Durable response to pembrolizumab plus axitinib in platinum-resistant ovarian clear cell carcinoma: A case report.

A 39-year-old Caucasian female with a history of OCCC presented with recurrent, platinum-resistant disease. At initial diagnosis, the patient presented with left lower extremity swelling and pain and was found to have severe anemia and deep vein thrombosis. She had a prior history of right oophorectomy performed approximately one year prior for benign findings. At presentation, her hemoglobin level was 5.5 g/dL, and imaging revealed a large complex lesion at the splenic hilum as well as a left iliopsoas mass. Magnetic resonance imaging (MRI) of the abdomen demonstrated a malignant-appearing cystic and solid lesion within the splenic hilum measuring 7.0 × 8.7 × 8.9 cm, along with a left iliopsoas mass exhibiting both cystic and solid components. Additional findings included an aortocaval lymph node measuring 3.7 × 2.7 cm and confluent adenopathy superior to the pancreatic neck within the gastrohepatic ligament. A 2.1 × 1.0 cm liver lesion was also identified and interpreted as consistent with a hemangioma. Tumor markers at initial diagnosis were notable for CA-125 of 667 U/mL, CA 19–9 of 120 U/mL, CA 27–29 of 47.6 U/mL, and alpha-fetoprotein (AFP) of 0.7 ng/mL. The patient underwent diagnostic laparoscopy with left ovarian cystectomy and biopsies. Diagnostic laparoscopy demonstrated a grossly normal-appearing remaining left ovary with dense scar formation involving the posterior uterus and left pelvic sidewall, initially thought to represent endometriosis. No overt peritoneal carcinomatosis or obvious intra-abdominal masses were identified. A cystic-appearing splenic hilar lesion was visualized but was not excised or biopsied. Initial pathology was interpreted as high-grade serous carcinoma with clear cell features. Subsequent external review refined the diagnosis to include ovarian clear cell carcinoma, with histopathologic features demonstrating glandular and papillary architecture and cytologic atypia consistent with clear cell carcinoma ( Fig. 1 A–C). Fig. 1 Histopathologic findings. A: Low-power (40×) hematoxylin and eosin (H&E) stain demonstrating glandular and papillary architecture. B: Intermediate-power (100×) view showing tumor cell clustering and stromal interface. C: High-power (200×) view demonstrating atypical epithelial cells with clear cytoplasm and prominent nucleoli. Fig. 1 Histopathologic findings. A: Low-power (40×) hematoxylin and eosin (H&E) stain demonstrating glandular and papillary architecture. B: Intermediate-power (100×) view showing tumor cell clustering and stromal interface. C: High-power (200×) view demonstrating atypical epithelial cells with clear cytoplasm and prominent nucleoli. Within several weeks of diagnosis, the patient was initiated on first-line systemic therapy with four cycles of carboplatin and paclitaxel followed by two cycles of carboplatin, paclitaxel, and bevacizumab. This regimen produced a mixed radiographic response, with regression of some lesions and progression of others, and CA-125 decreased from 667 U/mL to 104 U/mL. She then received four cycles of maintenance paclitaxel and bevacizumab, during which CA-125 increased from 104 U/mL to 179 U/mL. CT imaging subsequently demonstrated progression of malignancy. She was evaluated locally and at a tertiary referral center and was deemed not to be a surgical candidate because of the distribution of metastatic disease and chemotherapy-resistant disease. Comprehensive molecular profiling revealed microsatellite stability, low tumor mutational burden, PD-L1 expression with a tumor proportion score (TPS) of 5%, ARID1A G784fs*27 alteration, MTAP loss involving exons 5–8, and TP53 W91 mutation. 6 months after completion of first-line therapy, the patient pursued alternative second-line treatment at an outside institution with intratumoral and adjacent lymph node chemoimmune precision injections (CIPI), consisting of Vaxelis, alpha-2-macroglobulin, paclitaxel, haptens, and gemcitabine, in combination with systemic pembrolizumab. The patient received two treatments over approximately 3 months. This treatment was administered outside of a clinical trial setting as part of individualized care at an external institution. Specific dosing parameters for the intratumoral therapy were not available. Follow-up PET/CT imaging after this treatment demonstrated a mixed response, with improvement in some lesions, enlargement of others, and new lesions including left supraclavicular lymphadenopathy. At that time, CA-125 had increased to 287 U/mL. Notable findings included a left supraclavicular lymph node measuring 1.2 cm with a standardized uptake value (SUV) of 3.4 and a splenic hilar mass measuring 6.6 cm, which had decreased in size from 9.1 cm but demonstrated increased metabolic activity, with SUV rising from 2.4 to 13.4. Retroperitoneal and right iliac nodal metastases appeared improved; however, new right inguinal and left iliac nodal metastases were identified. The left iliopsoas mass measured 5.6 cm with an SUV of 24.9, compared to prior measurements of 7.4 cm and SUV of 3.7. Baseline PET/CT imaging demonstrated multiple FDG-avid metastatic lesions involving the spleen and nodal regions, consistent with significant disease burden prior to initiation of combination therapy ( Fig. 2 ). Fig. 2 Pretreatment imaging findings. PET/CT demonstrating FDG-avid metastatic lesions involving the splenic hilum and multiple nodal regions prior to initiation of pembrolizumab plus axitinib. Fig. 2 Pretreatment imaging findings. PET/CT demonstrating FDG-avid metastatic lesions involving the splenic hilum and multiple nodal regions prior to initiation of pembrolizumab plus axitinib. At the time pembrolizumab plus axitinib was considered, the patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Her CA-125 had risen during the preceding treatment course, with values ranging from 173 to 287 U/mL across the interval of progression. Clinically, she reported mild left-sided abdominal and pelvic pain, poor appetite, and difficulty maintaining weight. She was able to palpate both a right inguinal lymph node and a left supraclavicular lymph node. Alternative systemic options were discussed, including gemcitabine, pegylated liposomal doxorubicin, and clinical trial enrollment. Given progression after prior bevacizumab-containing therapy, alternative VEGF-targeted strategies were considered. Following multidisciplinary tumor board discussion, axitinib was added off-label to pembrolizumab 1 month after documented progression, at a starting dose of 5 mg orally twice daily, with pembrolizumab continued at 400 mg every six weeks. The decision to initiate axitinib was based on the limited standard options specifically for platinum-resistant OCCC, the patient's preference for a biologically rational approach, and the demonstrated efficacy of pembrolizumab plus axitinib in clear cell renal cell carcinoma ( Rini et al., 2019 ). Although the patient had active health insurance, axitinib was not covered because its use for ovarian clear cell carcinoma was off-label. Access to therapy therefore required coordination with the clinical pharmacy team to obtain the medication. The patient experienced rapid symptomatic improvement within several weeks of initiating combination therapy, including increased energy, improved appetite, and weight stabilization, allowing her to resume regular physical activity. Early follow-up imaging performed 2 months after initiation of axitinib demonstrated improvement in lymphadenopathy and reduction in the size of abdominal masses. Clinically, the patient noted regression of previously palpable left supraclavicular and right inguinal lymph nodes. Further PET/CT imaging performed 6 months after initiation of axitinib demonstrated continued response, including resolution of left supraclavicular hypermetabolic lymphadenopathy, reduction in the splenic hilar mass to 3.5 cm with a maximum SUV of 3.5 (previously 24.9), and resolution of iliac and inguinal nodal metastases, with the exception of a left common iliac node demonstrating mildly increased metabolic activity despite decreased size. The left iliopsoas mass also demonstrated interval reduction in size. Overall, these findings were consistent with a marked metabolic response on PET/CT imaging ( Fig. 3 B). At that time, CA-125 had normalized to 16.7 U/mL. Fig. 3 Radiographic response to therapy. A: Baseline PET/CT demonstrating multiple FDG-avid metastatic lesions prior to initiation of pembrolizumab plus axitinib. B: Follow-up PET/CT demonstrating marked reduction in metabolic activity after initiation of pembrolizumab plus axitinib. C: PET/CT demonstrating sustained response prior to axitinib dose escalation, with residual low-level metabolic activity. D: PET/CT obtained approximately eight months after axitinib dose escalation demonstrating increased uptake in the left pelvic sidewall lesion and a new FDG-avid presacral retroperitoneal nodule, findings suspicious for disease progression. Fig. 3 Radiographic response to therapy. A: Baseline PET/CT demonstrating multiple FDG-avid metastatic lesions prior to initiation of pembrolizumab plus axitinib. B: Follow-up PET/CT demonstrating marked reduction in metabolic activity after initiation of pembrolizumab plus axitinib. C: PET/CT demonstrating sustained response prior to axitinib dose escalation, with residual low-level metabolic activity. D: PET/CT obtained approximately eight months after axitinib dose escalation demonstrating increased uptake in the left pelvic sidewall lesion and a new FDG-avid presacral retroperitoneal nodule, findings suspicious for disease progression. Treatment was continued without modification. Repeat PET/CT imaging 12 months after initiation of axitinib demonstrated further radiographic improvement, with continued decrease in fluorodeoxyglucose (FDG) avidity of the splenic hilar and iliopsoas lesions. CA-125 further improved to 14.9 U/mL. At 15 months after initiation of axitinib, PET/CT imaging demonstrated stable size of the splenic hilar mass (2.9 × 1.5 cm) but increased metabolic activity, with SUV rising from 7.1 to 17.1. The left internal iliac/pelvic sidewall lymph node remained stable in size, measuring 1.7 × 0.8 cm, without evidence of new metastatic disease ( Fig. 3 C). Given the increased metabolic uptake, continued tolerability, young age, and the option for higher-dose axitinib used in clear cell renal cell carcinoma, the axitinib dose was increased to 7 mg orally twice daily after discussion with the patient. After axitinib dose escalation, the patient elected to return to the outside institution for additional CIPI directed at the two visible residual lesions. CT imaging obtained before this treatment demonstrated that the lesions were already decreasing in size following the higher axitinib dose. PET/CT performed approximately four months after dose escalation demonstrated complete resolution of the previously hypermetabolic splenic hilar lesion, stable to slightly decreased left external iliac/pelvic sidewall lymphadenopathy, and no new FDG-avid disease. Approximately eight months after dose escalation, PET/CT demonstrated increasing metabolic activity within the left pelvic sidewall lesion and a new FDG-avid presacral retroperitoneal nodule, findings suspicious for disease progression ( Fig. 3 D). Overall, the patient experienced approximately 23 months of disease control following initiation of pembrolizumab plus axitinib, including approximately eight months after axitinib dose escalation ( Fig. 3 A–D). Because additional CIPI was administered after dose escalation, the relative contribution of higher-dose axitinib versus repeat CIPI to the prolonged disease control cannot be determined. The patient's treatment course and response pattern are summarized in Fig. 4 . Fig. 4 Clinical treatment timeline and disease course. Timeline summarizing the patient's diagnosis, systemic therapies, treatment duration, serum CA-125 trend, radiographic response, and key clinical decision points from initial diagnosis through the most recent follow-up. PET/CT performed approximately 4 months after axitinib dose escalation demonstrated complete resolution of the previously hypermetabolic splenic hilar lesion, stable to slightly decreased left external iliac/pelvic sidewall lymphadenopathy, and no new FDG-avid disease. The most recent PET/CT, obtained approximately 8 months after dose escalation (approximately 23 months after initiation of pembrolizumab plus axitinib), demonstrated increased metabolic activity within the left pelvic sidewall lesion and a new FDG-avid presacral retroperitoneal nodule, findings suspicious for disease progression. Because additional chemoimmune precision injections (CIPI) were administered after axitinib dose escalation, the relative contribution of higher-dose axitinib versus repeat CIPI to the prolonged duration of disease control cannot be determined. Abbreviations: BID, twice daily; CA-125, cancer antigen 125; CIPI, chemoimmune precision injections; CT, computed tomography; FDG, fluorodeoxyglucose; LN, lymph node; OCCC, ovarian clear cell carcinoma; PET/CT, positron emission tomography/computed tomography; RCC, renal cell carcinoma; SUV, standardized uptake value. Fig. 4 Clinical treatment timeline and disease course. Timeline summarizing the patient's diagnosis, systemic therapies, treatment duration, serum CA-125 trend, radiographic response, and key clinical decision points from initial diagnosis through the most recent follow-up. PET/CT performed approximately 4 months after axitinib dose escalation demonstrated complete resolution of the previously hypermetabolic splenic hilar lesion, stable to slightly decreased left external iliac/pelvic sidewall lymphadenopathy, and no new FDG-avid disease. The most recent PET/CT, obtained approximately 8 months after dose escalation (approximately 23 months after initiation of pembrolizumab plus axitinib), demonstrated increased metabolic activity within the left pelvic sidewall lesion and a new FDG-avid presacral retroperitoneal nodule, findings suspicious for disease progression. Because additional chemoimmune precision injections (CIPI) were administered after axitinib dose escalation, the relative contribution of higher-dose axitinib versus repeat CIPI to the prolonged duration of disease control cannot be determined. Abbreviations: BID, twice daily; CA-125, cancer antigen 125; CIPI, chemoimmune precision injections; CT, computed tomography; FDG, fluorodeoxyglucose; LN, lymph node; OCCC, ovarian clear cell carcinoma; PET/CT, positron emission tomography/computed tomography; RCC, renal cell carcinoma; SUV, standardized uptake value. Pembrolizumab plus axitinib was overall well tolerated. No grade ≥ 3 immune-related adverse events were observed. The patient experienced grade 1 mucositis, which improved with supportive care.

Nikhil S. Patel: Writing – review & editing, Writing – original draft, Investigation. Joshua J. Cook: Writing – review & editing, Writing – original draft, Visualization, Project administration, Data curation, Conceptualization, Investigation, Methodology. Danielle E. Valcana: Writing – review & editing, Validation. Michael J. Poiesz: Writing – review & editing, Supervision. Shailesh J. Patel: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization, Resources.

This project was reviewed by Advarra institutional review board (IRB) and determined not to meet the regulatory definition of human subjects research under 45 CFR 46. Consequently, ongoing IRB oversight and informed consent were not required. Informed consent for publication was not obtained, as this study was classified as non-human subjects research and involved retrospective analysis of de-identified clinical data. All efforts were made to protect patient privacy and confidentiality, and no identifiable information is included in this report.

We report a case of platinum-resistant ovarian clear cell carcinoma demonstrating approximately 23 months of disease control with pembrolizumab plus axitinib despite microsatellite stability, low tumor mutational burden, and prior mixed response to bevacizumab-containing therapy. In a disease setting with limited effective options, this case suggests that VEGFR tyrosine kinase inhibition combined with PD-1 blockade may provide meaningful clinical benefit in selected patients. Careful consideration of tumor biology, prior treatment response, and patient functional status is essential when evaluating such combination strategies in refractory disease.

This case highlights durable disease control with pembrolizumab plus axitinib in platinum-resistant ovarian clear cell carcinoma (OCCC) despite microsatellite stability, low tumor mutational burden, and prior mixed response to bevacizumab-containing therapy. The observed response suggests potential clinical activity of combined VEGFR inhibition and PD-1 blockade in a setting with otherwise limited therapeutic options. OCCC is frequently characterized by ARID1A alterations, which have been implicated in modulation of the tumor immune microenvironment ( Takahashi et al., 2021 ; Xia et al., 2024 ). Preclinical and translational studies suggest that ARID1A loss may enhance susceptibility to immune checkpoint inhibition through effects on chromatin remodeling, interferon signaling, and tumor immunogenicity ( Takahashi et al., 2021 ; Shen et al., 2018 ). In this context, the presence of an ARID1A mutation in our patient may have contributed to sensitivity to pembrolizumab-based therapy, although this relationship remains hypothesis-generating and requires further validation. VEGF-pathway inhibition may further augment antitumor immune response by normalizing tumor vasculature, reducing immunosuppressive myeloid signaling, and facilitating T-cell trafficking and activation ( Zhang et al., 2021 ; Fukumura et al., 2018 ). Anti-angiogenic therapy is an established component of treatment in ovarian cancer, including platinum-resistant disease ( Pujade-Lauraine et al., 2014 ), and combination strategies with immune checkpoint inhibitors have demonstrated encouraging activity ( Wang et al., 2025 ). These mechanisms provide a rationale for combining VEGF/VEGFR-directed therapy with PD-1 blockade, particularly in tumors with immunomodulatory alterations. An additional notable feature of this case is that pembrolizumab had been used previously in combination with CIPI, followed by mixed response and eventual progression. The subsequent durable disease control observed after addition of axitinib suggests that VEGFR inhibition may have modified the tumor microenvironment in a manner that enhanced responsiveness to PD-1 blockade despite prior pembrolizumab exposure. However, this interpretation remains hypothesis-generating given the patient's complex prior treatment course. Axitinib has a well-characterized toxicity profile, including hypertension, fatigue, diarrhea, mucositis, thromboembolic events, hemorrhage, proteinuria, and cardiac dysfunction; in this case, treatment was generally well tolerated, with only grade 1 mucositis reported. Mechanistically, bevacizumab and axitinib target different components of the angiogenic pathway, raising the possibility that VEGFR inhibition with a tyrosine kinase inhibitor may retain clinical activity after limited benefit from prior bevacizumab-containing therapy, as observed in this case. Combination VEGFR TKI and PD-1 blockade has demonstrated meaningful activity across tumor types. In renal cell carcinoma, axitinib plus pembrolizumab achieved an objective response rate of 59.3%, supporting the clinical feasibility and efficacy of this combination strategy ( Rini et al., 2019 ). Although data specific to platinum-resistant OCCC remain limited, emerging evidence suggests that VEGFR-targeted immunotherapy combinations may have broader relevance in clear cell histologies. For example, pembrolizumab combined with lenvatinib has demonstrated encouraging outcomes in gynecologic malignancies, including OCCC, with progression-free survival exceeding 6 months in a substantial proportion of patients ( Lee et al., 2025 ; Makker et al., 2022 ). This evolving body of evidence supports further exploration of VEGFR-targeted immune combinations, while recognizing that axitinib and lenvatinib represent distinct agents within this therapeutic class. Taken together, this case suggests potential activity of axitinib plus pembrolizumab in platinum-resistant OCCC, even in the setting of microsatellite stability, low tumor mutational burden, and prior mixed response to bevacizumab-containing therapy. The presence of an ARID1A alteration may be biologically relevant and warrants further study as a potential modifier of response to immunotherapy-based combinations. The limitations of this report include its single-patient design and the patient's prior exposure to multiple therapies, including intratumoral chemoimmune precision injections administered at an outside institution. The patient's exposure to CIPI also complicates attribution of response. CIPI has been described as a personalized, image-guided intratumoral drug-delivery approach intended to increase local drug exposure when surgery is difficult or standard options are limited ( Goklany et al., 2025 ). However, published evidence remains sparse and largely limited to preliminary case-based experience. In this patient, the initial CIPI plus pembrolizumab course was followed by mixed response and progression before axitinib was added, supporting a temporal association between axitinib initiation and subsequent disease control. Following axitinib dose escalation, the patient received additional CIPI and subsequently remained without evidence of progressive disease for approximately eight months before PET/CT demonstrated findings suspicious for disease progression. Accordingly, the relative contribution of higher-dose axitinib versus repeat CIPI to the prolonged disease control cannot be determined.

Ovarian clear cell carcinoma (OCCC) accounts for approximately 5–10% of epithelial ovarian cancers and is associated with intrinsic chemoresistance and poorer clinical outcomes compared with high-grade serous histology ( Shu et al., 2015 ). In addition to its distinct clinical behavior, OCCC is characterized by unique molecular features, including frequent ARID1A alterations and a tumor microenvironment influenced by angiogenic and immune regulatory pathways ( Takahashi et al., 2021 ; Xia et al., 2024 ). Standard platinum-based regimens are often associated with low response rates and limited durability in recurrent OCCC due to its intrinsic platinum resistance ( Okamoto et al., 2014 ). Angiogenesis plays a critical role in ovarian tumor biology, and anti-VEGF therapies such as bevacizumab have demonstrated clinical benefit in platinum-resistant disease ( Pujade-Lauraine et al., 2014 ). Beyond direct anti-angiogenic effects, VEGF pathway inhibition may enhance antitumor immunity by promoting vascular normalization and reducing immunosuppressive signaling within the tumor microenvironment ( Fukumura et al., 2018 ; Zhang et al., 2021 ). More recently, VEGFR tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors have demonstrated synergistic activity across several malignancies, including renal cell carcinoma and endometrial carcinoma ( Rini et al., 2019 ; Makker et al., 2022 ). Emerging data suggest that VEGFR-targeted therapy may have particular relevance in OCCC, especially in tumors harboring ARID1A alterations. ARID1A loss has been associated with altered chromatin remodeling, enhanced interferon signaling, and increased tumor immunogenicity, which may sensitize tumors to immune checkpoint blockade ( Takahashi et al., 2021 ; Xia et al., 2024 ; Shen et al., 2018 ). These biologic features provide a rationale for combining VEGFR inhibition with PD-1 blockade in this histologic subtype. Axitinib is a selective VEGFR1–3 TKI that produces anti-angiogenic effects and shows preclinical relevance for potential treatment of epithelial ovarian cancer ( Paik et al., 2020 ). Axitinib is approved for use in advanced renal cell carcinoma, including in combination with pembrolizumab, a regimen that achieved an objective response rate of 59.3% in KEYNOTE-426 ( Rini et al., 2019 ). Bevacizumab is a VEGF-A inhibitor, whereas axitinib inhibits VEGFR1–3, suggesting that VEGFR-directed tyrosine kinase inhibition may have biologic relevance even after limited benefit from prior bevacizumab-containing therapy. Here, we describe a patient with platinum-resistant OCCC who achieved durable disease control with pembrolizumab and axitinib despite microsatellite stability, low tumor mutational burden, and prior mixed response to bevacizumab-containing therapy.

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.