Citations

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

7002 Background: ZUMA-3 is a Phase 1/2 multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in adult pts with R/R B-ALL. Phase 1 efficacy results at the recommended Phase 2 dose (1×106 CAR T cells/kg) were encouraging (Shah et al. ASCO 2019 #7006). Here, we present the pivotal Phase 2 results. Methods: Eligible adults had R/R B-ALL, > 5% bone marrow (BM) blasts by local evaluation, and ECOG 0–1. Pts received a single infusion of KTE-X19 after conditioning chemotherapy. The primary endpoint was the overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) by central review. Key secondary endpoints were duration of remission (DOR), relapse-free survival (RFS), overall survival (OS), measurable residual disease negativity (MRD–) rate by flow cytometry, and safety. Data are reported in all treated pts. Results: As of 9/2020, 55 of 71 enrolled pts received KTE-X19, with a median follow-up of 16.4 mo (range, 10.3–22.1). Adverse events (AEs; n = 8) and ineligibility (n = 4) were the most common reasons enrolled pts did not receive KTE-X19 infusion. Median age was 40 y (range, 19–84), median BM blasts at screening were 65% (range, 5–100), and 47% of pts had ≥3 prior therapies, with 45%, 22%, and 42% having previously received blinatumomab, inotuzumab ozogamicin, or allogeneic stem cell transplant (alloSCT), respectively. The CR/CRi rate was 71% (95% CI, 57–82; 56% CR, 15% CRi); 31% of responders had ongoing responses. Median (95% CI) DOR, RFS, and OS were 12.8 mo (8.7–not estimable [NE]), 11.6 mo (2.7–15.5), and 18.2 mo (15.9–NE), respectively. In responders, median (95% CI) RFS and OS were 14.2 mo (11.6–NE) and not reached (16.2–NE). The MRD– rate was 97% among pts with CR/CRi. Among 25 pts with prior blinatumomab treatment, the CR/CRi rate was 60%. Ten pts (18%) received subsequent alloSCT at a median 98 days post–KTE-X19 infusion. Median DOR remained unchanged when not censoring for alloSCT. Grade ≥3 AEs occurred in 95% of pts, most commonly anemia (49%) and neutropenia (49% [febrile 13%]). Grade ≥3 cytokine release syndrome (CRS; per Lee at al. Blood 2014) and neurologic events occurred in 24% and 25% of pts, respectively, and were generally reversible. Two Grade 5 KTE-X19–related events occurred (brain herniation, n = 1; septic shock, n = 1). Median times to onset of CRS and neurologic events were 5 d and 9 d, with median durations of 7.5 d and 7 d, respectively. Median peak CAR T-cell levels (cells/µL) were 40.5 (range, 1.3–1533.4) in pts with CR and 0 in nonresponders. CAR T cells were undetectable by 9 mo in ongoing responders. Conclusions: After a median follow-up of 16.4 mo, KTE-X19 demonstrated compelling clinical benefit in heavily pretreated adults with R/R B-ALL, with the median OS not yet reached for responding pts and a manageable safety profile. Clinical trial information: NCT02614066.

TPS4165 Background: Oncogenic activation of FGFR2 via genomic rearrangement, gene amplification, or point mutation in advanced solid tumors provides the opportunity for rapid clinical development of highly selective FGFR2 inhibitors using a precision oncology approach to deliver clinical benefit to genomically-defined patient (pt) populations. Unfortunately, this opportunity remains largely unrealized as current, non-selective small molecule inhibitors (pan-FGFRi) suffer from off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance leading to only modest efficacy primarily limited to FGFR2-fusion+ intrahepatic cholangiocarcinoma (ICC). RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFRi by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. We initiated a first-in-human (FIH) precision oncology study of RLY-4008 in advanced solid tumor pts with FGFR2 alterations with primary objectives to define the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) and adverse event (AE) profile of RLY-4008 and key secondary objectives to assess FGFR2 genotype in blood and tumor tissue, pharmacokinetics (PK), and anti-tumor activity. Methods: This is a global, multi-center, FIH dose escalation/expansion study of RLY-4008 (NCT04526106) in adult pts who have unresectable or metastatic solid tumors with FGFR2 alteration per local assessment, ECOG performance status 0-2, measurable or evaluable disease per RECIST 1.1, and who are refractory, intolerant, or declined standard therapy including pan-FGFRi. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. For the dose escalation (Ñ50), RLY-4008 is administered QD/BID on a continuous schedule with 4-week cycles according to a Bayesian Optimal Interval design that allows accelerated dose titration, additional accrual to dose levels declared tolerable, and exploration of alternative schedules if warranted. The MTD is determined via logistic regression of the dose limiting toxicity rate across all dose levels and an RP2D less than the MTD may be considered based on observed AEs, PK, and anti-tumor activity. Following dose escalation, the dose expansion (Ñ75) will treat pts with RLY-4008 at the MTD/RP2D and includes 5 groups with any prior therapy (except group 2): 1. FGFR2 fusion+ ICC pts; 2. FGFR2 fusion+ ICC pts with no prior FGFRi; 3. FGFR2 fusion+ pts with other solid tumors; 4. FGFR2-mutation+ solid tumor pts and 5. FGFR2-amplified solid tumor pts. The primary endpoints are MTD/RP2D and AE profile; key secondary endpoints are FGFR2 genotype in blood and tumor tissue, PK parameters; overall response rate, and duration of response per RECIST 1.1. US enrollment began SEP2020 and Europe/Asia start-up is underway. Clinical trial information: NCT04526106.

1561 Background: Surgical interventions are studied less often than medical or radiation interventions in oncology clinical trials. We characterized surgical oncology trials registered on ClinicalTrials.gov, analyzed funding sources and identified features associated with early discontinuation and results reporting. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded all 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020. After excluding non-interventional trials, applying cancer/oncology specific Medical Subject Heading terms to the remaining trials and excluding phase 1 trials, 27,915 trials were identified for manual review. Primary exposure variables were trial focus: neoplasia site and treatment modality (surgical interventions included investigations of outcomes from surgical resection or intra-operative/peri-operative changes), and funding: industry, U.S. government, academic. Results: 26,815 trials were found to have true oncology content; 1,661 (6.2%) involved surgical oncology, representing 311,789 patients. Funding sources were: 82.7% by academic institutions, 10.9% by industry, and 6.2% by U.S. government. The most studied neoplasia sites were colorectal (17.4% of trials), breast (10.7%), gastric (10.5%), hepatic (8.6%), lung (7.5%), brain/CNS (6.7%) and cervical (6.6%). U.S. government funded surgical oncology trials had the lowest risk of early discontinuation (adjusted HR 0.50, 95% CI: 0.26-0.99, p<0.047) and the highest odds of results reporting (adjusted OR 1.08, 95% CI: 0.55-2.11, p=0.83) (Table 1). Conclusions: There is a paucity of surgical oncology clinical trials compared to other treatment modalities, especially in context of surgery’s role in overall cancer care. From 2008-2020 only 6.2% of trials focused on surgical oncology, and U.S. government funded trials displayed the lowest hazard of early discontinuation and highest odds of results reporting. Stakeholders should look to government funded trials as models of improvement, but must increase representation and results dissemination of surgical oncology trials to guide treatment recommendations. Surgical oncology trial features and associated early discontinuation/results reporting. [Table: see text]

Background Brugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden cardiac death (SCD) as a risk predictor of MAE remains controversial. We aimed to examine the association between family history of SCD and MAEs stratified by age of SCD with a systematic review and meta‐analysis. Methods and Results We searched the databases of MEDLINE and EMBASE from January 1992 to January 2020. Data from each study were combined using the random‐effects model. Fitted metaregression was performed to evaluate the association between the age of SCD in families and the risk of MAE. Twenty‐two studies from 2004 to 2019 were included in this meta‐analysis involving 3386 patients with Brugada syndrome. The overall family history of SCD was not associated with increased risk of MAE in Brugada syndrome (pooled odds ratio [OR], 1.11; 95% CI, 0.82–1.51; P =0.489, I 2 =45.0%). However, a history of SCD in family members of age younger than 40 years of age did increase the risk of MAE by ≈2‐fold (pooled OR, 2.03; 95% CI, 1.11–3.73; P =0.022, I 2 =0.0%). When stratified by the age of cut point at 50, 45, 40, and 35 years old, a history of SCD in younger family member was significantly associated with a higher risk of MAE (pooled OR, 0.49, 1.30, 1.51, and 2.97, respectively; P =0.046). Conclusions A history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE.

Abstract Modern AI-based clinical decision support models owe their success in part to the very large number of predictors they use. Safe and robust decision support, especially for intervention planning, requires causal, not associative, relationships. Traditional methods of causal discovery, clinical trials and extracting biochemical pathways, are resource intensive and may not scale up to the number and complexity of relationships sufficient for precision treatment planning. Computational causal structure discovery (CSD) from electronic health records (EHR) data can represent a solution, however, current CSD methods fall short on EHR data. This paper presents a CSD method tailored to the EHR data. The application of the proposed methodology was demonstrated on type-2 diabetes mellitus. A large EHR dataset from Mayo Clinic was used as development cohort, and another large dataset from an independent health system, M Health Fairview, as external validation cohort. The proposed method achieved very high recall (.95) and substantially higher precision than the general-purpose methods (.84 versus .29, and .55). The causal relationships extracted from the development and external validation cohorts had a high (81%) overlap. Due to the adaptations to EHR data, the proposed method is more suitable for use in clinical decision support than the general-purpose methods.

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Introduction: Drug challenge testing is performed to unmask Type-1 Brugada pattern. The safety and prevalence of its complications during the test are unclear. We aimed to assess the relation of complications in patients with positive and negative results by a systematic review and meta-analysis. Hypothesis: The prevalence of arrhythmic complications is higher in patients with positive drug challenge testing. Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to June 2020. Included studies were cohort studies that reported ventricular arrhythmia that required interventions (VAI) (sustained ventricular tachycardia [VT], polymorphic VT, ventricular fibrillation, appropriate implantable cardioverter defibrillator [ICD] shock, or sudden cardiac arrest) and ventricular arrhythmias that did not required interventions (VANI) (premature ventricular complexes and non-sustained VT) during drug challenge testing. Data were combined using the random-effects model. Results: Thirteen studies involving 2,688 patients (62.7% positive) were included. The overall prevalence of VAI and VANI were 3.7% (95% confidence interval [CI]: 1.8-5.7) and 0.5% (95% CI: 0.1-0.9), respectively. VAI were more common in positive when compared to negative test result patients (1.5% [95% CI: 0.6-2.4] and 0%, respectively) but the prevalence of VANI were similar (2.7% [95% CI: 0.8-4.6] and 2.6% [95% CI: 0.8-4.6], respectively). VAI in positive result patients were more common with flecainide followed by pilsicainide and ajmaline (2.4% [95% CI: -4.3 to 9.2], 2.2% [95% CI: 0.5-4.0], and 1.5% [95% CI: 0.6 to 2.4], respectively). Most of patients with VAI during drug challenge testing underwent ICD implantation (94%). VAI during drug challenge testing in positive result patients carries an increased risk of VAI during 8.6 ± 4.9 years follow-up (odds ratio 3.73, 95% CI: 1.77-7.86, p=0.001). Conclusions: VAI were more common in patients with positive drug challenge testing, more often occurring with positive flecainide challenge, and carries an increased risk of VAI over long-term follow-up in patients with positive drug challenge testing.