Sotorasib in KRAS p.G12C-Mutated Pulmonary Sarcomatoid Carcinoma: Therapeutic Efficacy of a KRAS Inhibitor in Symptomatic Brain Metastases

Pulmonary sarcomatoid carcinomas (PSCs) are a group of rare malignancies, which are defined as heterogenous non-small cell lung cancer (NSCLC) composed of 5 different pathologic types: carcinosarcoma, spindle cell sarcoma, pleomorphic sarcoma, giant cell carcinoma, and pulmonary blastoma [1]. Sarcomatoid carcinomas of the lung account for less than 1% of all lung tumors and are associated with poor prognosis with survival rates at 1, 3 and 5 years being 33.7%, 18.4%, and 14.4%, respectively [2]. This clinical outcome is significantly worse compared to patients with other histological subtypes of NSCLC. This could be in part explained by the fact that conventional treatments such as chemotherapy and radiation usually show limited efficacy and randomized controlled trials exploring innovative systemic therapies for advanced pulmonary sarcomatoid carcinomas do not exist [3, 4].

Therefore, it is very important to investigate the role of alternative treatments such as tyrosine-kinase-based targeted therapies. Tyrosine kinase inhibitors targeting the epidermal growth factor receptor are now well-established parts of standard therapy algorithms in NSCLC harboring EGFR mutations. Unfortunately, EGFR mutations are rarely detected in patients with PSC and therefore none of the known TKI such as gefitinib, erlotinib, osimertinib, afatinib seem to be an effective treatment approach. On the other hand, KRAS mutations are found in about 30% of patients with PSC, most of them being Gly12Cys which could be targeted by sotorasib [5]. Here, we present the case of a patient with sarcomatoid-differentiated lung carcinoma with symptomatic brain metastases and describe the therapeutic effect of the KRAS inhibitor sotorasib in the presence of a proven G12C mutation in the KRAS gene.

The 66-year-old patient presented through the emergency department with night sweats for 3 days, productive cough, dyspnea and breath-dependent chest pain. After sonographic detection of pleural effusion on the right side, performed pleural puncture showed a hemorrhagic punctate without cytopathological evidence of malignancy. Antibiotic therapy was given on initial suspicion of pneumonia.

CT scan of the thorax confirmed the large effusion on the right side with atelectasis as well as nodular presentation of the pleura, which was evaluated as primarily inflammatory with atypical presentation of possible pleural carcinomatosis (Fig. 1). Initially, the thoracic surgeon inserted a chest drain for a suspected pleural empyema and performed video-assisted thoracoscopic surgery on the right side with histological confirmation of the pleural process. This revealed a spindle cell, highly pleomorphic malignancy with expression of vimentin and small focus expression of epithelial markers in the sense of pleural carcinomatosis of a sarcomatoid-differentiated carcinoma (Fig. 1). The subsequent molecular pathological analysis revealed low-level PD-L1 expression in the tumor cells (TPS = 40%), and NGS showed a KRAS mutation (G12C) with an allele frequency of 39%, a TP53 mutation (R273L) with an allele frequency of 27%, and a PIK3CA mutation (E726K) with an allele frequency of 23%.

For further staging diagnostics, CT scan of the abdomen revealed a singular liver metastasis (1.5 × 1.2 cm). Brain MRI revealed no evidence of brain metastases. Bone scintigraphy showed no sign of bone metastases. PET-CT was not performed due to a lack of therapeutic consequence and high therapeutic pressure.

Transfer to the Department of Hematology, Oncology, Palliative Medicine, and Stem Cell Therapy for initiation of immunochemotherapy with carboplatin (cycle 1: 2 AUC = 223 mg abs.; cycle 2–4: 4 AUC = 350 mg abs.) and pembrolizumab (200 mg abs.) with omission of pemetrexed in the setting of high therapeutic pressure and lack of premedication with folate and vitamin B12 was performed. Absence of pemetrexed was maintained during the course due to reduced general condition (initial ECOG 3).

After four cycles had been performed, the patient presented externally through emergency room with passager hemiparesis of the right arm and focal seizures. Emergency CT scan revealed the initial diagnosis of symptomatic brain metastases (Fig. 2). Restaging by CT of the thorax and abdomen showed a significant remission of the effusion with only residual findings present (Fig. 2); there was no evidence of further distant metastases. In case of disconcordant response with regredience of local findings but new brain metastases and reduced general condition, immunochemotherapy was discontinued and therapy with KRAS inhibitor sotorasib was initiated with proven G12C-KRAS mutation after completion of brain radiation. Under clinical controls during the course, the patient showed increasing agitation with restlessness and progressive cognitive deficits. Full-day care by the family was necessary in the meantime. Planned cMRI examination 8 weeks after the start of therapy had to be canceled due to severe restlessness. A CCT scan performed instead showed progression of the brain metastases described before (Fig. 3).

Due to the clinical and morphological progression and the patient’s inability to take oral medication, we decided in consultation with the patient’s family against continuing sotorasib therapy after 48 days of being on drug and in favor of a best supportive care concept in the home environment. The patient died approximately 2 weeks after discontinuation of therapy and 6 months after initial diagnosis.

Sarcomatoid-differentiated lung carcinomas, known as a rare subgroup of non-small cell lung carcinomas, are overall associated with a significantly worse prognosis compared to other NSCLCs [6]. This can be seen in two characteristics in particular: first, PSC tumors tend to metastasize rapidly, sometimes atypically. Ma et al. [7] presented a case with gastrointestinal bleeding in an ileum metastasis and peritoneal carcinomatosis after surgical resection of the PSC 6 months earlier. Another case showed primary diagnosis of PSC due to oral mandibular metastasis, with hematemesis as the primary reason for presentation [8].

Second, it can be attributed to a relative resistance of the tumors to radiochemotherapy. In this case, although there was a good pulmonary response to the initiated chemotherapy with clear regression of the tumorous pleural effusion, there were also clinical and CT morphological signs of rapid progression in the sense of symptomatic cerebral metastases. The additional immunotherapy with pembrolizumab also showed no significant effect on the brain metastases. The switch to sotorasib also showed no relevant therapeutic success. The patient’s preexisting neurological symptoms persisted, and the metastases progressed morphologically.

The patient’s failure to respond to therapy with sotorasib, despite the presence of the G12C-KRAS mutation, emphasizes the special character of sarcomatoid-differentiated lung carcinomas. Other NSCLCs show a significantly better response to the KRAS inhibitor sotorasib with regression or stabilization of tumor disease when KRAS mutation is present [9]. 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/10.1159/000540675).

PSCs, previously listed as a histologic subgroup of NSCLC, although frequently associated with KRAS mutation (G12C), might not be good candidates for molecular targeted therapy with sotorasib, but further clinical research is needed to evaluate the therapeutic efficacy in these patients.

Written informed consent was obtained from next-of-kin of the patient for publication of the details of their medical case and any accompanying images. Ethical approval is not required for this case report in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

The authors received no funding relevant to this case report.

J.F.S. and D.E. – medical treatment and case preparation. F.B. – histopathologic classification. M.G. – case preparation and supervision.

The data that support the findings of this article are available in PubMed at https//pubmed.ncbi.nlm.nih.gov/or as described in the reference list. Further inquiries can be directed to the corresponding author.