SCLC has an abnormally high proliferation rate, a strong tendency for early metastasis, and a bleak prognosis. As the first-line standard treatment for ES-SCLC in the past 40 years, the PFS of platinum-etoposide chemotherapy is about 5 months, and the median OS is about 10 months. Based on the IMpower133 and CASPIAN clinical trials, PD-L1 plus platinum-etoposide chemotherapy has become the new first-line standard therapy in recent years. Although, it only brought the OS benefit for 2 to 3 months[7, 8]. Angiogenesis serves a pivotal role in tumor occurrence, invasion, and metastasis. However, the efficacy of antiangiogenic therapy in SCLC is limited, such as bevacizumab, sorafenib, sunitinib and so on, except for anlotinib[17–20]. In China, anlotinib has been approved by CFDA as the third-line and above treatment for SCLC based on the ALTER 1202 study. Several small sample size single arm phase II clinical trials of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC are being carried out in China and the preliminary results have shown the favorable clinical efficacy[13–15].
Antiangiogenic therapy can improve drug delivery efficiency by opening the vascular normalization window, thus exerting a synergistic effect when combined with other regimens. In addition, the non-overlapping toxicity spectrum and excellent tolerance of anlotinib allow it to be used in combination with other drugs. In Kong T’s clinical study, 20 ES-SCLC patients received anlotinib plus platinum-etoposide chemotherapy as the first-line therapy, the median PFS was 10.0 months, and the median OS was 15.0 months. Similarly, in Deng P’s study, the median PFS and OS were 9.4 and 13.9 months, respectively. Supported by these encouraging preliminary results, phase III clinical trials have already begun in China. In this real-world study, the median PFS was 6.0 months, the median OS was 10.5 months, the ORR was 58.6%, and the DCR was 89.6%. Our results are similar to the efficacy of traditional platinum-etoposide chemotherapy. But 20 (34.5%) patients with ECOG PS 2 were included in this study. In contrast, there were no patients with ECOG PS >1 in these clinical trials. The median PFS and OS of patients with ECOG PS 0-1 in this study were 8.5 and 15.0 months, respectively. Multivariate Cox regression analysis showed that ECOG PS was the independent influencing factor of PFS and OS. This result showed better efficacy compared with traditional chemotherapy and PD-L1 plus chemotherapy, and the OS was similar to the clinical studies of anlotinib plus platinum-etoposide chemotherapy. Since there is no control group in our study, the efficacy of combination therapy still requires further verification by prospective studies with larger sample size.
ES-SCLC patients first receive chemotherapy to control the spread of metastasis. Subsequently, chest radiotherapy is recommended to control local lesions for patients who achieve CR or PR after chemotherapy. Some studies found that antiangiogenic therapy can increase the local oxygen partial pressure and oxygen content of tumor tissue, inhibit the angiogenesis induced by radiotherapy, and play the role of radiotherapy sensitization. In our study, patients combined with radiotherapy had more extended PFS (8.3 vs. 4.2 months, P =0.002) and OS (16.8 vs. 7.7 months, P <0.001) benefits in univariate analysis. However, there were no statistical differences in multivariate analysis.
Hypertension and hand-foot syndrome are the most common adverse reactions of anlotinib. Interestingly, more extended PFS benefits were observed in ES-SCLC patients with post-medication hypertension or hand-foot syndrome in Song PF’s study. In this research, patients with post-medication hypertension (8.5 vs. 5.4 months, P =0.008) and hand-foot syndrome (8.5 vs. 5.5 months, P =0.040) had longer PFS benefits in univariate analysis. Additionally, we also found that patients with post-medication hypertension (15.9 vs. 8.3 months, P <0.001) had longer OS benefits. Multivariate analysis showed that post-medication hand-foot syndrome (yes vs. no: HR=0.23, 95%CI 0.07-0.72, P =0.012) was the independent predictor of PFS, and post-medication hypertension (yes vs. no: HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS.
Furthermore, we observed that sex (male vs. female: HR=6.05, 95%CI 1.74-20.98, P =0.005) and T stage (T3-4 vs. T1-2: HR=3.82, 95%CI 1.59-9.18, P =0.003) were the independent influencing factors of PFS. Age (≥65 vs. <65: HR=4.87, 95%CI 1.71-13.82, P =0.003) and hepatic metastases (yes vs. no: HR=3.83, 95%CI 1.41-10.41, P =0.008) were associated with OS in multivariate Cox regression analysis. However, only 11 (19.0%) female patients were included in our study, which might influence the result.
In this research, the toxicity of anlotinib plus platinum-etoposide chemotherapy was generally well tolerated. The grade 3 and above adverse reactions were manageable with dose reduction or drug discontinuation. Similar to previous research, myelosuppression was the most frequent adverse reaction[13–15]. As the most common adverse reactions of anlotinib, the incidence of hypertension and hand-foot syndrome were 41.1% and 24.1%, respectively. There were no new anlotinib-related adverse reactions observed in this study, and the toxic profile was similar to other studies of anlotinib in SCLC. The incidence of adverse reactions in this research might be lower than actual data in the real world because of the bias of the retrospective study.
This study provides real-world data of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC at the first time. However, as a retrospective study, our research still has some unavoidable limitations. First, as a real-world study, the Chinese undiversified population and small sample size might affect the universality of the results. Thus, future study with larger sample size is needed. Second, the proportion of female patients is low, which may affect the representation of the population. Last but not least, since the dosage was determined by different doctors according to the actual situation of patients, and this may affect the efficacy.