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Efficacy and safety of pembrolizumab for patients with previously treated advanced vulvar squamous cell carcinoma: Results from the phase 2 KEYNOTE-158 study

Open AccessPublished:March 28, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.01.029

      Highlights

      • We evaluated antitumor activity and safety of pembrolizumab monotherapy in patients with advanced vulvar cancer.
      • Among 101 patients with vulvar cancer, pembrolizumab demonstrated an objective response rate of 10.9%.
      • Responses occurred regardless of tumor PD-L1 expression (PD-L1–positive, 9.5%; PD-L1–negative, 28.6%).
      • Among patients with a response, median duration of response was 20.4 months.
      • Treatment-related adverse events occurred in 50.5% of patients, including 11.9% with grade 3–5 events.

      Abstract

      Objective

      Treatment options for advanced vulvar cancer are limited. We evaluated pembrolizumab monotherapy in patients with advanced vulvar squamous cell carcinoma (SCC) enrolled in the phase 2 multicohort, open-label KEYNOTE-158 study (NCT02628067).

      Methods

      Eligible patients had histologically or cytologically documented advanced vulvar SCC with prior treatment failure, measurable disease per RECIST v1.1, ECOG performance status 0–1, and a tumor sample available for biomarker analysis. Pembrolizumab 200 mg was administered intravenously Q3W for up to 35 cycles (approximately 2 years). The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central radiologic review in all patients and subgroups based on PD-L1 combined positive score (≥1 [PD-L1–positive] versus <1 [PD-L1–negative]).

      Results

      101 patients were enrolled. Median time from first dose to data cutoff was 36.0 months. The ORR (95% CI) was 10.9% (5.6%–18.7%) among all patients, 9.5% (4.2%–17.9%) among the 84 patients with PD-L1–positive tumors, and 28.6% (3.7%–71.0%) among the 7 patients with PD-L1–negative tumors. Among patients with a response, median DOR was 20.4 (range, 2.1+ to 28.0) months. Median (95% CI) PFS and OS were 2.1 (2.0–2.1) and 6.2 (4.9–9.4) months, respectively. Treatment-related AEs occurred in 50.5% of patients (grade 3–5, 11.9%) and led to discontinuation of treatment in 5.0% of patients. Two deaths were considered treatment-related (hepatitis, n = 2).

      Conclusions

      Pembrolizumab monotherapy was associated with durable responses in a subset of patients with vulvar SCC. Responses occurred regardless of tumor PD-L1 status. No new safety signals emerged; overall, pembrolizumab was well tolerated.

      Keywords

      1. Introduction

      Vulvar cancer occurs in 0.85/100,000 women per year worldwide (approximately 45,000 total new cases estimated in 2020) [
      • World Health Organization International Agency for Research on Cancer (IARC), GLOBOCAN
      ]. Nearly all vulvar cancers are squamous cell carcinomas (SCCs) [
      • PDQ Adult Treatment Editorial Board
      Vulvar Cancer Treatment (PDQ®): Health Professional Version.
      ]. Infection with a carcinogenic strain of human papillomavirus (HPV) is a key risk factor for the development of vulvar cancer [
      • PDQ Adult Treatment Editorial Board
      Vulvar Cancer Treatment (PDQ®): Health Professional Version.
      ] and accounts for 69% of vulvar cancers [
      • Saraiya M.
      • Unger E.R.
      • Thompson T.D.
      • et al.
      US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines.
      ]. However, advanced vulvar cancer typically affects patients 55 years or older (median age of 69 years) and is more likely to be HPV-negative in the older population compared with younger patients [
      • Gillison M.L.
      • Chaturvedi A.K.
      • Lowy D.R.
      HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women.
      ].
      Survival is poor among patients diagnosed with advanced disease, with 5-year survival rates of 22% for those with metastatic disease [
      • Chung H.C.
      Pembrolizumab treatment of advanced cervical cancer: updated results from the phase II KEYNOTE-158 study.
      ]. Treatment options for recurrent or metastatic vulvar cancer are limited, and no clear standard-of-care treatment exists [
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ]. Despite resistance to chemotherapy [
      • Reade C.J.
      • Eiriksson L.R.
      • Mackay H.
      Systemic therapy in squamous cell carcinoma of the vulva: current status and future directions.
      ,
      • Witteveen P.O.
      • van der Velden J.
      • Vergote I.
      • et al.
      Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer--Gynaecological Cancer Group).
      ,
      • Cormio G.
      • Loizzi V.
      • Gissi F.
      • et al.
      Cisplatin and vinorelbine chemotherapy in recurrent vulvar carcinoma.
      ,
      • Muss H.B.
      • Bundy B.N.
      • Christopherson W.A.
      Mitoxantrone in the treatment of advanced vulvar and vaginal carcinoma. A Gynecologic Oncology Group study.
      ,
      • Thigpen J.T.
      • Blessing J.A.
      • Homesley H.D.
      • Lewis Jr., G.C.
      Phase II trials of cisplatin and piperazinedione in advanced or recurrent squamous cell carcinoma of the vulva: a Gynecologic Oncology Group study.
      ], advanced recurrent or metastatic vulvar cancer has generally been treated with chemotherapy or chemoradiation [
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ]. Recent studies have evaluated additional treatment options, including immunotherapy, in patients with vulvar cancer. The phase 1b KEYNOTE-028 study evaluated the anti–programmed death 1 (anti–PD-1) monoclonal antibody pembrolizumab in patients with advanced vulvar cancer (n = 18) that expressed programmed death ligand 1 (PD-L1; as evaluated by a prototype 22C3 antibody assay) and showed a 6% objective response rate (ORR; 1 partial response [PR]), median progression-free survival (PFS) of 3.1 months, and median overall survival (OS) of 3.8 months [
      • Ott P.A.
      • Bang Y.J.
      • Piha-Paul S.A.
      • et al.
      T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028.
      ].
      Herein we report the results from the vulvar cancer cohort of the KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067), in which patients with previously treated advanced vulvar SCC (irrespective of tumor PD-L1 expression) received pembrolizumab monotherapy.

      2. Methods

      2.1 Study design and patient eligibility

      KEYNOTE-158 is an ongoing, phase 2, multicenter, multicohort, single-arm, open-label study of the efficacy and safety of pembrolizumab monotherapy for patients with rare, advanced solid tumors. Patients who met eligibility criteria were assigned to one of 13 cohorts according to primary tumor type and biomarker status. Cohort F comprises patients with vulvar SCC.
      Women were eligible to enroll in Cohort F if they were 18 years or older and had a histologically or cytologically documented advanced (metastatic and/or unresectable) vulvar SCC that was deemed incurable and had experienced treatment failure on or intolerance to prior standard therapy. Patients were required to have radiologically measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, confirmed by blinded independent central radiologic review, with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 during screening and within 3 days before the first dose of pembrolizumab, life expectancy of at least 3 months, and adequate hematologic, renal, and hepatic function and coagulation status. Patients' cancer must have had progression on or have been intolerant to therapies known to provide clinical benefit. A tumor tissue sample from a non-irradiated lesion, from which PD-L1, gene expression profile (GEP), and microsatellite instability (MSI) status could be assessed, was required from all patients during screening. Women were excluded if pregnant or breastfeeding, and all eligible patients were required to use reliable contraceptive methods during the study. Patients were ineligible to participate if they had active autoimmune disease that required immunosuppressive drugs or disease-modifying agents within the previous 2 years, had a diagnosis of immunodeficiency, or had received systemic steroid therapy or other immunosuppressive therapy within 7 days before the first pembrolizumab dose. Additional exclusion criteria were receipt of prior anticancer monoclonal antibody therapy within 4 weeks before start of study treatment; chemotherapy, targeted small-molecule therapy, or radiation within 2 weeks before start of study treatment; additional malignancy within 2 years before enrolling; active central nervous system metastases or carcinomatous meningitis; active infection requiring systemic therapy; history of non-infectious pneumonitis that required steroids; or any other condition, therapy, or laboratory abnormality that in the opinion of the investigator might have confounded the study results or interfere with the patient's ability to participate in the trial.
      The study was conducted according to the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and all applicable local and/or national regulations. The study protocol was approved by the appropriate institutional review board or independent ethics committee prior to enrolling the first patient at each study site. All patients provided written informed consent to participate.

      2.2 Study treatment and assessments

      Pembrolizumab 200 mg was administered intravenously once every 3 weeks. Treatment continued until progressive disease (PD), unacceptable adverse event (AE), intercurrent illness that prevented pembrolizumab treatment, physician decision, patient withdrawal of consent, noncompliance with protocol, or completion of 35 treatment cycles (approximately 2 years). Patients who stopped pembrolizumab treatment and subsequently experienced disease progression were allowed to receive up to 1 year of additional pembrolizumab therapy if they achieved stable disease (SD), PR, or complete response (CR) and completed 35 cycles of pembrolizumab or if they achieved a CR after receiving ≥8 doses of pembrolizumab.
      Tumor imaging (using computed tomography [preferred] or magnetic resonance imaging) was conducted at baseline, every 9 weeks for 1 year, then every 12 weeks thereafter. AEs were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 and were monitored throughout the study and for 30 days (90 days for serious AEs) after treatment discontinuation.
      PD-L1 expression in tumor samples was evaluated using PD-L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA) by Neogenomics Laboratories. PD-L1 status was determined according to a combined positive score (CPS) of ≥1 (PD-L1–positive) or <1 (PD-L1–negative), where CPS was defined as the number of PD-L1–staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100.

      2.3 Study endpoints and statistical analyses

      The primary endpoint was ORR according to RECIST v1.1, by independent central radiologic review, in all patients and in subgroups defined by tumor biomarker status (ie, PD-L1 positivity). Secondary endpoints included duration of response (DOR; time from first documented evidence of CR or PR through disease progression or death), PFS (time from first dose of study treatment to the first documented disease progression according to RECIST v1.1 or death), OS (time from first dose of study treatment to death), and safety in all patients and in subgroups defined by tumor biomarker status. No statistical hypothesis testing was planned for the study.
      The study was planned to enroll approximately 100 patients in Cohort F regardless of primary tumor biomarker status. Efficacy and safety analyses included all patients who received at least 1 dose of pembrolizumab. Patients with missing or unknown response data were treated as nonresponders. Analyses of ORR used point estimates, accompanied by Clopper-Pearson 95% confidence intervals (CIs). DOR, PFS, and OS were estimated using the Kaplan-Meier method. Statistical analyses were done using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

      3. Results

      3.1 Patients

      Between March 2, 2016 and June 25, 2019, 101 patients were enrolled at 38 sites in 17 countries (Fig. 1). All patients received at least 1 dose of pembrolizumab and were included in the efficacy and safety analyses. At the time of data cutoff (October 5, 2020), 4 patients were ongoing on study treatment, 95 discontinued, and two had completed pembrolizumab treatment. None of the patients received a second course of pembrolizumab. Median time from first dose to data cutoff was 36.0 (range, 15.4–55.2) months. Median (range) patient age was 64 (31–87) years (Table 1). Thirty-four (33.7%) patients had received at least 2 lines of prior systemic therapy and most had received radiation therapy (n = 93 [92.1%]). The majority of patients had stage IV disease (n = 87 [88.1%]), and 84 (83.2%) patients had PD-L1–positive tumors (ie, CPS ≥1).
      Fig. 1
      Fig. 1Patient disposition at data cutoff (October 5, 2020). aAmong the 30 patients who discontinued due to clinical disease progression, 29 had PFS events per independent central review (progressive disease, n = 13; death, n = 16; censored for PFS analysis after initiating a new anticancer therapy, n = 1). ECOG PS, Eastern Cooperative Oncology Group performance status; PFS, progression-free survival.
      Table 1Patient demographics and baseline characteristics for all patients as treated.
      N = 101
      Age, median (range), y64.0 (31–87)
       ≥65 y49 (48.5)
       ≥75 y17 (16.8)
      Region of enrollment
       US19 (18.8)
       Non-US82 (81.2)
      ECOG performance status
       016 (15.8)
       185 (84.2)
      Metastatic stage
       M020 (19.8)
       M181 (80.2)
      Disease stage
       II3 (3.0)
       III10 (9.9)
       IV88 (87.1)
      Number of prior lines of systemic therapy
       None
      Patients received prior surgery and/or radiation.
      9 (8.9)
       Adjuvant/neoadjuvant/definitive1 (1.0)
       157 (56.4)
       223 (22.8)
       34 (4.0)
       4 or more7 (6.9)
      Prior radiation therapy
       Yes93 (92.1)
       No8 (7.9)
      PD-L1 status
       CPS <17 (6.9)
       CPS ≥184 (83.2)
       Not evaluable
      Tumor sample could not be evaluated for PD-L1 expression.
      4 (4.0)
       Not assessed
      Sample received after cutoff date for immunohistochemistry analysis.
      6 (5.9)
      ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; CPS, combined positive score.
      Values are presented as n (%) unless stated otherwise.
      a Patients received prior surgery and/or radiation.
      b Tumor sample could not be evaluated for PD-L1 expression.
      c Sample received after cutoff date for immunohistochemistry analysis.

      3.2 Antitumor activity

      The ORR in the total population was 10.9% (95% CI, 5.6%–18.7%), with 1 CR and 10 PRs (Table 2). Clinical benefit, defined as a CR, PR, or SD, was observed for 29 (28.7%) patients. Furthermore, 34 (43.6%) of the 78 patients who had at least 1 postbaseline tumor assessment had a decrease in the size of target lesions relative to baseline (Fig. 2A ). The 11 patients who achieved a PR or CR had a median time to response of 4.0 (range, 1.6–6.0) months and median DOR of 20.4 (range, 2.1+ to 28.0) months; in some instances, responses were maintained after cessation of study treatment (Fig. S1). Based on Kaplan-Meier estimates, the DOR was ≥6 months for 80% of patients and ≥12 months for 60% of patients. The median time from first dose to disease progression or death among those with best overall response of CR, PR, and SD was 8.2 (range, 2.5–31.9) months.
      Table 2Antitumor activity of pembrolizumab, according to RECIST v1.1 criteria, as assessed by blinded independent central radiologic review.
      Data cutoff date, October 5, 2020.
      All Patients (N = 101)Patients With PD-L1–Positive Tumors (n = 84)
      Four (4.0%) patients had tumors that were not evaluable for tumor PD-L1 status. PD-L1 status was not assessed in 6 (5.9%) patients. PD-L1 status was determined according to a combined positive score ≥1 for PD-L1–positive or <1 for PD-L1–negative.
      Patients With PD-L1–Negative Tumors (n = 7)
      Four (4.0%) patients had tumors that were not evaluable for tumor PD-L1 status. PD-L1 status was not assessed in 6 (5.9%) patients. PD-L1 status was determined according to a combined positive score ≥1 for PD-L1–positive or <1 for PD-L1–negative.
      ORR, % (95% CI)
      Includes patients with confirmed CR or PR. At the time of analysis, all responses were confirmed.
      10.9 (5.6–18.7)9.5 (4.2–17.9)28.6 (3.7–71.0)
      Best overall response, n (%)
       CR1 (1.0)1 (1.2)0
       PR10 (9.9)7 (8.3)2 (28.6)
       SD
      Best overall response assessment required SD of at least 6 weeks duration.
      18 (17.8)14 (16.7)0
       PD48 (47.5)43 (51.2)3 (42.9)
       Not evaluable
      One patient had a best overall response of SD on day 19 but no subsequent evaluation and was therefore classified as not evaluable.
      1 (1.0)1 (1.2)0
       No assessment
      No postbaseline assessment available for response evaluation. Seventeen patients discontinued treatment on day 1 owing to clinical progression (n = 10), adverse events (n = 6), or patient withdrawal (n =1).
      23 (22.8)18 (21.4)2 (28.6)
      Time to response, median (range), months4.0 (1.6 to 6.0)4.1 (1.6 to 6.0)4.0 (3.9 to 4.0)
      DOR, median (range), months20.4 (2.1+ to 28.0)11.9 (3.7 to 18.4+)28.0 (2.1+ to 28.0)
      Patients with response ≥12 months, %
      From product-limit (Kaplan-Meier) method for censored data.
      60.050.0100
      CI, confidence interval; CR, complete response; DOR, duration of response; ORR, objective response rate; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
      a Data cutoff date, October 5, 2020.
      b Four (4.0%) patients had tumors that were not evaluable for tumor PD-L1 status. PD-L1 status was not assessed in 6 (5.9%) patients. PD-L1 status was determined according to a combined positive score ≥1 for PD-L1–positive or <1 for PD-L1–negative.
      c Includes patients with confirmed CR or PR. At the time of analysis, all responses were confirmed.
      d Best overall response assessment required SD of at least 6 weeks duration.
      e One patient had a best overall response of SD on day 19 but no subsequent evaluation and was therefore classified as not evaluable.
      f No postbaseline assessment available for response evaluation. Seventeen patients discontinued treatment on day 1 owing to clinical progression (n = 10), adverse events (n = 6), or patient withdrawal (n =1).
      g From product-limit (Kaplan-Meier) method for censored data.
      Fig. 2
      Fig. 2(A) Best percentage change from baseline in target lesion sizea and Kaplan-Meier estimate of (B) PFS by independent central radiologic review, per RECIST v1.1, and (C) OS. aIncludes patients with ≥1 evaluable postbaseline tumor assessment (n = 78). Thirty-four of the 78 patients (43.6%) who had at least 1 postbaseline tumor assessment had a decrease in the size of target lesions relative to baseline. OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.
      The ORR was 9.5% (95% CI, 4.2%–17.9%) among the 84 patients with PD-L1–positive tumors (CPS ≥1), including the patient who achieved CR, and 28.6% (95% CI, 3.7%–71.0%) among the 7 patients with PD-L1–negative tumors (CPS <1). One of the 10 patients whose PD-L1 status was not evaluable or not assessed was reported to have a PR. Objective response was achieved by 5/67 (7.5%) patients who had received 0–1 prior lines of therapy and 6/34 (17.7%) patients who had received 2 or more lines of therapy. Fig. S2 shows ORR in subgroups defined by patient demographics and baseline disease characteristics.
      At data cutoff, 95 (94.1%) patients had experienced disease progression or death. Median PFS was 2.1 (95% CI, 2.0–2.1) months and estimated 6- and 12-month PFS rates were 19.8% and 9.9%, respectively (Fig. 2B). Eighty-nine (88.1%) patients died during the study. Median OS was 6.2 (95% CI, 4.9–9.4) months and estimated 6- and 12-month OS rates were 50.5% and 34.7%, respectively (Fig. 2C).

      3.3 Safety

      In the total population, treatment-related AEs occurred in 51 (50.5%) patients (Table 3). The most common treatment-related AEs were nausea (7.9%), diarrhea (6.9%), and hypothyroidism (6.9%). Most treatment-related AEs were mild or moderate in severity; 11.9% of patients experienced grade 3–5 treatment-related AEs and 5.0% discontinued treatment because of a treatment-related AE. No treatment-related grade 3 or 4 event occurred in more than 1 patient. Two (2.0%) patients died due to hepatitis AEs that were considered related to treatment (reported by investigators as hepatitis, n = 1 and hepatitis fulminant, n = 1). Neither patient had comorbidities, pre-existing liver disease, or any other factor that might have contributed to their deaths.
      Table 3Adverse events in all treated patients (N = 101)
      Data cutoff date, October 5, 2020.
      .
      Adverse Events, n (%)Any GradeGrade 3–5
      Any treatment-related AE51 (50.5)12 (11.9)
      Two patients had fatal treatment-related AEs (hepatitis, n = 2) that were also classified as immune-mediated AEs.
      Treatment-related AEs occurring in ≥2 patients
       Nausea8 (7.9)0
       Diarrhea7 (6.9)1 (1.0)
       Hypothyroidism7 (6.9)0
       Asthenia6 (5.9)0
       Decreased appetite6 (5.9)0
       Fatigue6 (5.9)1 (1.0)
       Pruritus6 (5.9)0
       Hyperthyroidism5 (5.0)0
       Rash5 (5.0)1 (1.0)
       Alanine aminotransferase increased4 (4.0)0
       Aspartate aminotransferase increased4 (4.0)0
       Pyrexia4 (4.0)0
       Blood alkaline phosphatase increased3 (3.0)1 (1.0)
       Blood thyroid stimulating hormone increased2 (2.0)0
       Dyspnea2 (2.0)0
       Headache2 (2.0)0
       Myalgia2 (2.0)0
       Pain in extremity2 (2.0)0
       Pneumonitis2 (2.0)1 (1.0)
      Any immune-mediated AE
      Events were based on a list of terms specified at the time of analysis and were included regardless of attribution to study treatment or immune relatedness by the investigator. Related terms were included. There were no infusion reactions.
      18 (17.8)6 (5.9)
      Two patients had fatal treatment-related AEs (hepatitis, n = 2) that were also classified as immune-mediated AEs.
       Hypothyroidism10 (9.9)0
       Hyperthyroidism6 (5.9)0
       Pneumonitis3 (3.0)1 (1.0)
       Hepatitis2 (2.0)2 (2.0)
       Severe skin reactions2 (2.0)2 (2.0)
       Colitis1 (1.0)1 (1.0)
       Thyroiditis1 (1.0)0
       Vasculitis1 (1.0)0
      AE, adverse event.
      a Data cutoff date, October 5, 2020.
      b Two patients had fatal treatment-related AEs (hepatitis, n = 2) that were also classified as immune-mediated AEs.
      c Events were based on a list of terms specified at the time of analysis and were included regardless of attribution to study treatment or immune relatedness by the investigator. Related terms were included. There were no infusion reactions.
      Immune-mediated AEs occurred in 18 (17.8%) patients (Table 3). The most frequent of these were hypothyroidism (9.9%) and hyperthyroidism (5.9%). Two grade 5 immune-mediated AEs occurred; both were hepatitis, were considered treatment-related, and are described above. Three (3.0%) patients discontinued treatment owing to an immune-mediated AE. No infusion reactions were reported.

      4. Discussion

      In patients with heavily pretreated vulvar SCC in the KEYNOTE-158 study, 10.9% of patients had an objective response to pembrolizumab monotherapy. Responses were durable, with a median DOR of 20.4 months, and more than half of patients had an estimated response duration ≥12 months. Notably, responses occurred both in patients with PD-L1–positive tumors (n = 84; ORR, 9.5%) and in patients with PD-L1–negative tumors (n = 7; ORR, 28.6%). These data represent the largest prospective study of patients with vulvar cancer treated with an anti–PD-1 antibody and extend previous findings by demonstrating durable activity in patients with PD-L1–negative disease. Previous studies, such as KEYNOTE-028 and CheckMate 358, included much smaller patient populations that mostly or entirely comprised patients with PD-L1–positive tumors.
      In KEYNOTE-158, a meaningful subset of patients with vulvar SCC experienced prolonged PFS and OS. In the current analysis, median PFS was 2.1 (95% CI, 2.0–2.1) months and median OS was 6.2 (95% CI, 4.9–9.4) months. At 12 months, the PFS rate was 9.9% and the OS rate was 34.7%. These findings confirm and extend those from the KEYNOTE-028 study (n = 18), in which 18 patients with PD-L1–positive vulvar cancer had a median PFS of 3.1 months, median OS of 3.8 months, and 12-month PFS and OS rates of 7% and 28%, respectively [
      • Ott P.A.
      • Bang Y.J.
      • Piha-Paul S.A.
      • et al.
      T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028.
      ]. Few prior studies have described OS outcomes with systemic therapy among patients with advanced vulvar cancer, and caution must be taken when comparing these results with those from our study given the potential for differences in demographic and clinical characteristics between study populations. Nonetheless, our findings compare favorably with the median 3.2 month OS reported in a study (n = 11) evaluating mitoxantrone to treat advanced vulvar cancer [
      • Muss H.B.
      • Bundy B.N.
      • Christopherson W.A.
      Mitoxantrone in the treatment of advanced vulvar and vaginal carcinoma. A Gynecologic Oncology Group study.
      ] and are similar to the 6.9 month OS reported in a study (n = 29) evaluating paclitaxel in patients with unresectable recurrent, metastatic, or locally advanced vulvar cancer [
      • Witteveen P.O.
      • van der Velden J.
      • Vergote I.
      • et al.
      Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer--Gynaecological Cancer Group).
      ]. Notably, in both of these studies, the majority of patients had not received prior systemic chemotherapy.
      Given the relatively low incidence of advanced vulvar SCC and consequent limited availability of data on effective systemic therapy, treatment recommendations for advanced, recurrent, or metastatic vulvar SCC are often extrapolated from regimens used to treat cervical cancer [
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ]. A recent update to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for vulvar cancer includes the anti–PD-1 agents nivolumab (for HPV-related advanced or recurrent/metastatic vulvar cancer) and pembrolizumab (for tumor mutational burden-high TMB-H, MSI-high [MSI-H], or PD-L1–positive tumors) as second-line treatment options [
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ]. These recommendations were based on results from a very small subset of patients enrolled in the phase 1/2 CheckMate 358 study [
      • Naumann R.W.
      • Hollebecque A.
      • Meyer T.
      • et al.
      Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial.
      ], from the cervical cancer cohort of the multicohort phase 2 KEYNOTE-158 trial [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • et al.
      Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
      ], and from analyses of outcomes among patients with any tumor histology in the KEYNOTE-158 study according to tissue TMB (tTMB) [
      • Marabelle A.
      • Fakih M.
      • Lopez J.
      • et al.
      Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
      ] and MSI-H status [
      • Marabelle A.
      • Le D.T.
      • Ascierto P.A.
      • et al.
      Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.
      ]. In CheckMate 358, one PR was reported among 5 patients with vaginal (n = 2) or vulvar (n = 3) cancer following treatment with nivolumab monotherapy [
      • Naumann R.W.
      • Hollebecque A.
      • Meyer T.
      • et al.
      Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial.
      ]. Among the 98 patients with cervical cancer treated with pembrolizumab monotherapy in KEYNOTE-158, the ORR was 14.3% (95% CI, 8.0%–22.8%), with all responses occurring in patients with PD-L1–positive disease. The ORR among the 82 patients with PD-L1–positive tumors was 17.1% (95% CI, 9.7%–27.0%). Median DOR was not reached (range, 3.7+ to 35.2+ months) [
      • Chung H.C.
      Pembrolizumab treatment of advanced cervical cancer: updated results from the phase II KEYNOTE-158 study.
      ,
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • et al.
      Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
      ]. Although no data had been reported for patients with vulvar cancer from KEYNOTE-158 at the time, the NCCN Panel felt that, based on these data, pembrolizumab was likely to be effective in patients with PD-L1–positive vulvar tumors [
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ]. The outcomes for patients with vulvar cancer (any PD-L1 expression level) who received pembrolizumab in the KEYNOTE-158 study provide support for inclusion of pembrolizumab monotherapy in the current NCCN vulvar cancer guidelines [
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ].
      We observed responses both in patients with PD-L1–positive vulvar SCC and in patients with PD-L1–negative disease. In KEYNOTE-158, a prespecified cutpoint was used to determine tumor PD-L1 expression of CPS ≥1 (where CPS was defined as the number of PD-L1–staining cells divided by the total number of viable tumor cells, multiplied by 100) [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • et al.
      Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
      ]. Using these criteria, few patients in the cervical or vulvar cohorts had PD-L1–negative tumors: 83% and 84% of patients with vulvar and cervical cancer [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • et al.
      Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
      ], respectively, had PD-L1–positive tumors. Given the limited number of patients with PD-L1–negative disease in the cervical and vulvar cancer cohorts, it is difficult to assess the influence of PD-L1 expression on response to treatment in either cohort. Notably, prior reports have described PD-L1 expression in approximately 25% of vulvar cancers [
      • Hecking T.
      • Thiesler T.
      • Schiller C.
      • et al.
      Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with non-viral etiology.
      ,
      • Choschzick M.
      • Gut A.
      • Fink D.
      PD-L1 receptor expression in vulvar carcinomas is HPV-independent.
      ]. However, it should be noted that those studies included patients across all disease stages [
      • Hecking T.
      • Thiesler T.
      • Schiller C.
      • et al.
      Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with non-viral etiology.
      ,
      • Choschzick M.
      • Gut A.
      • Fink D.
      PD-L1 receptor expression in vulvar carcinomas is HPV-independent.
      ], whereas KEYNOTE-158 only included patients with advanced disease. Given that PD-L1 positivity has been associated with worse prognosis in patients with vulvar cancer [
      • Hecking T.
      • Thiesler T.
      • Schiller C.
      • et al.
      Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with non-viral etiology.
      ], and that most patients in KEYNOTE-158 had experienced disease progression on prior therapies, it is possible that the KEYNOTE-158 vulvar cohort population may have been enriched for patients with PD-L1–expressing disease. Alternatively, differences in methods of PD-L1 assessment may also have contributed to the difference in reported PD-L1 positivity. It is possible that other biomarkers may be discovered that better predict treatment response in patients with vulvar SCC.
      No unanticipated safety signals were detected among patients with vulvar SCC. The safety results for this cohort were similar to those reported for patients with other cancer types who received pembrolizumab monotherapy [
      • Marabelle A.
      • Fakih M.
      • Lopez J.
      • et al.
      Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
      ,
      • Marabelle A.
      • Le D.T.
      • Ascierto P.A.
      • et al.
      Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.
      ,
      • du Rusquec P.
      • de Calbiac O.
      • Robert M.
      • Campone M.
      • Frenel J.S.
      Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data.
      ,
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater.
      ,
      • Schachter J.
      • Ribas A.
      • Long G.V.
      • et al.
      Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).
      ], including the cervical cancer cohort of KEYNOTE-158 [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • et al.
      Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
      ]. Treatment-related AEs occurred in 50% (grade 3–5, 12%) of patients in this current analysis compared to 65% (grade 3–5, 12%) in the cervical cancer cohort. The proportions of patients who experienced immune-mediated AEs were also similar at 18% (grade 3–5, 6%) and 26% (grade 3–5, 5%) in the vulvar and cervical cohorts, respectively [
      • Chung H.C.
      • Ros W.
      • Delord J.P.
      • et al.
      Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
      ].
      A strength of the current clinical trial is the large size of the overall study population, particularly given the relatively low incidence of vulvar SCC. Enrollment of 101 patients in this study at 38 institutions in 17 countries required more than 3 calendar years. Nonetheless, the size of certain subgroups was small, and this prevents meaningful interpretation of OS and PFS in these subgroups (ie, patients with PD-L1–negative tumors). Additionally, while the multicohort study design allowed for the collection of data on characteristics specific to individual tumor types, information was not collected on tumor-infiltrating lymphocytes (TILs) or whether patients had a medical history of HPV infection or lichen sclerosis. Incidence of HPV positivity is known to be high in patients with vulvar cancer [
      • Saraiya M.
      • Unger E.R.
      • Thompson T.D.
      • et al.
      US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines.
      ,
      • National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Vulvar Cancer (Squamous Cell Carcinoma). Version 3.
      ]; it is therefore probable that many patients in this analysis had a history of HPV infection. Vulvar cancer is more likely to be associated with prior HPV infection in younger patients than in older patients, and HPV-related etiology may influence tumor biology and treatment response [
      • Gillison M.L.
      • Chaturvedi A.K.
      • Lowy D.R.
      HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women.
      ].
      In summary, pembrolizumab monotherapy demonstrated antitumor activity that led to durable responses in a subset of patients with advanced vulvar SCC, regardless of PD-L1 status. This study confirms and extends the results of the previous, smaller studies in this population and supports the use of pembrolizumab in patients with advanced vulvar SCC for which prior standard-of-care therapy has failed.

      Author contributions

      Ott: conceptualization
      All authors: data curation and formal analysis.
      Shapira-Frommer, Mileshkin, Piha-Paul, Girda, Lopez Martin, van Dongen, Italiano, Ott: investigation/interpretation.
      All authors: writing – review/editing.
      All authors: decision to submit the manuscript for publication.

      Funding/support

      Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

      Role of the funder/sponsor

      The sponsor was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

      Data sharing statement

      Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

      Previous presentation

      Results from this analysis were presented at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women's Cancer (March 19–22, 2021; Virtual Meeting).

      Additional contributions

      We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. Medical writing assistance was provided by Autumn Kelly, MA, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

      Declaration of competing interest

      Ronnie Shapira-Frommer: study funding to the institution from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD), to support study conduct; honoraria for serving as a speaker from MSD, BMS, AstraZeneca, Novartis, and Roche; personal fees for advisory boards from MSD, Clovis Oncology, and VBL Therapeutics.
      Linda Mileshkin: study funding to the institution from MSD to support study conduct.
      Ludmila Manzyuk: study funding to the institution from MSD to support study conduct.
      Nicolas Penel: study funding to the institution from MSD to support study conduct.
      Sarina A. Piha-Paul: study funding to the institution from MSD to support study conduct; clinical trial research support from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Ltd., Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., HiberCell, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Lytix Biopharma AS, MedImmune, LLC, Medivation, Inc., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Synlogic, Taiho Oncology, Tesaro, Inc., TransThera Bio, and NCI/NIH (CCSG Shared Resources Grant# P30Ca016672).
      Matthew Burge: honoraria and study funding to the institution from MSD to support study conduct.
      Eugenia Girda: study funding to the institution from MSD to support study conduct.
      Jose A. Lopez Martin: study funding to the institution from MSD to support study conduct; grants, personal fees, and non-financial support from MSD during the conduct of the study; grants, personal fees, and non-financial support from BMS ; grants from Merck-Serono; grants and personal fees from Pfizer; personal fees from Bayer|grants and personal fees from Lilly; grants, personal fees, and non-financial support from PharmaMar ; grants, personal fees, and non-financial support from Roche ; grants and personal fees from Novartis; and personal fees from Pierre-Fabre; current employee of PharmaMar (beginning after this study was conducted).
      Marloes G.J. van Dongen: study funding to the institution from MSD to support study conduct.
      Antoine Italiano: study funding to the institution from MSD to support study conduct, grants from MSD, grants from BMS, grants and personal fees from Bayer, personal fees from Springworks, grants from AstraZeneca, grants and personal fees from Roche, grants from Ipsen, grants from PharmaMar.
      Lei Xu: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Owns stock in Merck & Co., Inc., Kenilworth, NJ, USA.
      Fan Jin: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Owns stock in Merck & Co., Inc., Kenilworth, NJ, USA.
      Kevin Norwood: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Owns stock in Merck & Co., Inc., Kenilworth, NJ, USA.
      Patrick Ott: study funding to the institution from MSD to support study conduct; grants from BMS, Genentech, Celldex, Cytomx, Pfizer, Neon Therapeutics, Armo Biosciences, AstraZeneca, Xencor, and Oncorus; personal fees from Alexion, Amgen, BMS, Genentech, Celldex, Cytomx, Pfizer, Novartis, Neon Therapeutics (now BioNTechUS), and Array.

      Appendix A. Supplementary data

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