SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent an extremely rare and aggressive malignancy associated with smoking and mainly affecting males. It is characterized by inactivation of SMARCA4, a gene encoding an ATPase subunit of the switch/sucrose nonfermenting (SW1/SNF) chromatin remodeling complex, which plays an important role in development, differentiation, and DNA repair [1]. Whereas SMARCA4-UT is associated with somatic mutation of SMARCA4, germline mutations of the gene are known molecular drivers of such malignancies as small cell carcinoma of ovary, hypercalcemic type, as well as malignant rhabdoid tumors in the context of rhabdoid tumor predisposition syndrome type 2 [2].

Histologically, SMARCA4-UT are poorly differentiated tumors, with epithelioid to rhabdoid cells with high mitotic rates. Furthermore, they are often located in the mediastinum, lung, or pleura. Prognosis is extremely poor, with median overall survival of approximately 7 months [3].

In the 2021 classification of thoracic tumors by the World Health Organization (WHO), SMARCA4-UT was defined as a stand-alone entity, distinct from SMARCA4-deficient non-small cell lung cancer (NSCLC) [4]. There have been various names for the disease in the past, such as SMARCA4-deficient thoracic tumor, SMARCA4-deficient thoracic sarcomatoid tumor, or SMARCA4-deficient thoracic sarcoma. This circumstance makes it somewhat difficult to research available literature. The terms “sarcoma” or “sarcomatoid” have been discarded based on detailed analysis of clinicopathologic, immunohistochemical, and genomic characteristics [5] and should thus be avoided by authors in future publications.

There is currently no consensus on optimal systemic therapy in SMARCA4-UT. Thus, as is often the case with rare entities, treatment regimens for more common tumors are implemented.

As mentioned above, SMARCA4-UT has previously been characterized as a sarcoma and—in some cases—treated as such. In a retrospective series of 30 patients who received diverse chemotherapy regimens, including vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) or doxorubicin, ifosfamide, dacarbazine, and mesna (MAID), therapeutic response was described as very poor, with a median overall survival of 6 months [6].

On the other hand, protocols analogous to non-small cell lung cancer (NSCLC) treatment have been implemented. For example, the combination of atezolizumab, bevacicumab, paclitaxel, and carboplatin was investigated in 3 patients with SMARCA4-UT. Two of the patients had high PD-L1 expression (40% and 80%), whereas the remaining patient had a PD-L1 score of 0%. Interestingly, all 3 patients achieved a partial response [7]. PD-L1 expression seems to have poor value as a prognostic marker [2].

In any case, therapy with immune checkpoint inhibitors (ICIs) is controversially discussed. Gantzer et al. described SMARCA4-UT as an “immune desert”, referring to the lack of tertiary lymphoid structures (TLS) in a series of 9 patients, with the exception of one individual who exhibited TLS and was also the only patient in the series with response to ICI [8]. However, multiple publications view ICI as promising in SMARCA4-UT [9,10,11]. Most notably, Lin et al. reported impressive improvement in progression-free survival (PFS) with ICI plus chemotherapy vs. traditional chemotherapy as first-line treatment in a comparatively large series of 25 SMARCA-UT patients (26.8 vs. 2.73 months, p = 0.0437) [12].

As cases of SMARCA4-UT are so few and far apart, and in the lack of prospective data, treatment decisions are largely left to physician’s choice. The rationale for selecting the VDC-IE protocol in the presented case is based mainly on our center’s previous experience in implementing this regimen in other rare pulmonary malignancies, such as NUT carcinoma, as well as the general consideration of achieving rapid cytoreduction in a highly proliferative cancer.