Two-time champion Rafael Nadal crashed to his earliest US Open exit in 10 years when Italy’s Fabio Fognini pulled off a sensational 3-6 4-6 6-4 6-3 6-4 third-round victory.

The stunning result confirmed the decline of the 14-time major winner, who until Friday had won 151 grand slam matches when he had taken the first two sets.

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Nadal will also finish the season without at least one Grand Slam title for the first time since 2004.

It was the 15th defeat of his miserable year, which has seen him beat just two top-10 players and where his best performances at the majors were quarter-final runs at the Australian and French Opens.

Fognini, the 32nd seed, becomes the first Italian in the last 16 at the US Open since Davide Sanguinetti in 2005 and will face Spain’s Feliciano Lopez for a place in the quarter-finals.

“It was very tough against him,” said Fognini, who smashed 70 winners, commited 57 unforced errors and saved 11-of-19 break points in his all-or-nothing assault.

“It was an incredible match to come from two sets down against Rafa who is one of the best players in the world.”

Top seed Novak Djokovic defeated Italy’s Andreas Seppi for the 11th time in 11 meetings to reach the US Open fourth round on Friday.

The world No.1 and 2011 champion triumphed 6-3 7-5 7-5 as the 28-year-old inched closer to a sixth final in New York.

Djokovic, who also recorded his 31st successive win over Italian opponents, goes on to face Spain’s No.23 Roberto Bautista Agut for a place in the quarter-finals.

The Serb star had dropped just 10 games in his first two rounds, not facing a break point, but was pushed hard by 25th seed Seppi, who knocked Roger Federer out of the Australian Open in January.

He dropped serve for the first time in the second set and was broken again as he served for the match in the 10th game of the third.

But the 31-year-old Seppi was unable to capitalise on his break and handed the advantage straight back to the world No.1 in the 11th game.

“I had to hang in there and try and play at my pace,” said Djokovic.

“He was aggressive and went for backhands down the line. I just had to stay patient and wait for my opportunities which is easier said than done.”

Djokovic ended with 11 aces and 37 winners but will look to reduce the error count of 31 in the fourth round, where victory would put him into a 25th consecutive Grand Slam quarter-final.

Joining him in the fourth round is defending champion Marin Cilic, who was given a lengthy test by Kazakh Mikhail Kukushkin.

Cilic, who won his lone grand slam title by defeating Kei Nishikori in last year’s final took four hours and 18 minutes to win through in an epic 6-7 (7-5) 7-6 (7-1) 6-3 6-7 (7-3) 6-1 victory.

“It wasn’t easy but I stayed together and got it done,” Cilic said.

France’s Benoit Paire reached the fourth round of a grand slam for the first time with a 7-6 (7-3) 6-1 6-1 victory over Spain’s Tommy Robredo.

He next faces countryman Jo-Wilfried Tsonga, who ousted Ukraine’s Sergiy Stakhovsky 6-3 7-5 6-2.