Kwiatkowski's long-range escape from Van Avermaet, Wellens and Zdenek Stybar (Quickstep) came on the penultimate Colle Pinzuto sector as Tom Dumoulin (Team Sunweb), Luke Durbridge and Christopher Juul-Jensen (Orica-Scott) recovered further behind.
The Pole crossed the line with a 15 second advantage over Van Avermaet and 17 seconds clear of Wellens.
But the action really began 50 kilometres from home when Wellens ripped a 15 rider group apart on the Monte Sante Marie (or the Cancellara) sector, dragging along Stybar, Kwiatkowski, Van Avermaet, Tiesj Benoot (Lotto-Soudal), Dumoulin and Durbridge.
Luis Leon Sanchez (Astana), Matteo Trentin (Quickstep) Edvald Boasson Hagen, and Scott Thwaites (Dimension Data) soon bridged, these twelve catching the break 35 kilometres from the finish.
"We started to play a game after the Sante Marie section," Kwiatkowski said.
"I actually didn't feel so good there – but I thought the best situation was to do my own thing, that's why I went from so far out and I'm glad it worked out well.
“I didn’t think they’d cooperate well behind me and I could choose my own pace, my own tempo, and go to the finish. I’m so happy that it worked out.”
A crash on the sixth gravelled sector decimated the main bunch allowing the 15 rider group freedom from the chaos to hunt down the early six rider breakaway that formed after the third gravel sector and whose lead grew to a maximum of five minutes.
Sagan abandoned the race with 70 kilometres to go due to illness and bigger Classics fish to fry.