摘要:
<p>Antitumor activity per RECIST version 1.1</p>
5017 Background: The VISION and TheraP trials have established the safety and efficacy of 177 Lu-PSMA-617 in mCRPC with a 50% PSA response rate (PSA50-RR) of 46% and 66% and median progression free survival (PFS) of 8.7 and 5.1 months, respectively. More effective treatments are required as disease progression remains universal. Immunotherapy has limited single-agent efficacy in mCRPC. We hypothesise that by potentially inducing immunogenic cell death, 177 Lu-PSMA-617 may act synergistically with pembrolizumab, an anti-programmed death 1 inhibitor, to enhance the depth and durability of response. PRINCE is a Phase I trial evaluating the safety and efficacy of this combination. Methods: mCRPC patients with high PSMA expression (SUVmax ≥ 20 in an index lesion, SUVmax > 10 for all lesions ≥ 10mm), and no FDG+ve/PSMA-ve lesions on paired baseline PET/CT screening, received up to 6 cycles of 177 Lu-PSMA-617 (starting at 8.5 GBq, reducing by 0.5 GBq with each cycle) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. Response evaluation was undertaken as per PCWG3 and RECIST criteria. Co-primary endpoints were safety and PSA50-RR. Secondary endpoints included PSA-PFS, radiographic PFS (rPFS), overall survival (OS), and patient reported outcomes (PROs). This analysis was undertaken after the last patient had 12 months follow-up. Results: 37 patients (median age 72 years; prior docetaxel 73%; prior androgen receptor targeted agent 100%) received a median of 5 cycles (range: 2 to 6) of 177 Lu-PSMA-617 and 12 doses (range: 6 to 19) of pembrolizumab. The median follow up was 16 months. PSA50-RR was 76% (28/37 [95% CI 59-88]) and 7/10 (70%) patients with RECIST-measurable disease had a partial response. Median rPFS, PSA-PFS and OS was 11.2 months (95% CI: 5.1-14.1), 8.2 months (95% CI: 5.1-11.2) and 17.8 months (95% CI:13.4-not estimable). 12-month rPFS and OS was 38% (95% CI: 22-54) and 83% (95% CI: 67-92), respectively. Common (≥10%) treatment-related adverse events (TRAE) were mainly Grade (G) 1-2, including xerostomia (78%), fatigue (43%), pruritus (27%), nausea (27%), rash (24%), diarrhoea (14%), anorexia (16%), thrombocytopenia (16%), elevated ALT (11%), arthralgia (11%) and a flare in bone pain (11%). Haematologic TRAEs included G2-3 anaemia (8%), G1-2 thrombocytopenia (16%), and G1 neutropenia (3%). G3 immune-related AEs occurred in 10 (27%) patients with no dominant manifestation. 5 (14%) patients discontinued pembrolizumab due to toxicity. PROs including BPI-SF and FACT-P were stable throughout the study. Conclusions: The combination of 177 Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were generally consistent with those of single-agent 177 Lu-PSMA-617 and pembrolizumab and were not clearly augmented by combination use. No new safety concerns were observed. Clinical trial information: NCT03658447.
Progressive collapse occurs due to the propagation of localized initial failures caused by extreme or abnormal events. Current design methods attempt to prevent such collapses by enhancing connectivity between building components and improving the strength of individual members. These measures ensure that the loads previously carried by failed components are effectively redistributed to the remaining structural system. However, existing design methods have primarily been developed based on studies of framed buildings, with limited attention on mid-rise cold-formed steel (CFS) load-bearing wall buildings. This highlights the need for a specific design approach for the building to resist progressive collapse, as pursued in this paper. To analyse the structural performance after stud wall removal, numerical simulations of entire buildings were employed. An 8-storey archetype building was first designed, considering vertical gravity and wind (leeward) loads, which incorporated the recently proposed joist-to-joist bottom plate (JJ) connection from the literature to enhance the structural robustness. Numerical analysis of the archetype building was then performed under five stud wall removal cases. To reduce computational cost, a simplified finite element (FE) model was proposed. Based on observations from the simulation results, a hand calculation design approach was developed. This approach includes methods to account for dynamic effects and tributary areas, as well as a design strategy to reduce the required design strengths of structural members. Comparisons are made between the proposed hand calculation approach and the predictions obtained from numerical analysis. • Design of an archetype mid-rise cold-formed steel building. • Simplified finite element model for mid-rise cold-formed steel buildings. • Numerical analysis of cold-formed steel buildings under stud removal scenarios. • Design approach for cold-formed steel buildings to resist progressive collapse.
5016 Background: LuPSMA improves progression-free survival (PFS) and overall survival (OS) in patients with mCRPC. Immune checkpoint inhibitors (ICI) have limited single-agent activity in mCRPC. Radiation may enhance ICI activity by inducing immunogenic tumor cell death and altering the tumor microenvironment. We evaluated the activity and safety of ipi plus nivo plus LuPSMA in mCRPC. Methods: Eligibility: prior androgen receptor pathway inhibitor therapy, PSMA-positive disease, normal organ function, no contraindications to ICIs, <= 1 line of chemotherapy. Randomized (1:2) to LuPSMA alone (7.4 GBq every 6 weeks, up to 6 doses) or LuPSMA plus induction ipi (3 mg/kg every 6 weeks for 4 doses) and nivo (1 mg/kg every 3 weeks for 8 doses) followed by maintenance nivo (480 mg every 4 weeks for 18 doses) (LuPSMA+ICI). Primary endpoint: PSA PFS at 12 months (PSA-PFS 12m). Secondary endpoints: PSA response rate (PSA-RR), adverse events (AEs), radiographic-PFS (rPFS), PSA-PFS, and OS. Results: 93 of 100 planned participants (pts) were randomized from July 2022 to July 2023. Recruitment was stopped early due to 4 cases of treatment-related myocarditis in pts assigned LuPSMA+ICI. Of 93 randomized, 30 pts received LuPSMA, 57 pts received LuPSMA+ICI. 6 pts who did not receive assigned LuPSMA+ICI (1 ineligible; 5 ceased ICI at the direction of the central study team) were excluded from the efficacy intention to treat analysis. However, 5 were included in the safety analysis. Median age was 70 years [range: 45-83]; 80% had prior docetaxel. The median follow-up was 18 months (IQR: 16-22). PSA-PFS 12m was higher in pts assigned LuPSMA+ICI than LuPSMA-alone (33% vs. 17%, see table). Grade 3-4 AEs were reported in more pts assigned LuPSMA+ICI than LuPSMA-alone (75% vs 29%). Among those assigned LuPSMA+ICI, Grade 3-4 AEs in ≤5% were: colitis (19%), anemia (11%), hypophysitis (14%), lung infection (9%), fatigue (7%), thrombocytopenia (7%), hepatitis (7%), pneumonitis (7%), thromboembolic event (5%) and rash (5%). Myocarditis was reported in 4 pts (7%) assigned LuPSMA+ICI. There were 2 deaths during LuPSMA+ICI treatment: myocarditis (treatment related) and sepsis (not treatment related). Conclusions: LuPSMA+ICI was associated with improved PSA-PFS 12m in mCRPC. The spectrum of AEs were keeping with established toxicities however significantly higher with LuPSMA+ICI, and frequency of ICI-related myocarditis lead to early trial cessation. Clinical trial information: NCT05150236 . LuPSMA+ICI (N=57) LuPSMA alone (N=30) Median (IQR) LuPSMA cycles 5 (4-6) 6 (4-6) Median (IQR) cycles of ipi 2 (1-3) Median (IQR) cycles of nivo 3 (2-5) PSA-PFS 12m, % 33 17 PSA-PFS, median, months 7.6 (95% CI: 6.5, 11) 7.1 (95% CI: 4.9, 10) HR (95% CI) 0.70 (0.43, 1.13) PSA 50% (95% CI) 75% (62, 85) 67% (47, 82) PSA 90% (95% CI) 46% (33, 59) 43% (26, 62) Pts with grade 3-4 AEs 43/57* (75%) 10/35* (29%) *Safety population.
