Lifespan or life span may refer to:.
Initial results from a Phase 1/2 trial (NCT03972657) of the co-stimulatory PSMA×CD28 bsAb nezastomig (REGN5678) plus anti-PD-1 antibody cemiplimab in mCRPC suggested a correlation between clinical activity and high-grade immune-mediated adverse reactions (imARs). Here, we present updated safety and efficacy results, and new survival and biomarker analyses. Pts with mCRPC who had received ≥2 prior lines of systemic therapy, including ≥1 prior second-generation anti-androgen, were enrolled. Dose levels (DLs) of intravenous (IV) nezastomig ranged from 0.1 to 300 mg weekly (QW). Most pts received nezastomig monotherapy for 3 weeks, followed by combination with cemiplimab 350 mg IV every 3 weeks (Q3W) until disease progression or unacceptable toxicity. Primary and secondary endpoints included safety, tolerability, pharmacokinetics, and PSA50 and PSA90 responses. Exploratory endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Biomarker analyses included immune cell phenotyping and cytokine profiling from peripheral blood. At data cutoff (Feb 16, 2024), 78 pts had been treated in combination with cemiplimab. Treatment-related adverse events of any grade occurred in 60 pts (77%); most commonly fatigue (27%), cytokine release syndrome (13%; all G1 except one G2), and nausea (13%). imARs ≥G3 occurred in 11 pts (14%), primarily in pts with PSA50 responses (8/11). All imARs ≥G3 occurred after cemiplimab addition. Two pts (3%) experienced G5 imARs (HLH, hepatitis). Clinical responses were observed exclusively at nezastomig DLs ≥30 mg (n=61), where 15 pts (25%) achieved PSA50 and 10 pts (16%) achieved PSA90. Kaplan-Meier (KM)-estimated median rPFS (95% CI) was 5.0 months (2.1-12.0) at DLs ≥30 mg and 2.1 months (1.9-3.5) at DLs <30 mg. As of an additional data cutoff performed for longer term survival (Jul 19, 2024, median follow-up of 22.7 months [IQR 16.3-36.7]), the KM-estimated median OS (95% CI) was 17.3 months (11.0-not estimable) at DLs ≥30 mg and 10.3 months (3.7-12.6) at DLs <30 mg. Peripheral blood analyses suggest increased T-cell activation and inflammatory signaling following nezastomig plus cemiplimab treatment. Updated results provide further evidence of durable clinical anti-tumor activity in mCRPC at nezastomig DLs 30-300 mg QW combined with cemiplimab 350 mg Q3W. In preliminary analyses, encouraging survival outcomes were observed with the higher nezastomig DLs plus cemiplimab. Anti-tumor responses were tightly associated with high-grade imARs. Exploration of nezastomig dose ranging is ongoing along with additional combination strategies. The mechanism linking clinical anti-tumor activity and toxicity is being investigated. Bilal A. Siddiqui, Jingsong Zhang, Benedito A. Carneiro, Kevin K. Zarrabi, Mark N. Stein, David R. Wise, Edward P. Gelmann, Che-Kai Tsao, Gerald Falchook, Joseph W. Kim, Xin Gao, Przemyslaw W. Twardowski, Divya Rana, Fang Fang, Shilpa Govindraj, Jennifer S. Sims, Dimitris Skokos, Frank A. Seebach, Israel Lowy, Pradeep Thanigaimani, Matthew Ingham, Sabina Sandigursky, Elizabeth Miller. Updated safety and efficacy results from a phase 1/2 study of nezastomig, a first-in-class co-stimulatory PSMA×CD28 bispecific antibody (bsAb), plus cemiplimab (anti-PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT064.
3100 Background: SPYK04 is a novel MEK1/2 inhibitor designed to enhance RAF-MEK binding and potentially inhibit feedback activation of MEK1/2. This approach was developed to address the limited efficacy of conventional MEK inhibitors in RAS-mutated cancers, which is thought to be due to feedback activation of the MAPK pathway. Methods: This first-in human study of SPYK04 is conducted in the US and Japan (NCT04511845). Patients with locally advanced or metastatic solid tumors harboring MAPK pathway alterations were eligible in its DE part. The primary endpoints included assessment of pharmacokinetics, adverse events (AEs) and dose-limiting toxicities (DLTs); the secondary endpoint was objective response rate (ORR). SPYK04 was administered orally once daily in continuous 28-day cycles. Results: A total of 23 patients were enrolled in DE. SPYK04 was evaluated at doses ranging from 0.1 to 1.3 mg/day. An accelerated titration design was employed for doses of 0.1, 0.2, and 0.4 mg/day, followed by a transition to a 3+3 design starting from 0.8 mg/day. Over the dose range of 0.1 to 1.3 mg/day, systemic exposure demonstrated a dose-dependent increase. Grade 3 or higher treatment-related adverse events (TRAEs) were observed in 30.4% of patients. TRAEs observed in >= 20% of patients were: dermatitis acneiform and blood creatinine phosphokinase increased (60.9% each); AST increased (30.4%); nausea and stomatitis (26.1%, each). DLTs were observed in one patient each at dose levels of 0.8, 1.0 and 1.3 mg/day. All DLTs were due to receiving <75% of the planned dose. A decision was made to not escalate beyond 1.3 mg/day. The ORR was 8.7% (n = 2 of 23), with both partial responses (PRs) occurring amongst the 5 enrolled ovarian cancer patients. The disease control rate (DCR; PR+SD) was 52.2% (n = 12 of 23). Conclusions: SPYK04 was tolerated at doses up to 1.3 mg/day in patients with advanced solid tumors. PRs were observed in two patients with ovarian cancer. Further evaluation of safety and efficacy will occur in the expansion part of this study. Clinical trial information: NCT04511845 . SPYK04 dose, mg/day 0.1 0.2 0.4 0.8 1 1.3 Patients, n 1 1 1 8 6 6 Safety, n (%) TRAE 0 1 (100.0) 1 (100.0) 8 (100.0) 6 (100.0) 6 (100.0) Grade 3 or higher TRAE 0 0 0 1 (12.5) 4 (66.7) 2 (33.3) TRAE leading to discontinuation of study treatment 0 0 0 0 1 (16.7) 0 Confirmed best response, n (%) Responders 0 0 0 1 (12.5) 1 (16.7) 0 Partial Response 0 0 0 1 (12.5) 1 (16.7) 0 Stable Disease 0 0 1 (100.0) 2 (25.0) 3 (50.0) 4 (66.7)
In endometriosis, helplessness and hopelessness (demoralization) and having one's illness dismissed by others (illness invalidation) are reported qualitatively. Selfcompassion may protect against such adverse psychological outcomes. We investigated whether the association between illness invalidation and demoralization is moderated by self-compassion. Participants (n=177) completed an online survey: Demoralization Scale II, Illness Invalidation Inventory, Self-Compassion ScaleSF. Regression analyses confirmed an association between illness invalidation, self-compassion and demoralization, with no moderating effect. Illness invalidation from family, healthcare professionals, and the workplace was greatest. These findings suggest the need for targeted psychoeducation and communication skills interventions to increase awareness in social and dyadic contexts.
