Purpose CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. Methods Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). Results Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. Conclusion Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2– ABC. Trial registration linicalTrials.gov NCT02941926.

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OBJECTIVE: Psychedelics have over recent years been subject to a fast-paced growth in scientific research, clinical applications, commercial investment, and substance use trends by the general public. Yet, concerningly little is known about the frequency of adverse side effects of psychedelic use, despite a breadth of anecdotal reports and largely untested assumptions that inform the screening criteria in modern controlled research. This study aimed to evaluate the frequency and predictive factors of specific, enduring, and potentially undesirable, cognitive and perceptual changes, including symptoms related to delusional ideation, magical thinking and hallucinogen persisting perception disorder (HPPD), following real-world psychedelic use in naturalistic settings.METHOD: In this prospective online cohort study, participants were assessed at 3 timepoints: 1 week before (N = 654) a planned psychedelic experience, and at 2 weeks (N = 305) and 4 weeks afterwards (N = 212). Correlational analyses were performed between lifetime psychedelic use, delusional ideation and magical thinking reported at baseline. Additionally, longitudinal changes in these variables were investigated using Friedman’s test, differentiating between novice (≤ 5 times psychedelic use) and experienced users (> 5 times psychedelic use). Further exploratory analyses of longitudinal increases in delusional and magical ideation were performed using logistic regression to identify predictors of change. The frequency of enduring visuo-perceptual effects indicative of HPPD was assessed at the 4 week endpoint. Predictor variables for the occurrence of such effects were determined via logistic regression.RESULTS: Frequency of lifetime psychedelic use was positively, albeit negligibly, correlated with higher baseline levels of delusional ideation rs = .11, p = .01), and magical ideation (rs = .12, p = .003). Contradictorily, delusional ideation was significantly reduced 4 weeks after the reported psychedelic experience. Baseline personality trait absorption was found to be a predictor of persistent increases in magical thinking at 4 weeks after the acute psychedelic experience. Approximately a third (32.7%) of participants, reported symptoms related to HPPD, with ‘intensified colours’ reported most frequently. However, in line with previous findings, only 2.94% (n = 2) of these respondents perceived these symptoms as distressing. Younger age, female gender, absorption, less non-psychedelic substance use in the last 6 months and non-retreat setting were found to be significant predictors of HPPD-like symptoms.CONCLUSION: The present study found an association between the measured cognitive thinking styles and lifetime psychedelic use at baseline. However, observed longitudinal reductions in delusional ideation from before to after the assessed psychedelic experience suggest that this relationship may not be causative, and that the observed correlation with psychedelic use might be driven by other underlying factors. Although HPPD-like symptoms were more common than expected, the absence of associated distress might explain the relatively low incidence of HPPD diagnoses. Predictors of HPPD have been identified, which may help to inform an at-risk profile. Nevertheless, these results warrant further controlled research on the frequency of enduring, yet subtle, adverse side-effects in clinical and non-clinical populations, being limited by the observational nature of the current study.

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1055 Background: Real-world evidence is important as it complements data from randomized controlled trialse report updated results from CompLEEment-1, a Phase IIIb trial evaluating RIB+LET in an expanded population, the largest CDK4/6i trial in ABC to date. Methods: Patients (pts) with HR+, HER2– ABC, ≤ 1 line of prior CT and no prior ET for ABC received RIB+LET. Study design has been reported previously (De Laurentiis, et al. ASCO 2019). Primary endpoints were safety and tolerability. Results: 3,246 pts received ≥ 1 dose of study treatment. Median duration of follow-up was 25.4 months (mos) (15 additional mos since interim analysis [De Laurentiis, et al. ABC5 2019]). Median treatment exposure was 17.8 mos. Baseline characteristics indicated a diverse population, including men (1.2%), premenopausal women (22.2%), and pts aged ≥ 70 years (19.5%); 112 (3.5%) pts had an ECOG PS of 2, 194 (6.0%) pts received prior CT for ABC, and 51 (1.6%) pts had stable CNS lesions. The most common adverse events (AEs) were neutropenia (61.1%), nausea (35.9%), and fatigue (23.4%). Grade 3/4 hematologic abnormalities ( > 5.0 %) were decreased neutrophils (54.8%), leukocytes (25.9%), and lymphocytes (12.6%). Grade 3/4 biochemical abnormalities ( > 5.0 %) were increased ALT (9.1%) and AST (6.7%). An increase of > 60 ms in QTcF interval from baseline occurred in 189 (5.9%) pts, while post-baseline QTcF of > 480 to ≤ 500 ms and > 500 ms occurred in 59 (1.8%) and 42 (1.3%) pts, respectively. Treatment-related AEs led to treatment discontinuation in 418 (12.9%) pts. Of 74 (2.3%) on treatment deaths, 38 (1.2%) were due to breast cancer. Median time to progression was 27.1 mos (95% CI, 25.7-NE), overall response rate was 43.6% (95% CI, 41.5-45.8%), and clinical benefit rate was 69.1% (95% CI, 67.1-71.1%) for pts with measurable disease at baseline. Conclusions: This analysis confirms the safety and efficacy of RIB+LET in a large, diverse cohort of pts with HR+, HER2– ABC (with no previous ET for ABC), closely resembling real-world clinical practice. Safety and efficacy data were consistent with those observed in the MONALEESA trials, supporting the use of RIB+LET in the first-line setting. NCT02941926. Clinical trial information: NCT02941926 .

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Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: 1)Higher doses of venetoclax are tolerable and more effective, and 2)Azacitidine can be discontinued after deep remissions. Forty-two newly-diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine + Venetoclax (HiDDAV) Study. Patients received 1-3 “induction” cycles of venetoclax 600mg daily with azacitidine. Responders received MRD-positive or negative “maintenance” arms: azacitidine with 400mg venetoclax or 400mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD-negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital PCR. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD-negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

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