Citations

e17539 Background: Chemotherapy with Docetaxel (D) or androgen pathway inhibition (API) with Abiraterone Acetate plus prednisone (AAP), Aplautamide(APA) and Enzalutamide(E) are acceptable, FDA approved treatment options for mCSPC. It is not clear whether the magnitude of benefit varies by the choice of initial agent [chemotherapy vs API] or by volume of disease [High vs Low]. Data is now available from all registration trials by volume status and motivated this analysis to inform initial treatment choice in mCSPC. Methods: We systematically searched MEDLINE(Ovid), Embase, and Scopus for randomized controlled trials of chemotherapy(D) or APIs (AAP, APA, ENZ) that had available hazard ratios (HRs) for overall survival (OS) and Progression Free Survival (PFS) according to patient’s volume of disease. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled overall survival HR and 95% CI by chemotherapy and APIs and by high volume(HVD) and low volume(LVD) using a random effect model, and tested for heterogeneity to assess the null hypothesis that no difference in the survival advantage exists by choice of initial agent and volume of disease. Results: Of 4456 studies identified in our search, there were 8 eligible randomized controlled trials that were included in the analysis. Both D and APIs significantly improved PFS [HR 0.48; 0.45-0.51] and OS [0.72; 0.64-0.81] when added to ADT, however the latter was associated with significantly higher improvement in PFS( P < 0.01) and OS (P = 0.03). In patients treated with D, patients with HVD derive significantly more benefit as compared to LVD( P = 0.046) and patients treated with APIs both HVD and LVD patients derive similar benefit( P = 0.80) (Table). Conclusions: mCSPC patients derive higher magnitude of survival benefit when treated with APIs as compared to D; however, D may be preferred in HVD patients. [Table: see text]

5583 Background: FDA has approved three novel AAs [Apalutamide(A), Darolutamide(D) and Enzalutamide(E)] in combination with Androgen deprivation therapy ( ADT) for treatment of (nmCRPC) patients (pts). We report the cost-effectiveness of these drugs from the US perspective to help facilitate the choice of these agents for clinical practice. Methods: A life time Markov state-transition model was constructed with three health states (Metastasis-Free Survival[MFS], Metastatic disease, and Death) to compare cost-effectiveness of AA therapies for treatment of nmCRPC based on US healthcare payer perspective. A network meta-analysis of MFS and OS was conducted due to the lack of head to head trials. An approximation of the original individual-level patient time-to-event data were derived from digitized Kaplan-Meier curves for OS and MFS. Weibull distributions was selected as the best fitted model fitted and extrapolated as per the NICE decision support unit recommendations. Medication costs were based on wholesale acquisition cost. Adverse event (AE) grades 3/4 management costs were incorporated in the model. Discount rate of 3% per year was applied to costs and effects. Life years (LYs) and quality adjusted life years (QALYs) for each treatment as well as the incremental cost effectiveness (ICER) and cost utility (ICUR) ratios were estimated. Base case analyses (BCA) and probabilistic sensitivity analyses (PSA) were estimated. Results: The table summarizes the results form BCA analyses. A+ADT offers best gain in LYs (8.37yrs) and QALYs (5.30 yrs) but at higher cost. Conclusions: Apalutamide was associated with gains in LYs and QALYs traded off with higher lifetime cost relative to other AA alternatives. ADT was associated with lower gains in LYs and QALYs traded off with lower lifetime cost relative to other alternatives. Based on a $150,000/QALY threshold pay off, A+ADT is likely more cost effective compared to E+ADT or ADT alone; while E+ ADT may be more cost effective compared to D+ ADT. [Table: see text]

2054 Background: Systematic reviews that summarize the toxicity of Immune checkpoint inhibitors (ICIs) become outdated very soon after publication. Therefore, we reported results of a toxicity meta-analysis at 2019 ASCO meeting and informed the intent to create a living systematic review (LSR). LSRs combine human and machine effort and support rapid evidence synthesis and living clinical practice guidelines. Now, we report our experience maintaining a LSR on toxicity of ICIs. Methods: Steps include quarterly literature searches to identify new clinical trials reporting ICI-associated adverse events (AEs), AI-enabled screening of new citations which meet the inclusion criteria, automated cumulative meta-analysis and an online reporting platform. Standard data formats and protocols were designed for inputting text, tables and graphics. Software was written to interpret these data and output the information in the appropriate format, such as a forest plot and summary tables. Finally, a dynamic interface that enables user inputs and displays the associated output was designed. Results: The LSR is continuously updated incorporating toxicity data from new clinical trials as it becomes available. We have screened 8000 relevant citations and summarized the odds of Grade 3 or higher AEs and AEs of special interest in patient receiving ICIs. The results are updated on quarterly basis and are available online. The results are updated on quarterly basis and will be available on a website at the time of publication. Prototype with dummy data is available at this link . This interface can also be manipulated via user input to organize and sort data tables and forest plots by type of cancer, name or mechanism (PD-1 or PD-L1) of ICI agent, single agent or combination, type of control arm, line of treatment and several other clinically relevant filters. For example, a user can instantaneously generate a meta-analysis summarizing the risk of colitis or pneumonitis in metastatic lung cancer trials with pembrolizmuab. Conclusions: This LSR engine can prospectively synthesize toxicity data from ICI trials in an efficient manner providing accurate and timely information for advanced clinical decision support at point-of-care. Efforts are ongoing to improve efficiency of screening, improve AI-enabled processes for automated screening and data abstraction, and test across multiple clinical questions.

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]

709 Background: Several immunotherapy (IMT) combinations either as an IMT doublet or IMT in combination with TKIs are now available for first-line therapy of metastatic renal cell carcinoma (mRCC). In the absence of head-to-head clinical trials, we performed an indirect comparison of frontline treatment options to provide clinical guidance. Methods: Medline, Embase and Cochrane Library were searched to identify relevant trials. Hazard ratios (HR) and confidence interval (CI) for primary outcome of progression-free survival (PFS) and secondary outcome of overall survival (OS) were abstracted. Network meta-analysis was performed using a multivariate, consistency model, random-effects meta-regression. Data on Grade 3 or higher AEs was abstracted and meta-analyzed. Pre-specified subgroup analyses were performed based on risk categories (high risk vs low and intermediate vs), history of prior nephrectomy, PD-L1 positivity, age and sex. Risk for bias(RoB) was assessed using the Cochrane Collaboration’s tool. Results: Nine studies were included for PFS analysis, and 6 studies for OS analysis. Avelumab-axitinib (AA) (HR 0.69, 0.48-0.96), and Pembrolizumab-Axitinib (PA) (HR 0.89, 0.50-0.96) significantly improved PFS, while there was no significant PFS benefit with atezolizumab-bevacizumab (AB) (HR 0.83, 0.62-1.13) and nivolumab-ipilimumab (NI) (HR 0.85, 0.63-1.15) as compared to Sunitinib. PA (HR 0.53, 0.38-0.75) and NI (HR 0.63, 0.44-0.90) significantly improved OS, while AB (HR 0.93, 0.75-1.12) showed no significant OS benefit as compared to Sunitinib. NI and AB had significantly fewer grade ≥3 AE than sunitinib. No significant interaction was found by risk group, age, sex or prior nephrectomy. Significant interaction was found by PD-L1 expression(p<0.001), with significant PFS improvement in PD-L1 positive (HR 0.62, 0.53-0.73) but not in PD-L1 negative patients (HR 0.92, 0.81-1.05). Overall, RoB was low amongst included studies. Conclusions: AA improved PFS, NI improved OS, whereas PA improve both PFS and OS as compared to sunitinib monotherapy. However, no IMT combination was superior to other combinations. Cost effectiveness analysis will be reported separately.

708 Background: Patients with high risk non-metastatic renal cell cancer (RCC) are at significant risk of recurrence following nephrectomy. Previously, we reported no benefit of adjuvant tyrosine kinase inhibitor (TKI) treatment in high-risk patients. Since our most recent publication, efficacy results from the multicenter double-blind SORCE trial have become available. We updated our meta-analysis to include these additional data and performed a cumulative meta-analysis. Methods: PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched to identify relevant RCTs. A generic variance-weighted random effects model was used to derive estimates for efficacy. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. The primary outcome was disease-free survival (DFS), defined as the interval between randomization and the first recurrence, the occurrence of metastasis or a secondary cancer, or death due to any cause. Statistical analysis was performed using Comprehensive Meta-Analysis version 3 (Biostat). Results: Five phase 3 trials were identified, enrolling 6531 patients. Two trials compared sunitinib with placebo (S-TRAC and ECOG-ACRIN), two compared sorafenib with placebo (ECOG-ACRIN and SORCE) and one trial each compared pazopanib (PROTECT) and axitinib (ATLAS) vs placebo. Cumulative evidence suggests that adjuvant therapy with TKIs showed no significant improvement in (DFS) hazard ratio [HR] of 0.93 (95% CI, 0.85-1.02), compared to placebo. There was no significant heterogeneity among included trials ( I2= 52%, P= .41). Overall, the trials were at low risk of bias. Conclusions: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve DFS as compared to placebo. Improved patient selection using better prognostic biomarkers or scoring systems may identify subsets of patients who can benefit from adjuvant treatments. Toxicity estimates will be updated as data from SORCE trial publication becomes available.

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.