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Clinical Trial
. 2025 Aug;6(8):1370-1383.
doi: 10.1038/s43018-025-01004-2. Epub 2025 Jun 30.

Efficacy of pembrolizumab and vorinostat combination in patients with recurrent and/or metastatic squamous cell carcinomas: a phase 2 basket trial

Edith Borcoman  1   2   3   4 , Bastien Cabarrou  5 , Miguel Francisco  6   7 , Frédéric Bigot  8 , François Ghiringhelli  9 , Damien Vansteene  10 , François Legrand  11 , Maral Halladjian  1 , Célia Dupain  1 , Olivia Le Saux  12 , Clelia Coutzac  12 , Christian Borel  13 , Raphael Chaltiel  14 , Benoit You  15 , Carlos Gomez-Roca  16 , Sophie Cousin  17 , Elodie Coquan  18 , Aurélien Lambert  19 , Esma Saada-Bouzid  20   21 , Xavier Durando  22 , Mathilde Saint-Ghislain  1 , Gianmaria Frige  23 , Elena Guerini-Rocco  24   25 , Maria Manuela Tonini  26 , Ivan Bièche  27 , Zahra Castel-Ajgal  1 , Grégoire Marret  1 , Marie-Paule Sablin  1 , Emmanuelle Jeannot  28 , Fabrice Andre  29 , Thomas Filleron  5 , Marta Jimenez  11 , Luca Mazzarella  30   31   32 , Nicolas Servant  6 , Maud Kamal  1 , Christophe Le Tourneau  33   34   35
Affiliations
Clinical Trial

Efficacy of pembrolizumab and vorinostat combination in patients with recurrent and/or metastatic squamous cell carcinomas: a phase 2 basket trial

Edith Borcoman et al. Nat Cancer. 2025 Aug.

Abstract

Immune checkpoint inhibitors improve the treatment of many solid tumors and have shown encouraging results in advanced squamous cell carcinoma (SCC), yet only a minority of patients respond to immune checkpoint inhibitor monotherapy. We conducted the PEVOsq trial, an open-label, nonrandomized, multicenter, basket phase 2 trial to evaluate the combination of pembrolizumab and vorinostat in recurrent/metastatic SCC of various origins. The primary endpoint was the objective response rate (ORR) in each tumor cohort during treatment as per the investigators' assessment. Secondary endpoints included safety and antitumor activity evaluation in terms of centrally confirmed ORR, progression-free survival, overall survival and duration of response. In the efficacy population (n = 107), the ORR was met in cervical (39%), anal (31%) and vulvar/vaginal (19%) cancer cohorts, but not in head and neck SCC (19%) or penile (18%) cancer cohorts (overall ORR = 26%). Median progression-free survival was 4.0 months (95% confidence interval: 2.6-4.3), and median overall survival was 11.1 months (95% confidence interval: 9.2-17.4). In the safety population, 101 (91%) of 111 patients developed at least one treatment-related adverse event, with 39% and 5.4% of patients experiencing at least one grade 3 and grade 4 treatment-related adverse event, respectively. Vorinostat-related toxicity prompted a dose reduction/interruption in 66% of patients. Whole-exome sequencing analyses revealed several potential predictive biomarkers of response to treatment. Further studies in a larger number of patients are required to validate these findings. ClinicalTrials.gov identifier: NCT04357873 .

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Conflict of interest statement

Competing interests: E.B. received honoraria from Eisai, Merck Sharp and Dohme (MSD), Sandoz and Amgen and meetings/travel grants and nonfinancial support from Daiichi Sankyo, Eisai, Amgen, Sandoz, MSD, Bristol Myers Squibb (BMS), Novartis, Pfizer and Roche and has consulted for Egle Tx, all outside of the submitted work. F.G. received fees for oral communication from Eli Lilly, Sanofi, BMS, AstraZeneca and Amgen, received funding for clinical trials from AstraZeneca, received travel grants from Roche France, Amgen and Servier and is an advisory board member for Merck Serono, Amgen, Roche France and Sanofi, all outside of the submitted work. O.L.S. reports honoraria from MSD and Clovis and travel/accommodation/expenses from Eisai. C.C. participated on advisory boards from Amgen, BMS, Merck Serono, Pierre Fabre and Servier and received personal fees from BMS, Merck Serono, Pierre Fabre and Servier and institutional fees from Amgen, AstraZeneca, BMS, Daiichi Sankyo, MSD and ImCore Roche Genentech. C.B. participated on advisory boards from AstraZeneca, Merck Serono and MSD and received personal fees from AstraZeneca, BMS, Merck Serono and MSD. E.S.-B. participated on advisory boards and received travel expenses from MSD and Merck Serono. C.G.-R. has previously received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from BMS, F. Hoffmann-La Roche, Genentech, Foundation Medicine and Pierre Fabre, has supported or attended meetings and/or travel for MSD and F. Hoffmann-La Roche and has participated on a data safety monitoring board or advisory board for Macomics and Pharmamar. E.G.-R. has relevant relationships (advisory fees, honoraria, travel accommodation and expenses, grants and/or nonfinancial support) with AstraZeneca, Exact Sciences, GSK, Illumina, MSD, Novartis, Roche, Sophia Genetics and Thermo Fisher Scientific, unrelated to the current work. T.F. reports receiving personal fees from Jansen outside the submitted work and institutional fees from Roche and Lilly outside the submitted work. C.L.T. participated on advisory boards from MSD, BMS, Merck, AstraZeneca, Celgene, Seattle Genetics, Roche, Novartis, Rakuten, Nanobiotix and GSK. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Trial design and CONSORT diagram.
Images source: Unicancer library; H&N, head and neck.
Fig. 2
Fig. 2. Waterfall plot based on the best target lesion reduction in the per-protocol population.
N = 102 patients, 5 patients were excluded from the N = 107 per-protocol population due to no measurable lesions to calculate the best change in target lesion. Source data
Fig. 3
Fig. 3. Swimmer plots showing the antitumor activity of pembrolizumab plus vorinostat by cancer type.
a, Head and neck cancer (N = 26 patients). b, Anal cancer (N = 29 patients). c, Cervical cancer (N = 23 patients). d, Vulvar/vaginal cancer (N = 16 patients). e, Penile cancer (N = 11 patients). No statistical test was used. Source data
Fig. 4
Fig. 4. Oncoprint of druggable alterations in 77 patients with available WES data experiencing an objective response versus others.
Frequently altered genes that were altered in at least 5% of the samples were grouped according to CR/PR status. Clinical features, TMB, MSI, aneuploidy score (AS), major mutational signatures and somatic alterations are indicated in the legend. The bar chart on the top indicates the composition of alterations per sample, while the bar chart on the right indicates the composition of alterations per gene of interest. To compare alteration rates between patients experiencing an objective response and patients not experiencing an objective response, a Fisher’s exact test was performed. The resulting P values were adjusted using the Benjamini–Hochberg procedure. Results of the statistical tests are provided in Supplementary Tables 11 and 12; indel, insertion/deletion; LOH, loss of heterozygosity; MSS, microsatellite stable; ROS, reactive oxygen species. Aristol ac, aristolochic acid exposure; Deamin 5MC, deamination of 5-methylcytosine; HRD, homologous recombination deficiency; Platin, prior chemotherapy treatment with platinum drugs; POL, polymerase epsilon exonuclease domain mutations; TSG, tumor suppressor genes. Source data
Fig. 5
Fig. 5. Main altered pathways in 77 patients with available WES data experiencing an objective response versus others.
Frequently altered genes are grouped according to curated signaling pathways detailed in Supplementary Table 2. Clinical features, TMB, MSI, aneuploidy score and major mutational signatures are indicated in the legend. The bar chart on the top indicates the composition of alterations per sample, and the bar chart on the right indicates the composition of alterations per gene of interest. To compare mutational pathways between patients experiencing an objective response and patients not experiencing an objective response, a Fisher’s exact test was performed. The resulting P values were adjusted using the Benjamini–Hochberg procedure. Results of the statistical tests are provided in Supplementary Tables 13 and 14. Source data
Extended Data Fig. 1
Extended Data Fig. 1. Progression-free survival (PFS) in the per-protocol population (n = 107) and according to tumor type.
Median PFS are provided below each graph. N = 107 patients comprising N = 26 Head and neck cancers, N = 29 anus, N = 16 vulva/vagina, N = 11 penis, N = 23 cervix. No statistical test was performed. Source data
Extended Data Fig. 2
Extended Data Fig. 2. Overall survival in the per-protocol population (n = 107) and according to tumor type.
Median OS are provided below each graph. N = 107 patients comprising N = 26 Head and neck cancers, N = 29 anus, N = 16 vulva/vagina, N = 11 penis, N = 23 cervix. No statistical test was performed. Source data
Extended Data Fig. 3
Extended Data Fig. 3. Progression-free survival (PFS) according to biomarkers in the per-protocol population.
N = 107 patients are included among which N = 98 with available CPS evaluation, N = 107 with HPV status and N = 77 patients with available TMB status. P-values from Log-rank test are reported. All statistical tests were two-sided. No adjustments were made for multiple comparisons. Median PFS for each population according to biomarkers are reported on the right of each graph. Source data
Extended Data Fig. 4
Extended Data Fig. 4. Overall survival according to biomarkers in the per-protocol population.
N = 107 patients are included among which N = 98 with available CPS evaluation, N = 107 with HPV status and N = 77 patients with available TMB status. P-values from Log-rank test are reported. All statistical tests were two-sided. No adjustments were made for multiple comparisons. Median PFS for each population according to biomarkers are reported on the right of each graph. Source data
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