Most advanced NSCLC patients inevitably have disease progression after first-line and second-line treatment, and need further treatment. A Phase III clinical study (ALTER-0303)showed that The median OS(9.63 vs 6.3 months,P = 0.0018), PFS༈5.37vs1.4 months༌P < 0.0001༉, DCR༈81.0% vs 37.1%༌P < 0.0001༉and ORR༈9% vs 1%༌P < 0.0001༉of anlotinib were significantly better than those of placebo group, and the adverse reactions were generally tolerable, similar to those reported in previous studies.
In the present study, the result of patients who received anlotinib showed that the median PFS was 4.7 months, and the median OS was 6.4 month. In addition, the ORR and DCR were 9.9% and 51.6%. Although the survival time was shorter than that of ALTER-0303, one of the result was considered that there were 28 patients with PS 2 in this study, this may be an important reason for the difference in survival time. According to Di Maio et alshowed that physical condition has a greater impact on the choice of treatment options and drug tolerance, and is also an important indicator reflecting the severity of patients' condition for advance NSCLC treatment. Furthermore, if we exclude patients with PS 2, the median PFS, OS were 5.5 and 9.2 months, which was similar to the ALTER-0303. And also the same study showed that bevacizumab combined with chemotherapy was an effective and tolerable treatment for NSCLC patients with low PS score. For patients with PS 2, the median PFS, OS were only 2.7 and 4.3 months. Furthermore, according to analysis of short-term therapeutic effect of anlotinib with PS, the PS 0–1 of ORR(ORR, 45.1% vs 6.6%), DCR(8.8% vs 1.1%) was significanly more than PS 2. On the other hand, the adverse reactions of anlotinib on PS, our result also shows that the PS 0–1 group of I-II adverse reactions was high than PS 2 group(52.3% vs 32.1%), but the III-IV adverse reactions were less than PS 2 group(9.5% vs 10.7%). which may indicated that PS was an important factor affecting the treatment of advanced NSCLC by anlotinib, and high PS may lead to patients' difficulty in benefited from anlotinib treatment.
Previous studies have showed that the growth characteristics of lung squamous cell carcinoma(LUSC) are mainly central type, slow growth, local invasion and low regional lymph node metastasis rate[2,21−23]. The tumor tissues have relatively rich blood supply, and the main cause of death is that the tumor lesions in the chest are not effectively controlled or local recurrence occurs after treatment[2, 24]. The anti-angiogenic drug bevacizumab combined with paclitaxel and carboplatin has only been approved first-line treatment for advanced non-squamous NSCLC without EGFR mutations[25–26]. And a multi-center phase II clinical trial of apatinib in third- and further-line for advanced NSCLC showed that apatinib can significantly improved the survival time of advanced non-squamous NSCLC, with PFS 4.7 months, DCR 12.2%, and ORR 68.9%[2, 27].
The characteristics of LUSC is characterized by central type and more cavitives, which maybe the result that antiangiogenic drugs bevacizumab and apatinib are prohibited for the treatment of advanced LUSC due to the high risk of bleeding. So what is the efficacy and safety of anlotinib third- and further-line in the treatment of advanced LUSC. We divided the pathological type into adenocarcinoma group(n = 43) and squamous group(n = 48) with unselected PS patients, the result shows that there were not significanly differences between in two groups with OS(7.4 vs 6.1 months, P > 0.05) and PFS(5.2 vs 3.8 months, P > 0.05). Furthermore, in subgroups analysis the pathological type and ECOG PS for anlotinib treatment, the combination of squamous and PS 0–1 has significantly longer PFS(6.7 vs 2.95 months, P = 0.001) as well as OS(8.1 vs 3.2 months, P < 0.0001) than PS 2. Moreover, in Adenocarcinoma + ECOG PS of Subgroup, the result of PS 0–1 had significantly longer PFS than PS 2(4.1 vs 2.2 months, P = 0.0049); although the OS was no significantly difference between two groups(6.6 vs 4.4 months, P = 0.068), the PS 0–1 of OS was nearly two months longer than PS 2. This study may shows that the advanced LUSC recived anlotinib treatment with the same efficacy which is comparable to adenocarcinoma, advanced LUSC patients with PS 0–1 and recived anlotinib treatment may benefit the most than PS 2, no matter in mPFS or mOS.
The number of metastasis organs in advanced lung cancer is an important factor for survival and prognosis of patients, the more metastasis organs, the worse prognosis[28–29]. Patients with liver metastases are associated with poor outcomes and the worst prognosis (median PFS 1.15 vs 3.24months, median OS 3–4 vs 5-8months) than non-liver metastases in the advanced NSCLC[30–32]. Therefore, a study of bevacizumab in the treatment of advanced non-squamous of NSCLC patients with liver metastasis shows that bevacizumab regimens subgroup was associated with significantly longer PFS(4.2 vs 2.6 months, P < 0 .01) and OS(7.1 vs 4.4 months, P < 0 .01) than non-bevacizumab regimens subgroups in patients with baseline liver metastases. So what is the effect of anlotinib in the treatment of advanced NSCLC with liver metastasis?. In our study, the patients was divided into two groups according to the number of metastatic sites in advanced NSCLC. The ≥ 3 metastatic sites of mPFS(3.2 vs 5.4months, P = 0.021) and mOS(4.6 vs 9.2months, P = 0.013) in patients with anlotinib was significantly shorter than < 3 metastatic sites, and also was an independent risk factor for PFS(HR = 1.632, 95%CI: 1.004–2.656,P < 0.05). Furthermore, we made a subgroup univariate analysis of liver metastasis, the patients oraled the anlotinib showed that non-liver metastases of median OS(8.4 vs 4.4months, P < 0.05) and PFS(5.4 vs 3.2 months, P < 0.05) was longer than liver metastases, the liver metastases patients with higher costs and health care resource. Our study may be considered most similar to that of research[31–34], which examined the prognostic effect of liver metastases had a significantly shorter OS.
The clinical studies of anlotinib in the treatment of advanced NSCLC have shown better efficacy and survival benefits. However, the current study has several limitations. Firstly, because the study was a retrospective analysis, the small sample size, the results are easy to be affected by many other factors, and also lack of information regarding quality-of-life benefits. Secondly, most patients take anlotinib outside the hospital, many syndromes were not found in the course of treatment, and the related syndromes were not given timely intervention, which made the later related syndromes more serious. Although the data of patients for analysis was retrospective, the patients recived anlotinib treatment were benefit and adverse reactions can be tolerate.
In conclusion, the present study showed that the single drug of anlotinib has definite efficacy and mild adverse reactions in the treatment of advanced NSCLC. Furthermore, the patients in advanced NSCLC with an ECOG PS 0–1 get better PFS and OS than PS2 followed by anlotinib treatment. And the results of univariate and multivariate analyses shows that the patients with PS score of 0–1, no liver metastasis, squamous cell carcinoma, third-line treatment and non-smoking may get better curative effect. In adverse reactions, the PS 0–1 of patients were more tolerance than PS 2. All of that may shows us that the important of PS scores for advanced NSCLC recived anlotinib treatment.