Immunotherapy in Carcinoma of the Vulva: A Comprehensive Evidence-Based Overview

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1. Background and Disease Context

• HPV-associated VSCC (~30-40%): Linked to high-risk HPV (especially HPV-16), younger patients, better prognosis, p16-positive
• HPV-independent VSCC (~60-70%): Associated with lichen sclerosus, TP53 mutations, older patients, worse prognosis

• Berek & Novak's Gynecology, p. 2437

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2. Rationale for Immunotherapy in Vulvar Cancer

2a. Immune Evasion Mechanisms

2b. PD-L1 Expression in Vulvar Cancer

• All cases had PD-L1 CPS ≥1
• Median CPS = 66 (IQR 28-100) - strikingly high
• HPV-independent tumors had higher CD8+ and CD68+ infiltration and higher median CPS compared to HPV-associated tumors - suggesting HPV-negative tumors may be immunologically active and warrant ICI evaluation

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3. Key Clinical Trials - Immune Checkpoint Inhibitors in VSCC

Table 1: Summary of Published Clinical Trials

• 6 trials, n=181 patients
• Pooled ORR: 21% (combination: 46% vs monotherapy: 11%)
• Median PFS: 2.2 months; Median OS: 6.4 months
• Grade ≥3 AEs: 23%; treatment-related deaths: 3%
• No statistically significant difference in ORR between PD-L1+ vs PD-L1- subgroups (CPS not reliably predictive)

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4. Approved Agents and Current Indications

Table 2: Approved/Guideline-Supported Agents for Vulvar Cancer

Note: No agent has a dedicated FDA approval specifically for vulvar cancer (as of 2026). Use is guided by tumor-agnostic approvals, guideline extrapolation, and biomarker status.

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5. Predictive Biomarkers

Table 3: Biomarkers and Their Predictive Value in VSCC Immunotherapy

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6. Combination Strategies

Table 4: Combination Immunotherapy Approaches Under Investigation

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7. Treatment Algorithm / Flowcharts

Flowchart 1: Biomarker Testing Strategy for VSCC Before Immunotherapy

ADVANCED / RECURRENT / METASTATIC VSCC
                    │
                    ▼
        ┌─────────────────────┐
        │  Comprehensive      │
        │  Biomarker Testing  │
        └─────────┬───────────┘
                  │
    ┌─────────────┼──────────────────┐
    ▼             ▼                  ▼
MSI-H/dMMR    TMB ≥10          PD-L1 CPS
  testing       mut/Mb           (22C3 IHC)
  (IHC/PCR)   (NGS panel)      ─────────────
    │              │           CPS ≥1  CPS <1
    ▼              ▼              │       │
 Tumor-agnostic  Tumor-agnostic  ▼       ▼
 pembrolizumab   pembrolizumab  Eligible  Limited
 (any line)      (any line)    for pembro  benefit
    │                              │
    └──────────────┬───────────────┘
                   │
                   ▼
          ┌──────────────┐
          │ HPV Status   │
          └──────┬───────┘
                 │
          ┌──────┴──────┐
          ▼             ▼
      HPV+          HPV-
   Nivolumab       Consider ICI
   (2nd line)      (HPV-independent
                    TME is also
                    immunogenic)

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Flowchart 2: Treatment Algorithm for Advanced/Recurrent/Metastatic VSCC

RECURRENT OR METASTATIC VSCC
            │
            ▼
    ┌───────────────┐
    │ Is patient    │
    │ fit for chemo?│
    └───────┬───────┘
            │
      ┌─────┴─────┐
      ▼           ▼
    YES           NO
      │           │
      ▼           ▼
 Check PD-L1    Pembrolizumab
  (CPS ≥1?)     monotherapy
      │         (if PD-L1+, TMB-H,
 ┌────┴────┐     MSI-H)
 ▼         ▼
CPS≥1    CPS<1
  │         │
  ▼         ▼
1st LINE:  1st LINE:
Pembrolizumab  Carboplatin/
+ Carbo/Pacli  Paclitaxel
± Bevacizumab  ± Bevacizumab
(Preferred)
      │
      ▼
   PROGRESSION?
      │
      ▼
 2nd LINE OPTIONS:
┌─────────────────────────────────┐
│ • Pembrolizumab mono (if PD-L1+,│
│   not previously given)         │
│ • Nivolumab (HPV-positive)      │
│ • Cemiplimab (extrapolated)     │
│ • Pembro + Vorinostat (clinical │
│   trial preferred)              │
│ • Dual ICI (clinical trial)     │
│ • Cisplatin-based chemo         │
└─────────────────────────────────┘
      │
      ▼
 3rd LINE+:
┌─────────────────────────────────┐
│ • Tumor-agnostic ICI if         │
│   MSI-H/dMMR or TMB-H           │
│ • ADC trials (TROP2, TF,        │
│   NECTIN4 targets)              │
│ • Best supportive care          │
│ • Clinical trial enrollment     │
└─────────────────────────────────┘

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Flowchart 3: HPV Status and ICI Response Prediction

VSCC PATHOLOGIC SPECIMEN
          │
          ▼
   p16 IHC / HPV PCR
          │
    ┌─────┴─────┐
    ▼           ▼
  HPV+        HPV-
(30-40%)     (60-70%)
    │           │
    ▼           ▼
Better ICI  Poorer overall
response    prognosis BUT:
historically  - Higher CD8+ TIL
              - Higher PD-L1 CPS
              - Active TME
              - TP53 / FAT1 /
                NOTCH1 mutations
    │           │
    └─────┬─────┘
          ▼
  BOTH subtypes may benefit
  from ICI - HPV status alone
  should NOT exclude ICI use

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8. Immune-Related Adverse Events (irAEs)

Table 5: Safety Profile of ICIs in VSCC Trials

Vorinostat + pembrolizumab (PEVOsq): 66% required dose reduction due to vorinostat toxicity; 39% had Grade ≥3 AEs. Dual ICI (ipilimumab + nivolumab) carries higher irAE burden.

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9. Ongoing and Future Directions

Table 6: Emerging Therapies and Future Directions

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10. Key Evidence Synthesis

Table 7: Hierarchy of Evidence for Immunotherapy in VSCC

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11. Clinical Pearls and Limitations

• ICIs have demonstrated modest but durable activity in advanced VSCC (pooled ORR ~21%)
• Combination strategies (dual ICI, ICI + chemo, ICI + HDAC inhibitor) show higher ORR (~40-46%) than monotherapy (~11%)
• All VSCC tumors express PD-L1 (median CPS 66), suggesting broad eligibility
• HPV status does not reliably exclude benefit - HPV-independent tumors have an immunogenic TME

• No randomized controlled trial exists specifically in VSCC (disease rarity is the major barrier)
• Reliable predictive biomarkers have not been validated - neither PD-L1 CPS, HPV status, nor TMB reliably stratifies responders
• Optimal agent, combination, and sequence remain undefined
• Long-term survival data are scarce (current trials show short median PFS of ~2.2 months)

• Biomarker-driven, molecularly stratified clinical trials in VSCC
• Collaboration in rare gynecological cancer consortia (GOG, GCIG)
• Basket trial designs enrolling HPV-related genital tract cancers together

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References

1. Maiorano MFP et al. Immunotherapy and Advanced Vulvar Cancer: A Systematic Review and Meta-Analysis of Survival and Safety Outcomes. Cancers. 2025. PMID 40723274
2. Arenhardt MP et al. Efficacy and safety of targeted therapy and immunotherapy in advanced vulvar squamous cell carcinoma: A scoping review. Crit Rev Oncol Hematol. 2025. PMID 40068805
3. Borcoman E 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. 2025. PMID 40588522
4. Rhind M et al. Exploring novel therapeutic targets in vulvar squamous cell carcinoma. Gynecol Oncol. 2026. PMID 41275789
5. Moufarrij S et al. Molecular and microenvironmental landscapes of HPV-independent invasive squamous cell carcinoma of the vulva. Int J Gynecol Cancer. 2025. PMID 39971436
6. Santoro A et al. The emerging and challenging role of PD-L1 in patients with gynecological cancers. Gynecol Oncol. 2024. PMID 38295614
7. Zafar M et al. Advances and Challenges in HPV-Associated Lower Genital Tract Cancers by ICBs. Cancers. 2025. PMID 40282436
8. Yanaihara N et al. Immune checkpoint inhibitors in gynecologic oncology: Current status and perspectives. Int J Gynaecol Obstet. 2025. PMID 40908776
9. Nasso C et al. Immune checkpoint inhibitors in gynecological cancers: a narrative review on the practice-changing trials. Immunotherapy. 2025. PMID 39893504
10. Berek & Novak's Gynecology. 16th ed. Chapter on Vulvar Cancer, p. 2437.

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Key Takeaways

1. Modest but real efficacy - Pooled ORR of 21% across 6 trials (181 patients), rising to ~46% with combination strategies vs ~11% with monotherapy alone (Maiorano et al., 2025 meta-analysis).
2. No dedicated FDA approval exists for vulvar cancer specifically - clinical use is guided by tumor-agnostic approvals (MSI-H/dMMR, TMB-H) and extrapolation from cervical cancer data (KEYNOTE-826).
3. All VSCC tumors express PD-L1 (median CPS = 66 in a 2026 study of 108 cases), meaning virtually all patients are technically biomarker-eligible - but CPS does not reliably predict response.
4. Both HPV+ and HPV- subtypes may benefit - HPV-independent tumors paradoxically show higher immune infiltration (CD8+ TILs, CD68+ macrophages, PD-L1), supporting ICI trials across both subtypes.
5. Combination approaches are superior - ICI + chemotherapy, dual ICI (nivo + ipi), and ICI + HDAC inhibitors (pembrolizumab + vorinostat: ORR 19%, OS 11.1 months in PEVOsq Phase II basket trial, Nature Cancer 2025) all outperform monotherapy.
6. The biggest gap is the absence of randomized controlled trials specific to VSCC due to disease rarity. Biomarker-driven, molecularly stratified trials are the top research priority.