Carelizumab and rivoceranib for advanced extramammary Paget’s disease: an investigator-initiated multicenter, single-arm, phase II trial

TL;DR

This trial tested a combination of two drugs for a rare cancer called extramammary Paget’s disease but found no significant improvement in patient outcomes.

Contribution

The first clinical trial to evaluate a PD-1 inhibitor combined with a VEGFR inhibitor for advanced extramammary Paget’s disease.

Findings

No patients achieved complete or partial response to the treatment combination.

Median progression-free survival was 2.4 months.

Half of the patients experienced grade 3 adverse events.

Abstract

Extramammary Paget’s disease (EMPD) is a rare cancer without standard therapy. We evaluated the safety and efficacy of a combination of the humanized monoclonal antiprogrammed death-1 (PD-1) antibody, carelizumab, with rivoceranib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in patients with advanced EMPD.

This multicenter, single-arm, phase II trial included 12 patients with EMPD. The primary endpoint is the objective response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. It is hypothesized that the ORR will be less than 10% if the treatment is ineffective and will reach 35% if effective. Secondary endpoints include progression-free survival (PFS) and safety assessments. Eligible patients are aged ≥18 years, with histologically confirmed advanced EMPD. Treatment consists of carelizumab (200 mg intravenously every 3 weeks) and rivoceranib (250 mg orally once daily), with dose adjustments permitted based on toxicity profiles.

Between June 2024 and February 2025, 12 patients were enrolled. One patient withdrew from the trial because of nontreatment-related accidents, and a total of 11 patients completed at least 1 cycle of treatment. The median PFS is 2.4 months (95% CI, 2.1-4.4 months). Among these 11 patients, no patients achieved CR or PR. Six patients (50%) experienced grade 3 adverse events.

This is the first trial evaluating the combination of a PD-1 inhibitor and a VEGFR inhibitor in advanced EMPD. This combination therapy is well tolerated but does not appear to have clinically meaningful activity in advanced EMPD. This trial was registered at the Chinese Clinical Trial number registration: 2400086153.

Figures

(A) The timeline of the treatment evaluation among 11 patients who completed at least 2 cycles. (B) PFS of the 11 patients who completed at least 2 cycles. Abbreviations: PD, progression disease; SD, stable disease.

Study schema.

Tables

Disease	Advanced Extramammary Paget’s disease
Stage of Disease	IV
Prior Therapy	No limitation.
Type of Study	Phase II
Primary Endpoints	objective response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR)according to RECIST v1.1 criteria.
Secondary Endpoints	progression-free survival (PFS) and safety assessments.
Additional Details of Endpoints or Study Design The study was reviewed and approved by the Institutional Review Board of the Shanghai Cancer Center, Fudan University, and all participating centers. The trial was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. All participating patients provided written informed consent. Twelve patients were enrolled. One patient withdrew from the trial because of nontreatment-related accidents, and a total of 11 patients completed at least 1 cycle of treatment.

Generic/Working name	Carelizumab and Rivoceranib
Company Name	Hengrui Pharmaceuticals, China
Drug Type	Carelizumab is an anti-PD-1 monotherapy. Rivoceranib is a VEGFR inhibitor.
Drug Class	Carelizumab is an ICI. Rivoceranib is a targeted therapy
Dose	Carelizumab 200 mg + Rivoceranib 250 mg
Route	Carelizumab is intravenous (IV). Rivoceranib is oral.

Median age (range)	69.5 (60-86)
Number of Patients, Female/Female	11/1
Stage	IV (100%)
Location of primary tumor
Scrotum	8(67%)
Vulva	3(8%)
Penis	1(25%)
Prior Surgery
Yes	9(75%)
No	3(25%)
Prior Radiotherapy
Yes	6(50%)
No	6(50%)
Number of Prior Chemotherapy
0-2	9(75%)
>2	3(25%)
Metastatic site(s)
Inguinal lymph nodes	12(100%)
Nonlnguinal lymph nodes	8(67%)
Lung	4(34%)
Liver	6(50%)
Bone	7(58)
Yes	9(75%)
No	3(25%)
Prior Radiotherapy
Yes	6(50%)
No	6(50%)
ECOG Score
0	3(25%)
1	9(75%)
PD-L1 Positive	1(9%)
TMB High	0

Statistical Analysis	It is hypothesized that the ORR will be less than 10% if the treatment is ineffective and will reach 35% if effective. Simon’s MinMax 2-stage design was employed, with a power of 80% and a significance level (α) of 0.05. In the first stage, 11 patients were enrolled. If 2 or more patients achieve ORR, the study will proceed to the second stage, where an additional 7 patients will be enrolled, bringing the total to 18 patients. If a combined total of 5 patients achieves ORR across both stages, the study will be considered successful.
Number of Patients Screened	18
Number of Patients Enrolled	12
Number of Patients Evaluable for Toxicity	11
Number of Patients Evaluated for Efficacy	11
Evaluation Method	The response of patients with measurable target lesions on CT imaging was evaluated according to RECIST version 1.1. The efficacy of those with skin lesions but deemed as not measurable was evaluated according to WHO criteria. Disease progression was defined as the deterioration of the subject’s condition caused by the indication of the study. The progression of imaging and clinical symptoms and signs was included. Disease progression was considered to be the presence of a new metastasis relative to the primary tumor or the progression of an existing metastasis.
Response assessment, CR/PR	0/0
Response assessment, SD/PD	0/11
Outcome Notes Response assessment: Figure 1.

Adverse event	Grade 1	Grade 2	Grade 3	%
Fatigue	3	5	1	82
Nausea	1	1	0	18
Vomiting	2	1	0	27
Abdominal pain	1	1	0	18
Diarrhea	1	2	0	27
Skin and subcutaneous tissue disorders	2	4	1	64
Constipation	0	2	0	18
Cough	0	1	0	9
Dry skin	2	1	1	36
Dyspnea	0	0	0	0
Edema limbs	0	0	0	0
Flank pain	1	1	0	18
Flu-like symptoms	0	0	0	0
Musculoskeletal and connective tissue disorder	1	2	0	27
Noncardiac chest pain	0	1	0	9
Anemia	0	0	0	0
Hypertension	4	2	2	73
Sciatic pain	0	0	0	0
Tachycardia	3	1	1	45

Full text

Trial information

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Drug information

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Patient characteristics

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Primary assessment method

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(A) The timeline of the treatment evaluation among 11 patients who completed at least 2 cycles. (B) PFS of the 11 patients who completed at least 2 cycles. Abbreviations: PD, progression disease; SD, stable disease.

General toxicity profile

Common and grade 3 or higher adverse events observed with the combination therapy

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Discussion

Extramammary Paget’s disease (EMPD) is a rare epithelial malignancy, primarily occurring in the skin with rich apocrine glands, including vulva, scrotum, penis, and axilla.^1^ EMPD tends to be indolent and is often identified as carcinoma in situ at the time of diagnosis.^2^ However, when distant metastases occur, 5-year survival rates are <10%.^3^ For now, there have not been established treatments for metastatic EMPD, and treatment experience is based on case reports or small case series. Chemotherapy regimens, such as docetaxel, fluoropyrimidines, S-1, platins, and their combination therapy, are attempted and achieve limited progress.^4^ In general, the treatment efficacy is limited with the risk of adverse effects. Therefore, it is essential to find more effective and tolerable treatment options for advanced EMPD.

The programmed death-1 (PD-1)/PD-L1 pathway is crucial for the normal physiological regulation and suppression of immune responses in healthy tissues. Numerous tumors manage to evade immune detection and attack by increasing their PD-L1 expression. Humanized monoclonal antibodies targeting PD-1 and PD-L1 have demonstrated both safety and efficacy in treating a variety of cancers.^5^ We noticed several researchers have published case reports about the role of immune-checkpoint-inhibitors monotherapy in patients with EMPD.^6-8^ But the conclusions are conflicting and there is still a lack of clinical trials to provide higher-quality evidence. Furthermore, the treatment landscape for the combination of ICI and vascular endothelial growth factor receptor (VEGFR) inhibitor for EMPD remains underexplored, particularly there has been substantial evidence that the combination has a significant synergistic anticancer effect in various kinds of solid tumors.^9^ Research indicates that combining carelizumab, with rivoceranib, significantly decreases peripheral blood regulatory T cell (Treg) levels and increases the effector T cell (Teff) to Treg ratio. Additionally, the combination appears to enhance objective tumor response rates while maintaining the durability of immunotherapy. Consequently, numerous clinical trials have been conducted on this combination therapy, targeting advanced cancers such as hepatocellular carcinoma, lung cancer, intrahepatic cholangiocarcinoma, gastric adenocarcinoma, triple-negative breast cancer, and other solid tumors. These studies have investigated the safety, tolerability, and preliminary efficacy of camrelizumab in combination with rivoceranib across various malignancies.^10-12^

Thus, we hypothesized the combination of the PD-1 antibody, carelizumab, with the VEGFR inhibitor, rivoceranib, would be a potential strategy for patients with advanced EMPD. To our knowledge, this is the first clinical trial to investigate the objective response rate (ORR) and safety profile of this combination therapy in patients with advanced EMPD. Figure 2 shows the study schema.

Study schema.

The primary endpoint is the ORR, defined as the proportion of patients achieving complete response or partial response according to RECIST v1.1 criteria. Secondary endpoints include progression-free survival (PFS) and safety assessments. Patients receive carelizumab intravenously (i.v.) with 200 mg on day 1 every 3 weeks. The administration regimen for rivoceranib is as follows: 250 mg, orally once daily (q.d.), to be taken within half an hour after a meal, with continuous dosing. The treatment cycle is for 3 weeks. If tolerated, the dose can be escalated to a maximum of 500 mg q.d. Treatment was continued until documented disease progression, development of unacceptable level of toxic effects, withdrawal of consent, or decision by investigator to discontinue treatment.

From June 2024 to March 2025, 12 patients were enrolled (see Patient characteristics table). Median age was 69.5 years (range 60-86 years). 11 patients (92%) are male, and 1 patient (8%) is female. All patients had EMPD histology and were diagnosed as advanced EMPD. Primary tumor locations included vulva in 1 patient, scrotum in 8 patients, and penis in 3 patients. Metastatic sites included inguinal lymph nodes in all 12 patients, and noninguinal lymph nodes in 8 patients. Also, there are pulmonary metastases in 4 patients, liver metastases in 6 patients, and bone metastases in 7 patients. The median number of previous chemotherapy lines of treatment was 2 (range 1-6). Nine patients (75%) received prior surgery, and radiotherapy as a previous line of therapy for 6 patients (50%).

We found that camrelizumab in combination with rivoceranib was tolerated in this study with no immune-related adverse events reported. Unfortunately, this clinical trial did not show clinical activity for the combination in patients with advanced EMPD. All patients discontinued the combination therapy because of disease progression. One patient achieved stable disease for 9 months. The median PFS is 2.4 months, 95% CI, 2.1-4.4 months (Figure 1). Per study protocol, at least 2 objective responses were required to continue enrolling on the second stage of the study; therefore, the trial was closed at the completion of the first stage.

The main reason for the negative result may be the lack of PD-1/PDL1 expressions. Only one patient was identified as PD-L1 positive. In fact, there is still limited understanding of the relationship between EMPD and PD-1/PDL1 expression. A study evaluated PD-L1 expressions in 18 EMPD surgical pathology cases. PD-L1 was found in 3 cases (17%), including 2 of 4 invasive cases (50%) and 1 of 14 noninvasive cases (7%). Invasive cases with lymph node metastasis also showed PD-L1 expression. TAI cells had higher PD-L1 positivity (83%) compared to tumor cells (17%).^13^ Goto et al. investigated the relationship between EMPD and PD-L1/PD-1 expression in 39 Japanese EMPD patients using immunohistochemical staining. Results showed that Paget’s cells did not express PD-L1, but some tumor-infiltrating mononuclear cells (TIMCs) expressed PD-L1 and PD-1. However, no correlation was found between PD-L1/PD-1 expression in TIMCs and patient characteristics. The study concluded that further clinical research is needed to explore other immune escape pathways in EMPD.^14^ A study investigates the Warburg effect in EMPD, finding that elevated glycolytic enzymes like LDHA are associated with increased immunosuppressive cells and cytokines.^15^ These studies suggest that the tumor microenvironment of EMPD leads to immunotherapy resistance, suggesting that EMPD patients have a poor response to immunotherapy, which is consistent with our observation.

In conclusion, this is the first reported clinical trial evaluating carelizumab in combination with rivoceranib in advanced EMPD. This combination did not demonstrate clinical benefit in this cohort of patients with advanced EMPD. Further investigation requires evaluation of the mechanism of resistance and a possible new combination strategy.