Systematic Review Of Phase Research Articles

A Systematic Review of Phase II/III Trials of Hypofractionated versus Conventionally Fractionated Radiation Therapy in Stage III Non-Small Cell Lung Cancer Patients

Introduction: This systematic review evaluated whether curative intent hypofractionated radiation therapy improved survival (primary endpoint) as compared to standard conventionally fractionated radiation therapy for stage III non-small cell lung cancer (NSCLC) patients. Toxicity was also examined as a secondary endpoint. Methods: Electronic bibliographic databases were searched from 1 January 1990 to 31 March 2024. Phase II and phase III trials were included to assess survival (primary outcome) and toxicity (secondary outcome) for newly diagnosed stage III NSCLC patients. Results: Eight phase II trials (n = 349 participants), 3 randomized phase II trials (n = 382 participants), and 5 randomized phase III trials (n = 811 participants), for a total of 1542 participants, were identified. The published trials were heterogeneous, with a wide variety of dose prescriptions. A wide range of survivals (median survival 13.6 months–42.5 months) and toxicities such as grade 3 or higher esophagitis (0–42%) and grade 3 or higher pneumonitis (0–18%) were reported. Conclusions: There is no level 1 evidence to date that suggests that any hypofractionated regimen (dose escalated or not) improves survival as compared to conventionally fractionated radiation. The published phase III trials have been powered for superiority (not equivalence) for the hypofractionated arm. Toxicity with hypofractionated regimens may be similar to conventionally fractionated regimens when normal tissue radiotherapy constraints are kept within tolerance limits. It is unclear how the use of systemic therapy may negatively affect radiation toxicity with hypofractionated radiation therapy.

32 - Reporting of dietary intake and dietary quality in interventions evaluating the effects of liraglutide, semaglutide or tirzepatide on weight-loss and/or blood glucose in patients of all age groups with obesity and/or T2D: A systematic review of phase 3 and 4 randomised controlled trials

32 - Reporting of dietary intake and dietary quality in interventions evaluating the effects of liraglutide, semaglutide or tirzepatide on weight-loss and/or blood glucose in patients of all age groups with obesity and/or T2D: A systematic review of phase 3 and 4 randomised controlled trials

Inconsistent Adverse Event Reporting: A Systematic Review of Phase 3 Lymphoma or Myeloma Trials Presented at ASH Annual Meetings between 2017-2021

Introduction In recent decades, many novel anticancer therapies have been developed resulting in improved patient outcomes across numerous tumor types - including lymphoid malignancies. However, new treatments and treatment combinations have also introduced new and sometimes serious toxicities. Transparent, objective, and complete toxicity reporting is critical to ensuring patient-centered, evidence-informed care. Unfortunately, subjective terms such as "tolerable” or "acceptable toxicity” are widely used and may normalize high rates of toxicity (Gyawali et al. BMJ 2018). The patterns of toxicity reporting and subjective terminology use in clinical trials presented at major conferences such as ASH, where practice changing data is often first shared, remains largely unknown. We conducted a systematic review of lymphoma and myeloma abstracts presented at ASH annual meetings from 2017-2021 to determine patterns of toxicity reporting and to measure the use of subjective, minimizing language in phase 3 clinical trials. Methods Following an initial pilot phase to characterize common subjective, minimizing language terms, we performed a systematic review of abstracts presented at ASH between 2017 - 2021. We included abstracts of adult or pediatric, phase 3, randomized control trials (RCTs) in lymphoma and multiple myeloma (MM). Abstracts reporting on subset analyses of a larger trial, long-term follow up, supportive care interventions, and non-pharmacological interventions were ineligible. Publication year, study population, treatment, AE/toxicity reporting, and minimizing language were extracted and analyzed. Subjective, minimizing language was defined as the use of: "acceptable", "tolerable", "manageable", "feasible", "favorable", "limited", and "safe". Results 902 abstracts were reviewed, of which 65 met criteria for inclusion (30 lymphoma and 35 myeloma). The characteristics of eligible studies are presented in Table 1. A majority of abstracts reported on systemic therapies, 3 reported on CAR-T (all in lymphoma), and 4 on autologous stem cell transplant, (all in MM). AE reporting was variable. Six abstracts did not provide any information on AE (2 lymphoma and 4 MM). Notably, only 15 (50%) of the lymphoma abstracts and 9 (26%) of the MM abstracts provided information on the occurrence or absence of fatal adverse events. Most abstracts included quantitative data on AE (83% of lymphoma abstracts and 74% of MM): however, the toxicity reporting was not uniform with some trials reporting cumulative and/or specific Common Terminology Criteria for Adverse Events (CTCAE)s, others citing only specific toxicities (e.g., cytopenia), and others reporting only "treatment related” and/or "treatment emergent” AE. Encouragingly, all 3 CAR-T trials presented standardized, quantitative data on cytokine release syndrome (CRS) and neurotoxicity AE. Subjective, minimizing language was used in 37% of abstracts (Table 2). Among those abstracts using subjective minimizing language, 33% provided information on fatal AE rates (Table 2). The rates of fatal AE in the experimental arms ranged from 0.6 - 10%. The rates of > grade 3/SAE experimental arm toxicities in abstracts that used subjective language ranged from 58.7 - 90%. Data on reporting of quality of life, patient reported outcomes, and treatment discontinuation will be presented. Discussion Our systematic review of phase 3, lymphoma and MM RCTs presented at recent ASH Annual Meetings suggests that the use of subjective, minimizing language to describe drug toxicity is common. Moreover, trials using subjective, minimizing language reported relatively high rates of serious, and even fatal, AE. In addition, reporting of AE outcomes was inconsistent and variable across both disease types. Patient-centered, evidence-informed care requires transparent, objective, and complete reporting of benefits and risks of new therapies- including in abstracts which can be practice changing. Implementation of policies to standardize AE reporting, and to discourage use of subjective, minimizing language in conference abstracts should be considered. ^ - co-first authors; # - co-senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ranking of transarterial and targeted therapies for advanced hepatocellular carcinoma in the era of immuno-oncology: A network meta-analysis of randomized sorafenib-controlled trials.

To date, no studies have compared the new first‐line atezolizumab+bevacizumab with transarterial therapies combined with the prior standard‐of‐care, sorafenib, in patients with advanced hepatocellular carcinoma (HCC). We compared and ranked all relevant transarterial and targeted treatments competing with atezolizumab+bevacizumab for such disease, based on direct and indirect evidence. This network meta‐analysis was conducted as a systematic review of phase 2 and 3 randomized sorafenib‐controlled trials investigating systemic treatment strategies for HCCs unsuitable for or that progressed after surgery or locoregional treatments as first‐line option published between 2008 and 2021. We ranked the treatments based on overall survival (OS) as the primary outcome, together with progression‐free survival (PFS) and grade 3–4 adverse events. Subgroup analyses were also implemented to estimate intervention efficacies in particular groups. We identified 3451 publications, 15 trials consisting of 7158 patients, using 14 different therapies including combinations of sorafenib with transarterial chemoembolization (TACE), hepatic arterial chemoinfusion, and radioembolization. Regarding OS, atezolizumab+bevacizumab was the only regimen significantly superior to sorafenib (hazard ratio 0.42; 95% confidence interval [CI] 0.25–0.70), and it ranked first. This combination was also the best in the PFS analysis (0.59; 0.47–0.74), followed by lenvatinib (0.66; 0.57–0.76) and TACE+sorafenib (0.73; 0.59–0.91); all had significantly better outcomes than sorafenib alone. TACE+sorafenib (0.52; 0.27–1.00) was ranked first based on OS in a subset with portal invasion, but not in the metastatic series, with atezolizumab+bevacizumab second (0.58; 0.38–0.89). Lenvatinib (odds ratio 1.76; 95% CI 1.35–2.30) and TACE+sorafenib (2.02; 1.23–3.32), but not atezolizumab+bevacizumab (1.38; 0.93–2.05), were significantly less safe than sorafenib monotherapy. Conclusion: Our results indicate that atezolizumab+bevacizumab is the best first‐line clinically relevant systemic modality in advanced HCC. TACE+sorafenib may also be considered for the disease with portal invasion. (PROSPERO No. CRD42021250701).

P-144 Quality of life assessment in biliary tract cancer: A systematic review of phase 2 and 3 clinical trials published between 2010 and 2021

In the last decades quality of life (QoL) has emerged as a fundamental parameter in clinical trials to evaluate the impact of a drug, beyond traditional oncological endpoints such as survival and cancer response. However, QoL is rarely included among study endpoints remaining an unmet need mainly in poor prognosis neoplasms such as biliary tract cancer (BTC). In this study we aimed to describe the assessment and reporting of QoL in phase 2 and 3 clinical trials conducted in patients (pts) affected by BTC. We performed a literature search of primary publications of phase 2 and 3 clinical trials assessing anticancer drugs in BTC pts issued between 2010 and 2021 by 7 relevant scientific journals. We extracted from papers and study protocols data concerning the presence of QoL among primary, secondary or exploratory endpoints, presence of QoL results and methodology of QoL analysis. For every paper, secondary publications reporting QoL results were searched in PubMed. We identified 49 publications of phase 2 and 3 clinical trials in our analysis (2 in adjuvant setting, 27 in first line, 3 in first or further lines, 8 in second line and 9 in second and further lines). All studies included intrahaepatic and extrahaepatic cancers, 41/42 trials included also gallbaldder cancers and 6/42 ampullar neoplasms too. In 35/49 publications (71,4%) trials QoL was not listed among the endpoints, all of these trials were conducted in metastatic setting. The quota of primary publications without QoL among endpoints remained stable over time: QoL was not reported in 17/23 (73,9%) publications between 2010-2015 and in 18/26 publications (69,2%) between 2016-2021. Furthermore, the absence of QoL as an endpoint mostly involved 8/10 (80%) trials carried out in only Eastern population, compared to 26/37 (70,3%) trials conducted only in Western population and to 1/2 (50%) trials including both populations. In 1/2 (50%) trials in the adjuvant setting QoL was a primary endpoint and in 1/2 (50%) a secondary endpoint. In 10/47 (21,3%) trials in metastatic setting QoL was a secondary endpoints and in 2/47 (4,3%) was an exploratory one. Out of 14 primary publications of trials reporting QoL as primary, secondary or exploratory endpoint, QoL results were published in 6/14 (42,8%). Additionally, QoL results were available in 2/6 (33,3%) primary publications of trials with positive results. Unfortunately, we found no secondary publications reporting QoL results. Most common tools used to assess the QoL in patients were EORTC QLQ-C30 (8/14, 57,1%) and EuroQoL-5D (3/14, 21,4%). In the last decade, a very large percentage of the most significant phase 2 and 3 clinical trials did not mention QoL assessment among outcomes, even in metastatic setting where QoL data should be fundamental for an optimal management of pts. Moreover, QoL results were not reported in less than half of trials included in our study. Increasing the inclusion of QoL data in trials is a strong need.

Bispecific T-Cell Engager Antibodies in Multiple Myeloma- a Systematic Review of Phase 1 Clinical Trials

IntroductionOne of the emerging targeted strategies for treatment of multiple myeloma (MM) is the use of robust immune responses via T cell activation against tumor cells. B-Cell Maturation Antigen (BCMA), a cell surface protein, remains a potential target for therapeutic interventions. Recently, bispecific T cell engager therapy, targeting BCMA and CD3 antigens on plasma and T cells respectively, have shown promising results in preclinical and early clinical studies in the context of relapsed/refractory myeloma (RRMM). We conducted a systematic review of phase 1 trials to report the efficacy and safety of Bispecific T-Cell Engager antibodies for MM.Methodology:We systematically searched multiple databases, including PubMed, Embase, Cochrane, and Clinicaltrials.gov. We also searched major conferences for oral or poster presentations. MeSH terms and keywords for MM and bispecific antibodies were utilized. We included all original studies reported in English language published from 1990 until June 2021. The primary database search yielded 390 articles. After excluding review articles, duplicates, irrelevant articles, and non-human studies, six phase 1 clinical trials were included to evaluate the efficacy and safety outcomes.Results:A total of 253 patients were identified from the six phase 1 studies, among whom 247 were evaluable for response, while the safely analysis involved all the patients. A study conducted by Krishan et al. (n= 40) stated an overall response rate (ORR) of 65% among patients receiving subcutaneous (SQ) teclistamab with a median of five prior therapies, 30% and 58% of the responders had a complete response (CR) and very good partial response (VGPR), respectively. A similar ORR of 63% was reported in 28 patients with a median of 5.5 prior therapies receiving SQ talquetamab by Berdeja et al. Cohen et al reported an ORR of 51.7% in patients receiving IV BFCR4350A at doses ≥3.6/20mg (Partial response (PR):17.2% and CR: 10.3%). SQ elranatamab achieved an ORR of 75% in 17 patients who received doses ≥215 μg/kg. Madduri et al. evaluated REGN5458 monotherapy with dose escalation from 3 to 96 mg among 45 patients and reported an ORR of 60% at the highest dose levels. ORR of 31% was reported in 42 patients receiving IV BI836909/AMG 420 by Topp et al. The median time to response (TTP) was 1 month in the majority of the studies. (Table 1)The most common grade three or higher hematological toxicities were neutropenia and anemia, while among non-hematological toxicities, infections were the most common. The incidence of cytokine release syndrome and neurotoxicity varied from 24% to 74% and 2 % to 20%, respectively. (Table 3)Conclusion:The early clinical data of Bispecific T-Cell Engager therapy in heavily pretreated RRMM patients shows promising results regarding its efficacy and safety profile. It represents a whole new horizon of targeted approach towards RRMM. Phase II / III studies are being conducted to evaluate this potential treatment approach in patients with MM. [Display omitted] DisclosuresAnwer: GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding.

Estimation of sample size in randomized controlled trials in multiple sclerosis studying annualized relapse rates: A systematic review

Background: In multiple sclerosis (MS) studies, the most appropriate model for the distribution of the number of relapses was shown to be the negative binomial (NB) distribution. Objective: To determine whether the sample-size estimation (SSE) and the analysis of annualized relapse rates (ARRs) in randomized controlled trials (RCTs) were aligned and compare the SSE between normal and NB distributions. Methods: Systematic review of phase 3 and 4 RCTs for which the primary endpoint was ARR in relapsing remitting MS published since 2008 in pre-selected major medical journals. A PubMed search was performed on 30 November 2020. We checked whether the SSE and ARR analyses were congruent. We also performed standardized (fixed α/β, number of arms and overdispersion) SSEs using data collected from the studies. Results: Twenty articles (22 studies) were selected. NB distribution (or quasi-Poisson) was used for SSE in only 7/22 studies, whereas 21/22 used it for ARR analyses. SSE relying on NB regression necessitated a smaller sample size in 21/22 of our calculations. Conclusion: SSE was rarely performed using the most appropriate model. However, the use of an NB model is recommended to optimize the number of included patients and to be congruent with the final analysis.

Total neoadjuvant therapy for initially inoperable pancreatic cancer: A systematic review of phase 2–3 studies

IntroductionPatients with initially inoperable non-metastatic pancreatic cancer (PC) have a poor prognosis, often similar to those with metastatic disease. Neoadjuvant chemotherapy (CT) plus concomitant or sequential radiotherapy (RT) may cause tumor shrinkage and allow for radical surgery. We pooled data of studies in which patients with locally advanced (unresectable) or borderline resectable PC were treated with a course of induction (or consolidation) CT followed or preceded by neoadjuvant CTRT regimen. Materials and methodsWe searched articles, including phase 2 or 3 studies, published in English from 2010 up to December 2020 in PubMed, SCOPUS, the Cochrane Library, and EMBASE. The primary outcomes were the pooled radical and R0 resection rates, median PFS and OS of included patients (those included in the intent to treat analysis). ResultsA total of 28 studies were finally considered eligible for inclusion in quantitative analysis for a total of 2446 patients with locally advanced/borderline resectable PC. Overall the pooled rate of resection was 29.7% (95%CI 26.7–32.8%). In patients who completed the CT + CTRT program, the overall resection rate was 31.8% (95% 28.4–35.4%). After exclusion of studies that included resectable PCs, the overall resection rate was 19.9% (95%CI 17.3–22.7%). In studies were all patients had unresectable PC (n = 20 studies), the resection rate was 12.1% (95%CI 10–14.5%). In two studies that enrolled all borderline resectable PCs the resection rate was 59.2% (95%CI 48.9–68.8%). The pooled R0 resection rate was 68.7% (95%CI 64.7–72.3%). The median pooled OS was 15.7 months (95%CI 14–17.2 months) and the median pooled PFS was 10.7 (95%CI 9.3–12.1 months). ConclusionsSurgery is a treatment option in about one third of patients with initially inoperable PC, following total neoadjuvant therapy. In unresectable cases the resection rate was 12%. Median OS and PFS rates were comparable with historical data of advanced PCs. Optimal integration and sequence of chemo- and radiotherapy in unresectable PC must still be defined.

Immunogenicity and Safety Analysis of Inactivated Virus Vaccine against SARS-CoV-2: A Systematic Review of Phase 1/2 Clinical Trials

Introduction: The lingering Severe Acute Respiratory System-Coronavirus-2 (SARS-CoV-2) pandemic worldwide has called scientists to accelerate vaccine production and reduce the spread of the virus. The inactivated virus vaccine has been administered widely due to its potency. Following its recent public use, we aim to summarize the efficacy and safety of the inactivated vaccine, especially following Indonesia’s settlement on the SinoVac vaccine.
 Materials and Methods: A systematic review was performed, searching for randomized controlled trials, according to the PRISMA statement throughout four online databases with studies published up to 2 February 2021. Critical appraisal was further conducted utilizing the Cochrane Risk of Bias Tool 2.0.
 Results and Discussions: The search yielded six phase ½ clinical trials with a total of 3251 subjects. The outcome was obtained in seroconversion rates (%) after two doses of vaccine. Four studies administered the CoronaVac inactivated vaccine and resulted in a high seroconversion rate, ranging from 89—90%. The other two studies administered the BBV152 and BBIBP-CorV inactivated vaccine and showed similar results. Furthermore, a dose dependent relation is shown with higher doses showing higher seroconversion rates. The safety analysis reported injection site pain as an insignificant but most prevalent local adverse reaction, with other adverse reactions being mild to moderate respiratory tract infections
 Conclusion: The inactivated vaccine’s efficacy has been proven to stimulate antibody response regardless of dosage, period of administration, and age, with insignificant adverse effects. Further phase 3 clinical trials and widespread administration with the help of non-governmental and medical student organizations are recommended

Spleen and Symptom Responses of JAK Inhibitors in Myelofibrosis; A Systematic Review of Phase 2 and 3 Trials

Background: The JAK-STAT pathway is a vital signaling pathway for various cytokines and growth factors. An abnormal upregulation of this pathway is seen in myeloproliferative disorders, especially the classic BCR-ABL negative myelofibrosis (MF). Janus kinase inhibitors (JAKi) have been evaluated in various clinical trials regarding their efficacy in improving the outcomes for MF patients. In this review, we looked at the reduction of splenomegaly and symptom improvement as markers for efficacy of JAKi. Methods: We did a comprehensive literature search, following PRISMA guidelines, on PubMed, Cochrane, clinicaltrials.gov and Embase databases. We used MeSH terms and related keywords for MF and JAKi, including generic and trade names. We screened 3261 articles and selected 23 trials for our study. Case reports, case series, meta-analysis, review articles, observational studies, phase I trials and studies not reporting spleen response were excluded. Spleen and symptom responses were used to determine the efficacy of JAK inhibitors. Spleen volume reduction (SVR) by >35%, spleen length reduction (SLR) by >50% and total symptom score (TSS) improvement by >50% were set as benchmarks for a positive response. Results: We included 23 trials (n= 4739) in our review. There were 15 phase II trials (n=964) and 8 phase III trials (n=3775). Of these 23 trials, 7 trials (n=598) included patients with median age below 65 years, while 16 trials (n=4141) included patients of median age more than 65 years. Of the 9 of trials of ruxolitinib, 4 were phase III trials (n= 2809) and 5 were phase II trials (n= 416). The dose of ruxolitinib used in these trials ranged from 5 mg twice daily to 20 mg twice daily. The percentage of patients who achieved spleen response ranged from 15.6% to 71.7%. There were 5 trials (n= 861) that evaluated efficacy of momelotinib. Three were phase II trials (n= 221), while 2 were phase III trials (n=326). The doses ranged from 150mg to 300mg. The splenic response in patients ranged from 7% to 48%. In one phase 3 randomized control trial, efficacy of momelotinib (N=215)and roxulotinib (N=217) were compared, and were found to be equally efficacious in terms of spleen response (26.5% in the momelotinib group while 29% in the ruxolitinib group) and symptom response (28.4% in the momelotinib group and 42.2% in the ruxolitinib group). In 4 trials (n= 453) of fedratinib, there were 2 phase II trials (n= 127) and 2 phase III trials (n=326). The splenic response ranged from 31% to 73% of the patient population. In phase II JAKARTA2 study, patients who were resistant or intolerant to ruxolitinib showed SVR of 31%. Lestaurtunib, Ilgitanib, pacritinib and itacitinib were studied in 2,1,1, and 1 phase II trials, respectively. The splenic response was 75%, 31%, 31%, and 68.8% respectively. Symptom response was reported in 12 studies (N=1477). The percentage of patients who achieved symptom response receiving roxulotinib were 20.8-49%, momelotinib (28.4-30.7%), ictatinib (51.1-59.4%), practinib (48%), and fedratinib (27-36%). In terms of safety, the most common hematological side effects seen were anemia (15% - 65%), thrombocytopenia (1.3% - 64%) and neutropenia (1% - 28%). These side effects were seen equally with different medications. The most common non hematological adverse effects included diarrhea (4% - 32%), abdominal pain (2.6% - 27.1%) and fatigue (1.3% - 10%). Conclusion Splenomegaly and associated symptoms are major source of morbidity in MF patients. The rapid advancement in novel agents in the last decade changed the treatment paradigm in this disorder. Our systematic review summarizes the effect of JAKi on spleen and symptom responses. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

A Systematic Review of Phase III Clinical Trials of Daratumumab Addition to Standard Care Regimen for Newly Diagnosed Multiple Myeloma

Introduction: In multiple myeloma (MM), plasma cells including malignant cells show expression of CD38, which is the target for daratumumab (Dara), an IgG1k monoclonal antibody, approved for MM treatment. This review highlights the efficacy and safety of Dara addition to the standard of care therapy in newly diagnosed MM (NDMM) patients (pts). Methods: We conducted a literature search using four databases (PubMed, Embase, Web of Science, and Clinicaltrials.gov). Our search strategy included MeSH terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to April 2020. A total of 587 articles were screened, and after excluding review articles, duplicates, and non-relevant articles, we included three phase III trials reporting daratumumab addition to the standard of care regimens for NDMM patients. Results: A total of 2528 patients were enrolled and evaluated in three phase III randomized controlled trials. A total of 1261 patients were in the daratumumab group and 1267 patients were in the control group. Total 1085 were transplant eligible and 1443 patients were transplant ineligible. Transplant eligible: Moreau et al. (2019) underlined the efficacy of Dara + bortezomib (V) + thalidomide (T) + dexamethasone (d) in NDMM pts (n=1085) in CASSIOPEIA phase III trial. Addition of Dara to VTd group showed marked improvent in progression free survival (PFS): 93% vs 85% at 18 months (hazard ratio (HR) 0.42 [0.34-0.51]; p<0.0001), and overall response rate (ORR) of 92.6% (CI: 95%, P <0.0001) in Dara + VTd group as compared to VTd group (89.9%). Minimal residual disease (MRD) negative status (10-⁵ sensitivity threshold, assessed by multipara metric flow cytometry) in bone marrow was 64% (P<0.0001) in Dara using VTd vs 44% in VTd group. Transplant ineligible: Bahlis N et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) in NDMM pts (n=737) in MAIA phase III trial. Mateos et al. (2018) reported the role of Dara + V + melphalan (M) + prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). Addition of Dara to Rd, and VMP group showed marked improvent in PFS: 68% vs 46% at 36 months [confidence interval [CI], 0.44-0.71; P<0.0001], and 63% vs 36 at 24 months (HR: 0.47, 95% CI 0.33-0.67, p<0.0001), and ORR: 93% vs 82% (P<0.0001), and 90.9% vs 73.9%, respectively. MRD negative status in bone marrow was observed higher with Dara compared to without Dara using Rd (24.2% vs 7.3%) (P<0.001), and Dara + VMP group (28% vs 7%) (p<0.0001) respectively. Significant toxicities mainly included pancytopenias and opportunistic infections (table 2). Standard care regimen (VTd, VMP, Rd) with Dara addition achieved superior outcomes in terms of ORR and PFS. Addition of Dara improved MRD negative status. Conclusion: NDMM treatment with Dara plus standard care therapy (VTd, VMP, Rd) has shown promising outcomes and has set a benchmark for future studies. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

P-100 Quality of life assessment and reporting in gastric cancer treatment: A systematic review of phase 3 clinical trials published between 2010 and 2019

Quality of life (QoL) has emerged as a fundamental outcome in cancer clinical trials. The importance of integrating QoL with other traditional oncological outcome measures has been particularly emphasized in poor-prognosis malignancies such as gastric cancer. The present study aimed to evaluate the assessment and reporting of QoL in phase 3 clinical trials conducted in patients affected by gastric cancer.

Novel androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer: A network meta-analysis.

131 Background: Novel non-steroidal anti-androgens (NSAAs) including enzalutamide, apalutamide, and darolutamide with androgen deprivation therapy (ADT) have proven efficacy in men with high-risk non-metastatic castrate resistant prostate cancer (nmCRPC). However, in the absence of direct comparative trials, there is little evidence to guide therapeutic choice. Our objective was to perform a network meta-analysis to compare agents and perform a class-level meta-analysis of NSAAs with androgen deprivation therapy (ADT) versus ADT-alone. Methods: We performed a systematic review of phase III parallel-group RCTs in men ≥18 years of age with nmCRPC using EMBASE and MEDLINE, indexed as of March 8, 2019. Our primary outcome was metastasis free survival (MFS). Secondary outcomes included OS, PSA progression free survival (PFS), and rates of grade 3-4 adverse events (AEs). Three RCTs were identified. We performed a random effects meta-analysis of NSAA versus ADT-alone using the inverse variance technique for meta-analysis for efficacy outcomes and the Mantel-Haenszel method for meta-analysis of dichotomous data for AEs. We then performed a network meta-analysis to compare outcomes between NSAAs using fixed-effect models in a Bayesian framework. We estimated the relative ranking of the different treatments for each outcome. Results: Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (HR:0.32,95%CI:0.25-0.41, HR:0.08,95%CI:0.05-0.13, and HR:0.74,95%CI:0.61-0.90, respectively). Apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. There was a 61% chance that darolutamide was preferred with respect to AEs. Conclusions: NSAAs improve survival outcomes in patients with high-risk nmCRPC. Apalutamide and enzalutamide may offer improved oncological outcomes. Darolutamide may result in fewer adverse events. These differences, if confirmed, would be meaningful to patients and practitioners when selecting treatment.

A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies.

Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11 years (range 3-21 years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.

Burden of Asthma and Role of 2.5µg Tiotropium Respimat® as an Add-On Therapy: A Systematic Review of Phase 2/3 Trials.

IntroductionTiotropium, a long-acting muscarinic antagonist, is approved for maintenance treatment of asthma in patients at least 6 years of age in the USA. We systematically reviewed published evidence on the efficacy and safety of 2.5 µg tiotropium Respimat® add-on therapy to inhaled corticosteroid (ICS) with or without additional controller medication(s) in children, adolescents, and adults with asthma.MethodsWe searched PubMed from inception until October 3, 2018, for phase 2 and 3 randomized controlled trials (RCTs) evaluating the effects of 2.5 µg tiotropium Respimat® on lung function parameters in patients with asthma. We extracted adjusted mean differences for lung function data and adverse events (AEs) from relevant articles.ResultsOverall, 11 RCTs (three phase 2 and eight phase 3 studies) including 3244 patients (2.5 µg tiotropium Respimat®, n = 1642; placebo, n = 1602) met the predefined inclusion criteria. Once-daily 2.5 µg tiotropium Respimat® improved lung function parameters, including peak and trough forced expiratory volume in 1 s and peak and trough forced vital capacity, versus placebo. Overall, the safety profile of 2.5 µg tiotropium Respimat® was comparable to that of placebo, with the most commonly reported AEs being asthma worsening, reduction in peak expiratory rate, nasopharyngitis, and respiratory tract infections.ConclusionOn the basis of the results of phase 2 and 3 studies, 2.5 µg tiotropium Respimat® as add-on to ICS therapy was safe and associated with consistent improvements in lung function in patients with asthma of varying severities across different age groups.FundingDevelopment of the manuscript was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01062-w) contains supplementary material, which is available to authorized users.

Quality-of-Life Assessment and Reporting in Prostate Cancer: Systematic Review of Phase 3 Trials Testing Anticancer Drugs Published Between 2012 and 2018

Quality of life (QoL) is not included among the end points in many studies, and QoL results are underreported in many phase 3 oncology trials. We performed a systematic review to describe QoL prevalence and heterogeneity in QoL reporting in recently published prostate cancer phase 3 trials. A PubMed search was performed to identify primary publications of randomized phase 3 trials testing anticancer drugs in prostate cancer, issued between 2012 and 2018. We analyzed QoL inclusion among end points, presence of QoL results, and methodology of QoL analysis. Seventy-two publications were identified (15 early-stage, 20 advanced hormone-sensitive, and 37 castration-resistant prostate cancer [CRPC]). QoL was not listed among study end points in 23 studies (31.9%) (40.0% early stage, 40.0% advanced hormone sensitive, and 24.3% CRPC). QoL results were absent in 15 (30.6%) of 49 primary publications of trials that included QoL among end points. Overall, as a result of absent end point or unpublished results, QoL data were lacking in 38 (52.8%) primary publications (53.3% early stage, 55.0% in advanced hormone sensitive, and 51.4% in CRPC). The most commonly used QoL tools were Functional Assessment of Cancer Therapy-Prostate (FACT-P) (21, 53.8%) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (14, 35.9%); most common methods of analysis were mean changes or mean scores (28, 71.8%), time to deterioration (14, 35.9%), and proportion of patients with response (10, 25.6%). In conclusion, QoL data are lacking in a not negligible proportion of recently published phase 3 trials in prostate cancer, although the presence of QoL results is better in positive trials, especially in CRPC. The methodology of QoL analysis is heterogeneous for type of instruments, analysis, and presentation of results.

P-108 - Quality of life assessment and reporting in colorectal cancer: a systematic review of phase 3 trials published between 2012 and 2018

P-108 - Quality of life assessment and reporting in colorectal cancer: a systematic review of phase 3 trials published between 2012 and 2018

Possible Causes of Failing to Meet Primary Endpoints: A Systematic Review of Randomized Controlled Phase 3 Clinical Trials in Patients With Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality worldwide and represents a huge unmet medical need. Despite the favorable results of phase 2 clinical trials, many phase 3 clinical trials fail to meet primary endpoints. Therefore, we investigated the causes of failure to meet primary endpoints in phase 3 clinical trials. We performed a systematic review of phase 3 clinical trials in patients with NSCLC. The results of phase 3 clinical trials collected from the survey were categorized as "negative" (failed to meet the primary endpoint) or "positive" (met the primary endpoint). Of a total of 106 trials collected from this survey, 40 positive trials (38%) and 66 negative trials (62%) were identified. The majority of the primary endpoints were overall survival (OS) or progression-free survival (PFS) (94%). More trials using OS as the primary endpoint were negative (42 of 56 trials), and more trials using PFS as the primary endpoint were positive (24 of 44 trials). The median OS in the control arm in negative trials was significantly longer than the pretrial estimate ( P < .001), whereas the median PFS in the control arm in positive trials was relatively consistent with the pretrial estimate. Our findings suggest that the selection of the primary endpoint and the pretrial estimate can potentially impact the results of phase 3 clinical trials in patients with NSCLC and are critical success factors when planning phase 3 clinical trials.

Quality-of-life (QoL) assessment and reporting in prostate cancer: A systematic review of phase III trials published between 2012 and 2016.

219 Background: We previously reported that QoL is not included among endpoints and QoL results are significantly underreported in a high proportion of recently published phase III trials in oncology. In this study our aim was to describe QoL prevalence and heterogeneity in QoL reporting in prostate cancer (PC) phase III trials. Methods: Whole database included all primary publications (P) of phase III trials evaluating anticancer drugs published between 2012 and 2016 by 11 major journals. For this analysis, we extracted the subset of PC trials. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis. Results: 35 P were identified (21 in castration-resistant [CRPC], 9 in advanced hormone sensitive [aHSPC], incl. both metastatic and biochemical relapsed, and 5 in earlier stages). In 13 (37.1%) QoL was not listed among study endpoints: 7/21 (33.3%) in CRPC, 3/9 (33.3%) in aHSPC, and 3/5 (60%) in earlier stages. Out of 22 primary P of trials including QoL among endpoints, QoL results were not reported in 9 (40.9%). Overall, no QoL data were available in 22/35 (62.9%) primary P (61.9% in CRPC, 44.4% in aHSPC and 100% in earlier disease). QoL data were not available in 15/25 (60%) trials with overall survival (OS) as primary endpoint, and in 7/10 (70%) trials with other primary endpoints. QoL data were not available in 7/16 (43.8%) trials with a positive result (25% in CRPC, 40% in aHSPC, 100% in earlier stages). In 18 trials with available QoL results (incl. secondary publications), most common QoL tools were FACT-P (11, 61.1%) and EORTC QLQ-C30 (6, 33.3%). Common methods of analysis were mean changes (6, 33.3%), mean scores over time (6, 33.3%), time to deterioration (6, 33.3%) and proportion of responders (3, 16.7%). QoL analysis was focused on the impact of toxicity in 10 cases (mostly in earlier stages), and on disease symptoms in 10 cases (mostly in CRPC). Conclusions: QoL is absent in a high proportion of recently published phase III trials in PC, although presence of QoL results is better in positive trials, especially in CRPC. Methodology of QoL analysis is heterogeneous in terms of type of instruments, analysis and presentation of results.

Systemic therapy for recurrent epithelial ovarian cancer: a clinical practice guideline.

The purpose of this guideline is to recommend systemic therapy options for women with recurrent epithelial ovarian cancer, including fallopian tube and primary peritoneal cancers. This document updates the recommendations published in the 2011 Optimal Chemotherapy for Recurrent Ovarian Cancer guideline from Cancer Care Ontario. Draft recommendations were formulated based on evidence obtained through a systematic review of phase ii and iii randomized controlled trials (rcts). The draft recommendations underwent internal review by clinical and methodology experts, and external review by clinical practitioners through a survey assessing the clinical relevance and overall quality of the guideline. Feedback from the internal and external reviews was integrated into the clinical practice guideline. The primary literature search yielded thirty-six primary research papers representing thirty rcts that met the eligibility criteria. The guideline provides recommendations for patients with serous tumour histologies and with recurrent, platinum-resistant, and platinum-sensitive ovarian cancer. The body of evidence from trials that included olaparib and bevacizumab consistently shows a benefit in progression-free survival (pfs) without a corresponding benefit in overall survival (os). The Working Group for this guideline designated pfs, which is associated with symptom control, as a critical outcome. A finding of net benefit can therefore be concluded based on significant differences in pfs. However, that benefit is not without identified harms. Given the identified harms, patient involvement in the decision-making process must take into consideration the side effect profiles of olaparib and bevacizumab within the context of improved pfs but minimal change in os.