Asghar, Noureen

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]

132 Background: Treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) is rapidly evolving. Recent updates of relevant trials and presentation of PEACE-1 results warranted mixed treatment comparisons to inform the choice of treatment in mCSPC. Methods: MEDLINE and EMBASE, along with conference proceedings were searched using a systematic search strategy to identify relevant abstracts and full-text publications of phase II/III randomized controlled trials (RCTs) assessing first-line treatment options in mCSPC. Outcomes of interest included overall survival (OS), radiographic progression-free survival (rPFS), and grade ≥3 adverse events (AEs). Direct comparisons were made using DerSimonian-Laird random-effects meta-analysis. Fixed-effect frequentist NMA was conducted to compute network estimates using a multivariate meta-regression approach. Relative treatment rankings were assessed in congruency with direct estimates using P-scores. Secondary NMAs were conducted in several substrata (young, and old; Gleason score < 8 and ≥8; performance status 0 and 1-2, low and high volume of disease). Results: This NMA included nine trials (23 references) with nine unique treatments. rPFS was improved with abiraterone acetate and prednisone-docetaxel-androgen deprivation therapy combination (AAP-D-ADT; rank 1) when compared against most treatment options including AAP-ADT (HR: 0.58, 95% CI: 0.44-0.76; rank 5), apalutamide (APA)-ADT (HR: 0.63, 95% CI: 0.46-0.87; rank 4), TAK-ADT (HR: 0.55, 95% CI: 0.36-0.84; rank 6), and enzalutamide(E)-AAP-ADT (HR: 0.70, 95% CI: 0.51-0.97; rank 3), however no significant differences were observed between AAP-D-ADT, and E+ADT (rank 2). Improved OS was observed with AAP-D-ADT (HR: 0.75, 95% CI: 0.59-0.95; rank 2), E-AAP-ADT (HR: 0.68; 95% CI: 0.48-0.97; rank 1), and AAP-ADT (HR: 0.82, 95% CI: 0.70-0.96; rank 3) compared to D+ADT (rank 6). However, most of the mixed treatment comparisons were statistically insignificant in terms of OS. Similarly, in patients with high volume of disease, AAP+D+ADT (rank 1) was observed to significantly improve rPFS compared to AAP-ADT, APA-ADT, E-ADT, and D-ADT; however, no significant differences were observed among treatment comparisons with regards to OS improvement. E+ADT (rank 1) improved rPFS compared to other treatment in low volume disease but was not different for OS. No significant differences were observed among different treatment options when compared across prespecified subgroups. Moreover, AAP+D+ADT was ranked as the least safe with significantly increased risk of grade 3 AEs relative to other treatments. Conclusions: Current NMA suggests that triplet therapy options were ranked as most likely to improve rPFS and OS at the cost of increased toxicity. Doublet combinations may still be preferred for older patients with low volume of disease.

PURPOSE Multiple large clinical trials have investigated adjuvant tyrosine kinase inhibitors (TKIs) to reduce the risk of cancer recurrence and progression to metastasis in high-risk renal cell carcinoma. We sought to maintain living and interactive evidence on this topic, until a high level of certainty is reached for key clinical outcomes such that further updates become unnecessary and unlikely to change clinical practice. METHODS We created a living interactive evidence synthesis platform to maintain a continuously updated meta-analysis on TKI monotherapy in adjuvant renal cell carcinoma. We implemented an automated search strategy with weekly updates to identify randomized phase 2 and 3 clinical trials. Study selection, appraisal, and data extraction were done in duplicate. Cumulative meta-analysis was performed using Analyzer Module in Living Interactive Evidence platform. For each outcome (overall survival [OS], disease-free survival [DFS], and all-cause and treatment-related adverse events), we assessed certainty of evidence using GRADE approach and conducted trial sequential analysis. RESULTS This final update includes five randomized trials including recently updated data from PROTECT trial. Meta-analysis shows that adjuvant TKI monotherapy offers no benefit in OS (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) or DFS (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) and significantly increases adverse event risk. Lack of benefit was consistent across subgroups including highest-risk patients (test for subgroup differences: P = .32). Optimal information size criteria were met, and there was high certainty of evidence for lack of DFS and OS benefit for adjuvant TKIs. CONCLUSION There is no guidance on when to stop maintaining a living review. In this example, we used trial sequential analysis and high certainty of evidence (future clinical trials unlikely to change current conclusions) as a benchmark to conclude a living review in view of convincing evidence.

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.

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.

241 Background: In a rapidly moving field, such as cancer immunotherapy, where immune checkpoint inhibitors (ICIs) are used across 14 different tumor types, patients may receive suboptimal treatment or even be harmed if information on toxicity is not readily translated for use in clinical practice. Every single systematic review and meta-analysis which attempted to summarize toxicity of immune checkpoint inhibitors (ICIs) quickly became outdated. A living systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situation. Methods: The process of creating a living systematic review started with the creation of a comprehensive search designed by a librarian experienced in systematic reviews in collaboration with the study’s principle investigator. Search was constantly updated every 3 months and evidence is synthesized in a series of steps (microtasks) using a combination of human and augmented intelligence. A complete infrastructure is being developed and it includes automated cumulative meta-analysis and an online reporting platform which will constantly update information for clinicians and patients in a live manner. Results: We screened 6746 studies during Sep 2018-March 2019 and identified 6746 studies and we were able to successfully maintain up-to-date toxicity estimates for immune mediated adverse events over this period while maintaining the rigor of a conventional systematic review. Eventually, we will integrate the steps of LSR into one, user-friendly, semi-automated format which can independently provide accurate estimates and feed into and support a living guidelines platform through shared Application Programing Interface (APIs). Conclusions: LSRs are feasible, efficient, and when fully developed can reduce redundancy and waste in medical research, improve the quality of evidence, reduce human effort and support living and dynamic guidelines to facilitate truly informed shared decision making.

80 Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune Checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Methods: In order to dynamically display content -- including textual data, tables, charts, and graphs – standard data formats and protocols were designed for various components of the systematic reviews carried out by researchers. Given these standardized formats, software was written to interpret this data and output the information in the appropriate format, such as a forest plot or data table. Finally, a dynamic interface that enables user inputs (such as which aspect of the meta-analysis to view) and displays the associated output was designed. The overall living Systematic Review infrastructure includes monthly literature searches, cumulative meta-analysis, and an online reporting platform. Results: We have developed a Living Systematic Review engine that can take in standardized data and reflect this data in an interactive, intuitive manner in the form of text, tables, and plots. This interface can also be manipulated via user input to organize and sort data tables or omit/highlight specific pieces of data. Conclusions: We have initiated the first living systematic review in immune-oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. The Living Systematic Review interface allows users to easily and intuitively access the most recent available clinical evidence on toxicity of ICIs.

e13119 Background: Tyrosine kinase inhibitors (TKIs) are routinely used in the treatment of metastatic RCC and Sunitinib is approved for the use in adjuvant setting. Arterial thromboembolic events (ATEs) have been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to determine the incidence associated with the use of FDA approved TKIs used in treatment of RCC. Methods: PubMed, EMBASE, Cochrane Central and Scopus databases were searched to identify phase 2 and 3 RCTs of TKI therapy in RCC. Trials were included if they reported ATEs defined as arterial thrombosis, cerebral ischemia or infarction, myocardial ischemia and myocardial infarction. The DerSimonian-Laird random effects meta-analysis was performed using CMAv3 software to derive pooled estimates of incidence rates of ATEs with its 95% confidence interval (CI). I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: 1755 studies retrieved in the initial search, and 13 phase 2 and 3 clinical trials (n = 4983) were included in the quantitative analysis. The trials had open label design which can potentially result in bias. Risk of bias was low in all other domains. TKIs used for the treatment of RCC included sunitinib (n = 2632), sorafenib (n = 981), cabozantinib (n = 78), pazopanib (n = 844), axitinib (n = 189) and tivozanib (n = 259). The incidence of ATEs with the use of TKIs was 2.9% (95% CI: 2-3%). Cabozantinib was associated with the highest rate of ATEs (11.5%, 95% CI: 6-21%), followed by sunitinib (2.6%, 95% CI:2-3%) pazopanib (2.6%, 95% CI:2-4%) and axitinib (2.1%, 95% CI: 1-6%). The TKI with lowest event rate of ATE was tivozanib (0.8%, 95% CI:0.2-3%). Conclusions: The use of TKIs is associated with increased risk of developing ATEs. Clinicians should be aware of the possibility of increased ATEs and counsel the patients about this increased risk to enhance the process of informed decision making.