
==== Front
Gynecol Oncol Rep
Gynecol Oncol Rep
Gynecologic Oncology Reports
2352-5789
Elsevier

S2352-5789(24)00166-8
10.1016/j.gore.2024.101487
101487
Case Report
Induction chemotherapy with cemiplimab in a patient with coexistent vulvar cancer and autoimmune disease: A case report
Thayer Elizabeth G. elizabeth.gilbert.thayer@emory.edu
a⁎
Weirich M. Larissa a
Roecker Zoe A. a
Brenner Sara E. a
Remick Jill S. b
Patel Ashish B. b
Starbuck Kristen D. c
a Department of Gynecology and Obstetrics, Emory University School of Medicine, United States of America
b Department of Radiation Oncology, Emory University School of Medicine, United States of America
c Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, United States of America
⁎ Corresponding author at: Department of Gynecology and Obstetrics, Emory University School of Medicine, 1364 Clifton Rd NE, Atlanta, GA 30322, United States of America. elizabeth.gilbert.thayer@emory.edu
14 8 2024
10 2024
14 8 2024
55 10148730 6 2024
11 8 2024
14 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• Data regarding immunotherapy for patients with vulvar squamous cell carcinoma and coexisting autoimmune disease are limited.

• The use of cemiplimab in vulvar cancer is extrapolated from cervical and other cutaneous squamous cell carcinomas.

• Our patient had a robust response to induction chemotherapy and cemiplimab and her autoimmune conditions remained stable.

• Ongoing exploration of cemiplimab’s efficacy in vulvar cancer and safety in immunosuppressed patients is critical.

There is limited data regarding the use of immunotherapy for patients with vulvar squamous cell carcinoma and coexisting autoimmune disease. Cemiplimab is a PD-1 inhibitor approved for use in patients with locally advanced and metastatic cutaneous squamous cell carcinoma. However, little is known about its efficacy in the setting of vulvar cancer. We present a case of advanced vulvar squamous cell carcinoma treated with induction chemotherapy and immunotherapy with cemiplimab followed by definitive chemoradiation in the setting of multiple autoimmune diseases. She achieved a complete clinical response and experienced no worsening of her autoimmune conditions despite cessation of her immunosuppressants and initiating an immune checkpoint inhibitor. We review existing data on neoadjuvant treatment of vulvar cancer and the use of cemiplimab in genital and inguinal squamous cell carcinomas. Ongoing exploration of cemiplimab’s efficacy in vulvar cancer and safety in immunosuppressed patients is critical.

Keywords

Cemiplimab
Immunotherapy
Vulvar cancer
Cutaneous squamous cell carcinoma
Neoadjuvant chemotherapy
Induction chemotherapy
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pmc1 Introduction

Vulvar cancer is a rare gynecologic malignancy, accounting for 4–6 % of female reproductive cancers; an estimated 6,470 new cases of vulvar cancer were diagnosed in 2023 (Siegel et al., 2023). Squamous cell carcinoma is the predominant histologic subtype; comprising about 80 % of cases. Because vulvar cancer is rare and studies in this population are limited, management, especially for advanced or recurrent disease, is often guided by data extrapolated from other disease sites with similar pathology, such as cervical cancer and other cutaneous squamous cell carcinomas (CSCC).

Chemoradiation is the mainstay of treatment for locally advanced and metastatic vulvar squamous cell carcinoma (VSCC) not amenable to primary surgical resection; the recently reported NRG/GOG-0207 trial achieved a 73.1 % complete pathologic response using intensity-modulated radiation therapy (IMRT) with concurrent cisplatin and gemcitabine, although current standard of care uses only concurrent cisplatin (Horowitz et al., 2023). Data on response rates for chemotherapy alone in recurrent; progressive, or metastatic VSCC are extremely limited, as are available therapeutic options. Immunotherapy has recently become an important addition to the treatment of advanced stage or unresectable squamous cell carcinomas, including in cervical cancers, however its use in vulvar cancer is currently limited to subsequent treatment lines after chemotherapy in patients with advanced, metastatic or recurrent disease (Praiss et al., 2022).

Cemiplimab is an immune checkpoint inhibitor that has shown favorable response rates in patients with locally advanced and metastatic cutaneous squamous cell carcinoma (laCSCC and mCSCC). It acts via blockade of programmed cell death 1 (PD-1) receptor and objective response rates have ranged 44–57 % in laCSCC and mCSCC regardless of PD-L1 status (Migden et al., 2018). Based on these data cemiplimab is approved for management of locally advanced and metastatic CSCC in patients who are not candidates for curative surgery or radiotherapy, which can include vulvar SCC. Cemiplimab has been included in treatment guidelines for advanced or metastatic disease despite a lack of vulvar cancer patients in the original EMPOWER-CSCC-1 trial (Praiss et al., 2022, Migden et al., 2018).

There are also emerging data specifically on the use of cemiplimab in gynecologic cancer treatment, although data on its use in vulvar cancer remain extremely limited. The EMPOWER-Cervical 1/GOG-3016 trial compared cemiplimab with investigator’s choice single-agent chemotherapy in cervical cancer patients with disease progression after first-line platinum-based chemotherapy. The study showed improved overall survival (12 months versus 8.5 months) with cemiplimab regardless of PD-L1 status or histologic subtype of cancer (Tewari et al., 2022). This suggests that cemiplimab could be a safe and effective treatment option in this patient population.

Given the robust response to cemiplimab seen in other cutaneous squamous cell carcinomas and recent data showing promising results in cervical SCC, the addition of cemiplimab to traditional platinum-based chemotherapy should be further explored in patients with advanced vulvar cancer. We present the case of a patient with coexistent advanced vulvar squamous cell carcinoma and autoimmune disease who was treated with induction chemotherapy and cemiplimab prior to definitive chemoradiotherapy.

2 Case report

A 61-year-old woman was referred to gynecologic oncology for evaluation of a right vulvar mass that had been increasing in size over several years, causing significant pain and difficulty with sitting and walking. She additionally reported intermittent heavy bleeding from the mass.

Her medical history included systemic lupus erythematosus (SLE) and rheumatoid arthritis for which she was followed by rheumatology and managed with hydroxychloroquine, methotrexate, prednisone, and sulfasalazine.

At her initial presentation, she was found to have a tender, exophytic, 12 x 6 cm mass originating from the right labia majora and exerting mass effect on both the urethra and rectum without clear invasion of either structure on exam (Fig. 1A). There was palpable bilateral inguinal lymphadenopathy. A biopsy of the mass returned at least differentiated vulvar intraepithelial neoplasia (dVIN) with suspicion for HPV-independent invasive squamous cell carcinoma (p16 negative, p53 aberrant, PD-L1 positive) given her clinical presentation. A PET/CT scan confirmed FDG-avidity of the vulvar mass and additionally noted mildly FDG-avid bilateral inguinal and right external iliac lymphadenopathy (Fig. 2A). An MRI confirmed enlargement of the right external iliac lymph nodes and noted focal contact of the mass with the external anal sphincter without definite invasion. Her evaluation was consistent with Stage IVB disease.Fig. 1 Vulvar mass (A) on initial presentation, (B) after induction chemotherapy and immunotherapy, and (C) after completing chemoradiation.

Fig. 2 PET/CT imaging (A) prior to treatment, (B) after induction chemotherapy and immunotherapy, and (C) after completing chemoradiation and adjuvant chemotherapy and immunotherapy.

Given the size of her tumor, definitive radiation was not considered achievable upfront due to concern for toxicity. We elected to give induction chemotherapy with immunotherapy prior to chemoradiation for cytoreduction. She received four cycles of carboplatin (AUC 5 IV), paclitaxel (175 mg/m2 IV), bevacizumab (15 mg/kg IV; held cycle 3 due to hypertension), and cemiplimab (350 mg IV) every 3 weeks. The vulvar mass decreased in size to 7 x 4 cm (Fig. 1B) and PET/CT (Fig. 2B) showed a decrease in the size and avidity of the bilateral inguinal and right external iliac lymph nodes. She then underwent radiation with volumetric arc radiation therapy (VMAT) to a dose of 50 Gy to the primary site, inguinal and pelvic lymph node regions with a sequential boost of 16 Gy to the primary vulvar tumor with concurrent weekly cisplatin (38 mg/m2 IV [70 mg]). She had a clinical complete response with exam showing resolution of all palpable vulvar tumor and inguinal lymphadenopathy (Fig. 1C). After completing chemoradiation, she received an additional two cycles of carboplatin, paclitaxel, bevacizumab, and cemiplimab (same doses as she received before chemoradiation; bevacizumab held for final cycle due to hypertension) followed by three cycles of single-agent cemiplimab maintenance (350 mg IV every 3 weeks). PET/CT three months after completing chemoradiation (between cycles 1 and 2 of single-agent cemiplimab) showed a radiographic complete response with resolving radiation-related changes (Fig. 2C). On exam, the area was hypopigmented and soft, with no residual clinical mass, although the right labia remained slightly enlarged compared to the left.

Three months after completing all therapy she was seen for a routine surveillance exam and a new 1 x 1 cm area on the inferior right labia majora was noted, however the overall size of the right labia was smaller than prior and no palpable mass was felt. Resection showed only dVIN and a PET/CT confirmed ongoing response to therapy.

Despite stopping her rheumatologic medications prior to receiving immunotherapy and chemoradiation, she had no symptoms of rheumatoid arthritis or SLE during her initial treatment course; she did notice some increasing arthritic pain while on maintenance cemiplimab. She still reported feeling better than she had in years at the completion of her therapy.

3 Discussion

We present a patient with Stage IVB HPV-independent and PD-L1 positive squamous cell carcinoma of the vulva in the setting of multiple autoimmune diseases who had a complete clinical and pathologic response to induction chemotherapy with cemiplimab immunotherapy followed by chemoradiation and additional adjuvant chemotherapy with cemiplimab.

Induction chemotherapy is not standard of care, however the successful use of a variety of agents has been reported in patients with locally advanced vulvar cancer with overall response rates of 40–86 % (Nooij et al., 2022, Bogani et al., 2023). Many patients who received induction therapy were ultimately able to undergo surgical resection (Nooij et al., 2022). The use of immunotherapy in the induction setting remains an area of investigation; cemiplimab has shown promising results as a single agent in patients with resectable laCSCC (Gross et al., 2022). We elected to use both chemotherapy and cemiplimab in our patient’s induction regimen in an effort to optimize cytoreduction.

Data on the efficacy of cemiplimab specifically in VSCC are extremely limited. A single patient with VSCC was included in the first-in-human phase I trial of cemiplimab, however did not respond (Papadopoulos et al., 2020). No patients with vulvar carcinoma were included in the original EMPOWER-CSCC-1 study that lead to FDA approval of cemiplimab for laCSCC and mCSCC, and subsequent gynecologic-specific evaluation of cemiplimab efficacy has focused on cervical cancer (Migden et al., 2018, Tewari et al., 2022). Several real-world reports of cemiplimab use in squamous cell carcinomas of the genital and inguinal regions have been reported; however most do not specify the patient’s sex and none are specifically described as vulvar (Hober et al., 2021, Saponara et al., 2020, Pabianek et al., 2022, Baggi et al., 2021, Challapalli et al., 2022, Valentin et al., 2021). These patients primarily received cemiplimab as a single agent and most often in the recurrent setting. Pabianek et al. describe a recurrent inguinal squamous cell carcinoma with impressive clinical response to single agent cemiplimab (Pabianek et al., 2022). Baggi et al. included 10 patients with relapsed locally advanced or metastatic squamous cell carcinoma of the genitals in their real-world review and noted a worse overall response rate compared to tumors from other primary sites (40.8 % versus 72.7 %; p = 0.041) on univariate analysis, however this association was no longer significant on multivariate analysis (Baggi et al., 2021).

The EMPOWER-CSCC-1 study that led to the approval of cemiplimab in CSCC excluded patients with “ongoing or recent (within 5 years) autoimmune disease” on immunosuppressive therapy (Migden et al., 2018) and little is understood about the potential adverse effects in this patient population. Specifically, it is unclear if the use of immunotherapy could exacerbate underlying autoimmune conditions or if immunosuppressive therapy should be held during treatment. Real-world data contribute important information regarding these concerns; our patient tolerated immunotherapy well with only mild worsening of her arthritic symptoms towards the end of her treatment course.

We included cemiplimab in this patient’s induction regimen based on its established efficacy in advanced CSCC. Our patient had a robust response to induction carboplatin, paclitaxel, bevacizumab and cemiplimab, and a complete response with her subsequent chemoradiation. While the relative contribution of each of the four agents in her induction regimen is uncertain, her impressive response and tolerance of immunotherapy despite multiple autoimmune conditions, emphasizes that further investigation of cemiplimab in vulvar squamous cell carcinoma in a prospective clinical trial setting is warranted.

CRediT authorship contribution statement

Elizabeth G. Thayer: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. M. Larissa Weirich: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Zoe A. Roecker: . Sara E. Brenner: Writing – review & editing, Writing – original draft. Jill S. Remick: Writing – original draft, Writing – review & editing. Ashish B. Patel: Writing – review & editing, Data curation, Conceptualization. Kristen D. Starbuck: Writing – review & editing, Supervision, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

The authors would like to thank the patient for granting permission for the presentation of her case. Written informed consent was obtained for the publication of the case report and images.
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