PRT543, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Advanced Adenoid Cystic Carcinoma: An Open-Label, Phase I Dose-Expansion Study

OBJECTIVES: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. MATERIALS AND METHODS: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. RESULTS: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. CONCLUSION: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC

A phase III randomized controlled trial of a stepped collaborative care intervention versus standard of care

e24191 Background: The aims of this study were to screen patients for symptoms of depression, pain, and/or fatigue and test the efficacy of a stepped collaborative care (SCC) intervention compared to standard of care (SC). When compared to SC, we expected that the patients randomized to the SCC intervention would report greater improvements in patient quality of life (QoL) and lower health care utilization and costs. Family caregivers, of patients randomized to the SCC, were expected to have lower risk of cardiovascular disease when compared to family caregivers, of patients randomized to SC. Methods: Of the 459 patients and 211 caregivers enrolled in this trial, patients’ mean age was 66 years, the majority were female (56.2%) and Caucasian (92.6%). Family caregivers had a mean age of 62 years, the majority were female (69%) and Caucasian (87%). Patients were screened for clinical levels of depression, pain, and/or fatigue and then were randomized to the SCC intervention or SC arm (referral to a community provider for treatment). Family caregivers were administered questionnaires and provided blood and anthropometric data to assess risk of CVD using the ASCVD calculator. Family caregivers did not receive the intervention. Health care utilization was collected from the patients' medical record and activity-based costs were used to assess health care savings. Intent to treat analyses using general linear mixed models were employed to test the hypotheses. Results: General linear mixed models revealed an interaction of quadratic time by arm effect with patients who were randomized to the SCC intervention having greater 0-to-6-month improvement in overall QoL versus patients randomized to the SC arm [t(579) = 2.23, p = .0259]. No group difference was observed in 6-to-12 month change in QoL suggesting maintenance of gains were observed at 12 months [t(561) = -1.34, p > .10]. Multivariate analyses showed a similar pattern of more rapid gains in the subscales of QoL at 6-months in the patients randomized to the SCC intervention when compared to patients in the SC arm on the emotional well-being [t(1,856) = 2.27, p = 0.012], functional well-being [t(1, 891) = 1.73, p = 0.042]; and physical well-being subscales [t(1,777) = 1.84, p = 0.033]. Family caregivers, of patients who were randomly assigned to the SCC intervention, had lower lifetime cardiovascular risk, when compared family caregivers of patients who were randomized to the SC (uMV χ 2 =9.00, p = 0.027). Activity based costs savings of $12,546 per patient per year in activity-based costs were observed for patients randomized to the SCC intervention versus SC. The drivers of the activity-based cost savings appear to be reductions in complication and readmission rates. Conclusions: Cancer centers, and payors, interested in novel delivery and payment models may consider this integrated strategy to improve patient quality of life and save health care costs. Clinical trial information: NCT02944136

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with >= 25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy

BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. PATIENTS AND METHODS: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). RESULTS: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. CONCLUSION: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.status: publishe