3.1.1. Molecular Landscape

Clear cell carcinoma of gynecologic origin shares several defining molecular features that distinguish it from other histologic subtypes. Loss-of-function mutations in ARID1A, a SWI/SNF chromatin remodeling gene, are present in 40% - 60% of ovarian CCC and up to 30% of endometrial CCC, representing one of the most frequent somatic alterations in this histotype [11]. ARID1A mutations carry significant immunologic implications: ARID1A-deficient tumors demonstrate impaired mismatch repair capacity, accumulation of DNA damage, and upregulation of PD-L1 expression via activation of the IFN-γ/JAK-STAT signaling pathway, thereby establishing a theoretical basis for ICI sensitivity [12].

Mutations in PIK3CA are observed in approximately 33% - 40% of ovarian CCC, with attendant activation of the PI3K/AKT/mTOR pathway driving proliferation and survival [13]. HER2 amplification occurs in a small but targetable subset (~14% - 18%) of endometrial CCC [14]. PTEN loss, KRAS mutation, and TP53 alterations are relatively infrequent in ovarian CCC, further distinguishing it from high-grade serous carcinoma. Importantly, BRCA1/2 mutations are uncommon in CCC, limiting the utility of PARP inhibitors as single agents.

Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) status, the most well-established predictors of ICI response across tumor types, occur in only 5% - 10% of ovarian CCCs but in up to 13% - 17% of endometrial CCCs [15]. While representing a minority of cases, dMMR/MSI-H CCC patients may theoretically derive meaningful benefit from pembrolizumab or other PD-1 inhibitors, analogous to their pan-tumor efficacy. Similarly, TMB-H (defined as ≥10 mutations per megabase) is observed in a subset of CCC tumors and has been associated with ICI response independent of MSI status.

3.1.2. Tumor Immune Microenvironment

What makes ovarian CCC biologically distinct is not any single molecular aberration, but the manner in which its oncogenic drivers conspire to simultaneously fuel tumor growth and disable immune surveillance. Co-occurring mutations in ARID1A and PIK3CA sit at the apex of this immunosuppressive network, unleashing PI3K/AKT/mTOR and JAK/STAT3 signaling that collectively amplifies IL-6, upregulates VEGF, and stabilizes HIF-1α, a triad that locks the stroma into a hypoxic, angiogenic, and metabolically reprogrammed state [16]. ARID1A loss compounds immunosuppression through a separate arm: HDAC6 induction drives IL-10 secretion, skewing macrophages toward a pro-tumorigenic M2 phenotype [17]. Concomitant PTEN loss further cements the immune-evasive phenotype by inducing PD-L1, while PI3K/AKT hyperactivation simultaneously co-upregulates LAG-3, combination that enforces T-cell anergy, enhances regulatory T-cell (Treg) function, and blunts cytotoxic lymphocyte activity on multiple fronts. The physical tumor microenvironment (TME) adds an additional layer of immunosuppression: myofibroblastic cancer-associated fibroblasts sustain HIF-1α through PDGF signaling, iron-donating endometriosis-derived stromal cells fuel proliferation, and the resulting Treg- and tumor-associated macrophage (TAM)-rich milieu renders antigen-presenting function ineffective [18]. Paradoxically, this same molecular architecture, rich in targetable possibilities including PD-L1, LAG-3, VEGF, IL-6, and HDAC6, renders CCC a compelling, if challenging, candidate for rationally designed combination immunotherapy [19][20].

Tables 1-3 summarize the clinical trials for ovarian, endometrial, and cervical cancers that include clear cell carcinoma subtypes.

3.2.1. Disease Site: Ovarian Clear Cell Carcinoma

Clinical evidence for anti-PD-1/PD-L1 agents in OCCC derives from histology-specific subset analyses of broader gynecologic oncology trials, dedicated single-arm Phase II studies, and emerging randomized data, several of which have prospectively stratified by CCC histology.

KEYNOTE-100 was a Phase II, open-label, multicenter study evaluating single-agent pembrolizumab 200 mg every three weeks in 376 patients with advanced recurrent ovarian cancer across two cohorts: cohort A (1 - 3 prior lines, platinum-free interval [PFI] 3 - 12 months) and cohort B (4 - 6 prior lines, PFI > 3 months), with PD-L1 expression by combined positive score (CPS) as the primary biomarker endpoint. In the clear cell carcinoma subgroup of 19 patients, the ORR was 15.8% (95% CI: 3.4 - 39.6), numerically the highest among all histologic subtypes and nearly double the overall cohort ORR of 8.0%, suggesting a trend toward preferential responsiveness of the CCC histotype to PD-1 blockade, though the small subgroup size precluded definitive conclusions [21].

NRG-GY003 (NCT02498600) was an open-label, randomized Phase II trial comparing nivolumab alone versus nivolumab plus ipilimumab induction followed by nivolumab maintenance in 100 patients with recurrent or persistent ovarian cancer of all histologic subtypes (except mucinous and carcinosarcoma), with a platinum-free interval under 12 months. Clear cell carcinoma represented 12% of the study population—six patients per arm and while the subgroup was underpowered for definitive conclusions, exploratory analysis revealed an approximately five-fold higher odds of response in CCC patients compared with other histologic subtypes. Patients with CCC also appeared to derive preferential benefit from the combination arm, with the forest plot demonstrating a PFS hazard ratio favoring nivolumab plus ipilimumab over nivolumab alone specifically in this subgroup (interaction P = 0.0498) [22].

NINJA (JapicCTI-153004) was a Phase III, multicenter, randomized, open-label trial comparing nivolumab 240 mg every two weeks against investigator-choice chemotherapy (gemcitabine or pegylated liposomal doxorubicin [PLD]) in 316 patients with platinum-resistant epithelial ovarian cancer, with CCC vs non-CCC histology as a prespecified stratification factor, making it one of the few large randomized trials to prospectively account for the CCC subtype. Clear cell carcinoma represented approximately 21% of the study population, with 34 patients in the nivolumab arm and 33 in the comparator arm, constituting the largest CCC cohort within any randomized ICI trial in ovarian cancer to date. While the trial was negative overall, nivolumab failing to improve OS (HR 1.0; 95% CI 0.8 - 1.3) or PFS (HR 1.5; 95% CI 1.2 - 1.9) versus chemotherapy, the CCC subgroup demonstrated a numerically favorable OS trend with nivolumab (HR 0.78; 95% CI 0.46 - 1.32), in contrast to the non-CCC serous carcinoma subgroup where the HR favored chemotherapy (HR 1.11; 95% CI 0.81 - 1.52). This CCC-specific OS signal is hypothesis-generating for future biomarker-stratified studies [23].

PEACOCC (NCT03425565) was a single-arm Phase II trial, the only study designed exclusively for clear cell gynecological cancer, evaluating pembrolizumab 200 mg every three weeks in 48 patients (85% ovarian CCC) with a median of three prior lines of therapy across five United Kingdom centers. The trial met its primary endpoint with a 12-week PFS rate of 42% (95% CI: 28 - 57). Best ORR was 25%, median duration of response 13.1 months, median PFS 2.7 months, and median OS 14.8 months at a mature median follow-up of 46.9 months. The safety profile was favorable with no grade 4/5 treatment-related adverse events (TRAEs). Critically, 98% of evaluable patients had MMR-proficient tumors, establishing that pembrolizumab activity in clear cell gynecological cancer is independent of MSI-H status and driven by the distinct immunobiology of this histotype. There was no evidence of a difference in PFS or OS for patients with tumors that harbored MMR deficiency, ARID1A loss, aberrant expression of p53, or expressed PD-1, PD-L1 or a combination of PD-1/PD-L1 [24].

JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, Phase III trial, done at 149 hospitals and cancer treatment centres in 24 countries. 614 patients were enrolled across three arms; for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) to avelumab (10 mg/kg intravenously every two weeks), avelumab plus PLD (40 mg/m² intravenously every four weeks), or PLD. Clear cell histology represented approximately 13% of patients (n = 73 across arms). In the subgroup forest plot, the HR for combination avelumab versus PLD was 0.79 (0.41 - 1.54) for PFS and 0.89 (0.38 - 2.06) for OS in the CCC subgroup—confidence intervals widely crossing 1.0, indicating no demonstrable benefit. The overall trial was negative, and clear cell carcinoma remains an unmet need where ICI combinations cannot currently be recommended based on this data alone [25].

MOCCA (Phase II RCT, n = 48) randomized recurrent OCCC patients 2:1 to durvalumab versus physician’s choice chemotherapy—the first randomized ICI versus chemotherapy trial specifically designed for recurrent OCCC. Durvalumab failed to improve PFS (7.6 vs 14.0 weeks, HR 1.6, P = 0.92), OS (37.9 vs 40.6 weeks, HR-1.5; P = 0.85), or ORR (9.7% vs 18.8%; P = 0.83), with chemotherapy numerically outperforming immunotherapy across all endpoints. Notably, only 28.9% of tumors were PD-L1 CPS ≥1%. All tumors were MMR-proficient/MSS, and PIK3CA mutations were exploratorily associated with longer time to progression on durvalumab, while ERBB2 amplification predicted worse PFS. These results indicate that PD-L1 monotherapy has no role in unselected recurrent OCCC; future directions lie in combination strategies and biomarker-selected populations [26].

BrUOG 354 (Phase II RCT, n = 44; 82% ovarian CCC) compared nivolumab monotherapy versus nivolumab plus ipilimumab (N + I) in relapsed extra-renal CCC. N + I demonstrated superior activity over monotherapy with ORR 33% (including four complete responses (CRs)) versus 14.3%, and median PFS 5.6 versus 2.2 months, with median OS 24.6 versus 17 months. Notably, four patients (12%) achieved durable CR with N + I. Grade ≥ 3 TRAEs were higher with N + I (47% vs 21%) but no treatment-related deaths occurred [27].

MoST-CIRCUIT (Phase II, n = 28; 24 OCCC + four uterine CCC) evaluated nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks for four doses, followed by nivolumab 480 mg every four weeks for 96 weeks in advanced gynecological CCC. Dual checkpoint blockade demonstrated an ORR of 50% (13% CR + 37% PR) across both subgroups, with median duration of response not reached and all responses ongoing at six months; 6-month PFS was 52%. TMB correlated with response (3.1 vs 1.15 mut/MB; p = 0.03), and responses were predominantly observed in ARID1A wild-type tumors. Grade 3/4 immune-related adverse events (irAEs) occurred in 25%, including one fatal myocarditis. Combined anti-CTLA-4/PD-1 blockade shows the highest ORR reported to date in gynecological CCC and warrants further randomized evaluation [28].

LARA (Phase II, single-arm, n = 27; 89% ovarian CCC;11% endometrium CCC) evaluated pembrolizumab 200 mg every three weeks plus lenvatinib 20 mg daily in recurrent clear cell gynecological cancer; notably, 63% of patients had received prior anti-angiogenic therapy and all tumors were MMR-proficient/MSS. The primary endpoint was met with an ORR of 40% at 24 weeks (95% CI 21 - 61), clinical benefit rate 84%, median PFS 6.4 months, and median OS 15.6 months—including a 47% ORR in the prior anti-angiogenic subgroup, suggesting lenvatinib may overcome VEGF-resistance through its broader multi-kinase inhibitory profile. Grade 3 - 4 TRAEs occurred in 52%, predominantly hypertension, with no treatment-related deaths. Responses occurred irrespective of PD-L1 CPS or TMB status, and findings are directionally consistent with the INOVA trial results [29].

NRG-GY016 (Phase II, single-arm, n = 14) evaluated pembrolizumab 200 mg every three weeks plus epacadostat (IDO1 inhibitor) 100 mg twice daily in recurrent OCCC. The combination yielded an ORR of 21% (three partial responses [PRs]), DCR 50%, median PFS 4.8 months, and median OS 18.9 months; however, the study closed prematurely after stage 1 due to insufficient drug supply, precluding definitive conclusions. The concurrent failure of epacadostat plus pembrolizumab in the ECHO-301/KEYNOTE-252 melanoma Phase III trial, alongside concerns regarding subtherapeutic IDO1 inhibition at the 100 mg twice-daily dose, further limits enthusiasm for this combination. IDO1 inhibition combined with PD-1 blockade is unlikely to be pursued further in this setting [30].

INOVA (Phase II, single-arm, n = 41; 37 evaluable) evaluated sintilimab (anti-PD-1) 200 mg plus bevacizumab 15 mg/kg every three weeks in relapsed or persistent ovarian CCC—the first prospective study evaluating an ICI plus anti-angiogenic combination exclusively in this histotype. The primary endpoint was met with an ORR of 40.5% (95% CI 24.8 - 57.9), comprising five complete responses (14%) and ten partial responses (27%). Median PFS was 6.9 months, and median OS was 28.2 months. Grade ≥ 3 TRAEs occurred in only 7% of patients with no treatment-related deaths, confirming a favorable toxicity profile and establishing this chemotherapy-free regimen as a promising option pending randomized validation [31].

3.2.2. Disease Site: Endometrial Clear Cell Carcinoma

Endometrial CCC, though rarer than its serous or endometrioid counterparts, has been investigated as part of broader endometrial cancer ICI trials. Dedicated histotype-specific data remain sparse, and conclusions are largely extrapolated from subgroup analyses and molecular phenotype-based evidence.

KEYNOTE-775 (randomised Phase III trial) enrolled all endometrial histologies except carcinosarcoma and sarcoma with clear cell carcinoma comprising 7.3% (n = 30) of the lenvatinib plus pembrolizumab arm. Although no histology-specific efficacy data are reported for clear cell carcinoma, the subgroup analysis favored lenvatinib plus pembrolizumab over chemotherapy across all histologic subtypes, including less-common aggressive histologies. As endometrial CCC is predominantly pMMR, the significant PFS (6.6 vs 3.8 months; HR 0.60; p < 0.001) and OS (17.4 vs 12.0 months; HR 0.68; p < 0.001) benefit demonstrated in the pMMR population represents the most clinically applicable evidence for this histology to date [32].

The NRG-GY018 Phase III trial randomized 816 patients with advanced/recurrent endometrial cancer to pembrolizumab plus carboplatin-paclitaxel versus placebo-chemotherapy, enrolling all histologic subtypes except carcinosarcoma. Clear cell carcinoma represented 6.3% of the overall population (37 patients), virtually all in the pMMR cohort (17 + 20 patients across arms), consistent with the predominantly pMMR phenotype of ECCC. The trial demonstrated significant PFS benefit in both dMMR (HR 0.30) and pMMR (HR 0.54) cohorts, with the authors explicitly noting benefit observed across less common histologic subtypes including clear cell—though no CCC-specific subgroup analysis was reported [33].

The RUBY trial was a Phase III randomized trial of dostarlimab plus carboplatin-paclitaxel versus placebo-chemotherapy in primary advanced or recurrent endometrial cancer (n = 494). Clear cell adenocarcinoma represented 3.3% - 3.6% of the overall population (8 - 9 patients per arm), making CCC-specific conclusions statistically untenable. The trial demonstrated significant PFS benefit overall (24-month PFS 36.1% vs 18.1%; HR 0.64) and a particularly striking benefit in the dMMR/MSI-H cohort (24-month PFS 61.4% vs 15.7%; HR 0.28). Crucially, a PFS benefit was also observed in the pMMR/MSS population (HR 0.76; 95% CI, 0.59 - 0.98), which is the predominant molecular phenotype of endometrial CCC, suggesting potential applicability to this histotype. Endometrial CCC patients were explicitly eligible under the inclusion criteria, but subgroup-level outcomes were not separately reported [34].

DUO-E was a Phase III trial randomizing 718 patients with advanced/recurrent endometrial cancer 1:1:1 to carboplatin-paclitaxel plus durvalumab followed by maintenance durvalumab ± olaparib versus chemotherapy alone. Clear cell adenocarcinoma represented only 1.7% - 3.3% of the overall population (4 - 8 patients per arm), rendering CCC-specific conclusions entirely untenable. The trial demonstrated significant ITT PFS benefit for both the durvalumab (HR 0.71) and durvalumab plus olaparib (HR 0.55) arms versus control, with benefit observed in the pMMR/MSS subgroup (HR 0.77 and 0.57 respectively)—directly relevant to the predominantly pMMR phenotype of endometrial CCC. Notably, the addition of olaparib appeared to confer incremental benefit specifically in the pMMR population (HR 0.76, durvalumab plus olaparib vs durvalumab alone), raising a hypothesis-generating question as to whether PARP inhibition may augment ICI activity in pMMR clear cell tumors through synthetic lethality with ARID1A loss—a biologically plausible interaction given ARID1A’s role in homologous recombination repair—warranting dedicated investigation [35].

DOVE is the largest ongoing Phase II RCT specifically designed for recurrent gynecologic CCC, randomizing 198 ICI-naive patients 1:1:1 to dostarlimab monotherapy, dostarlimab plus bevacizumab, or investigator’s choice chemotherapy, with crossover to the combination arm permitted at progression. Uniquely, the trial enrolls all anatomical CCC subtypes including endometrial, cervical, vaginal, and vulvar CCC—directly addressing the critical evidence vacuum in non-ovarian subtypes—with comprehensive biomarker analyses including MMR, TMB, and ARID1A/PIK3CA profiling planned. Results are awaited as the potential practice-defining evidence for this histotype [36].

3.2.3. Disease Site: Clear Cell Carcinoma of the Cervix

Dedicated ICI trial data for clear cell carcinoma of the cervix are virtually non-existent. The PEACOCC trial included only one cervical clear cell gynecological cancer patient (2%) among 48 enrolled, making any histotype-specific conclusions impossible [24]. Cervical CCC is a rare, predominantly non-HPV-driven tumor—associated with diethylstilbestrol (DES) exposure or arising de novo—with a distinct molecular biology from the squamous and adenocarcinoma subtypes for which ICI approvals exist [37]. Clear cell histology was not separately analyzed in any of the pivotal cervical cancer ICI trials, representing a critical evidence gap.

3.2.4. Disease Site: Clear Cell Carcinoma of the Vulva

This is an exceedingly rare entity with essentially no ICI-specific data. The role of ICIs in vulvar cancer is mainly extrapolated from trials in cutaneous squamous cell and cervical cancers. Clear cell histology of the vulva was not represented in any published ICI basket trial with reportable outcomes, and management of this entity remains entirely empiric.