Cracking the code: the emerging role of immune checkpoint inhibitors in PEComas

Perivascular epithelioid cell tumors (PEComas) constitute a rare subset of mesenchymal neoplasms within the broader category of soft tissue sarcomas (STS), affecting around 0.12 to 0.24 per million individuals annually [1,2]. They constitute a wide spectrum of tumors ranging from benign to malignant tumors, including angiomyolipoma, lymphangioleiomyomatosis, or other high-grade tumors [3]. While the majority of PEComas occur sporadically, a minority are associated with the tuberous sclerosis complex (the Bourneville-Pringle disease). These tumors predominantly affect middle-aged to older adults, with a reported age range between 47.5 and 67 years, and exhibit a strong female predominance [1]. The uterus and kidneys represent the most frequently involved primary sites and they are generally considered to have a favorable prognosis, with an overall survival (OS) often exceeding five years [4]. Molecular profiling of 35 patients with PEComa revealed TSC1 or TSC2 mutations in approximately 40% of cases. Among tumors harboring TSC2 mutations, 33% demonstrated high expression of the PI3K-Akt-mTOR signaling pathway, whereas TSC1-mutated tumors exhibited comparatively lower pathway activation. High PD-L1 (programmed death – ligand 1) expression was observed in 29% of patients. Additionally, microsatellite instability (MSI) and high tumor mutational burden (TMB) were identified in only 2.9% of cases, indicating their rarity in this tumor type [5]. Another genomic analysis reported alterations in TSC2 in 32.3% of cases, TSC1 mutations in 9.6%, and TFE3 alterations in 16.1%, all of which were identified as gene fusions [6]. In PEComa patients treated with chemotherapy or mTOR inhibitors, no significant differences in survival outcomes were observed between tumors harboring TSC1 versus TSC2 mutations, nor between TSC1/TSC2-mutated tumors and those with other genomic alterations [4].

The primary approach to treatment involves complete surgical resection with optimal margin resection when feasible, and may be supplemented by adjuvant radiotherapy (RT) or chemotherapy (CT) based on individual patient risk profiles and tumor-specific factors [1]. In the advanced or metastatic setting, there is a limited efficacy of systemic chemotherapy while radiation therapy plays a primarily palliative role in select cases. Mammalian target of rapamycin (mTOR) inhibitors – such as nab-sirolimus, sirolimus, temsirolimus, and everolimus – have demonstrated notable clinical efficacy in a subset of patients with PEComa [7]. Nab-sirolimus is the only FDA (Food and Drug Administration)-approved drug for adult patients with locally-advanced, inoperable or metastatic malignant PEComa based on the results of the AMPECT trial, a single-arm phase II trial demonstrating an overall response rate (ORR) of 39% [8]. This therapeutic activity is biologically supported by molecular studies showing the activation of the mTORC1 pathway, frequently resulting from inactivating mutations or loss of function in the TSC1/TSC2 tumor suppressor complex [7]. Furthermore, TFE3 gene rearrangements, which activate the downstream mTOR signaling pathway, have been detected in a minority of PEComa patients [4]. Data suggested that TFE3-rearranged PEComas might constitute a distinct entity characterized by poorer prognosis, an increased propensity for distant metastasis, and reduced sensitivity to mTOR inhibitors [9]. Despite these encouraging results, the duration of response of mTOR inhibitors remains limited, highlighting the urgent need for alternative therapeutic strategies with more durable clinical benefit.

Immune checkpoint inhibitors (ICIs) have markedly transformed the therapeutic landscape of several malignancies, offering substantial improvements in survival and durable responses in various tumor types [10,11]. However, in STS, results from pivotal trials assessing ICIs – either as monotherapy or in combination regimens – have generally shown limited efficacy [12,13]. Given the considerable histological diversity within STS, comprising over 100 distinct subtypes, many rare histological subtypes, including PEComas, have not been adequately represented in clinical trials evaluating immunotherapeutic agents. Consequently, it is imperative to analyze the available case reports and small case series that suggest the potential clinical benefit of ICIs in patients with PEComa to better inform future therapeutic strategies.

Given the rarity of PEComas among STS, initial evidence regarding the efficacy of ICIs in PEComas was provided by McBride et al., who reported a case of metastatic abdominal PEComa that recurred following initial management with surgery and RT. Owing to elevated programmed death-ligand 1 (PD-L1) expression, the patient was treated with pembrolizumab (a PD-1 inhibitor) at a dose of 2 mg/kg administered every three weeks. A complete response (CR) was achieved after 21 cycles, and the response was sustained following 40 cycles, with treatment interruption; disease control was maintained for over 19 months from the start of surveillance off therapy [14]. In another report, Remond et al. described a case of metastatic peri-rectal PEComa treated with a combination of pembrolizumab (an anti-PD1 inhibitor), everolimus (an mTOR inhibitor), and localized therapeutic modalities. Comprehensive molecular profiling revealed a high TMB of 23 mutations per megabase and marked PD-L1 expression exceeding 50%, potentially accounting for the tumor’s pronounced sensitivity to ICIs. The patient exhibited a near-complete response in the primary lesion and a partial response (PR) at metastatic sites. Additional local treatments, including radioembolization of hepatic metastases and radiation to peritoneal lesions, contributed to prolonged disease stabilization lasting for more than 13 months [15]. Additionally, a retrospective analysis by Testa et al. involving 23 patients with PEComa reported that three individuals received immune checkpoint inhibitors (ICIs) as part of their treatment. Among these, two demonstrated notable responses: one achieved a complete response with pembrolizumab monotherapy (High tumor mutational burden (TMB = 17)), and the other experienced a partial response with pembrolizumab combined with radiation therapy [16]. In another case, the anti-PD-1 agent tislelizumab was administered, at a dose of 200 mg every three weeks, in combination with stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in a patient with metastatic uterine PEComa exhibiting positive PD-L1 expression, resulting in a PR [17]. It has been hypothesized that the addition of GM-CSF and radiotherapy may promote abscopal effects at metastatic sites and exert synergistic activity, thereby enhancing systemic anti-tumor immune responses [18]. Additional evidence is provided by a case involving a patient with Lynch syndrome who developed metastatic PEComa and achieved a CR following treatment with pembrolizumab. Next-generation sequencing (NGS) revealed microsatellite instability-high (MSI-high) status, a high TMB of 21.4 mutations per megabase, and no pathogenic alterations in the TSC1 or TSC2 genes [19].

Furthermore, a retrospective analysis conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) recently evaluated 13 patients with previously treated PEComa who received ICI-based therapy. The median patient age was 62 years. Of the cohort, seven patients were treated with ICI monotherapy, while six received combination regimens. All individuals had previously been treated with mTOR inhibitors as part of their therapeutic regimen. Genomic profiling revealed TFE3 gene fusions in 23% of cases and TSC1/TSC2 mutations in 15%. The ORR was 23%, comprising three PRs, two of which were durable, persisting for more than 18 months-one in a patient treated with nivolumab and ipilimumab, and the other with pembrolizumab monotherapy. The median progression-free survival (PFS) was 3 months, while the median overall survival (OS) reached 26 months; the 12-month OS rate was 59%. Notably, patients achieving durable responses often underwent local therapeutic interventions, which appeared to contribute to extended disease-free intervals. Molecular analyses of responding tumors identified several alterations, including TFE3 fusions and mutations in FLT4, NOTCH1, and RB1 [20]. On the other hand, in the Alliance A091401 evaluating Nivolumab as monotherapy or in combination with Ipilimumab in advanced STSs, only one case of PEComa was included in the cohort but did not demonstrate a significant response [12]. Moreover, the sole PEComa patient enrolled in the AcSé Pembrolizumab phase II trial – designed to evaluate the efficacy of pembrolizumab in rare cancers – achieved stable disease as the best observed response [21]. Although key prospective clinical trials of ICIs did not show significant efficacy in STSs overall, subsequent studies have demonstrated promising activity in certain rare histological subtypes, such as alveolar soft part sarcoma and angiosarcoma, leading to their inclusion in treatment strategies [21–23]. This underscores the importance of reporting ICI activity in rare tumors like PEComa, to ensure potentially effective therapies are not overlooked.

In conclusion, ICIs have shown promising clinical activity in patients with advanced PEComa, supporting their potential role as an additional therapeutic option in this rare malignancy. Further research is warranted to identify potential biomarkers of response to ICIs and optimize the sequencing of ICIs in the presence of approved mTOR inhibitors, intending to establish more effective and personalized treatment strategies for patients with PEComa.

Funding Statement

This paper was not funded.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.