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Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Purpose:Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking.Patients and Methods:We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network.Results:From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities.Conclusions:Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Grade 3+ Adverse Events

Psychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomised, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μg LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed predominantly stronger interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of weakened interregional connectivity and increased self-inhibition in occipital brain regions as well as subcortical regions. Together, these findings suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Notably, whole-brain EC did not only provide additional mechanistic insight into the effects of LSD on the Excitation/Inhibition balance of the brain, but EC also correlated with global subjective effects of LSD and discriminated experimental conditions in a machine learning-based analysis with high accuracy (91.11%), highlighting the potential of using whole-brain EC to decode or predict subjective effects of LSD in the future.

Study design (A) and patient disposition (B); data cutoff December 31, 2014.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

Background and HypothesisIn a complex world, gathering information and adjusting our beliefs about the world is of paramount importance. The literature suggests that patients with psychotic disorders display a tendency to draw early conclusions based on limited evidence, referred to as the jumping-to-conclusions bias, but few studies have examined the computational mechanisms underlying this and related belief-updating biases. Here, we employ a computational approach to understand the relationship between jumping-to-conclusions, psychotic disorders, and delusions.Study DesignWe modeled probabilistic reasoning of 261 patients with psychotic disorders and 56 healthy controls during an information sampling task—the fish task—with the Hierarchical Gaussian Filter. Subsequently, we examined the clinical utility of this computational approach by testing whether computational parameters, obtained from fitting the model to each individual’s behavior, could predict treatment response to Metacognitive Training using machine learning.Study ResultsWe observed differences in probabilistic reasoning between patients with psychotic disorders and healthy controls, participants with and without jumping-to-conclusions bias, but not between patients with low and high current delusions. The computational analysis suggested that belief instability was increased in patients with psychotic disorders. Jumping-to-conclusions was associated with both increased belief instability and greater prior uncertainty. Lastly, belief instability predicted treatment response to Metacognitive Training at the individual level.ConclusionsOur results point towards increased belief instability as a key computational mechanism underlying probabilistic reasoning in psychotic disorders. We provide a proof-of-concept that this computational approach may be useful to help identify suitable treatments for individual patients with psychotic disorders.

Paranoid delusions or unfounded beliefs that others intend to deliberately cause harm are a frequent and burdensome symptom in early psychosis, but their emergence and consolidation still remains opaque. Recent theories suggest that aberrant prediction errors lead to a brittle model of the world providing a breeding ground for delusions. Here, we employ a Bayesian approach to test for a more unstable model of the world and investigate the computational mechanisms underlying emerging paranoia.We modelled behaviour of 18 first-episode psychosis patients (FEP), 19 individuals at clinical high-risk for psychosis (CHR-P), and 19 healthy controls (HC) during an advice-taking task, designed to probe learning about others’ changing intentions. We formulated competing hypotheses comparing the standard Hierarchical Gaussian Filter (HGF), a Bayesian belief updating scheme, with a mean-reverting HGF to model an altered perception of volatility.There was a significant group-by-volatility interaction on advice-taking suggesting that CHR-P and FEP displayed reduced adaptability to environmental volatility. Model comparison favored the standard HGF in HC, but the mean-reverting HGF in CHR-P and FEP in line with perceiving increased volatility, although model attributions in CHR-P were heterogeneous. We observed correlations between shifts in perceived volatility and positive symptoms generally as well as with frequency of paranoid delusions specifically.Our results suggest that FEP are characterised by a different computational mechanism – perceiving the environment as increasingly volatile – in line with Bayesian accounts of psychosis. This approach may prove useful to investigate heterogeneity in CHR-P and identify vulnerability for transition to psychosis.

BackgroundMismatch negativity (MMN) reductions are among the most reliable biomarkers for schizophrenia and have been associated with increased risk for conversion to psychosis in individuals at clinical high risk for psychosis (CHR-P). Here, we adopt a computational approach to develop a mechanistic model of MMN reductions in CHR-P individuals and patients early in the course of schizophrenia (ESZ).MethodsElectroencephalography (EEG) was recorded in 38 CHR-P individuals (15 converters), 19 ESZ patients (≤5 years), and 44 healthy controls (HC) during three different auditory oddball MMN paradigms including 10% duration-, frequency-, or double-deviants, respectively. We modelled sensory learning with the hierarchical Gaussian filter and extracted precision-weighted prediction error trajectories from the model to assess how the expression of hierarchical prediction errors modulated EEG amplitudes over sensor space and time.ResultsBoth low-level sensory and high-level volatility precision-weighted prediction errors were altered in CHR-P and ESZ groups compared to HC. Furthermore, low-level precision-weighted prediction errors were significantly different in CHR-P that later converted to psychosis compared to non-converters.ConclusionsOur results implicate altered processing of hierarchical prediction errors as a computational mechanism in early psychosis consistent with predictive coding accounts of psychosis. This computational model appears to capture pathophysiological mechanisms relevant to early psychosis and the risk for future psychosis in CHR-P individuals, and may serve as a predictive biomarker and mechanistic target for novel treatment development.

PURPOSE To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. RESULTS The panel considered peer-reviewed reports published in English. RECOMMENDATIONS The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC. Additional information is available at www.asco.org/genitourinary-cancer-guidelines

Negative symptoms occur frequently in individuals at clinical high risk (CHR) for psychosis and contribute to functional impairments. The aim of this study was to predict negative symptom severity in CHR after 9 months. Predictive models either included baseline negative symptoms measured with the Structured Interview for Psychosis-Risk Syndromes (SIPS-N), whole-brain gyrification, or both to forecast negative symptoms of at least moderate severity in 94 CHR. We also conducted sequential risk stratification to stratify CHR into different risk groups based on the SIPS-N and gyrification model. Additionally, we assessed the models’ ability to predict functional outcomes in CHR and their transdiagnostic generalizability to predict negative symptoms in 96 patients with recent-onset psychosis (ROP) and 97 patients with recent-onset depression (ROD). Baseline SIPS-N and gyrification predicted moderate/severe negative symptoms with significant balanced accuracies of 68 and 62%, while the combined model achieved 73% accuracy. Sequential risk stratification stratified CHR into a high (83%), medium (40–64%), and low (19%) risk group regarding their risk of having moderate/severe negative symptoms at 9 months follow-up. The baseline SIPS-N model was also able to predict social (61%), but not role functioning (59%) at above-chance accuracies, whereas the gyrification model achieved significant accuracies in predicting both social (76%) and role (74%) functioning in CHR. Finally, only the baseline SIPS-N model showed transdiagnostic generalization to ROP (63%). This study delivers a multimodal prognostic model to identify those CHR with a clinically relevant negative symptom severity and functional impairments, potentially requiring further therapeutic consideration.

Reductions in the auditory mismatch negativity (MMN) have been well-demonstrated in schizophrenia rendering it a promising biomarker for understanding the emergence of psychosis. According to the predictive coding theory of psychosis, MMN impairments may reflect disturbances in hierarchical information processing driven by maladaptive precision-weighted prediction errors (pwPEs) and enhanced belief updating. We applied a hierarchical Bayesian model of learning to single-trial EEG data from an auditory oddball paradigm in 31 help-seeking antipsychotic-naive high-risk individuals and 23 healthy controls to understand the computational mechanisms underlying the auditory MMN. We found that low-level sensory and high-level volatility pwPE expression correlated with EEG amplitudes, coinciding with the timing of the MMN. Furthermore, we found that prodromal positive symptom severity was associated with increased expression of sensory pwPEs and higher-level belief uncertainty. Our findings provide support for the role of pwPEs in auditory MMN generation, and suggest that increased sensory pwPEs driven by changes in belief uncertainty may render the environment seemingly unpredictable. This may predispose high-risk individuals to delusion-like ideation to explain this experience. These results highlight the value of computational models for understanding the pathophysiological mechanisms of psychosis.

BackgroundA significant number of melanoma patients treated with anti-PD-1 alone or in combination with anti-CTLA-4 have transient or no response to treatment. Sotigalimab is a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application. Preclinical studies suggest that sotigalimab can be combined with PD-1 blockade to trigger effective anti-tumor immunity. We conducted a multi-center, open label, Phase Ib-parallel arm phase II trial (NCT03123783) to evaluate the combination of sotigalimab with nivolumab in subjects with anti-PD-1/PD-L1 refractory metastatic melanoma.MethodsThe study objective was to evaluate the efficacy and safety of sotigalimab in combination with nivolumab in anti-PD-1/PD-L1 refractory advanced melanoma patients. Subjects received sotigalimab (0.3mg/kg) combined with nivolumab (360mg) every 3 weeks. Thirty-eight subjects with unresectable or metastatic melanoma who had confirmed progressive disease during treatment with anti-PD-1 therapy (documented by 2 consecutive tumor assessments) were enrolled (evaluable for safety) and 33 subjects were evaluable for efficacy.ResultsSix subjects had PR (including one unconfirmed PR) for an ORR of 18%. The mDOR was 18.7 months. Two subjects with PR received treatment for >2 years. Three of the six responding subjects remain off all therapy for ≥26 months, and one patient required stereotactic radiosurgery to a single brain lesion ten months after stopping therapy and has not required additional local or systemic therapy since. Three additional subjects had prolonged SD (12.6, 7.6, 6.2 months). The DCR was 48% and 33% of subjects experienced reduction in target lesions. Efficacy was observed in patients regardless of their tumor PD-L1 expression. The overall safety profile of the combination is consistent with the profiles of individual agents. The majority of AEs observed were of mild to moderate intensity (CTCAE Grade ≤2). The most commonly observed AEs were: pyrexia, chills, nausea, fatigue, pruritus, transaminitis, headache, asthenia, myalgia, rash, vomiting and arthralgia. There were no Grade 4 or 5 AEs related to study drugs. There were no treatment discontinuations due to AEs.ConclusionsThe combination of sotigalimab and nivolumab demonstrated treatment benefit (tumor response or prolonged disease control) in anti-PD-1/PD-L1 refractory melanoma patients with an overall favorable safety and tolerability profile. Notably, a subset of patients remain in response off treatment for ≥26 months. These results warrant further study of this combination in advanced, refractory melanoma.AcknowledgementsWe extend our gratitude to the patients and their families who made this trial possible and the clinical study teams involved in this trial. We thank BMS for providing the nivolumab for this study.Trial RegistrationNCT03123783Ethics ApprovalThis study was approved by the Institutional Review Boards at Yale University (#20170300), University of Nebraska Medical Center (#543-18-CB) and The Hospital Regional de Málaga (#19.03.1341E1-GHM).

9573 Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection

4504 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors (ICIs). COSMIC-021, a multicenter phase 1b study, is evaluating C + A (anti‒PD-L1 therapy) in various solid tumors (NCT03170960). C + A demonstrated encouraging clinical activity in cohort 2 of COSMIC-021 in patients (pts) with UC previously treated with platinum-containing chemotherapy (chemo) (Pal S et al. ASCO 2020. Abstract 5013). Outcomes of C + A from 3 other UC cohorts (C3, C4, C5) are presented. Methods: Pts with inoperable locally advanced/metastatic UC with transitional cell histology and ECOG PS 0‒1 were eligible. Pts enrolled in C3 and C4 had no prior therapy and were cisplatin-based chemo ineligible (C3) or eligible (C4). C5 enrolled pts with one prior ICI and no prior VEGFR-TKI therapy. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints: safety, duration of response (DOR), PFS, and OS. Results: Thirty pts each were enrolled in C3 and C4, and 31 in C5. Baseline characteristics for C3, C4, and C5, respectively: median age, 74 y, 66 y, 68 y; male, 67%, 73%, 55%; ECOG PS 1, 63%, 57%, 74%; lung/liver metastasis; 33%/17%, 40%/20%, 58%/23%; ≥3 tumor sites, 30%, 43%, 45%; bladder as primary site, 67%, 70%, 71%. As of Nov 30, 2021, the median follow-up for C3, C4, and C5 was 27.9, 19.1, and 32.9 mo, respectively, with 1, 6, and 1 pts on treatment. C + A demonstrated clinical benefit across all cohorts (Table). Most common treatment-related adverse events (TRAEs) of any grade across C3, C4, and C5, respectively, were diarrhea (43%, 33%, 35%), nausea (27%, 17%, 26%), fatigue (27%, 27%, 48%), and decreased appetite (33%, 27%, 39%); grade 3/4 TRAEs occurred in 63%, 43%, and 45%, and there was no grade 5 TRAE. Conclusions: C + A demonstrated encouraging clinical activity with manageable toxicity in inoperable locally advanced/metastatic UC as first-line systemic therapy in cisplatin-based chemo eligible/ineligible pts and as second- or later line in pts who received prior ICI. Clinical trial information: NCT03170960. [Table: see text]

PURPOSE Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC). METHODS The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). RESULTS The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT. CONCLUSION This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.

Despite the popularity of theraphosids, detailed reports on bite symptoms are still limited to few geographic regions and subfamilies. We therefore examined 363 published bite reports and noticed muscles cramps caused by theraphosids from nearly all continents and subfamilies. Symptoms are mostly locally restricted and mild, but 12.7% of victims experience pronounced cramps with highest incidence rates by Poecilotheriinae, Harpactirinae and Stromatopelminae subfamilies. We discuss how variations in venom quantity correlate with muscle cramp prevalence.

Background CDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb. Methods Patients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing. Results 92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response. Conclusions The CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma. Trial Registration NCT03329950 Ethics Approval The study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

Background Avelumab, a human anti–PD-L1 monoclonal antibody, has shown a manageable safety profile and antitumor activity in multiple tumor types, including platinum-resistant metastatic or recurrent NSCLC,1 and is approved for patients with locally advanced or metastatic UC who have progressed after ≥1 previous line of platinum-based chemotherapy2 3 and as maintenance treatment for those who have not progressed with platinum-based chemotherapy.4 JAVELIN Medley VEGF (NCT03472560) evaluated the efficacy and safety of avelumab + axitinib, a potent inhibitor of VEGFR 1, 2, and 3, in patients with advanced or metastatic NSCLC or UC. Methods Eligible patients with NSCLC had received ≥1 prior platinum-containing therapy and ≤2 prior lines of systemic therapy for locally advanced or metastatic disease; patients with UC were treatment naive in the locally advanced or metastatic setting and ineligible for cisplatin-containing chemotherapy. Patients were immune checkpoint inhibitor naive and received avelumab 800 mg intravenously every 2 weeks + axitinib 5 mg orally twice daily. The primary endpoint was confirmed objective response (OR) per investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS) and safety. PD-L1 expression was assessed in baseline tumor samples (Ventana SP263 assay). Data have not undergone standard quality checks and are subject to change due to COVID-19–related healthcare burden. Results A total of 41 patients with NSCLC and 20 with UC received avelumab + axitinib. The confirmed OR rate was 31.7% (95% CI, 18.1–48.1) in the NSCLC cohort and 10% (95% CI, 1.2–31.7) in the UC cohort (all partial responses); 16 patients (39.0%) and 5 (25.0%) had stable disease, respectively. Responses were observed regardless of PD-L1 expression status. Median PFS was 5.5 months (95% CI, 2.5–7.0) in the NSCLC cohort and 2.3 months (95% CI, 1.8–5.6) in the UC cohort. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 24 patients (58.5%) in the NSCLC cohort; the most common was hypertension (n=7 [17.1%]). Grade ≥3 TRAEs occurred in 9 patients (45.0%) in the UC cohort; the most common were amylase increased, asthenia, decreased appetite, and palmar-plantar erythrodysesthesia syndrome (n=2 [10%] each). One patient in each cohort experienced a TRAE that led to death (gastric perforation and urinary bladder hemorrhage). Conclusions Avelumab + axitinib showed antitumor activity and a manageable safety profile in patients with advanced or metastatic NSCLC or UC consistent with findings from studies of each drug alone and in combination. Trial Registration NCT03472560 Ethics Approval The study was approved by each site’s independent ethics committee. Consent N/A References Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18:599–610. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018;19:51–64. Bavencio(avelumab) injection. [package insert] Darmstadt, Germany: Merck KGaA; 2019. US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed August 19, 2020.

With a global estimate of tens of thousands of arachnid enthusiasts, spiders and scorpions are gaining increasing popularity as pets in industrialised countries in Europe, Northern America and Asia. As most spiders and all scorpions are venomous and due to their mostly negative image in the public media, several governments are already considering introducing legislation to regulate the domestic care of potentially dangerous captive animals. We aimed to investigate the circumstances and effects of exposure to arachnids kept in captivity. Thus, we collected and analysed data from 354 self-reported bites and stings attributed to pet arachnids. Our data revealed that on average there were less than 20 recorded envenomations per year with ~90% preventable by due care. We also categorized the severity of the resulting symptoms and found that the vast majority of symptoms were either local (60.7%) or minor (32.8%), 5.4% were asymptomatic, only 1.1% were severe and no fatalities were recorded. Based on our database of bite and sting reports, we performed a risk assessment for arachnid pet ownership and concluded that, with the proper care, arachnids can be safely kept as pets and pose a lower risk than many other recreational activities.

Background The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort. Patients and Methods Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival. Results Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable). Conclusions This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort.Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival.Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable).This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment. Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain. Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

Identifying robust markers for predicting the onset of psychosis has been a key challenge for early detection research. Persecutory delusions are core symptoms of psychosis, and social cognition is particularly impaired in first-episode psychosis patients and individuals at risk for developing psychosis. Here, we propose new avenues for translation provided by hierarchical Bayesian models of behaviour and neuroimaging data applied in the context of social learning to target persecutory delusions. As it comprises a mechanistic model embedded in neurophysiology, the findings of this approach may shed light onto inference and neurobiological causes of transition to psychosis.

Depressive symptoms in subjects at Clinical High Risk for Psychosis (CHR-P) or at first-episode psychosis (FEP) are often treated with antidepressants. Our cross-sectional study investigated whether brain morphology is altered by antidepressant medication. High-resolution T1-weighted structural MRI scans of 33 CHR-P and FEP subjects treated with antidepressants, 102 CHR-P and FEP individuals without antidepressant treatment and 55 controls, were automatically segmented using Freesurfer 6.0. Linear mixed-effects modelling was applied to assess the differences in subcortical volume, surface area and cortical thickness in treated, non-treated and healthy subjects, taking into account converted dosages of antidepressants. Increasing antidepressant dose was associated with larger volume of the pallidum and the putamen, and larger surface of the left inferior temporal gyrus. In a pilot subsample of separately studied subjects of known genomic risk loci, we found that in the right postcentral gyrus, the left paracentral lobule and the precentral gyrus antidepressant dose-associated surface increase depended on polygenic schizophrenia-related-risk score. As the reported regions are linked to the symptoms of psychosis, our findings reflect the possible beneficial effects of antidepressant treatment on an emerging psychosis.

BACKGROUND In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

Background Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. Methods Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIMSM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2–124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. Results Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. Conclusions Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. Trial registration PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011. Electronic supplementary material The online version of this article (10.1186/s40425-019-0567-3) contains supplementary material, which is available to authorized users.

A screening of compound libraries based on nipecotic acid derivatives with lipophilic residues attached to the scarcely explored 5-position of the core structure was used for the search of new inhibitors of the γ-aminobutyric acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With nipecotic acid derived hydrazone rac-16 h [rac-(3R,5S)-{5-[(E)-2-{[5-(2-phenylethynyl)thiophen-2-yl]methylidene}hydrazin-1-yl]piperidine-3-carboxylic acid}-sodium chloride (1/2)], one hit was found and evaluated displaying sub-micromolar potency (pKi =6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5-(2-phenylethynyl)thiophen-2-yl residue attached to the 5-position of nipecotic acid via a three-atom spacer, compound rac-16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5-substituted nipecotic acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1-mediated GABA transport.

Background: Recent network approaches suggest that transition to psychiatric disorders arise from divergent causal interactions among symptoms, whereby the emergence of one central symptom activates an interconnected set of other symptoms. Methods: Here, we used network analysis to test whether the transition to psychosis is preceded by aberrant symptom organisation. 63 at-risk mental state (ARMS) individuals without later transition to psychosis (ARMS-NT), 16 ARMS individuals with later transition to psychosis (ARMS-T), and 38 antipsychotic-free patients with first-episode psychosis (FEP group) were included. Symptoms were measured using Brief Psychiatric Rating Scale (BPRS) and graph theory was used to quantify global and local network properties. Group differences in symptom connectivity were assessed using functional data analysis and network-based statistics (NBS). Outcomes: While severity of BPRS items did not allow to differentiate ARMS-T and ARMS-NT patients, ARMS-T patients exhibited a widespread connectivity increase among symptoms relative to ARMS-NT individuals. AMRS-T and FEP patients also displayed highly segregated symptoms compared to ARMS-NT individuals. Furthermore, in both ARMS-T and FEP patients anxiety was the most binding (central) symptom. Interpretation: Our findings suggest that the risk of transition to psychosis relates to the consolidation of relationship among symptoms, but appears to be unrelated to the severity of symptoms per se. Phenomenological network approaches provide insight into novel prevention targets such as deconsolidation of symptom clustering. Funding Statement: This study was funded by CIHR Foundation Grant (375104/2017) to LP; AMOSO Opportunities fund to LP; Bucke Family Fund and Arcangelo Rea Family Foundation (London, Ontario). Declarations of Interests: LP reports personal fees from Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work. All other authors report no competing interests. Ethical Approval Statement: All participants provided written informed consent, and the study had research ethics committee permission.

e20594 Background: RRx-001 is a small molecule immunotherapeutic in Phase 3 for the treatment of SCLC that is associated with M2-M1 tumor associated macrophage (TAM) repolarization with CD47 downregulation, vascular normalization and reversal of chemoresistance. In a controlled, multicenter clinical trial called REPLATINUM that was prematurely halted due to COVID-19, data from 17 patients with third line or beyond SCLC was analyzed. Moving forward, REPLATINUM(restarted) has added SARS-CoV-2 exclusion criteria. Our aim was to explore the efficacy of RRx-001 in REPLATINUM and to assess the statistical assumptions of the REPLATINUM(restarted) trial in order to inform future clinical development in SCLC. Methods: Patients in REPLATINUM were randomized to receive 1 of 2 arms: 1) carboplatin AUC 5 IV on day 1 or cisplatin 60 mg/m2 IV on day 1 plus etoposide 100 mg/m2 IV on days 1 through 3 every 21 days for up to 4 cycles or 2) 4 mg of RRx-001 administered sequentially with 4 cycles of a platinum doublet (cisplatin or carboplatin plus etoposide as outlined above). Progression Free Survival (PFS) was the primary efficacy endpoint based on a blinded independent central review (BICR). Results: The trial was suspended prematurely after 17 patients had been enrolled due to widespread COVID-19 exposure with the plan to restart the trial. The decision to restart the trial has provided an opportunity to examine the data for preliminary evidence of treatment efficacy. At the time that the REPLATINUM trial was halted, there were 11 patients enrolled on the control arm and 6 on the investigational arm. The BICR assessed median PFS was approximately 7.1 months for RRx-001 + platinum doublet and 3.5 months for the platinum doublet alone based on the truncated database. The BICR assessed PFS hazard ratio was approximately 0.5. OS medians were approximately 8.2 and 6.3 months for RRx-001 + platinum doublet and platinum doublet alone, respectively. Additionally, patients on the RRx-001 + platinum doublet-treated experimental arm experienced less toxicity than patients on the platinum doublet-treated control arm. Conclusions: Despite the small sample size, preliminary results from REPLATINUM suggest a trend toward a favorable primary outcome and improved safety in RRx-001-treated patients and support the validity of the statistical assumptions that underlie the REPLATINUM(restarted) trial. Pivotal evidence will emerge from REPLATINUM(restarted), which is imminently recommencing. Clinical trial information: NCT03699956.

398 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, or locally advanced and unresectable have limited treatment options. DUART investigates if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. We recently reported that the combination was safe, tolerable and disease control rate (DCR) was 92% post durvaRT. Here we present interim efficacy data of our phase II study. Methods: Pts with pure or mixed urothelial bladder cancer (T2-4 N0-2 M0) were enrolled if their tumor was unresectable (35%), were unfit for surgery (50%) and/or cisplatin ineligible (89%). Primary endpoints: a) PFS at 1-yr b) DCR post adjuvant durva; Secondary endpoints: a) CR post durvaRT b) median PFS c) median OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy. Sample size was based on assumption that this regimen would increase 1 yr PFS by 25% compared to RT alone (50% to 75%); we assumed DCR of 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Twenty-six pts (19 males, 7 females) were enrolled, median age 74 yr (51-94). Sixty two percent of pts had >T2 disease, 31% had positive lymph nodes; 62% with unresectable tumor or were unfit for surgery due to comorbidities. At data cut off (9/30/2020) 20/26 pts were evaluable for DCR post adjuvant durva (3 pts with CR post durvaRT, did not get adjuvant therapy; 1 pt withdrew after 3 cycles for adjuvant durva and was on f/u with unconfirmed CR; 2 pts are still on adjuvant durva) and 25/26 for PFS and all 26 pts for OS. Post completion of adjuvant durva, DCR was seen in 70 % (14/20 with 10 CR; 3 PR; 1 SD; 6 PD). One-year probability of PFS was 73% (95% CI 56.4%, 94.4%), median PFS was 18.5 months. One-year OS probability was 83.8% (95% CI 70.4%, 99.7%) with two-year OS probability of 76.8 (95% CI 60.2%, 98%). Median OS has not been reached. We did not observe any correlation between clinical outcome and baseline tumor PD-L1 expression. Conclusions: DurvaRT followed by adjuvant durva demonstrated promising efficacy with 1-year PFS probability of 73%, 1- year OS probability of 83.8% and DCR of 70% in MIBC and locally advanced BC pts with comorbidities. Results will be updated prior to the final presentation. Efficacy was also seen in node (+) pts which led to the design of prospective randomized NCTN study. Induction chemo followed by chemo+durvaRT+ adjuvant durva vs. chemoRT combination is being evaluated in the ongoing EA8185 clinical trial (ECOG-ACRIN/NRG study) for node (+) BC pts. Clinical trial information: NCT02891161.

85 Background: Androgen receptor (AR) targeting therapies prolong survival of patients with metastatic castration-resistant prostate cancer (mCRPC); however, in many cases, resistance develops, resulting in disease progression. Activation of the PI3K/AKT/mTOR signaling pathway is common in mCRPC and contributes to resistance, mostly due to loss of PTEN, which occurs in 40–60% of patients. Preclinical studies have demonstrated reciprocal regulation between the AR and PI3K/AKT/mTOR pathways and significant anti-tumor activity when both pathways are inhibited, particularly in models with PTEN-loss. Thus, a rationale exists to inhibit both pathways in mCRPC patients. We report interim results of a phase 1 multicohort study (NCT04087174) to confirm the acceptable dose of capivasertib, a potent, selective pan-AKT inhibitor in combination with the androgen synthesis inhibitor abiraterone acetate (AA) in mCRPC patients. Methods: Patients who had received at least one prior systemic therapy (chemotherapy or novel hormonal agent) for mCRPC were given AA (1000 mg, once daily) with capivasertib (400 mg, twice daily, 4 days on/3 days off) until unacceptable toxicity or disease progression. Dose-limiting toxicity in the first 28 days of treatment and adverse events were recorded. Results: 15 patients, median age 67 (range 49–82) years, were recruited in the USA and Spain. Twelve patients had received prior chemotherapy; 7 had two or more prior lines. Seven patients had received prior AA and 10 had received prior enzalutamide. No dose-limiting toxicities were recorded. Eight patients reported at least one grade ≥ 3 adverse event (AE). Grade ≥ 3 AEs in 7 patients were related to capivasertib: allergic reaction to medication, asthenia, type 2 diabetes mellitus, diarrhea and fatigue were each reported in 1 patient, maculopapular rash − in 2 patients, both hypokalemia and acquired Fanconi syndrome − in 1 patient. Acute kidney injury was reported in 4 patients but was not considered related to capivasertib. The most common AEs of any grade related to capivasertib were: diarrhea, 6/15 patients (40%); maculopapular rash, 5/15 (33%); fatigue, 4/15 (27%); hyperglycemia/type 2 diabetes mellitus, 4/15 (27%); nausea, 3/15 (20%); hypokalemia, 2/15 (13%); hypophosphatemia, 2/15 (13%). Capivasertib was discontinued in 4/15 patients (27%) due to AEs. Between initial screening and day 29 of treatment, 5 patients had reduced (> 20%) PSA levels, with 3 patients showing sustained falls in PSA over 12 weeks. Conclusions: In this phase 1 study combined capivasertib and AA exhibits an acceptable safety and tolerability profile. Further data on the clinical efficacy and safety of the combination are being collected in the phase 3 CAPItello-281 trial. Acknowledgments: We thank Adam Errington, PhD, of Oxford PharmaGenesis, for medical writing assistance. Funding: This trial is funded by AstraZeneca. Clinical trial information: NCT04087174.

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

Purpose To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations. Results The ASCO Endorsement Panel determined that the recommendations from the European Association of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting the use of chemoradiotherapy for select patients with MIBC and recommending a preference for clinical trials in the treatment of metastatic disease in the second-line setting. Recommendations Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is recommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin. Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki .

TPS9083 Background: Despite several recent checkpoint inhibitor approvals extensive stage small cell lung cancer (SCLC) is associated with a poor prognosis and remains an area of high unmet need. RRx-001 is a first-in-class, minimally toxic small molecule immunotherapeutic that inhibits c-Myc, downregulates the antiphagocytic checkpoint, CD47, repolarizes tumor associated macrophages (TAM) from protumor M2 to antitumor M1 and resensitizes to previously active first line therapies. On the basis of favorable results from a Phase 2 trial called QUADRUPLE THREAT (NCT02489903) in combination with a platinum doublet in later line SCLC, a Phase 3 trial called REPLATINUM was started in 3rd line or beyond SCLC in Q4 2019. Enrollment is ongoing. Methods: This US-based, open-label, randomized, phase 3 study (NCT03777657) compares RRx-001 4mg + a platinum doublet (carboplatin or cisplatin + etoposide) versus a platinum doublet for pts with 3rd line or beyond SCLC that have previously received a checkpoint inhibitor. Approximately 120 pts from 25 centers will be randomized 1:1 to receive RRx-001 4 mg in combination with a platinum doublet vs. a platinum doublet. The platinum doublet will be administered on both arms for up to 4 cycles; on the RRx-001 arm only patients with stable disease or better are eligible to continue on RRx-001 4 mg + carboplatin AUC 2-4 maintenance therapy. If radiologic progression occurs on the control arm prior to the 4th cycle, patients are eligible to crossover to the RRx-001 treatment arm. PFS is the primary endpoint. Secondary endpoints include OS and ORR. Exploratory endpoints include c-Myc, CD-47 and PD-L1 on circulating tumor cells and SIRP-alpha expression on circulating monocytes. Clinical trial information: NCT03777657.