Pembrolizumab-Vorinostat Combination Shows Promise in Recurrent Squamous Cell Carcinoma
核心洞察
The PEVOsq phase 2 trial demonstrated a 26% overall response rate with pembrolizumab plus vorinostat in 107 patients with recurrent/metastatic squamous cell carcinoma (搜索) across multiple anatomical sites.
Primary endpoints were met in cervical cancer (搜索) (39% ORR), anal cancer (搜索) (31% ORR), and vulvar/vaginal cancer (搜索) (19% ORR) cohorts, with median overall survival reaching 18.8 months in anal cancer patients.
Treatment-related adverse events occurred in 91% of patients, with 75% requiring dose modifications, though the safety profile was deemed manageable despite substantial toxicity.
The combination of pembrolizumab and vorinostat demonstrated significant antitumor activity in patients with recurrent and/or metastatic squamous cell carcinoma (搜索) (SCC) across multiple anatomical sites, according to results from the multicenter phase 2 PEVOsq trial published in Nature Cancer.
The open-label basket trial enrolled 111 patients with recurrent and/or metastatic SCC from various locations, including 29 with anal cancer (搜索), 27 with head and neck SCC (HNSCC), 26 with cervical cancer (搜索), 17 with vulvar/vaginal cancer (搜索), 11 with penile cancer (搜索), and 2 with lung cancer. Patients received pembrolizumab 200 mg intravenously every 3 weeks combined with vorinostat 400 mg orally once daily with food.
Primary Efficacy Results
In the per-protocol population of 107 patients, the overall response rate (ORR) was 26% (95% CI: 18-36%), including 7 complete responses (6.5%) and 21 partial responses (20%). The study met its primary endpoint in three cohorts: cervical cancer (搜索) achieved an ORR of 39% (95% CI: 20-62%), anal cancer (搜索) reached 31% (95% CI: 15-51%), and vulvar/vaginal cancer (搜索) demonstrated 19% (95% CI: 4.0-46%).
The primary objective was not reached in the HNSCC cohort with an ORR of 19% (95% CI: 6.6-39%) or the penile cancer (搜索) cohort with 18% (95% CI: 2.3-52%).
The overall median duration of response was 9.7 months (95% CI: 3.1-15.2), with values ranging from 1.1 months in penile cancer (搜索) to 15.2 months in cervical cancer (搜索). The median duration of response was not reached in the anal cancer (搜索) cohort.
Survival Outcomes
The overall median progression-free survival was 4.0 months (95% CI: 2.6-4.3), varying from 1.3 months in vulvar/vaginal cancer (搜索) to 5.8 months in anal cancer (搜索). The median overall survival was 11.1 months (95% CI: 9.2-17.4), ranging from 4.4 months in penile cancer (搜索) to 18.8 months in anal cancer.
Biomarker Analysis
PD-L1 (搜索) status showed a positive association with response, with patients having a Combined Positive Score (CPS) ≥1 achieving a 30% ORR compared to 5.6% for CPS = 0 (P = 0.04). High tumor mutational burden (TMB) was also associated with better outcomes, with a 58% ORR in high TMB patients versus 20% in low TMB patients (P = 0.01).
HPV-positive tumors demonstrated superior response rates compared to HPV-negative tumors (34% versus 16%, P = 0.03). Age was the only clinical parameter associated with ORR, with patients ≥60 years showing higher response rates than younger patients (36% versus 15%, P = 0.01).
Genomic Biomarkers
Comprehensive genomic analysis of 77 samples revealed potential predictive biomarkers. Patients with alterations in RAD51 (搜索), NOTCH1 (搜索), or B2M (搜索) showed longer progression-free survival (P < 0.05). PIK3CA alterations were associated with improved overall survival (P < 0.05), while TP53 (搜索) alterations correlated with worse overall survival (P < 0.05).
Safety Profile
Treatment-related adverse events occurred in 91% of patients, with the most frequent being asthenia (61%), nausea (51%), diarrhea (37%), decreased appetite (37%), and vomiting (26%). Grade 3 or 4 treatment-related adverse events included grade 3 asthenia (8%), diarrhea (6%), decreased appetite (5%), and nausea (3%).
Treatment modifications due to toxicity occurred in 75% of patients, with 66% requiring vorinostat dose interruptions or reductions. Nine percent of patients permanently discontinued pembrolizumab due to adverse events, while 39% permanently discontinued vorinostat. Six grade 5 serious adverse events were reported, though none were definitively attributed to treatment toxicity.
Clinical Context
The results compare favorably to historical data with pembrolizumab monotherapy. In anal cancer (搜索), previous studies reported ORRs of 11-24% with single-agent anti-PD-1 (搜索) therapy, while the combination achieved 31% with improved survival outcomes. For cervical cancer (搜索), the 39% ORR with the combination substantially exceeded the 12% ORR reported with pembrolizumab monotherapy in previously treated patients.
Lead study author Dr. Edith Borcoman from Institut Curie noted that "the 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 (搜索), along with an overall manageable safety profile."
The study's basket design allowed inclusion of rare cancers such as vulvar/vaginal and penile cancers, for which dedicated trials are challenging due to recruitment difficulties. The researchers identified PD-L1 (搜索) positivity, HPV positivity, and high TMB as predictive biomarkers for response to the combination treatment.
The findings suggest that epigenetic modulation with vorinostat may enhance the efficacy of pembrolizumab in squamous cell carcinomas, particularly those with specific molecular characteristics. Further validation in larger randomized trials will be needed to confirm these promising results and establish the combination as a standard treatment option for selected patients with recurrent and/or metastatic SCC.