Recent advancements in gene sequencing technology including next-generation sequencing (NGS) have shed light on the similarities between PSC and traditional NSCLC (8). These shared characteristics, including a common origin in epithelial cells and similar immune profiles, suggest targeted therapy might benefit PSC patients who don’t respond well to standard treatments.
While the effectiveness of sevotinib for PSC patients with specific MET gene mutations is well-established, targeted therapies for other mutations like EGFR, ALK, BRAF V600E, and RET mutations rely mainly on case report evidence (9, 10).
This case report describes a patient with PSC harboring two previously unreported mutations: TP53 V157F and RET P766K. The TP53 V157F mutation is a known “lung-enriched mutation” occasionally found in lung adenocarcinoma and squamous cell carcinoma (11). Importantly, neither the TP53 V157F nor the RET P766K mutation has been documented in PSC patients before, and there are currently no available targeted drugs specifically designed for these mutations.
The PD-1/PD-L1 pathway and rationale for immunotherapy in PSC
The PD-1/PD-L1 pathway plays a critical role in maintaining immune homeostasis by preventing excessive inflammation and autoimmune responses (12, 13). However, tumor cells can exploit this pathway to evade immune attack through the interaction between PD-1 and PD-L1 (14). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, such as anti-PD-1 antibodies, can restore the anti-tumor activity of T cells by blocking this interaction.
PSC demonstrates higher PD-L1 expression compared to other NSCLC subtypes (8, 15). This case report highlights this observation with a tumor proportion score (TPS) of 90% for PD-L1 expression. Emerging evidence suggests the potential efficacy of anti-PD-1 antibodies in treating advanced or metastatic PSC (16, 17).
Rationale for the treatment regimen
Tislelizumab, an anti-PD-1 IgG4 antibody, is specifically engineered to minimize Fcγ receptor-mediated macrophage binding, thereby reducing T cell depletion through antibody-dependent cellular phagocytosis (ADCP) (22). It boasts a higher affinity for PD-1, a slower dissociation rate, and potentially enhanced anti-tumor activity (22).
Anlotinib is a novel, orally administered tyrosine kinase inhibitor with a broad-spectrum inhibitory effect on tumor angiogenesis and growth (23). It additionally enhances the efficacy of anti-PD-1 immunotherapy by promoting tumor vascular normalization and reversing the immunosuppressive TME (24). At the same time, effector T cells, revitalized following anti-PD-1 immunotherapy, reinforce tumor vascular normalization by enhancing IFN-γ and other pathways, which extends the therapeutic window of anlotinib’s vascular normalization properties (24). Consequently, a positive feedback loop is established, potentially amplifying the anti-tumor effects of both drugs.
A recent study by Qian et al. (17) demonstrated promising results with the combination of tislelizumab and anlotinib in PSC patients. Notably, two patients achieved PR, and four achieved SD. Building on this emerging evidence, the patient in this case report received this same combination (“tislelizumab + anlotinib”) as second-line therapy. Following the first cycle of treatment, chest scans revealed a significant decrease in tumor size and a substantial improvement in the patient’s ability to perform daily activities (KPS score). This indicated a near-partial response based on standard evaluation criteria. Subsequent chest scans confirmed continued tumor shrinkage, solidifying the PR classification.
ICIs can cause adverse effects, with checkpoint inhibitor pneumonitis (CIP) being the most common pulmonary toxicity, especially in patients with NSCLC (25). It’s a serious adverse effect, sometimes fatal, that typically occurs early in treatment with anti-PD-1 antibodies (26). A case reported by Facchinetti et al. linked rapid tumor shrinkage from immunotherapy to fatal hemoptysis in a patient with central lung cancer (27). This case highlights a potential risk but differs from the current case, where the patient received tislelizumab for several cycles with significant tumor shrinkage before experiencing hemoptysis. Combining anti-PD-1 antibodies with anlotinib appears safe in solid tumors like NSCLC, with no increased adverse effects compared to using either medication alone (28, 29). However, anlotinib, an anti-angiogenic drug, can weaken blood vessels and hinder wound healing by affecting blood vessel formation, platelet function, and blood clotting, especially in tissues that rely heavily on a protein called VEGF, like the airway lining (30, 31), as supported by studies showing anlotinib increases hemoptysis risk (32). In this case, the patient developed hemoptysis after anlotinib treatment. While the drug’s information and literature suggest a potential link, the absence of a definitive cause is due to no autopsy being performed. Additionally, the patient’s death prevents further testing. While ongoing CT scans showed tumor improvement, other potential causes of hemoptysis, like bleeding directly from the tumor, cannot be completely ruled out. Therefore, the hemoptysis is classified as “possibly related” to anlotinib with a score of 2 on the Naranjo scale. But this case highlights the importance of heightened awareness of hemoptysis risk, especially for patients with centrally located PSC treated with anlotinib. Hemoptysis risk should be continuously monitored throughout treatment. Interestingly, some studies suggest high-dose anti-angiogenic agents may worsen oxygen and acidosis within the tumor, potentially harming immune cells (33). Conversely, lower doses of anlotinib may normalize tumor blood vessels, potentially improving the safety and effectiveness of anti-PD-1 immunotherapy (34). This suggests a need for large-scale clinical trials to optimize anlotinib dosage in combination with ICIs.
In a word, this study reinforces the promising anti-tumor efficacy of combining anti-PD-1 antibodies with anlotinib for treating PSC patients. However, this case also underscores the importance of careful patient selection and risk assessment for anti-angiogenic therapy. Future research efforts should focus on optimizing combination therapies for PSC, with an emphasis on developing regimens that are both efficacious and have minimal toxicity profiles.