First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors.

PURPOSE: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab. PATIENTS AND METHODS: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated. RESULTS: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation. CONCLUSIONS: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.

Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody quavonlimab in combination with pembrolizumab: Safety and efficacy from a phase I study in previously treated extensive-stage small cell lung cancer.

OBJECTIVES: This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy. MATERIALS AND METHODS: Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints. RESULTS: Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (<1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%. CONCLUSIONS: Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities.

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment.

AIM: Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2 ). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function. METHODS: This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min(-1) 1.73 m(-2) , n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10. RESULTS: Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax ) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity. CONCLUSIONS: The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.

Computer simulation and validation of the Archimedes Lever hypothesis as a mechanism for aortic isthmus disruption in a case of lateral impact motor vehicle crash: a Crash Injury Research Engineering Network (CIREN) study.

OBJECTIVES: Can aortic isthmus disruption occurring in a lateral motor vehicle crash (LMVC) be explained by the Archimedes Lever Hypothesis, where the intrathoracic aorta, super-pressurized by the thoracic impact force, functions as a rigid lever system? The long arm of this lever system is the proximal aorta-aortic arch, the short arm is the aortic isthmus fixed distally at the descending aorta, and the fulcrum is at the great vessels, especially the left subclavian artery. METHODS: The theory was tested by a simulation technique using a computer-based finite element numerical model system. This simulation model included the dynamics of the crashed vehicles, the direction of force impact, and the structure of the thorax and intrathoracic viscera, including the entire intrathoracic aorta. The specific patient whose data were entered into the model was chosen from a study of 34 LMCV aortic injuries (AIs). The model was constrained by patient and vehicle data from this surviving case. RESULTS: Three sequential lateral thoracic levels impacted by the vehicle side structures were selected. At each level, the maximum mean intra-aortic pressure was 50 to 100 ms after impact, the structure dynamics of the actual crash and the resultant vehicle deformation were simulated; only when the lateral impact was induced in a transverse plane including the first 4 ribs at the level of the aortic arch/isthmus system, with intra-aortic pressures from 200 to 500 mm Hg, were AI-compatible stresses and deformations in the aortic wall achieved at the isthmus. CONCLUSIONS: In LMVC AI, the simulation suggests that the aorta functions as an Archimedes Lever System in which the magnified force mediated by the long lever arm produces sufficient strain on the short lever arm to rupture the aorta at the isthmus.

Spine and spinal cord injury in motor vehicle crashes: a function of change in velocity and energy dissipation on impact with respect to the direction of crash.

OBJECTIVE: To examine the effect of change in velocity (DeltaV) and energy dissipation (IE) on impact, above and below the test levels for Federal MVC Safety Standards, on the incidence of spine fractures (SF), spinal cord injury (SCI)), SF mortality and the associated injury patterns in Frontal (F) and Lateral (L) MVCs. Comparison of 214 patients with SF or SCI with 938 patients who did not have SF or SCI. METHODS: 1152 MVC adult drivers or front-seat passengers (701 F & 451 L) evaluated at 10 Level I CIREN study Trauma Centers together with vehicle and crash scene engineering reconstruction. Patient seat belt (SB) and/or airbag (AB) use correlated with clinical, or autopsy findings. RESULTS: The relationship between DeltaV and IE rose exponentially as DeltaV increased. Of the 1152 patients, all with AIS> or =3 injuries, there were 214 patients with spine fractures of AIS > or =2. In FMVCs there were more SF patients with Cervical SF than in LMVCs (68F versus 64 L) and more Thoracic (35F versus 21L) and Lumbar (39F versus 16L) SF. However, the incidence of spinal cord injury was greatest in the Cervical SF (33%), compared with the Thoracic SF (18%), or Lumbar SF (2%). Most important, in FMVCs 49% of SF, 47% of SCI and 71% of the SF deaths (p < 0.05) occurred at > mean of 47.4 kph. In contrast, in LMVCs 51% of SF, 52% of SCI and 67% of the SF deaths occurred at DeltaV > mean of 35.3 kph. However, 80% of all deaths in SCI occurred in Cervical SF cases, in these 74% also had a brain injury. In contrast, the deaths in Thoracic SF were due to combinations of brain (45%), thorax (95%) or associated pelvic fracture injuries (50%). Airbag (AB), or Seat belt (SB) restraints appeared to protect FMVC SF patients from SCI at lower DeltaV, but 84% of Cervical SCI patients at DeltaV > 47 kph had AB protection and in a few cases the AB appeared responsible for the SCI. In contrast, 82% of Lumbar SF patients had SB, but in FMVCs where jackknifing due to backloading occurred, improper SB positioning may have contributed to the SF. CONCLUSIONS: The implication for SCI in both front seat drivers and passengers in either FMVC or LMVC crashes above their respective DeltaV means is that improved spine fracture protection is necessary at higher DeltaV levels. More effective safety systems to prevent Cervical SCIs should be developed using two-level frontal and side AB & SB+pretensioner devices, which protect against SF at DeltaV both at and 1SD above the FMVC (47 & 72 kph = 30 & 45 mph) and LMVC (35 & 54 kph =22 & 34 mph) means.

Change in velocity and energy dissipation on impact in motor vehicle crashes as a function of the direction of crash: key factors in the production of thoracic aortic injuries, their pattern of associated injuries and patient survival. A Crash Injury Research Engineering Network (CIREN) study.

OBJECTIVE: To examine the effect of change in velocity (MV) and energy dissipation (IE) on impact, above and below the test levels for federal motor vehicle crash (MVC) safety standards, on the incidence of aortic injury (AI) and its mortality and associated injury patterns in frontal (F) and lateral (L) MVCs. Comparison of 80 AI and 796 non-AI patients of AIS=3. METHODS: Eight hundred seventy-six MVC adult drivers or front-seat passengers (552 F and 324 L) evaluated by 10 Level I CIREN study Trauma Centers together with vehicle and crash scene engineering reconstruction. Patient seatbelt and/or airbag use correlated with clinical or autopsy findings. RESULTS: In AI, 63% of cases were dead at the scene and only 16% survived to leave hospital. The relation between IE dissipated in the MVC and the DeltaV on impact was exponential as DeltaV increased, but the rise in IE for a given DeltaV was greater in LMVC than in FMVC (p <0.05). A more rapid rise in IE/DeltaV occurred above the mean DeltaV of 48 +/- 19.7 kph (30 mph) in FMVC and above the mean DeltaV of 36 +/- 16.2 kph (23 mph) in LMVC. As DeltaV increased above these means, 65% of 46 FMVC aortic injuries (AIs) and 64% of 34 LMVC AIs occurred. In AI patients there was evidence of focusing of the point of IE impact on the upper chest with a higher incidence of rib1-4 fractures than in non-AI (p <0.01) and more brain, heart, lung and spleen injuries (p <0.01) consequent to lower seatbelt use (p <0.01), but LMVC also had more pelvic fx (p <0.05). Airbags + seatbelts in FMVC and seatbelts in LMVC reduced mortality (p <0.05) Comparison of AI incidence in three successive 4-year vehicle model year periods showed a progressive decrease as new safety devices were introduced (p < 0.05). CONCLUSIONS: The implications for AI of the focused IE at the upper chest suggest a probable mechanism for MVC AI with the pressurized aortic arch acting as the long arm of a lever system with the fulcrum at the subclavian artery, producing maximum torsional strain at the short arm of the isthmus where 75% of the AIs occurred. AI mortality is also influenced by the associated injuries. To develop more effective safety systems to prevent AI, MVC safety testing with airbags and seatbelts should be carried out at DeltaVs of 1 SD above means for FMVC and LMVC.

Deceleration energy and change in velocity on impact: key factors in fatal versus potentially survivable motor vehicle crash (mvc) aortic injuries (AI): the role of associated injuries as determinants of outcome.

OBJECTIVE: To examine the difference in force mechanisms between fatal and potentially survivable MVC aortic injuries (AI) compared to non-AI severe thoracic injuries (ST). METHODS: Of 324 autopsied MVC driver or front seat passenger fatalities (1997-2000), there were 43 fatal AI (36 scene deaths, 7 hospital deaths) and 5 additional AI survivors. RESULTS: Of the 48 AI, there was only a 42% survival for those reaching hospital alive. 80% of AI survivors had isthmus lesions and all had no or minimal brain injury (GCS >= 13), no cardiac injury and only 20% ribs 1-4 fx or shock; of AI non-survivors reaching hospital alive, 67% had GCS <= 12, 50% cardiac injury, 83% ribs 1-4 fx and 83% shock; AI scene deaths had 78% severe brain injury, 56% cardiac injury, 69% lung injury and 78% ribs 1-4 fx. Quantifying forces in AI scene mortality: the Instantaneous Velocity on Impact of the subject vehicle (delta V1) and the Impact Energy Dissipated (IE) on the subject vehicle (V1) in joules demonstrated a linear regression in fatal car MVC AIs: Energy dissipated (joules) = -56.65 x (delta V1)(2) + 15972 x delta V1 - 454661, r(2) = 0.83. However, for 27 patients with non-AI but severe thoracic (ST) injury (AIS>=3), the relationship of IE to delta V1 had a linear regression of Energy dissipated (joules) = -5.0787 x (delta V1)(2) + 4282.1 x delta V1 - 57182 1, r(2) = 0.84, with the slope difference between the regression for AI scene deaths and that of ST and AI survivors being significant (p<0.05). Based on these relationships, a Critical Zone limited by MVC Impact Energy level of 336000 joules and a delta V1 of 64 kph appears to be the limit of potential survivability in MVCs producing aortic injuries. All AI above these thresholds died. In contrast, ST had greater use of seatbelts (AI 10% vs all ST 60%) and airbags (AI 50% vs all ST 72%), and an 83% survival. CONCLUSION: The data suggest different mechanisms of force delivery and injury patterns in fatal vs potentially survivable AI, and vs ST MVCs. They suggest that an approach to improving vehicle safety measures for AI may involve better safety devices and mechanisms for reducing that fraction of Impact Energy dissipated on V1 for a given delta V1 which is focused on the upper portion of the subject's thoracic cage between the levels of ribs1-8.