Authorities say it appears a BMW ran a red light and struck the UPS truck first, which then careened into multiple other vehicles in the 2800 block of Arlington Avenue just before noon on Thursday.
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Police said they believe the driver was going 100 mph.
LAPD says the car went airborne and hit several more cars. A female passenger was ejected from the vehicle and another male passenger died at the scene.
The UPS truck came to rest on the driveway and yard of a home in the area, while the BMW at the scene was shredded into pieces, its roof completely ripped off.
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Police say the driver tried to flee the scene but was arrested a short time later.
"Good Samaritans were in the area that gave chase and followed him," LAPD Detective Ryan Moreno said. "They called 911 ... They were telling him to stop, basically, but this guy kept going, so they went several blocks."
LAPD said they suspect the cause of the crash to be speed and possible DUI. Drug paraphernalia was also found in the car, police said.
Neighbors said it's not the first time a significant crash has happened in the area.
"They're racing, they're doing donuts in small residential areas, at the corner of schools," neighbor Catherine Guay said. "We hear every night screeching tires. It's inconsiderate, and it's really sad."
UPDATE: An earlier version of this story reported the two fatalities were pedestrians. Later information indicated they were passengers in the BMW.