Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Adapting to Unprecedented Times: Community Clinician Modifications to Parent-Child Interaction Therapy during COVID-19.

Parent-Child Interaction Therapy (PCIT) is an evidence-based practice that effectively prevents and treats child disruptive behaviors and child physical maltreatment and reduces parenting stress. PCIT was adapted for telehealth delivery, internet-delivered PCIT (iPCIT), before the COVID-19 pandemic but was not widely implemented until the rapid transition to telehealth during stay-at-home orders. To understand how clinicians adapted PCIT during COVID-19, we followed up on a previous study investigating community clinician adaptations of PCIT pre-COVID-19 using the Lau et al. (2017) Augmenting and Reducing Framework. Clinicians (N = 179) who responded to the follow-up survey and reported delivering PCIT remotely completed a quantitative measure of adaptations at both time points (Fall 2019; Summer 2020) to assess how adaptations to PCIT changed following lockdown measures. Clinicians (n = 135) also provided qualitative descriptions of adaptations made early in the COVID-19 pandemic. Clinicians in the full sample were 74.3% Non-Hispanic White and 14% Latinx. Most clinicians had a master's degree (66.5%), were licensed (80.4%), and were PCIT-certified (70.4%). Paired samples t-tests showed that clinicians reported similar levels of augmenting t(179) = -0.09, p=.926) and reducing adaptations t(179) = -0.77, p=.442) at both time points. Unlike quantitative findings, qualitative findings indicated that clinicians described engaging in many types of adaptations in response to the pandemic. Clinicians discussed engaging in augmenting adaptations by extending treatment length and integrating other practices into treatment. Clinicians also discussed engaging in reducing adaptations. Implications and future directions will be discussed.

Therapist Experiences and Attitudes About Implementing Internet-Delivered Parent-Child Interaction Therapy During COVID-19.

It has been widely recognized that access to mental health treatment is imperative to address current and long-term stressors for children and parents during COVID-19. Internet-delivered Parent-Child Interaction Therapy (iPCIT, previously referred to as I-PCIT) is a strong model for remote service delivery during social distancing restrictions due to its empirical base. However, this treatment modality was not widely implemented before COVID-19, likely due to barriers to providing telehealth services. This mixed methods study conducted a follow-up survey to gather therapist experiences (N = 223) in delivering iPCIT during COVID-19, including qualitative data on the benefits and challenges to delivering iPCIT. The vast majority of therapists (82%) indicated that they transitioned to deliver PCIT via telehealth in response to COVID-19. PCIT caseloads decreased slightly from the first survey to the COVID-19 follow-up survey, but the racial and ethnic composition of caseloads were not significantly different between the two surveys. Of the 183 therapists who transitioned to deliver PCIT via telehealth, 82% expressed interest in continuing to provide iPCIT following the COVID-19 pandemic. Reported benefits of iPCIT included decreased barriers to access and the ability to practice skills within the naturalistic home environment. Challenges to iPCIT were primarily issues with technology as well as other logistical barriers, which could limit engagement for some families. Findings from this study may be beneficial in improving future implementation of iPCIT during and post-COVID-19.