Pembrolizumab/Vorinostat Has Promising Activity in Squamous Cell Carcinoma

"Our comprehensive genomic analyses identified potential genomic biomarkers that may be used to better select patients who will derive a benefit from this therapeutic combination," according to the study authors.

Combining pembrolizumab (Keytruda) with vorinostat (Zolinza) demonstrated significant antitumor activity across different cohorts of patients with recurrent and/or metastatic squamous cell carcinoma (SCC), according to findings from the basket phase 2 PEVOsq trial (NCT04357873) published in Nature Cancer.1

Across the per-protocol population (n = 107), the objective response rate (ORR) was 26% (95% CI, 18%-36%), which included partial responses (PRs) in 20% and complete responses (CRs) in 6.5%. Data showed that the primary end point of ORR was reached in the cervical cancer cohort (39%; 95% CI, 20%-62%), anal cancer cohort (31%; 95% CI, 15%-51%), and the vulvar or vaginal cancer cohort (19%; 95% CI, 4.0%-46%). The ORR was 19% (95% CI, 6.6%-39%) in the head and neck SCC (HNSCC) cohort and 18% (95% CI, 2.3%-52%) in the penile cancer cohort; the primary end point was not met in these groups.

The median duration of response (DOR) was 9.7 months (95% CI, 3.1-15.2) across the per-protocol population, with values ranging from 1.1 months in the penile cancer group to 15.2 months in the cervical cancer cohort. Additionally, the study treatment produced a median progression-free survival (PFS) of 4.0 months (95% CI, 2.6-4.3) across all patients, with values ranging from 1.3 months in the vulvar or vaginal cancer cohort to 5.8 months in the anal cancer group. The median overall survival (OS) across the per-protocol population was 11.1 months (95% CI, 9.2-17.4); values ranged from 4.4 months among those with penile cancer to 18.8 months in those with anal cancer.

“[T]he combination of pembrolizumab and vorinostat showed promising antitumor activity in patients with recurrent and/or metastatic SCC and more specifically in patients with anal, cervical or vulvar/vaginal cancer, along with an overall manageable safety profile. Nonetheless, dosage of vorinostat had to be reduced in a substantial proportion of patients,” lead study author Edith Borcoman, MD, PhD, from the Department of Drug Development and Innovation (D3i), INSERM U932, Immunity and Cancer, and the Translational Immunotherapy Team in the Translational Research Department at Institut Curie in Paris, France, wrote with coauthors.1 “The predictive biomarkers identified consist of PD-L1 positivity, HPV positivity and high tumor mutational burden [TMB]. Our comprehensive genomic analyses identified potential genomic biomarkers that may be used to better select patients who will derive a benefit from this therapeutic combination.”

In the open-label, multi-center, phase 2 PEVOsq trial, 111 patients were assigned to receive pembrolizumab intravenously at 200 mg every 3 weeks plus vorinostat orally at 400 mg once daily with food for each 3-week cycle. The study population included 29 patients with anal cancer, 27 with HNSCC, 25 with cervical cancer, 17 with vulvar or vaginal cancer, 11 with penile cancer, and 2 with lung cancer who received at least 1 dose of study treatment.

The trial’s primary end point was investigator-assessed ORR per RECIST v1.1 criteria. Secondary end points included DOR, PFS, OS, and incidence of adverse effects (AEs).

Patients 18 years and older with an ECOG performance status of 0 or 1; histologically confirmed recurrent and/or metastatic SCC of the head and neck, cervix, lung, anus, vulva, or penis; disease amenable to surgery; and measurable disease per RECIST v1.1 guidelines were eligible for enrollment on the trial.2 Other eligibility criteria included having adequate renal, liver, and bone marrow function.

Across the overall population, the median patient age was 61 years (range, 18-85), and 63% were female. Additionally, most patients had an ECOG performance status of 1 (55%), p16-positive status (70%), HPV16 PCR typing (49%), low TMB (85%), microsatellite stable disease (96%), a PD-L1 combined positive score (CPS) of 1 to 19 (54%), and a PD-L1 tumor proportion score (TPS) of 1% to 49% (46%).

Data showed an ORR of 5.6% in patients with a PD-L1 CPS of 0 vs 30% in those with a CPS of 1 or higher (P = .04). Univariate analysis also showed a higher ORR in patients with high TMB (58%) vs those with low TMB (20%; P = .01).

Regarding potential genomic biomarkers of response, investigators observed a higher frequency of B2M alterations in those with a response, although this did not reach statistical significance (P <.05; adjusted P = .39). Additionally, RAD51, NOTCH1 or B2M alterations correlated with longer PFS (P <.05), and the presence of PIK3CA alterations correlated with improved OS (P <.05).

At least 1 treatment-emergent AE (TEAE) occurred in 91% of patients, with the most common including asthenia (61%), nausea (51%), diarrhea (37%), diminished appetite (37%), and vomiting (26%). The most common grade 3/4 TEAEs included grade 3 asthenia (8%), diarrhea (6%), decreased appetite (5%), and nausea (3%).

Treatment-related AEs (TRAEs) resulting in treatment modifications occurred in 75% of patients, with 9% permanently discontinuing pembrolizumab due to toxicity. Investigators noted 6 grade 5 serious AEs; deaths were attributed to an underlying disease (n = 2), infection and underlying disease (n = 1), stent thrombosis leading to a lower left limb ischemia (n = 1), and unknown causes (n = 2).

References

1. Borcoman E, Cabarrou B, Francisco M, et al. Efficacy of pembrolizumab and vorinostat combination in patients with recurrent and/or metastatic squamous cell carcinomas: a phase 2 basket trial. Nat Cancer. Published online June 30, 2025. doi:10.1038/s43018-025-01004-2.
2. A study of ADRX-0405 in subjects with select advanced solid tumors. ClinicalTrials.gov. Updated April 9, 2025. Accessed July 9, 2025. https://tinyurl.com/29r8ty9x