The collision occurred on PCH near its intersection with Kanan Dume Road, the Los Angeles County Sheriff's Department said in a tweet at 1:20 p.m.
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A sheriff's spokesperson later said the driver struck about half-a-dozen warning markers in the center median after coming down an incline at high speed.
At the intersection the vehicle struck a pickup truck, which spun and hit a motorcycle, the spokesperson said. The motorcyclist was waiting to make a left turn at the time of the impact.
Whether the driver of the truck and the motorcycle rider were seriously injured was unknown.
The Lexus then slammed into a 30-foot-high embankment, according to the Sheriff's Department. As bystanders attempted to extricate the driver from the vehicle, it caught fire and exploded.
Emergency responders airlifted the driver to a hospital. Whether the patient died at the medical center or while en route was unclear.
Video from AIR7 showed a severely mangled black Lexus that had overturned onto its roof at the base of cliff.
The investigation into the cause of the crash is ongoing.
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Along with PCH, southbound Kanan Durne was also shut down near the scene. Drivers were being diverted from PCH onto side streets in the Point Dume area.
No estimate of when lanes would be reopened was given.
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