Anlotinib, a newly developed oral antiangiogenic TKI, has exhibited the combination efficacy with PD-1inhibitor in preclinical models[12]. As we know, the present study is the first series analysis to evaluate the therapeutic effect and AEs for the combination of anlotinib and PD-1inhibitor for metastatic solid tumors such as NSCLC, SCLC, SC, and ICC.
Of the 30 patients, 66.6% patients had previous second-line treatments, whereas 43.3% patients had brain metastasis. The results showed adequate disease control in the treatment of different metastatic solid tumors. The DCR and ORR was 70% and 43.3%, respectively. The ORR for SCLC was 71%, for NSCLC was 57.1%, and ICC was 50%. Additionally, ORR for patients with brain metastasis was up to 53.8%. PD-1inhibitor alone could improve overall survival time than placebo in second- or later-line treatment for NSCLC and GC. However, the ORR for NSCLC and GC was only 16.6%[13] and 11.6%[14], respectively. Anlotinib also had clinical activity in NSCLC and GC; however, the ORRs were only 9.2%[15] and 4.9%[16], respectively. Our study revealed more favorable efficacy of this combination than those of single agents in other studies.
The toxicities of anlotinib or PD-1inhibitor were tolerable and manageable in clinical trials and real‑world[17–19], and the fatal complications associated with ICI was uncommon. However, the AEs associated with this combination are unclear and have not yet been investigated. In a study presented at American Society of Clinical Oncology in 2019, camrelizumab combined with apatinib was used in the first-line treatment for NSCLC. The ORR and DCR in this study were 29.7% and 81.3%, respectively. However, 56.2% of patients had ≥ Grade 3 therapy-related AEs[20]. The Checkmate 016 evaluated the clinical activity of the combination of nivolumab with sunitinib or pazopanib in the patients with metastatic RCC. Thirty-three patients received nivolumab and sunitinib, 19 of whom were treatment-naïve. The ORR of these patients was 55%, whereas PFS was 12.7 months. Twenty patients received nivolumab and pazopanib, who had ≥ 1 prior systemic therapy. The ORR of these patients was 45%, whereas PFS was 7.2 months. However, the addition of standard doses of sunitinib or pazopanib to nivolumab resulted in high incidence of ≥ Grade 3 therapy-related AEs (82% and 70%, respectively)[21]. Axitinib is a more selective VEGF inhibitor[22]. Thus, it could be combined safely with pembrolizumab and exhibit adequate antitumor activity in patients with treatment-naïve advanced RCC[23]. Although ORR was 73%, 54% patients had therapy-related serious AEs[24].
Lower doses are superior to higher doses for eliciting a relatively immune-supportive tumor microenvironment and reengineering the tumor microenvironment for active immunotherapies in the clinical setting. This is supported by the data from the phase Ib trial REGONIVO.20 This study evaluated the treatment effect of the combination of regorafenib and nivolumab for GC and CRC. Regorafenib 160 mg was associated with three dose-limiting toxicities (DLTs). However, no DLTs were observed with 120 or 80 mg regorafenib. The ORR was 45.5% with 80 mg regorafenib and 36.0% with 120 mg regorafenib[25]. The intolerable toxicities of PD-1inhibitor combined with antiangiogenic TKIs obstacled the further clinical research. Evidence indicates that the favorable efficacy of combination of PD-1inhibitor and antiangiogenic TKIs may be dependent on careful selection of TKIs and the dosage.
The present study evaluated the adverse events of anlotinib plus PD-1inhibitor for solid tumors. The toxicity profiles are consistent with those of antiangiogenic TKIs or PD-1inhibitor in other studies. Although AEs appeared in 50% of patients in the present study, most were of Grades 1–2. The combination treatment was generally well tolerated. The most common therapy-related AE was fatigue (33.3%), whereas the most common ≥ Grade 3 therapy-related AE was thrombocytopenia (16.6%). Treatment was stopped in 30% of patients on anlotinib due to side effects. However, no therapy-related deaths occurred. Hematotoxicity was a common toxicity associated with this combination suggesting immune-mediated events associated with this combination. Thrombocytopenia was observed in 16% of patients, the severity of which was beyond Grade 3. Additionally, 16% of patients experienced thromboembolic or hemorrhagic events. Therefore, the anlotinib dosage should be reduced from 12 mg to 10 mg in future studies.
The small sample size was the major limitation of our study. Thus, the analysis of the treatment effect was preliminary in nature. Most patients had superior ECOG PS despite had several lines of chemotherapy. Antitumor response was observed in patients with NSCLC and SCLC, the efficacy of other tumor patients was not statasticly evaluated because of the small sample size.
Therefore, the combination of anlotinib and PD-1inhibitor demonstrated a favorable efficacy and tolerable toxicities in patients with solid tumors, which can provide an alternative salvage therapy for such patients.