1. Background

Pulmonary sarcomatoid carcinomas (PSC) is a highly heterogeneous non-small cell lung cancer (NSCLC) with very rare incidence (about 0.1–0.4%) and extremely high malignant degree. It has strong invasion, poor prognosis, easy postoperative recurrence and non-specific clinical manifestation. PSC has poor sensitivity to chemoradiotherapy. With the rapid development of targeted drugs and immune checkpoint inhibitors in tumor treatment, the treatment of pulmonary sarcomatoid carcinoma is gradually exploring the field of precise targeted therapy and immune therapy ^[1–2].

2. Molecular Characteristics

Domestic scholars have conducted research and analysis on the molecular characteristics of PSC patients ^[3]. 28% of PSC patients carry EGFR mutation, but most of the mutations are rare mutations (such as D1014G, V845M, G485S, K757R, L861Q, etc.), and 22% of PSC patients carry KRAS activation mutation, including G12C/V and Q61K. MET mutations are present in 16% of patients with PSC and mainly include exon 14 skip mutations of the MET gene (MET 14 skip), 13del, and H904N (Figure 1).

Fig. 1. Mutation map of pulmonary sarcomatoid carcinoma in the China population

In this study, Kwon HJ included 31 patients with PSCs ^[4], of which 11 cases had both primary and metastatic tissues. All samples from the above patients were subjected to whole exon sequencing, as well as PD-L1 immunohistochemistry and digital PCR-based MET 14 skip detection. The results showed that TP53 was the most common mutated gene in primary (77%) and metastatic (73%) foci, and operable mutations such as EGFR (29%), KRAS(6%),ALK(6%), and MET exon 14 skip mutation (19%) were detected in approximately one-third of patients with primary PSC. Among them, jump process of MET 14 and TP53 mutation have mutual exclusion relationship. The MET 14 skip was usually accompanied by MDM2 amplification (Figure 2).

Figure 2. Mutation map of sarcomatoid carcinoma of the lung.

Whole exon group sequencing results of primary lesion (A) and metastatic lesion (B).

In conclusion, the mutation rate of MET in PSC is obviously higher and the expression of PD-L1 protein is stronger than other types of lung cancer.

3. Targeted Therapy

Alterations of the MET gene, including the MET 14 apophysis and the amplification and overexpression of the MET gene. The MET 14 skip mutation is the most common and well studied mutation type. Furthermore, the existing clinical data confirm the efficacy of MET-TKI in the treatment of PSC patients with MET changes. The proportion of PSC patients enrolled in the clinical registration study of sevotinib is the largest to date. Seventy patients with advanced NSCLC with MET ex14 jump mutation are included, and the proportion of PSC patients is 36%. The results, which showed PFS of 5.5 months and OS of 10.6 months after treatment with sevotinib in the PSC subgroup, confirmed that sevotinib provides a solid and reliable treatment option for PSC patients ^[5].

In its research, Tsuda T evaluated the efficacy of targeted therapy between different driving genes ^[6]. Among the five patients with driver variation, PFS was 1.3 months and 1.6 months in two patients treated with gefitinib, respectively. The PFS of two patients with ALK fusion variation were 2.1 and 14.0 months after treatment with crizotinib and 9.7 months after treatment with tiptoeing 1 patient with MET 14.

The response of different gene mutations to targeted therapy is different, and the therapeutic effect varies from individual to individual. Currently, targeted therapy for pulmonary sarcomatoid carcinoma is still being explored and further research is needed to identify more effective treatment options.

4. Immunotherapy

Given the high expression of PD-L1 in the PSC, immunotherapy may provide additional prognostic protection for this rare subtype. A multi-center study in China evaluated and analyzed the efficacy of immunization and immunotherapy in PSC ^[7].

Fig. 3.  113 Immunotherapy protocol and survival analysis results of PSC patients

The median follow-up time for 113 patients with PSC was 12 months, and the median PFS was 8.77 months. Of these patients, 43 (38.1%) experienced PR, 51 (45.1%) experienced SD, and 16.8% experienced PD with ORR and DCR of 38.1% and 83.2%, respectively (Figure 3). A significant increase in PFS (p = 0.04) was noted with ICIs in combination with anti-angiogenic agents when compared among the treatment outcomes of the different subgroups (Figure 4c).

^{Figure 4. Comparison of survival differences between treatment strategies. Group}

^{A: patients who received ICI alone; Group B: ICI+chemotherapy; Group C: ICI+anti-angiogenic therapy; Group D: therapeutic spectrum of ICI+chemotherapy+anti-angiogenic therapy. Whole exon group sequencing results of primary lesion (A) and metastatic lesion (B).}

5. Summary And Prospect

PSC is a rare pathological type of NSCLC. However, its biological and clinical characteristics are different from those of other types of NSCLC. The carcinoma is insensitive to conventional chemoradiotherapy and has a poor prognosis. With the development of molecular biology, targeted therapy and immunotherapy are gradually emerging in the field of PSC, which also indicates that the treatment of PSC begins with the precision treatment mode and provides the basis for subsequent large-scale clinical research.

References

[1]Gong T, Jia B, Chen C, Zhang Z, Wang C. Clinical analysis of 78 pulmonary sarcomatoid carcinomas with surgical treatment. J Int Med Res. 2022 Oct; 50(10):3000605221128092.

[2]Zhang WH, Lin J. Advances in the diagnosis and treatment of pulmonary sarcomatoid carcinomas [J]. J Cancer Control Treat, 2023,36(9)：732-737.

[3]Liang X, Li Q, Xu B, Hu S, Wang Q, Li Y, Zong Y, Zhang S,  Li C. Mutation landscape and tumor mutation burden analysis of Chinese patients with pulmonary sarcomatoid carcinomas. Int J Clin Oncol. 2019 Sep; 24(9):1061-1068. 

[4]Kwon HJ, Lee S, Han YB, Lee J, Kwon S, Kim H, Chung JH. Genomic Landscape of Pulmonary Sarcomatoid Carcinoma. Cancer Res Treat. 2024 Apr; 56(2):442-454.

[5]Gong C, Xiong H, Qin K, Wang J, Cheng Y, Zhao J and Zhang J (2022) MET alterations in advanced pulmonary sarcomatoid carcinoma. Front. Oncol. 12:1017026.

[6]Tsuda T, Ichikawa T, Matsumoto M, Mizusihima I, Azechi K, Takata N, et al. An observational study on the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma. Discov Oncol. 2024 Aug 29; 15(1):382.

[7]Xie M, Chu T, Dong X, Wang H, Chu Q, Cai X, Wang J, Yao Y, Wu L, Ye F, Zhu B, Zhou C,  Su C. Heterogeneity in advanced pulmonary sarcomatoid carcinoma and its efficacy to immune checkpoint inhibitors. Eur J Cancer. 2024 Sep; 209:114260. 

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