionComparable MH-related AEs were observed between smokers with and without MHDs, suggesting that cytisine, like varenicline, may be well-tolerated by those with MHDs. However, larger clinical trials focused on MH-related AEs are needed for more conclusive evidence.

Dexamethasone in adults with viral meningitis: an observational cohort study

ObjectivesTo investigate whether there is a dose-dependent association between empiric dexamethasone and outcome in viral meningitis. MethodsObservational cohort study of adults hospitalized for viral meningitis, both with and without a microbiologically confirmed diagnosis, in Denmark between 2015 and 2020. Dose-dependent associations between dexamethasone (one dose = 10 mg) and an unfavourable outcome (Glasgow Outcome Scale score 1–4) at 30 days after discharge were assessed using weighted logistic regression. Entropy balancing was used to compute weights. ResultsOf 1025 included patients, 658 (64%) did not receive dexamethasone, 115 (11%) received 1–2 doses, 131 (13%) received 3–4 doses, and 121 (12%) received ≥5 doses. Among patients treated with dexamethasone, the median number of doses was higher for those without an identified pathogen than for those with a microbiologically confirmed viral aetiology (5 [interquartile range (IQR) 3–8] vs. 3 [IQR 2–5]; p < 0.001). Using no doses of dexamethasone as a reference, the weighted OR for an unfavourable outcome were 0.55 (95% CI, 0.29–1.07) for 1–2 doses, 1.13 (95% CI, 0.67–1.89) for 3–4 doses, and 1.43 (95% CI, 0.77–2.64) for ≥5 doses. In the subgroup of enteroviral meningitis, the weighted OR was 3.08 (95% CI, 1.36–6.94) for ≥5 doses, but decreased to 2.35 (95% CI, 0.65–8.40) when the reference group was restricted to patients treated with antibiotics for suspected bacterial meningitis. DiscussionThis study showed no dose-dependent association between dexamethasone and an unfavourable outcome in patients with viral meningitis. In enteroviral meningitis, ≥5 doses were associated with an increased risk of an unfavourable outcome. However, sensitivity analysis indicated that the association was affected by unmeasured or residual confounding by severity.

Safety and effectiveness of mogamulizumab in relapsed or refractory CC chemokine receptor 4-positive peripheral T-cell lymphoma and relapsed or refractory cutaneous T-cell lymphoma: A post-marketing surveillance in Japan.

Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1-18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%-76.5%) [PTCL, 64.4% (54.0%-73.0%); CTCL, 90.5% (67.0%-97.5%)]. Safety and effectiveness were comparable between patients <70 and≥70years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.

Neoadjuvant-Intent Immunotherapy in Advanced, Resectable Cutaneous Squamous Cell Carcinoma

In clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with relevant comorbidities. To evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population. This cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5). Cemiplimab or pembrolizumab. Primary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease-specific survival, and overall survival. This cohort study included 27 patients (including 9 patients [33.3%] with a history of lymphoma). Most patients were male (18 of 27 [66.7%]), with a median age of 72 years (range, 53-87 years). Most primary tumors were located on the head/neck (21 of 27 [77.8%]). There were no unexpected delays in surgery. The median number of doses before surgery was 3.5 (range, 1.0-10.0). Five patients (18.5%) ultimately declined to undergo planned surgery due to clinical responses or stability, and 1 (3.7%) did not undergo surgery due to progressive disease. The overall pathologic response rate (pathological complete response [pCR] or major pathological response) was 47.4% (9 of 19), and the overall radiologic response rate (radiologic complete response or partial response) was 50.0% (8 of 16). The pCR rate (7 of 19 [36.8%]) was higher than the radiologic complete response rate (2 of 16 [12.5%]). The pCR rate among patients with cSCC and concomitant lymphoma was 25.0%. The 1-year recurrence-free survival rate was 90.9% (95% CI, 50.8%-98.7%), progression-free survival was 83.3% (95% CI, 27.3%-97.5%), disease-specific survival was 91.7% (95% CI, 53.9%-98.8%), and overall survival was 84.6% (95% CI, 51.2%-95.9%). The results of this cohort study support the reproducibility of neoadjuvant-intent immunotherapy for cSCC in the clinical setting, including for patients with a history of lymphoma. Outside of clinical trials, it is not infrequent for patients to opt out of surgery for regressing tumors. The inclusion of higher-risk patients and preference for nonsurgical treatment are 2 factors that might explain the numerically lower pathologic response rate in this institutional experience.

Effect of cancer cachexia on first-line chemotherapy in patients with advanced pancreatic cancer: a claims database study in Japan

BackgroundCancer cachexia is a multifactorial syndrome leading to progressive functional impairment. How cachexia affects the treatment course of chemotherapy in patients with pancreatic cancer has not been well understood.MethodsThis is an exploratory, retrospective, observational cohort study using the Japanese medical claims database from Medical Data Vision Co., Ltd. The study population included patients diagnosed with pancreatic cancer in whom first-line FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) was initiated between October 1, 2018, and September 30, 2020. In this study, we defined patients with cancer cachexia as those who had a weight loss of ≥ 5% in the preceding 6 months. The primary outcome was time-to-treatment failure (TTF). The observation period was six months from the initiation of first-line FFX or GnP treatment.ResultsA total of 1897 patients (421 patients into the cachexia group; 1476 patients into the non-cachexia group) were analyzed in this study. The median TTF was 121 days (95% confidence interval [CI] 94–146) in the cachexia group and 143 days (95% CI 134–152) in the non-cachexia group. The hazard ratio for TTF of the cachexia versus non-cachexia group was 1.136 (95% CI 0.979–1.319). The median number of doses was two doses fewer in the cachexia group than in the non-cachexia group for both FFX and GnP.ConclusionCancer cachexia was suggested to be associated with shorter TTF and a reduced number of doses in patients with pancreatic cancer who received first-line FFX or GnP treatment.Clinical Trial Registration clinicaltrials.jp: UMIN000045820.

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy

Introduction: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, the incidence and outcomes of CMV reactivation in patients undergoing chimeric antigen receptor T (CAR T) cell therapy remain poorly understood. Methods: Single-center retrospective study of 109 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV viral load was monitored at the discretion of the treating physician. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV (viremia or tissue invasive disease requiring antiviral treatment). The study was approved by our institutional review board and conducted consistent with the principles in the Declaration of Helsinki. A p-value of &amp;lt;0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism Software, version 10.0.0. Results: During the study period, there were a total of 148 patients who received CAR T cell therapy. Patients who were CMV seronegative, had history of previous allogeneic HCT, or those who received letermovir prophylaxis were excluded. In total, 109 patients who were CMV seropositive met the inclusion criteria. The patient characteristics are presented in Table 1. Of the 109 patients, 69% received Axicabtagene Ciloleucel (Yescarta), 15% received Brexucabtagene Autoleucel (Tecartus), 8% received Tisagenlecleucel (Kymriah), 5% received Idecabtagene Vicleucel (ABECMA), and 3% received Lisocabtagene Maraleucel (Breyanzi). Eighty-four patients (77%) developed any grade of CRS with the median day of CRS onset being 4 days (IQR, 2 to 6). Forty-six patients (42%) developed any grade of ICANS. Among patients who developed CRS, 74 (88%) received tocilizumab, 58 (69%) received dexamethasone, and 9 (11%) received anakinra. For dexamethasone group, the median dosage was 103 mg (IQR, 45 to 160). In those receiving tocilizumab, the median number of doses was 2.5 (IQR, 1 to 4) and the dosage was standard 8 mg/kg. 31 patients (28%) had evidence of CMV reactivation (any viremia) and 10 patients (9%) had clinically significant CMV reactivation requiring treatment. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9 to 31). Among those with clinically significant CMV reactivation, the median peak viremia was 2388 IU/mL; six of these patients (60%) developed CMV syndrome with none having tissue invasive disease; and 9 (90%) had documented clearance of the virus in response to antiviral therapy. In this group, there were 2 deaths but were not attributed to CMV reactivation. One was due to fungemia while the other patient's death was attributed to CAR T therapy related toxicities causing multiorgan failure. Among those who didn't reactivate CMV, 37 patients (47%) received dexamethasone, at a median dose of 90 mg (IQR, 25 to 145), whereas in the 10 patients with clinically significant CMV reactivation, 100% received dexamethasone (P=0.001) with a median dose of 130 mg (IQR, 74 to 263). Additionally, those who received tocilizumab and anakinra were also at a significantly higher risk for clinically significant CMV reactivation (p=0.027 and p=0.03, respectively). Conclusions: CMV reactivation is a common complication of CAR T cell therapy in CMV seropositive individuals. Although confirmatory studies are needed, our data shows that administration of immunosuppression, in particular steroids, for management of CAR T cell toxicities is a major risk factor for CMV reactivation, and close monitoring for preemptive therapy or antiviral prophylaxis might be indicated in this setting.

Simvastatin with Intrathecal Dexamethasone Reduces Neurotoxicity in Adults Receiving Chimeric Antigen Receptor (CAR) T-Cells Treatment

Background Chimeric antigen receptor (CAR) T-celltherapy has become the standard of care for many relapsed/refractory hematological malignancies. There are significant associated side effects, most importantly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can limit its use in older and vulnerable populations. The rate of ICANS with axicabtagene ciloleucel (axi-cel) in the pivotal studies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) was approximately 60% with grade 3 or higher (≥ G3) in the range of 19-28%. Similarly, with brexucabtagene autoleucel (brexu-cel), ICANS also occurred in approximately 60% with ≥ G3 occurring in 26-31% of patients. The mechanism underlying ICANS remains unclear. The current hypothesis is that endothelial injury caused by systemic immune activation leads to the breakdown of the blood-brain barrier with the influx of pro-inflammatory cytokines into the CSF and subsequent activation of resident immune cells and neuroglial cells leading to local production of cytokines and the clinical syndrome observed. ICANS is treated with systemic steroids that have good central nervous system (CNS) penetration. Statins have been shown to stabilize the endothelium and have anti-inflammatory effects. We are currently evaluating the safety and feasibility of administering simvastatin in addition to intrathecal dexamethasone to decrease the incidence and/or severity of neurotoxicity in CAR-T recipients and we are herein reporting preliminary results. Methods This is a feasibility study (NCT04514029) combining simvastatin 40 mg daily, starting 5 days prior to apheresis and continuing through day +30 with dexamethasone (8 mg) delivered intrathecally (IT) on days -1 and +6 in relation to CAR T-cell infusion. Adult patients (age ≥18 years) receiving axi-cel or brexu-cel for FDA-approved indications are included. The primary endpoint is the percentage of patients who complete 80% of this therapy (pills and intrathecal). Secondary endpoints include the incidence of CRS and ICANS as well as overall response rates (ORR). Results At the time of data cutoff, a total of 15 patients who received treatment with axi-cel or brexu-cel and completed follow-up were enrolled. Baseline demographics and clinical characteristics are summarized in Table 1. Among patients who received axi-cel, 10 patients had DLBCL and 1 patient had FL. For brexu-cel, 2 patients had mantle cell lymphoma (MCL) and 2 had B-acute lymphoblastic leukemia (B-ALL). Median prior lines of treatment was 3 (range 2 to 7) and 11 patients (46.7%) had progressive disease at the time of the treatment. Analysis of baseline inflammatory markers prior to the cell infusion showed that 2 patients (13.3%) had elevated lactate dehydrogenase (LDH; upper limit normal 250 U/L; median 180, range 100 to 279). Eight patients (53.3%) had elevated C-reactive protein (CRP; median 9.24 mg/L, range &amp;lt;3 to 67.8). Ferritin was elevated in 6 patients (40%) (median 382, range 34 to 1749). All patients received &amp;gt; 80% of the total assigned doses. One patient was unable to receive intrathecal therapy due to thrombocytopenia with platelet transfusion refractoriness. All evaluable patients completed oral simvastatin with no patients requiring dose reductions. CRS occurred in 13 patients (86.7%), with ≥ G3 occurring in 1 patient (6.7%). Tocilizumab (8 mg/kg) was administered to 11 patients (73.3%) with the median number of doses being 1 (range 1 to 4). ICANS occurred in 4 patients (26.7%), with ≥ G3 occurring in 2 patients (13.3%) - one G3 and one G4 in the patient who was unable to receive IT therapy. Glucocorticoids were used in 3 patients (20%) for the management of ICANS. There were no grade 4 CRS events and no deaths related to CRS or ICANS. One patient had a vasovagal syncopal episode prior to the beginning of a lumbar puncture. There were no other ≥ G3 AEs associated with the administration of simvastatin or IT dexamethasone. One patient with Richter's had progressive disease at day 30, 4 patients had partial remission, and 10 patients had a complete remission for an ORR of 93%. Conclusions Preliminary results show that simvastatin and intrathecal dexamethasone appear to be feasible, safe, and effective in reducing the incidence and severity of ICANS in patients receiving axi-cel and brexu-cel.

Systemic inflammation markers ratio in heavily pretreated NSCLC patients treated with nivolumab.

e21188 Background: Inflammatory cells have important effects on tumor development. Systemicinflammation markers can be used as prognostic factors. Numerous studiesshown that high pretreatment neutrophil-to-lymphocyte ratio (NLR) and/or platelet-to-lymphocyte ratio (PLR) levels are potential prognostic predictors for poor progression-free survival (PFS) and overall survival (OS) in NSCLC patients receiving immunotherapy. Methods: We performed a cohort study of patients with metastatic or recurrent NSCLC treated with nivolumab monotherapy in second‐line or further‐line treatment in Clinical hospital centre Zagreb. Pre-treatment NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. Patients were categorized in two sub-groups according to their NLR and PLR values. In previous meta-analyses it was suggested that significant cut-off value of NLR is NLR &lt; 5 and ≥5 and PLR &lt; 160 and ≥160. We analysed PFS and OS. Results: Overall 105 patients diagnosed with NSCLC were treated with nivolumab. The patients were enrolled from March 2017 until October 2017 and were observed them for disease progression and death until June 1st 2020. Most of the patients were male (71; 67.6%) with median age 60.3 years (36-77). Our patients were selected on the basis of good performance status, so most of them had ECOG PS 0 and 1 (103; 98.1%). Therapy was applied mostly in the second and third line (67; 64%), but even up to seventh line (2; 1.9%). Median duration of therapy was 34.5 weeks (2-149), while median number of doses was 17 (1-69).The median PFS was 7.2 months (95% CI 4.53-9.86). Regardless of previous treatment the mOS was 16.1 months (95% CI 11.26-20.93).We observed median value of NLR 4.08 (IQR 2.44-5.84) and PLR 200 (IQR 127.49-284.72). Patients with low PLR had better overall survival compared to patients with low PLR (mOS 20.5 months vs 11.9 months; 95%CI 14.07-26.92 vs 7.35-16.44; p = 0.039). The same was not as clear in mPFS, tendency of better mPFS was toward low PLR, but it did not reach statistical difference (low PLR mPFS 9.1 months vs high PLR mPFS 6.1 months; p = 0.49).Patients with low NLR had significantly better overall survival compared to patients with high NLR (mOS low NLR 18.2 vs high NLR 10.1 months; 95%CI 13.07-23.32 vs 6.04-14.15; p = 0.014). Again, the statistical significance was not reached for progression-free survival (mPFS low NLR 8.3 months vs high NLR 5.8 months; 95%CI 4.81-11.78 vs 2.91-8.68; p = 0.214). Conclusions: Here, we demonstrated that the presence of indicators of systemic inflammation suchas high NLR and high PLR are associated with poor overall survival, but not withprogression-free survival in pre‐treated NSCLC patients who received nivolumabtreatment. The limitation of our study is the lack of a randomizedcontrol and small sample size. The main strength of our study is that it is real-worldeveryday clinical setting.

Intravenous (IV) infusion of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, as monotherapy in advanced solid tumors: Preliminary results from an ongoing phase 1/2a study.

e14689 Background: Oncolytic virotherapy has emerged as a promising anticancer treatment. To date, almost all oncolytic viruses (OVs) are delivered via intratumoral (IT) injection, which limits its broad clinical application. Systemic delivery of OVs, a more practical option for patients (pts) without injectable lesions, allows both primary tumor and metastases treated simultaneously. However, due to concerns for immune clearance and the potential cytokine storms, very few studies thus far are conducted using OVs intravenously. T3011 is a genetically modified, next-generation oncolytic HSV-1 expressing IL-12 and PD-1 antibody. Extensive preclinical studies have demonstrated the feasibility, safety and efficacy of T3011 delivered intravenously. Here, we present preliminary results of IV T3011 as a single agent. Methods: In this phase 1/2a, multi-center, open label, dose escalation and expansion study, T3011 was administered intravenously on Days 1, 4, 8 of a 21-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of escalating doses of IV T3011, characterize dose limiting toxicities (DLTs) and identify the MTD and RP2D of IV T3011. Phase 1 portion used a 3+3 design in 4 escalating cohorts (1×106, 1×107, 1×108, 3×108 PFU). Pharmacokinetics, immunogenicities and pharmacodynamic profiles were studied in various samples. Results: As of Jan 2023, 10 pts received IV T3011 therapy: 4 in Cohort 1, 3 in Cohort 2, and 3 in Cohort 3. Median number of doses was 8. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (TRAEs) and no DLTs to date. Nausea and infusion-related reaction (including postdose delayed fever, chills, rigors, etc.) were the most common TRAEs. 7 of 10 pts had ≥ 1 tumor assessment, 4 achieved stable disease (SD) by RECIST 1.1 with a disease control rate of 57.1%, 2 had SD for ≥ 6 months. 1 pt had a postdose tumor biopsy revealing T cell activation via transcriptome profiling and gene ontology analysis. T3011 DNA was detected in blood in 9/10 pts at 0.5 hours after the 1st dose and its level was dose-dependent and increased with repeated doses. T3011 DNA clearance was observed at 4-7 days after dosing. Saliva and urine samples from all pts were tested for T3011 DNA, only one was positive with very low DNA copies in a saliva sample at 0.5 h after the 2nd dose from a pt in Cohort 1. Of note, pre-existing HSV-1 IgG had no impact on T3011 activity. Conclusions: IV T3011 monotherapy was well tolerated and safe at the first 3 dose levels, highly unlikely to be transmissible. Preliminary efficacy was encouraging. Our results also suggest T3011 IV treatment could stimulate anti-tumor immunity in the tumor microenvironment. Clinical trial information: NCT04780217 .

Risk factors associated with cisplatin-induced ototoxicity in Japanese patients with solid tumors.

Cisplatin, a first-generation platinum agent, is used for managing various cancers and is associated with dose-dependent side effects of hearing impairment and tinnitus. However, the safety of high-dose cisplatin in hearing impairment, has not been fully investigated in Japan. We performed pure-tone threshold audiometry before and every 3-4 weeks after chemotherapy for patients receiving cisplatin-containing chemotherapy between April 2015 and October 2017 at Kobe Minimally Invasive Cancer Center. Hearing impairment was evaluated prospectively using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. We enrolled 100 patients and analyzed 96 patients for whom post-chemotherapy audiometry could be performed. The median patient age was 65 years, and most patients were male (75). The cancer types were as follows: esophageal, 36; head and neck, 35; lung, 23; and gastric, 2. Cisplatin monotherapy and combination therapy were administered to 33 and 63 patients, respectively. A single cisplatin dose was 60-100 mg/m2 ; the median number of doses and total dose were 3 and 240 mg/m2 , respectively. Additionally, 78 and 18 patients were treated with concurrent chemoradiotherapy and chemotherapy alone, respectively. Twenty-seven patients had grade 2 or higher hearing impairment. Furthermore, the prevalence was significantly higher in patients receiving a total dose of ≥300 mg/m2 . Twenty and 32 patients were aware of deafness and tinnitus, respectively. No patient discontinued treatment owing to hearing impairment. The total cisplatin dose was considered related to post-treatment hearing impairment frequency in Japanese patients. However, routine audiometric monitoring is recommended during high-dose cisplatin-based chemotherapy.

Tissue plasminogen activator with prolonged dwell time effectively evacuates pleural effusions

ObjectivesFibrinolytic therapy can be effective for management of complex pleural effusions. Tissue plasminogen activator (tPA, 10 mg) and deoxyribonuclease (DNAse) every 12 h with a dwell time of one hour is a common strategy based on published data. We used a simpler protocol of tPA (4 mg) without DNAse but with a longer dwell time of 12 h, repeated daily. We reviewed our results.MethodsCharts were reviewed and demographics, clinical data and treatment information were abstracted. Outcomes were assessed based on radiographic findings and need for surgery.ResultsTwo hundred and fifteen effusions in 207 patients (8 bilateral) were identified. 85% were either infectious or malignant. Two hundred and forty nine chest tubes were used: 84% were 10 Fr or 12 Fr and 7% were PleurX®. Five hundred and thirty one doses of tPA were given. The median number of doses per effusion was 2 (range 1–10), and 84% of effusions were treated with three or fewer doses. There were no significant bleeding complications. Median time to chest tube removal was 6 days (range 1 to 98, IQR 4 to 10). Drainage was considered complete for 78% of effusions, while 6% required decortication.ConclusionsLow dose tPA daily with a 12 h dwell time may be as effective as the standard regimen of tPA and DNAse twice daily with one hour dwell. For most patients only three doses were required, and small pigtail catheters were sufficient. This regimen uses less medication and is logistically much easier than the current standard.

Tolerability and treatment outcome of pembrolizumab in patients with advanced urothelial carcinoma and severe renal dysfunction.

Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment of advanced urothelial carcinoma. However, the tolerability and outcomes of pembrolizumab in patients with severe renal dysfunction [creatinine clearance (CrCl) <30 ml/min] are unclear because no clinical trials included such patients. We analyzed the safety profile and outcomes of these patients in the real world. We extracted data for 739 pembrolizumab-treated patients from a Japanese nationwide cohort of platinum-refractory metastatic urothelial carcinoma. Using propensity score matching, the overall survival (OS) and adverse events (AEs) of patients with CrCl <30 and ≥30 were compared. Ninety-two patients (12.4%) had CrCl <30 ml/min. The median number of doses was similar between the CrCl ≥ 30 and CrCl <30 groups (5 and 4, respectively), and there was no difference in the frequency of grade ≥2 treatment-related AEs between the groups (35.5% vs. 35.7%). The overall response rate was similar between the groups (27.2% vs. 29.7%, P = 0.184). Using propensity score matching, the median OS times in the CrCl ≥30 and CrCl <30 groups were 10.3 (95% confidence interval [CI] = CI 7.3-13.0) and 8.1 months (95% CI = 5.4-14.6, P = 0.626), respectively. The 1-year OS rates in these groups were 41.5% and 38.2%, respectively, and the 2-year OS rates were 21.3% and 20.2%, respectively. In multivariate Cox regression analysis, performance status ≥2 (hazard ratio [HR] = 5.56, 95% CI = 2.64-11.71, P < 0.0001) and neutrophil-to-lymphocyte ratio ≥3 (HR = 2.20, 95% CI =1.15-4.19, P = 0.013) were independently associated with patient prognosis in the CrCl <30 group. This report illustrated that pembrolizumab can be safely administered to patients with severe renal dysfunction, who had similar outcomes as patients without severe renal dysfunction.

Phase I clinical trial of NEO-201, an anti-tumor-associated CEACAM-5/6 monoclonal antibody in solid tumors.

2531 Background: NEO201 is a humanized IgG1 monoclonal antibody generated against tumor-associated antigens from colorectal cancer which binds specifically to tumor-associated CEACAM-5 and CEACAM-6 variants without binding CECAM 5/6 on normal epithelial tissues. NEO-201 reactivity is positive in the majority of adenocarcinomas including colon (85%), pancreas (86%), lung (79%), and breast (53%). Preclinical data showed that NEO-201 exerts anti-tumor activity through antibody dependent cellular cytotoxicity and complement dependent cytotoxicity. Here we present outcomes from a phase I trial of NEO-201 in advanced solid tumors (NCT03476681). Methods: This was a classic 3+3 dose escalation trial, with cohort expansion at the RP2D. NEO-201 was administered intravenously every two weeks in a 28-day cycle. The primary objective was to assess the MTD/RP2D of NEO-201 in patients with advanced solid tumors. The secondary objective was to assess the preliminary antitumor activity and exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and possible relationships with response. Of 17 patients enrolled, 11 had colorectal, 4 had pancreatic and 2 had breast cancer. 4 patients received NEO-201 at dose level (DL) 1 (1 mg/kg), 6 patients at DL 1.5 (1.5 mg/kg) and 7 patients at dose DL 2 (2 mg/kg). Results: At the time of data cutoff, all patients had discontinued therapy. 11 of 14 evaluable patients discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia and prolonged neutropenia, each in 1/6 patients at DL2, and grade 3 febrile neutropenia in 1/6 patients at DL 1.5). Most common grade 3/4 toxicities were neutropenia (94%), white blood cell decrease (59%), lymphocyte decrease (29%), and febrile neutropenia (24%). Protocol was modified to allow administration of G-CSF and based on safety and PK data the RP2D was established as 1.5mg/Kg. Median number of doses received was 4.7. 13 subjects were able to undergo disease assessment after two cycles. The best response observed was stable disease (SD) in 5/9 evaluable patients with colorectal cancer. Minor CA-19-9 reductions were observed in two pancreatic cancer patients at DL 1.5. Correlative endpoints revealed that all patients enrolled in the trial expressed NEO-201 target antigen on their tumor tissue. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating T regulatory cells and depleted these cells especially in patients with SD. Conclusions: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg. Depletion of T regulatory cells suggests that the combination of NEO-201 with immune checkpoint inhibitor should be tested in future clinical trials. Clinical trial information: NCT03476681.

Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.

Initial results of a first-in-human, dose escalation study of a cell-based vaccine in HLA A*02+ patients (pts) with recurrent, locally advanced or metastatic HPV16+ solid tumors: SQZ-PBMC-HPV-101.

2536 Background: Ineffective MHC-I presentation of tumor antigens to CD8+ T cells limits T cell activation and the efficacy of cancer vaccines. The Cell Squeeze technology drives peripheral blood mononuclear cells (PBMCs) through a microfluidic chip leading to temporary cell membrane disruption and delivery of HPV16 E6 and E7 antigens cytosolically. These antigen presenting cells (APC) were matured with CpG7909 and were not genetically modified. Preclinically, this approach showed improvement in MHC-I presentation for human and murine cells. In murine tumor studies, m-SQZ-PBMC-HPV elicited robust CD8+ T cell responses and improved anti-tumor effects when compared to other vaccine modalities. Methods: SQZ-PBMC-HPV-101 included pts with incurable HPV16+ cancers progressing after unlimited prior therapy, ECOG 0-1, adequate organ function and a biopsiable lesion. After leukapheresis at the study site, manufacturing of the cryopreserved product took &lt; 24 hours with a vein-to-vein time of approx. 1 week. Out-patient SQZ-PBMC-HPV was given IV q 3 weeks without a conditioning regimen. Double antigen priming (DP) was introduced with Cohort 3 and occurred on Cycle 1 Days 1 and 2. Maximum treatment duration for each patient was determined by the cell batch size. Response was assessed via RECIST 1.1 and iRECIST. Investigational biomarkers were measured pre- and post-treatment. Results: 12 pts [anal (7), head and neck (3), and cervical (2)] were dosed in 3 cohorts (3 pts in 0.5 x10e6/kg, 5 pts in 2.5 x10e6/kg, and 4 pts in 2.5x 10e6/kg [DP]). Median lines of prior Tx were 4 (range 1 - 7) and all but one pt were pretreated with checkpoint inhibitors (CPI); 10 pts had liver or lung metastases. All batches of SQZ-PBMC-HPV demonstrated CD8 activation in vitro after thawing, and batch size did not limit therapy duration at dose levels tested to date. Median number of doses were 3 (3 - 10), 3 (2 - 4), and 3 (3 – 4) in the 3 cohorts, respectively. One pt (10 doses) remained on study for 42 weeks. Tx was well-tolerated and there were no DLTs, Grade (G) &gt;3 related SAEs or related G &gt;3 AEs. One pt in cohort 1 experienced both a G2 infusion-related reaction and cytokine release syndrome. One pt in cohort 2 was not evaluable for DLT. Four out of 10 evaluable pts had stable disease per RECIST 1.1 as the best response. Preliminary tumor analyses pre- and post-therapy indicated increased immune activity in some patients after SQZ infusion. Conclusions: SQZ-PBMC-HPV-101 demonstrated clinical feasibility of the Cell Squeeze technology and favorable tolerability of engineered APCs. The study allows for the characterization of the immunogenicity of engineered APCs in humans. Preliminary results warrant the testing in combination with CPI. Efficacy, safety, and correlative biomarker data will be presented, from pre- and post-therapy biopsies and blood samples. Clinical trial information: NCT04084951.

Ipilimumab + nivolumab in people with rare variant renal cell carcinoma refractory to nivolumab alone: Part 2 of UNISON (ANZUP 1602) nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma.

4565 Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

Monitoring C-reactive protein facilitates early discontinuation of immune oncology without compromising outcomes in stage IV non-small cell lung cancer.

e21107 Background: C-Reactive Protein (CRP) is a non-specific inflammatory marker and reflects tissue destruction seen in metastatic cancer (ca). We have observed a tight correlation with CRP trends mirroring ca activity, hence it may prove to be a valuable marker to monitor response to Immuno-Oncology (IO) in non-small cell lung cancer (NSCLC) patients (pts). Once CRP levels stabilized, IO discontinuation was offered, and consenting pts were closely observed. This strategy resulted in shortened IO duration and impressive treatment-free progression-free survival (tf-PFS). We sought to examine the validity of this strategy using the rate of return to any form of ca therapy within 6 months after stopping IO. Methods: We analyzed all pts of a single provider since 2016 with stage IV NSCLC who had CRP checked while on IO, totaling 23 pts. We excluded pts who stopped IO for reasons besides stable CRP values (5 progressed on IO, 3 died while on IO, 1 had side effects, 1 stopped for a clinical trial, 1 opted to complete 2 years of IO, and 2 are still on IO). Of the remaining 10 patient cohort, all pts were males treated at the VA with ages between 56-75 years at diagnosis. 50% of the cohort had adenocarcinoma and 50% had squamous cell carcinoma. Results: Using the CRP trend to shorten the duration of IO resulted in durable drug-free holidays with none of the cohort returning to any form of ca therapy within 6 months and comparable rates of overall survival (OS) despite shorter IO duration. In KEYNOTE-042, the median OS for pts on the pembrolizumab arm was 16.7 months in the overall population and 20 months in the TPS ≥50% subgroup. Pts were treated for up to 35 months. In our cohort, median OS was 38 months, with all pts currently still alive, and median number of doses of IO was 9 cycles, or approximately 7 months. Our pts had ongoing progression free survival (PFS) after stopping treatment, which we report as tf-PFS. The median tf-PFS of our cohort was 23.5 months. Conclusions: In pts with stage IV NSCLC treated with IO, CRP appears promising as a marker to tailor IO therapy addressing tumor and clinical heterogeneity. Responding pts with stable CRP levels can be safely taken off IO. CRP should be monitored with stable values indicating continued PFS. tf-PFS rather than PFS may serve as a surrogate for cure and carries significant impact for pts financially, socially, and psychologically. [Table: see text]

Observed survival benefit with limited exposure of durvalumab in unresectable stage III non-small cell lung cancer at a large community-based institution.

e20539 Background: The PACIFIC trial ushered in a paradigm shift in the management of unresectable, non-metastatic non-small cell lung cancer (NSCLC), demonstrating improvement in 12,24,36-month overall survival (OS) and leading to the 2018 FDA approval for durvalumab in unresectable or locally advanced stage III NSCLC. With almost 3 years of FDA approval, we performed a retrospective analysis of patient experiences and outcomes at Levine Cancer Institute analyzing patient data to assess survival and potential points of clinical significance. Methods: Patients over the age of 18, who met criteria similar to the PACIFIC trial (i.e. unresectable or locally advanced stage III NSCLC) from February 2018 through September 2020 were analyzed. Those who were receiving active treatment at the data cutoff were excluded. Patient characteristics, prior treatment, durvalumab administration, immune-related adverse events (irAEs), and efficacy data were summarized and evaluated. OS and progression free survival (PFS) were evaluated with Kaplan Meier methods. Results: A total of 159 patients were evaluated. 40.9% were female and 59.1% were male. The median age was 67 (range 38-83 years). Of note, 86.8% of patients were white, whereas 13.2% were nonwhite. 50.3% patients experienced an irAE. The most common reasons for discontinuation of durvalumab were completion (at least 24 doses), progressive disease, or toxicity (33.3%, 30.8%, 26.4%, respectively). The median number of doses of durvalumab received was 14 (range 1-26 doses). The median PFS was 15.3 months with 12-and 24-month PFS being 54% and 41.1 %, respectively. Median OS was 42 months with 12-and 24-month OS being 78.1% and 67.8%, respectively. Our analysis compared outcomes in those who completed adjuvant durvalumab versus those who did not complete adjuvant therapy (Table). Conclusions: Data shows the best survival in those who completed durvalumab (comparable to historic values) and novel data shows a perceived survival benefit in those completing 12 doses compared to those who did not. Thus, partial treatment may provide a survival advantage. Further multivariate analysis will look for possible correlations to increased immune events and inability to complete therapy. Further investigation will delve into this cohort’s small proportion of non-white patients, evaluating for possible barriers to care that may lead to more patients being diagnosed with stage IV NSCLC.[Table: see text]

Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and low Karnofsky performance status: Results from the CheckMate 920 trial.

315 Background: Combination therapy with nivolumab + ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability for patients (pts) with previously untreated advanced renal cell carcinoma (aRCC). Most pivotal clinical trials in pts with aRCC have excluded pts with low Karnofsky performance status (KPS; &lt; 70%). CheckMate 920 is a multi-arm, phase IIIb/IV, open-label clinical trial of NIVO+IPI treatment in pts enrolled in a community practice setting with aRCC and a high unmet medical need. We present safety and efficacy results for the cohort of pts with aRCC of any histology and KPS 50%–60% from CheckMate 920 (NCT02982954). Methods: Pts with previously untreated advanced/metastatic RCC and KPS 50%–60% received NIVO 3 mg/kg + IPI 1 mg/kg Q3W × 4 doses followed by 480 mg NIVO Q4W for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 25 treated pts with KPS 50%–60%, 76% were men; median age was 67 years (range, 34–81). IMDC risk was favorable in 0%, intermediate in 32%, and poor in 68% of pts; 84% had clear cell and 16% had non-clear cell RCC histology. With a minimum follow-up of 25 months, median duration of therapy (95% CI) was 2.3 months (2.1–7.7) for NIVO and 2.1 months (2.1–2.1) for IPI. The median number of doses (range) received was 4 (1–27) for NIVO and 4 (1–4) for IPI; 76% of pts received ≥ 4 NIVO doses and 68% received all 4 IPI doses. The only grade 3–4 imAEs by category were hepatitis (4.0%) and adrenal insufficiency (4.0%). No grade 5 imAEs occurred. Overall, 4 (16%) pts discontinued due to any-grade adverse events (n = 1 each for elevated AST, malignant neoplasm progression, back pain, and acetabulum fracture). Of 18 evaluable pts, ORR was 33.3% (95% CI, 13.3–59.0); no pts had a complete response and 6 had partial response. Median time to objective response was 4.5 months (range, 2.5–24.7). Median duration of objective response was 20.6 months (range, 0.03+–24.2+). Median PFS was 4.6 months (95% CI, 2.5–14.8). Median OS was 15.6 months (95% CI, 5.3–25.1). Conclusions: NIVO+IPI demonstrated an acceptable safety profile and promising antitumor activity in pts with previously untreated aRCC and KPS 50%–60%. The combination was tolerated at a dose intensity similar to that observed in clinical trials conducted in pts with higher KPS (≥ 70%). These data support the value of NIVO+IPI in pts who may not be considered ideal candidates for this therapy and consequently may have limited treatment options. Clinical trial information: NCT02982954 .