Four of England rugby's biggest names are missing from coach Eddie Jones' 34-strong squad for November's Tests against Tonga, Australia and South Africa.
Brothers Mako and Billy Vunipola along with Jamie George and George Ford failed to earn nods after Jones included four uncapped players and another eight who recently made their international debuts.
The Vunipola brothers and fellow forward George have been left out despite excelling for Saracens since their initial snub from the extended training squad named a month ago.
Ford also appeared unlucky after his generalship had been a key factor behind Leicester's emergence as runaway Gallagher Premiership leaders after five rounds. But the five-eighth, another mainstay of the Jones era, was omitted once more.
Jack Nowell, the Exeter wing with a lengthy injury history, and Wasps halfback Dan Robson have also been jettisoned ahead of a campaign that opens against Tonga at Twickenham on November 6.
England take on Australia at the same venue on November 13.
"This is a young but very good and talented squad who have all earned their places - it is one of the most competitive squads I have ever picked," said Jones, who has confirmed that Owen Farrell would continue as captain.
"There are a number of disappointed players who haven't been selected, but they know what they need to do and no door is closed to any player."
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Leicester hooker Nic Dolly and Northampton full-back Tommy Freeman make their first appearances in a senior England squad, while Gloucester centre Mark Atkinson and Sale half Raffi Quirke complete an uncapped quartet.
Marcus Smith is one of eight who made their debuts in the July victories over the USA and Canada to survive the cull from 45 to 34 players, with the Harlequins five-eighth's inclusion coming at Ford's expense.
Jamie Blamire, Callum Chick, Trevor Davison, Alex Dombrandt, Adam Radwan, Harry Randall and Freddie Steward are also present having impressed during the summer.
While Jones is looking to the future in his selection, some developing prospects have been unable to force their way into contention.
Ollie Lawrence, Louis Lynagh - son of Wallabies great Michael Lynagh - along with Joe Marchant, Lewis Ludlow and Beno Obano were removed after winning places in the initial training group.
Forwards: Jamie Blamire (Newcastle), Callum Chick (Newcastle), Luke Cowan-Dickie (Exeter), Tom Curry (Sale), Trevor Davison (Newcastle), Nic Dolly (Leicester), Alex Dombrandt (Harlequins), Charlie Ewels (Bath), Ellis Genge (Leicester), Jonny Hill (Exeter), Maro Itoje (Saracens), Courtney Lawes (Northampton), Lewis Ludlam (Northampton), Joe Marler (Harlequins), George Martin (Leicester), Sam Simmonds (Exeter), Kyle Sinckler (Bristol), Will Stuart (Bath), Sam Underhill (Bath)
Backs: Mark Atkinson (Gloucester), Owen Farrell (Saracens), Tommy Freeman (Northampton), George Furbank (Northampton), Max Malins (Saracens), Jonny May (Gloucester), Raffi Quirke (Sale), Adam Radwan (Newcastle), Harry Randall (Bristol), Henry Slade (Exeter), Marcus Smith (Harlequins), Freddie Steward (Leicester), Manu Tuilagi (Sale), Anthony Watson (Bath), Ben Youngs (Leicester)