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PURPOSE: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. PATIENTS AND METHODS: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2-1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. RESULTS: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1-2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. CONCLUSIONS: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related t

Although more individuals are relying on information provided by nonhuman agents, such as artificial intelligence and robots, little research has examined how persuasion attempts made by nonhuman agents might differ from persuasion attempts made by human agents. Drawing on construal-level theory, we posited that individuals would perceive artificial agents at a low level of construal because of the agents’ lack of autonomous goals and intentions, which directs individuals’ focus toward how these agents implement actions to serve humans rather than why they do so. Across multiple studies (total N = 1,668), we showed that these construal-based differences affect compliance with persuasive messages made by artificial agents. These messages are more appropriate and effective when the message represents low-level as opposed to high-level construal features. These effects were moderated by the extent to which an artificial agent could independently learn from its environment, given that learning defies people’s lay theories about artificial agents.

Although more individuals are relying on information provided by nonhuman agents, such as artificial intelligence and robots, little research has examined how persuasion attempts made by nonhuman agents might differ from persuasion attempts made by human agents. Drawing on construal-level theory, we posited that individuals would perceive artificial agents at a low level of construal because of the agents’ lack of autonomous goals and intentions, which directs individuals’ focus toward how these agents implement actions to serve humans rather than why they do so. Across multiple studies (total N = 1,668), we showed that these construal-based differences affect compliance with persuasive messages made by artificial agents. These messages are more appropriate and effective when the message represents low-level as opposed to high-level construal features. These effects were moderated by the extent to which an artificial agent could independently learn from its environment, given that learning defies people’s lay theories about artificial agents.