PSC is a highly malignant and extremely heterogeneous tumor that falls under the category of NSCLC, exhibiting characteristics of both epithelial and mesenchymal tissue (1). It represents 1% of the overall incidence of NSCLC (2). According to the 2015 WHO classification of lung tumors, PSC can be categorized into five subtypes: pleomorphic carcinoma (PC), spindle cell carcinoma (SCC), giant cell carcinoma (GCC), carcinosarcoma (CS), and pulmonary blastoma (PB) (3). The prevalence is higher in elderly males, heavy smokers, as well as individuals exposed to dusty, chemical, or radiative environments for prolonged periods. Clinical presentations are primarily associated with tumor size, growth location, and local invasion. Tumors situated in the hilar region may lead to obstructive pneumonia or atelectasis with accompanying symptoms such as coughing, sputum production, hemoptysis, dyspnea and fever. Tumors located in the periphery of PSC patients typically present with either mild or no symptoms, but as the tumor progresses and infiltrates the pleura, it can lead to chest pain (4). The treatment principles for PSC align with those for other types of NSCLC; however, the therapeutic efficacy is suboptimal, and there is a high propensity for recurrence and metastasis. Among the 7,965 PSC patients statisticed by the US National Cancer Database from 2001 to 2011, the median survival for Stage I-II PSC was 16.9 months, for Stage III was 5.8 months, and for Stage IV was 5.4 months (5). Therefore, PSC urgently needs new treatment modalities to maximize its clinical benefits.

In recent years, significant progress has been made in the field of molecular targeted therapy for NSCLC, particularly in the research of molecular markers for PSC. These breakthroughs have provided a solid foundation for targeted treatment of PSC, offering new hope to patients. There have been documented cases of successful application of targeted drugs for PSC (6–8). Furthermore, immunotherapy has also advanced notably in the realm of lung cancer. Immune checkpoint inhibitors (ICI) such as PD-1 and PD-L1 blockers have demonstrated efficacy by activating the body’s immune system while impeding immune checkpoint functions, enabling T cells to combat tumor cells (9). ICI have received approval for multi-line treatment of NSCLC. The positive rate and expression level of PD-L1 in PSC are significantly higher than those observed in other forms of NSCLC, suggesting that PSC patients may derive benefits from immune checkpoint inhibitors (10). Reports indicated that the use of ICI holds promise for advanced PSC (11, 12). For resectable NSCLC, targeted therapy or immunotherapy has become an important strategy for perioperative treatment (13, 14). However, for resectable PSC, there have been no relevant studies. We present the treatment outcomes of four patients with locally advanced PSC who underwent neoadjuvant immunotherapy combined with platinum-based chemotherapy, all of whom successfully achieved R0 resection and demonstrated significant therapeutic benefits. Additionally, we report the latest advancements in targeted therapies and immunotherapies for PSC

This study followed the guidelines of the Helsinki Declaration. The study protocol was reviewed and approved by the institutional review board and ethics committee of Shandong Cancer Hospital and Institute. Before treatment, all patients were provided with informed consent forms. The medical records were reviewed through the institution’s query system.

In comparison to NSCLC, PSC has a worse prognosis. A study utilizing surveillance, epidemiology, and end results databases tracked the prognosis of patients with PSC and found that this disease had significantly poorer overall and disease-specific survival compared to the population of conventional non-small cell lung cancer patients (15). Another extensive study using the National Cancer Database (NCDB) yielded similar unfavorable prognostic outcomes: it reported that the median survival period for PSC patients (6.4 months) was approximately half that of other non-small cell lung cancer patients, and this disparity in survival rates was statistically significant across all stages (5). Due to its rarity, research progress on PSC lags far behind other types of NSCLC. Given the bleak prognosis and lack of clear treatment guidelines, clinicians adopted a more pessimistic outlook on treatment and prognosis (16). Currently, evidence-based treatment strategies for PSC primarily consist of traditional methods such as surgery, radiotherapy, and chemotherapy.

A substantial number of PSC patients harbor targeted genomic mutations. Zhou et al. (12) conducted targeted gene analysis on 58 Chinese PSC patients, revealing gene mutations in 53 (91.4%) of them. Among the 175 patients included by Stephan-Falkenau et al., 61 (34.9%) had drug-accessible gene mutations (17). Reported gene mutations in PSC include TP53, KRAS, MET, EGFR, ALK, BRAF, PIK3CA, CDKN2A and PTEN. TP53 and KRAS exhibit a higher frequency of mutations in PSC, yet no targeted therapies have been reported for these two targets (12). There have been reports of PSC targeted therapies for MET, EGFR, ALK, and BRAF gene mutations. The MET14 exon skipping mutation is considered an adverse prognostic factor for advanced PSC patients. A multicenter clinical trial evaluating the efficacy of sevotinib in the treatment of NSCLC patients with MET14 exon skipping mutation enrolled 25 PSC patients, demonstrating an objective response rate of up to 40% and a median response duration of 17.9 months, a median progression-free survival (PFS) of 5.5 months, and mostly grade 1-2 treatment-related adverse reactions (6). This finding suggests that sevotinib demonstrates favorable efficacy and safety in PSC patients with MET14 exon skipping mutation. Currently, targeted therapies for EGFR, ALK, and BRAF targets are limited to case reports and have shown good clinical effects (7, 18–20). The patient in case 1 was found to have ROS1 rearrangement and TP53 mutation. ROS1 rearrangement in PSC has been rarely reported. C. Xu et al. included a total of 35 PSC patients, among whom three were detected to have ROS1 rearrangements by reverse transcription polymerase chain reaction. The incidence of ROS1 rearrangement in Chinese PSC patients was found to be higher than that in other subtypes of NSCLC. Crizotinib may represent an effective treatment option for ROS1 rearrangement-positive PSC (21). In case 1, the patient exhibited tumor progression during treatment with crizotinib. Previous studies have demonstrated that co-mutations of TP53 with ROS1 or EGFR significantly diminish the efficacy of targeted therapies (22). We believe that the patient developed primary resistance to crizotinib due to the coexistence of TP53 mutation. Given that TP53 mutation (74%) are common in PSC (12), the efficacy of targeted therapy may be lower compared to other types of NSCLC. Further research is warranted to identify the specific population that can benefit from targeted therapy in the future.

Biomarkers play an important role in predicting the efficacy of immunotherapy. We assessed the potential value of immunotherapy in PSC by analyzing the expression of biomarkers in PSC. PD-L1 expression currently stands as the most well-established biomarker for predicting the response and clinical efficacy of ICI in NSCLC (23). Similar to other NSCLC, high expression of PD-L1 is associated with better treatment outcomes (24). Babacan et al. (25)] analyzed the efficacy of ICI in 66 PSC patients with PD-L1 expression, with an objective response rate of 70.2% for 49 patients with PD-L1≥50%, a 50% objective response rate for 10 patients with PD-L1 of 1% to 49%, and a 28.6% objective response rate for 7 patients with PD-L1<1%. In a study of 22 patients with PSC exhibiting PD-L1 expression of ≥50%, pembrolizumab monotherapy demonstrated an objective response rate and disease control rate of 68.2% and 81.8%, respectively, indicating the potential efficacy of immune monotherapy for high PD-L1 expressing PSC (26). To our surprise, the positive rate and high expression rate of PD-L1 in the PSC were significantly higher than other NSCLC. Lee et al. (27) studied 125 PSC patients for PD-L1 expression, with 89.6% (112/125) testing positive and 80.0% (100/125) showing high levels of expression. Ma et al. (28) analyzed 32 PSC patients, observing that 59.4% (19/32) expressed PD-L1 positively, while 34.4% (11/32) exhibited greater than 50% expression. Due to the tendency of high expression of PD-L1, we believe that ICI has a broad application prospect in PSC patients. However, in clinical practice, some patients with high PD-L1 expression do not respond to immunotherapy, and in fact, some may even experience hyperprogression (HPD). Fricke J et al. (29) reported a case of advanced NSCLC patient with 100% PD-L1 expression who experienced HPD after two cycles of pembrolizumab treatment, which was controlled by chemotherapy and allowed for long-term stability. Oguri T et al. (30) reported a case of advanced PSC patient with high PD-L1 expression (90%) who died of HPD 13 days after receiving atezolizumab. PD-L1 expression alone may not reliably predict the efficacy of immunotherapy.

Gene mutations also frequently serve as crucial biomarkers for the effectiveness of immunotherapy. Fricke J et al. thought HPD of PSC may be associated with STK11 mutation (29). A recent study has shown that there is an association between STK11 and HPD in NSCLC patients, with (3/16) of the patients with HPD having STK11 mutations, while (0/28) of the patients without HPD were not found to have STK11 mutations (31). STK11 mutation have been linked to a diminished response to immunotherapy and poor prognosis (32). In addition to STK11 mutation, ICIs have limited efficacy for NSCLC with EGFR, HER2, ALK, ROS1, MET or RET mutations (33, 34). ICIs show good efficacy for NSCLC with TP53 gene mutations in NSCLC. Wu et al.’s study showed that patients with TP53 mutations had higher tumor mutation burden (TMB) and PD-L1 expression levels than those with wild-type TP53, and were associated with better median PFS (35). High prevalence of TP53 gene mutations in PSC suggest that immunotherapy may confer substantial clinical benefits to patients. Single KRAS gene mutation does not exhibit a significant correlation with the efficacy of immunotherapy except for PD-L1 is highly expressed (36, 37). However, co-mutations of KRAS and TP53 have been shown to enhance the efficacy of immunotherapy in NSCLC. A study of 696 patients with NSCLC who received pembrolizumab as first-line treatment revealed that the co- mutation of TP53 and KRAS G12C was associated with the longest PFS and OS, surpassing outcomes associated with single mutation or wild-type status (38). Terra SB et al. included 33 PSC patients in their study and found that 6 of them had a TP53/KRAS co-mutation (18%) (39).

TMB is an emerging biomarker for immunotherapy, in addition to PD-L1 expression. The correlation between PD-L1 expression and TMB is not significant in lung cancer, and assessing TMB can expand the patient population that may benefit from immunotherapy. In the CheckMate-026 study, high TMB ((10 variants/Mb) NSCLC patients receiving Nivolumab as first-line treatment demonstrated an ORR of 47%, compared to only 28% for those receiving chemotherapy, with a median PFS of 9.7 months and 5.8 months respectively. Conversely, middle and low TMB patients showed significantly worse median PFS when receiving immunotherapy compared to chemotherapy (40). Schrock et al. observed that more than 60% of patients with PSC exhibit high TMB (20). The median TMB in PSC is 8.1 mutations/Mb (12), with 37.9-87.5% of Chinese PSC patients having high TMB (12, 41). This suggests that PSC may benefit from ICIs.

Currently, the effect of immunotherapy in advanced PSC is very significant. Domblides et al. (42) observed that among 37 PSC patients who received nivolumab as a second-line or beyond second-line treatment after platinum-based chemotherapy, irrespective of PD-L1 status, there was an objective response rate of 40.5% and a disease control rate of 64.8%, with median OS of 12.7 months. Babacan NA et al. (25) reported that among the 90 PSC patients who received immune checkpoint inhibitor treatment, the rate of complete remission (CR) and partial remission (PR) was 54.5%, and the rate of disease stability (SD) was 15.9%, while the rate of disease progression (PD) was 29.6%. The median progression-free survival (PFS) was 7.0 months. Immunotherapy mainly consists of two modes: single-agent immunotherapy and combined immunotherapy alongside chemotherapy. Nevertheless, multiple clinical trials like KEYNOTE-024 have demonstrated that single-agent immunotherapy confers clinical benefits exclusively on patients exhibiting high PD-L1 expression (43–45). Consequently, it is apparent that standalone immunotherapeutic interventions are inadequate in addressing clinical needs. The combination of immunotherapy and chemotherapy has demonstrated superior efficacy compared to the use of immunotherapy alone, conferring benefits to patients irrespective of their PD-L1 expression level (46–49). Studies like Checkmate-816 and Keynote-671 have shown that immunotherapy combined with chemotherapy has a significant effect in resectable NSCLC, with high PCR rates and longer EFS (13, 14). In the Rationale 315 study, the combination of tislelizumab with chemotherapy achieved a PCR rate of up to 40.7% and an MPR rate of up to 56.2%, while significantly reducing the risk of disease recurrence and progression (HR for EFS: 0.56, 95% CI: 0.40-0.79). Additionally, it showed good tumor shrinkage, with an objective response rate of 71.2%, thereby reducing the difficulty of surgery (50). Given its significant therapeutic effect, we applied this treatment pattern to patients with locally advanced PSC. After the progression of the tumor on crizotinib therapy in case 1, we decided to initiate the treatment regimen of tislelizumab combined with chemotherapy. After 2 cycles of this combination therapy, a significant reduction in chest pain was observed in this patient, leading to an enhancement in their quality of life. Simultaneously, tumor downstaging occurred, reducing surgical complexity. The patient’s PCR test results indicated a high likelihood of survival. Currently, The EFS has surpassed 36 months, while the DFS after surgery has exceeded 32 months. Encouraged by the remarkable success achieved with neoadjuvant immunotherapy combined with chemotherapy in this case, we subsequently administered this regimen to three patients. Among them, 2 patients achieved complete pathologic response (MPR) and 1 patient achieved partial response (PR), with no evidence of recurrence detected during postoperative follow-up; Neoadjuvant immunotherapy combined with chemotherapy holds promise as a strategy for treating resectable PSC. However, due to its low incidence and limited surgical opportunities further prospective multicenter studies are warranted to validate ICI efficacy.

Given the high mutation rate of TP53 in PSC, the effectiveness of targeted therapy may be limited; thus, further research is essential to identify specific patient populations that could benefit from such interventions. Biomarkers including PDL1, TMB, and TP53 are significantly elevated in PSC, indicating substantial potential for immune checkpoint inhibitors in clinical applications. A combination of neoadjuvant immunotherapy and chemotherapy may be a promising strategy for treating potentially resectable PSC. However, its effectiveness and safety still need to be validated in the future.