Abstract 6413: Biomarkers of response and progression to Pembrolizumab and Vorinostat combination in late-stage squamous cell carcinoma patients of different locations included in the PEVOsq basket trial
Authors: Tourneau Christophe Le , Mazzarella Luca , Cabarrou Bastien , Francisco Miguel , Dupain Célia , Halladjian Maral , Frige Gianmaria , Duso Bruno , Zhan Yinxiu , Guerini-Rocco Elena , Noberini Roberta , Bonaldi Tiziana , Tonini Maria Manuela , Marret Grégoire , Coutzac Clélia , Coquan Elodie , Saint-Ghislain Mathilde , Saux Olivia Le , Chanas Laetitia , Legrand François , Filippini Daria Maria , Jeannot Emmanuelle , Bernhart Stephan , Balogh Gabor , Jimenez Marta , Filleron Thomas , Servant Nicolas , Kamal Maud 
Published: March 2024

Background: Epigenetic modulation plays a major role in escaping tumor immunosurveillance. PEVOsq (NCT04357873) was an open-label, non-randomized, multi-center, basket phase II trial evaluating the efficacy of pembrolizumab (P) and the vorinostat (V) HDAC inhibitor in 112 patients (pts) with recurrent and/or metastatic squamous cell carcinoma (SCC) of the cervix, head and neck, anus, vulva/vagina, penis, and lung. Results showed an objective response rate (ORR) of 25%, the highest being in anal (31%) and cervical (39%) (ASCO #397612). We report here early biomarkers of response and progression to P+V.

Patients and Methods: Pts had to undergo a tumor biopsy at baseline, and optional biopsies on-treatment (after cycle 2), and at progression for translational analyses. PD-L1 expression (n=102), tumor-infiltrating lymphocytes quantification (n=39), HPV typing (n=111), WES (n=83), RNAseq (n=82) and liquid chromatography-mass spectrometry (LC-MS) quantitative analysis of histone post-translational modifications (PTMs) (n=44) were performed on baseline samples.SNVs, CNVs, TMB, MSI status (by MSI sensor), aneuploidy score (AS), mutational signatures, immune signatures, and histone modifications were correlated with response and progression.

Results: Sixty-six pts were HPV+ (59%). Most frequently altered genes were PIK3CA (30%), TP53 (30%), KMT2D/C (18 and 17%), and FGF3/4 (17%). MSI was detected in 4 pts (5%), and TMB-high (&gt;10mut/Mb) in 13 pts (16%). High AS (&gt;10) was detected in 34 pts (40%), and was significantly associated with HPV- status (p=0.03). TMB high and MSI were associated with MMR mutational signatures (p&lt;0.01). TMB high was also associated with APOBEC (p=0.02) and DNA polymerase (POL) signatures (p &lt;0.01). Biomarkers associated with improved overall survival (OS) included HPV positivity (7.8 months versus 17.4 months, p&lt;0.01), high TMB (not reached versus 10.3 months, p=0.01), and high PD-L1 CPS score (13.2 months versus 7.0 months, p=0.06).Deconvolution of immune cell infiltration showed an expected trend for increased CD8 and decreased neutrophil infiltration in non progressor pts.Interestingly, LC-MS histone PTMs profiling showed a significant decrease in H4K5K8K12K16-4ac (p=0.05) and increase in H3K27me2K36me1 in non progressor pts (p=0.03). At the transcriptomic level, although not statistically significant, we observed modulation in the expression of genes associated with H3K36me1 (KDM2A, SETD3, SMYD2), and H3K27me3 (KDM6A) regulation, as well as HDAC genes.

Conclusions: HPV+ status was associated with improved OS, together with a high TMB and PD-L1 expression. CD8, macrophages and neutrophil signatures at baseline were associated with response. Promising epigenetic biomarkers were identified using LC/MS and will be correlated to transcriptomic and genomic data.

Citation Format: Christophe Le Tourneau, Luca Mazzarella, Bastien Cabarrou, Miguel Francisco, Célia Dupain, Maral Halladjian, Gianmaria Frige, Bruno Duso, Yinxiu Zhan, Elena Guerini-Rocco, Roberta Noberini, Tiziana Bonaldi, Maria Manuela Tonini, Grégoire Marret, Clélia Coutzac, Elodie Coquan, Mathilde Saint-Ghislain, Olivia Le Saux, Laetitia Chanas, François Legrand, Daria Maria Filippini, Emmanuelle Jeannot, Stephan Bernhart, Gabor Balogh, Marta Jimenez, Thomas Filleron, Nicolas Servant, Maud Kamal. Biomarkers of response and progression to Pembrolizumab and Vorinostat combination in late-stage squamous cell carcinoma patients of different locations included in the PEVOsq basket trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6413.