PPLELC is a rare subtype of NSCLC. In this era of targeted therapy and checkpoint inhibitors for non-small cell lung cancer, anti-angiogenic drugs still play an important role23. However, the prognosis of advanced PPLELC is poor, due to the lack of drug treatment data, the role of anti-angiogenic therapy in PPLELC is unknown. It is worth exploring the effect of anti-angiogenic therapy in PPLELC.
Induction of angiogenesis is one of the 10 characteristics of malignant tumors. Angiogenesis provides essential nutrients for tumor growth and is an important prerequisite for tumor hematogenous dissemination. The ECOG-4599 study established the status of bevacizumab combined with first-line chemotherapy24. Small molecule TKI drugs targeting angiogenesis have become one of the research hotpots in recent years. The biggest feature of small molecule drugs is that their target coverage is more comprehensive. In addition to VEGF/R and other pathways, they can also cover PDGF/R, FGF/FGFR and other pathways.
In this study, a patient with FGFR3-TACC3 fusion was reported. In general, operable FGFR3 gene fusion is found relatively commonly in glioma and bladder cancer25, FGFR3-TACC3 fusion has been reported in 2.5% of NPC26. However, FGFR3 alteration was rarely observed in NSCLC, and was detected in 0.1% of adenocarcinomas and 0.6% of squamous cell carcinomas, respectively2728. The prevalence of FGFR3 in LELC was 4%29. FGFR3-TACC3 is reported to be a relapsing drug resistance mechanism that can bypass EGFR blockade by all generations of EGFR TKI in NSCLC30. In this study, FGFR3-TACC3 fusion patients were treated with small molecule multi-target TKI, which inhibited VEGFR, PDGFR, FGFR and c-Kit targets, showing anti-tumor angiogenesis and tumor growth inhibition. PFS benefits were obtained in combination with chemotherapy, suggesting that FGFR3 aberrations may represent an opportunity to target therapy in PPLELC .
However, anti-angiogenic therapy alone does not significantly improve patient outcomes, as the removal of blood vessels transforms tumor cells into a hypoxic-tolerant phenotype. Combination of anti-angiogenic therapy with other therapies, including chemotherapy, radiotherapy, immunotherapy and anti-epidermal growth factor receptor (EGFR) therapy, has good efficacy due to the vasonormalization effect induced by anti-angiogenic agents31. Radiation alone as the sole means of treating cancer often triggers the angiogenesis pathway, leading to upregulation of multiple angiogenic growth factors, and anti-angiogenic inhibitors can help overcome this fact32. Randomized Phase III studies have also shown that treatment with antiangiogenic agents in combination with PD-L1 antibodies significantly improves survival compared with standard therapy in RCC, NSCLC and HCC. However, there are still many problems to be solved, such as how to choose a more reasonable combination partner for anti-angiogenic therapy, the timing, recommended dosage and the proportion of anti-angiogenic inhibitor combination therapy31. In this study, anti-angiogenic therapy combined with chemotherapy in patients with advanced PPLELC was included. The results showed that compared with chemotherapy alone, it can improve the short-term efficacy of patients. It is well known that immunotherapy can improve the long-term prognosis of patients. If anti-angiogenic combined with immunotherapy and chemotherapy is a better choice, it is worth further exploration.
Our study found that anti-angiogenic therapy combined with chemotherapy was more beneficial than chemotherapy alone in patients with advanced PPLELC, but there was no way to screen the dominant population, and some patients did not respond to anti-angiogenic therapy combined with chemotherapy. Both targeted therapy and immunotherapy have corresponding markers to accurately identify the population, but there is no recognized marker in the field of anti-angiogenic therapy. Bevacizumab is a monoclonal antibody with a clear target of VEGF, so it is logical that VEGF expression might predict benefit. However, clinical studies have found that VEGF expression does not predict the benefit of bevacizumab addition33. The tumor vasculature is a target for antiangiogenic drugs, but quantitative or qualitative measures of the vasculature cannot be used as biomarkers of efficacy because there is no standardized method for measuring microvessel density and there is considerable potential for selection and observer bias. The detection of vascular phenotype and tumor cell genotype is still in the stage of preclinical research34. Compared to using the tissue biomarkers to select effective anti-angiogenic drugs, the studies of discover and validation in the non-invasive, dynamic biomarker were at a more advanced stage, including measuring the circulating protein related to angiogenesis, circulating micrornas, secrete body outside, circulating endothelial cells and or estimates of progenitor cells and vascular imaging35.
Our study has some limitations. This study was from a retrospective cohort and the number of included patients was limited. This is due to the rarity of PPLELC and the small number of patients, even fewer patients in the advanced stage of metastasis. Moreover, the emergence and application of different anti-angiogenic drugs in clinical practice will affect the results. Differences in patients' chemotherapy regimens also affected the results. However, this study firstly reported the value of anti-angiogenic therapy in advanced PPLELEC. Data were collected from multiple centers in this study, and patients came from areas with high PPLELC incidence, which has certain advantages.
In conclusion, compared with the current treatment of patients with advanced PPLELC, anti-angiogenic therapy is clinically beneficial and sufficiently safe, and the number of patients should be further expanded or the follow-up period extended to further observe the survival benefit.