Two-time Geneva Open champion Stan Wawrinka was upset in the last 16 on Wednesday, while 2018 winner Marton Fucsovics also came unstuck.
Swiss star Wawrinka won in both 2016 and 2017 before losing to eventual champion Fucsovics in the quarterfinals last time out. But the duo suffered an earlier exit this year as second seed Wawrinka was stunned by Damir Dzumhur and Fucsovics, seeded fourth, fell well short against Federico Delbonis.
Wawrinka won the opening set against Dzumhur before going down 3-6, 6-3, 6-4, with the Bosnian now set to face Radu Albot.
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Elsewhere in the draw, third seed Cristian Garin lost in three sets to Taro Daniel.
The favourites fared much better in Lyon, where Nikoloz Basilashvili, Roberto Bautista Agut and Denis Shapovalov all advanced. Although Richard Gasquet retired, Jo-Wilfried Tsonga and Benoit Paire at least ensured there was some French representation in the last eight.
Tsonga was taken the distance in a 3-6, 7-6 (2), 6-3 win over Steven Diez, while Paire enjoyed a much more straightforward 6-4 6-3 triumph over Pablo Cuevas.
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