A phase 2 study of combined chemo-immunotherapy with cisplatin-pembrolizumab and radiation for unresectable vulvar squamous cell carcinoma

Abstract

Background Unresectable or metastatic vulvar cancer has relatively poor outcomes despite chemotherapy-sensitized radiation therapy and combination cytotoxic therapy. Despite the virus-associated and immunogenic nature of this disease, novel immunotherapy options that exploit this advantage are currently lacking. Platinum agents such as cisplatin have been shown to prime dendritic cells for T-cell costimulation, promote downregulation of inhibitory checkpoint molecules, and sensitize tumor cells to cytotoxic T-cell killing. Radiation therapy has also been shown to promote immunogenetic cell death as monotherapy and in combination with cisplatin. In combination with pembrolizumab, cisplatin-sensitized radiation is hypothesized to increase overall response rates and recurrence-free survival in patients with vulvar cancer, via induction of an anti-tumor inflammatory response. Methods We propose a single-arm phase II clinical trial of pembrolizumab combined with cisplatin-sensitized radiation therapy for women with unresectable, locally advanced, or metastatic vulvar cancer. The first three patients with locally advanced or unresectable disease will receive cycle 1 of pembrolizumab followed by a break and resumption of pembrolizumab at cycle 4 and as part of a safety cohort. All other patients, including the fourth patient with locally advanced/unresectable disease, will receive weekly cisplatin and pembrolizumab every 3 weeks, concurrently with daily radiation therapy. Following the completion of Cis-RT, patients will continue pembrolizumab maintenance for a total of 12 cycles. Archived tissue will be used for HPV status, MSI status, PD-L1, and TIL stratification post hoc. Imaging will be performed at baseline and every 3 cycles (21-day cycles) as per standard-of-care. Laboratory analysis will occur on the first day of each cycle. Discussion The combination of cisplatin-sensitized radiation and immune checkpoint blockade has not been evaluated in the upfront setting for vulvar cancer. In this rare malignancy, there are limited interventional clinical trials. This trial is designed to be as accessible as possible by allowing patients to receive cisplatin and radiation locally according to accepted standard-of-care while receiving pembrolizumab and adverse event monitoring at a centralized site. A robust suite of translational correlative studies has also been built into the trial to evaluate tumor-directed immune activation. Trial registration NCT04430699

Simultaneous and Spatially-Resolved Analysis of T-Lymphocytes, Macrophages and PD-L1 Immune Checkpoint in Rare Cancers

“…Different mechanisms of immune evasion have been studied in penile [ 11 , 21 , 53 , 54 ] vulvar [ 14 , 18 , 20 , 55 ] and anal cancers [ 17 , 19 ], and included immune checkpoint proteins and exhausted phenotypes for infiltrating-lymphocytes, suggesting that patients with these type of tumors can benefit from anti PD-L1 therapy [ 9 , 27 , 56 , 57 , 58 , 59 ]. Currently, there are several clinical trials ongoing for the use of immune therapy targeting PD-L1 (or its receptor PD-1) as treatment for penile, vulvar or anal cancer [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. Therefore, multiplexed immunofluorescence and an objective analysis of the tumor microenvironment may contribute significantly to improve the understanding of different therapeutic targets when the access to biological material is reduced or limited.…”

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

“…Based on these data, treatment with single ICIs has shown modest results overall, although interesting cases of disease remission were observed when ICIs were combined with RT. In fact, the evidence, although limited, supports the efficacy of this combination in gynecological cancers [ 165 , 166 ] and two trials on VSCC and vulvar melanoma are ongoing [ 107 , 133 ].…”

“…More recently, a single-arm phase II clinical study of pembrolizumab combined with cisplatin and RT for women with unresectable locally advanced or metastatic VC was proposed. This study is currently underway and recruiting patients [ 107 ]. Several pieces of data support the use of RT in combination with ICIs.…”

“…RT can trigger the expression of PD-L1 and PD-1 on tumor cells, making them targets for ICIs [ 108 ]. Furthermore, preclinical studies on murine models showed that RT plus ICIs leads to an increase in CD8+ TILs, a decrease in T reg lymphocytes and in MSCs, and in the upregulation of MHC class I, favoring the activity of ICIs [ 107 ].…”

Role of Chemotherapy in Vulvar Cancers: Time to Rethink Standard of Care?

“…The use of immunotherapy, alone or in combination with chemotherapy, is an emerging and evolving field of research in vulvar carcinoma, opening a new scenario in this rare tumor, although the inherent data are still limited [75]. Concerning its use in combination with chemotherapy, the administration of pembrolizumab with weekly cisplatin and concurrent radiotherapy is being evaluated in a phase II study in unresectable or metastastic vulvar carcinoma [76].…”