Abstract Background The shading of an object provides an important cue for recognition, especially for determining its 3D shape. However, neuronal mechanisms that allow the recovery of 3D shape from shading are poorly understood. The aim of our study was to determine the neuronal basis of 3D shape from shading coding in area V4 of the awake macaque monkey. Results We recorded the responses of V4 cells to stimuli presented parafoveally while the monkeys fixated a central spot. We used a set of stimuli made of 8 different 3D shapes illuminated from 4 directions (from above, the left, the right and below) and different 2D controls for each stimulus. The results show that V4 neurons present a broad selectivity to 3D shape and illumination direction, but without a preference for a unique illumination direction. However, 3D shape and illumination direction selectivities are correlated suggesting that V4 neurons can use the direction of illumination present in complex patterns of shading present on the surface of objects. In addition, a vast majority of V4 neurons (78%) have statistically different responses to the 3D and 2D versions of the stimuli, while responses to 3D are not systematically stronger than those to 2D controls. However, a hierarchical cluster analysis showed that the different classes of stimuli (3D, 2D controls) are clustered in the V4 cells response space suggesting a coding of 3D stimuli based on the population response. The different illumination directions also tend to be clustered in this space. Conclusion Together, these results show that area V4 participates, at the population level, in the coding of complex shape from the shading patterns coming from the illumination of the surface of corrugated objects. Hence V4 provides important information for one of the steps of cortical processing of the 3D aspect of objects in natural light environment.

Purpose

Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).

Patients and methods

Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.

Results

One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.

Conclusions

Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.