Metastatic SMARCB1-Deficient Renal Medullary Carcinoma without Hemoglobinopathy with Durable and Dramatic Response to Pembrolizumab plus Lenvatinib: Case Report

Renal medullary carcinoma (RMC) is a rare and aggressive epithelial malignant neoplasm initially described in the 1990s and was termed the “seventh sickle cell nephropathy” due to its appearance in individuals with sickle cell trait [1, 2]. RMC is characterized by loss of function in SMARCB1 (INI1/SNF5), a tumor suppressor gene that plays a role in the ATP-dependent chromatin-modifying complex [3]. A formal diagnosis of RMC has historically required that patients have a diagnosis of sickle cell trait, sickle cell disease, or other associated hemoglobinopathy [4]. In 2022, the WHO reclassified RMC and its subtypes with the loss of SMARCB1 expression as “SMARCB1-deficient RMC” [5]. RMC is a clinically aggressive malignancy with a majority of patients having metastatic disease at the time of presentation and poor overall prognosis with uncommon survival >2 years after diagnosis [6‒8].

This rare subtype of SMARCB1-deficient RMC presented is characterized by loss of SMARCB1 protein expression in patients without sickle cell trait or other hemoglobinopathies [9, 10]. This entity has previously been called “unclassified renal cell carcinoma (RCC) with medullary phenotype” in the literature [11]. Due to the rarity of the entity, there are no standard guidelines for systemic therapy for patients with SMARCB1-deficient RMC without hemoglobinopathy. Here we report a male patient with no identified hemoglobinopathy and metastatic SMARCB1-deficient RMC who has shown a durable and ongoing (2 years), near complete response to pembrolizumab and lenvatinib systemic therapy. This is the thirteenth documented case of this tumor type in the literature and the first case to receive this combination therapy while exhibiting such a response to our knowledge [12‒15].

A 53-year-old previously healthy Caucasian male presented with shortness of breath and a recent history of left flank and abdominal pain. Abdominal computed tomography (CT) scan showed a 6.5 × 4.6 cm hypoenhancing infiltrative mass involving the interpolar left kidney and two subcentimeter hypodensities in the right hepatic lobe (Fig. 1a, b). Chest CT scan showed a left pleural effusion and multiple bilateral pulmonary nodules (Fig. 2a, b). Ultrasound-guided thoracentesis showed atypical cells consistent with malignant pleural effusion. Nuclear medicine (NM) bone scan also revealed a right proximal manubrium metastasis. Pathology from biopsy of the left renal mass revealed nests and tubules of highly atypical neoplastic cells with associated neutrophilic infiltration and areas of necrosis. The tumor cells contained amphophilic eccentric cytoplasm with rhabdoid features (WHO/ISUP grade 4), pleomorphic nuclei with prominent nucleoli, and frequent mitoses. On immunohistochemistry, tumor cells showed positivity for PAX8, vimentin, EMA, CAM5.2, FH (retained), CK20 (rare cells), and loss of expression of SMARCB1/INI1. Other markers including CAIX, CK7, P504s, RCC, TTF1, napsin A, NKX3.1, PSA, CD117, CDX2, CK20, HMWK, and GATA3 were negative. Additionally performed immunostaining was significant for focal programmed death-ligand 1 (PD-L1) positivity with a tumor proportion score of 10% and p53 overexpression (Fig. 3).

After undergoing hemoglobin electrophoresis and not finding any evidence of sickle cell trait or other hemoglobinopathy, the patient was diagnosed with SMARCB1-deficient RMC without hemoglobinopathy. A pleural biopsy was subsequently performed, demonstrating tumor morphologically and immunophenotypically consistent with metastasis from the left renal mass.

First-line systemic therapy of lenvatinib, 20 mg orally once daily, and pembrolizumab, 200 mg intravenously once every 3 weeks was initiated 2 months after diagnosis. Imaging 6 weeks after the initiation of therapy showed regression of the left renal mass (5 × 2.8 cm) as well as substantial decreases in the pulmonary and pleural metastases. This excellent tumor control has continued, and imaging after 21 months of treatment showed the renal mass measured at 3.7 × 1.5 cm and resolution of the left pleural effusion and continued reduction in pulmonary nodules (Fig. 1c, d; 2c, d). This constituted a sustained partial response by RECIST criteria with well over 30% in the kidney and almost complete in the lung, which is ongoing after 27 months on therapy at the time of writing this report [16].

Next-generation sequencing (Altera) was performed on the pleural specimen and showed a loss of function mutation in SMARCB1 (Q130*), low tumor mutation burden (1 mut/Mb), MS-stable status, and TP53 mutation (F113L). Interestingly, circulating tumor DNA (Signatera assay) was analyzed in this patient 24 months post-diagnosis which resulted in a low, but detectable level of 0.45 MTM/mL. To date, the patient has continued on pembrolizumab and lenvatinib therapy with a plan for ongoing therapy with both agents due to minimal treatment-related toxicities.

To the best of our knowledge, this is the first SMARCB1-deficient RMC without hemoglobinopathy case of its kind in the literature to receive the regimen of a programmed death-1 inhibitor plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF receptor TKI), a contemporary and now standard regimen for clear cell RCC. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540937).

SMARCB1-deficient RMC without hemoglobinopathy is a rare form of this disease with few cases previously reported in the literature. While RMC is also rare, its underlying genetic abnormalities are better understood. RMC typically exhibits low tumor mutation burden, common gain in 8q chromosome, and common loss of chromosome 22, where SMARCB1 is encoded [6]. Versteege et al. [17] demonstrated that this mutation within the switch/sucrose non-fermenting (SWI/SNF) complex contributes to oncogenesis. SWI/SNF is a multi-subunit complex that uses ATP to reorganize nucleosomes via the sliding of these nucleosomes to either activate or repress transcription [18]. Although this case focuses on the SMARCB1 mutation, other mutated subunits within the SWI/SNF complex have been shown to lead to other human cancers [19]. Loss of SMARCB1 has been shown to alter MYC activity, repress p16INK4A expression, and elevate levels of EZH2, all of which could be potential drivers of tumorigenesis [19‒21]. Given the data behind the loss of SMARCB1-elevating levels of EZH2, evidence has shown that tazemetostat, an EZH2 inhibitor, has the potential to improve outcomes in patients with rhabdoid tumors and other tumors with SMARCB1 mutations [21‒24]. There is currently an ongoing phase II clinical trial studying the effects of tazemetostat in adults with SMARCB1-deficient tumors, including RMC (NCT02601950).

Currently, the recommended management for SMARCB1-deficient RMC is with first-line systemic therapy using platinum-based cytotoxic chemotherapy [25]. In a review of 166 RMC cases, the overall survival was seen to be 10 months for metastatic patients who received any platinum-based chemotherapy while those who did not receive this treatment had an overall survival of 5 months [26]. A retrospective study showed that of RMC patients who received chemotherapy, 29% had an objective response [7]. Other agents have also been examined in metastatic RMC, for example, RMC has been reported to be refractory to anti-VEGF TKIs [27]. Evidence has shown that SMARCB1 loss can protect renal cells from hypoxic stress that is caused by sickle cell trait, and that the loss of this tumor suppressor can protect tumor cells that are under a similar stress caused by angiogenesis inhibitors [28]. Therefore, this biology posits the question of whether anti-VEGF TKIs are effective when given to SMARCB1-deficient RMC patients that lack the hypoxic environment induced by sickle cell trait. However, lenvatinib specifically is a multi-receptor TKI, targeting VEGF receptor, but also targeting FGFR, PDGFRα, KIT, and RET [29]. This further complicates an assessment of the likely impact of lenvatinib on this patient as the anticancer response may be unrelated to lenvatinib, related to VEGF receptor activity of lenvatinib, or related to non-VEGFR TKI activity. Data have shown that RMC tumors do have unique immune expression showing increased PD-L1 [6, 30], but clinical data to support efficacy of sensitivity to immune checkpoint blockade are rare. RMC, tissue has been shown to exhibit higher levels of PD-L1 expression on both tumor cells and surrounding immune cells as well as increased levels of CTLA-4 and LAG-3 receptors [6, 31].

There is a case report suggesting response to nivolumab of 9+ months in a patient with RMC [32]. However, prospective clinical trials have not demonstrated sensitivity of RMC to immune checkpoint inhibitor (ICI) approaches. A trial of 5 patients with advanced RMC treated with pembrolizumab resulted in no objective responses and median time to disease progression of only 8.7 weeks, suggesting limited efficacy [33]. A prospective study of combination immunotherapy with ipilimumab/nivolumab in patients with RMC (NCT03274258) has been stopped for futility [27]. There is also an ongoing study of nivolumab + relatlimab in RMC patients (NCT05347212) [27].

Among non-clear cell RCC in general, there are data that combination therapy with anti-programmed death-1 and VEGFR TKI can have activity. The KEYNOTE-B61 trial showed that pembrolizumab plus lenvatinib exhibited promising antitumor activity as a first-line treatment for patients with nccRCC with an estimated 12-month overall survival rate being 82% [34]. In this study, RMC patients were allowed, and the study reported upon central pathologic review that 12 patients were determined to have “other” pathology [34]. We are unsure if any of these patients were SMARCB1-deficient patients with or without hemoglobinopathy. However, of the 9 patients observed, the objective response rate was 56% [34]. Similarly, nivolumab + cabozantinib has shown activity in a trial of patients with nccRCC with objective response rate 48% and median PFS 12.5 months among 40 patients with papillary, unclassified, or translocation RCC [35].

The specific responsiveness of SMARCB1-deficient RMC without hemoglobinopathy to ICIs and tyrosine kinase inhibitors remains largely confined to case reports due to its rarity. However, a limitation of the case presented is that it is unclear whether the tumor responded to the pembrolizumab, lenvatinib, or both. Valeri et al. [12] report a case that was treated with pembrolizumab and axitinib in the metastatic setting who was alive at the 8-month follow-up point without information available about response or response durability. Takeda et al. [14] report a case in which ICIs, nivolumab, and ipilimumab, are used in the first-line setting post-nephrectomy, where the patient survived 28-month post-diagnosis, but progressed on ICIs after 18 months, suggesting some possible immune-mediated cancer control.

We present an outstanding and ongoing durable anticancer response to immunotherapy/multi-targeted TKI therapy in a rare RCC subtype. This case suggests that this regimen may have activity in some patients with this rare entity and could be considered as a treatment option for this disease. Ideally, further research will be undertaken to confirm if this entity is biologically similar to RMC or if there are significant differences in response to molecular and immunotherapy approaches between these entities.

Written informed consent from the individual was obtained for the publication of his case. The individual signed a consent document that complied with University of Washington Human Subjects Division guidelines. Ethical approval is not required for this study in accordance with local or national guidelines.

All authors report no conflicts of interest.

No funding was received for this project.

All authors contributed to the writing of the manuscript. W.M., M.Y., and E.H. conceived of the idea for the case report and reviewed background literature. M.T. contributed pathology expertise through images, figure legends, and classification of disease. M.J. provided expertise on radiology images, figure legends, and radiographic description of disease.

All data in this report are included in this article. Further questions can be directed to the corresponding author.