Nicolas Roussot ^* Marion Thibaudin Jean-David Fumet Susy Daumoine Léa Hampe Cédric Rébé Emeric Limagne Aurélie Lagrange Victor Herreros Julie Lecuelle Hugo Mananet Alis Ilie David Rageot Romain Boidot Vincent Goussot Anthony Comte Pierre Jacob Françoise Beltjens Anthony Bergeron Céline Charon-Barra Laurent Arnould Valentin Derangère Sylvain LADOIRE Caroline Truntzer Francois Ghiringhelli

• Centre Georges François Leclerc, Dijon, France

A patient with a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated metastatic non-small cell lung cancer (NSCLC) experienced a multisite radiological progression at 3 months after initiation of chemoimmunotherapy as first-line treatment for metastatic disease. After the radiological progression, while she was not undergoing treatment, the patient had spontaneous lesions shrinkage and further achieved a prolonged complete response. Genomic and transcriptomic data collected at baseline and at the time of pseudoprogression allowed us to biologically characterize this rare response pattern. We observed the presence of a tumor-specific T-cell response against tumor-specific neoantigens (TNAs). Endogenous retroviruses (ERVs) expression following chemoimmunotherapy was also observed, concurrent with biological features of an anti-viral-like innate immune response with type I IFN signaling and production of CXCR3-associated chemokines. This is the first biological characterization of a NSCLC pseudoprogression under chemoimmunotherapy followed by a prolonged complete response in a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated NSCLC. These clinical and biological data underline that even patients with multiple factors of resistance to immune checkpoint inhibitors could trigger a tumor-specific immune response to tumor neoantigen, leading to complete eradication of the tumor and probably a vaccinal immune response.