Abstract and Introduction
Background: A paucity of strategies exist for extensive-stage small cell lung cancer (ES-SCLC) patients who fail the first-line chemotherapy. Apatinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), which has been demonstrated to have active anti-tumor activity in ES-SCLC when used only or combined with PD-1 inhibitors or chemotherapy with good tolerance. However, the efficacy and safety of apatinib monotherapy is unclear in second-line or beyond treatment of ES-SCLC.
Methods: In this prospective, exploratory, single-arm, multi-center study, eligible patients were aged 18 years or older with histologically confirmed ES-SCLC, and had progressed on, or were intolerant to previous systemic treatment. Patients received apatinib 500 mg (orally qd, every 4 weeks a cycle). The efficacy was assessed after 1 cycle and then every 2 cycles based on computed tomography imaging per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 (NCI-CTCAE 4.0). This study is registered in the Chinese Clinical Trial Registry, number ChiCTR-OPC-17013964.
Results: From 28 July 2017 to 21 June 2019, 62 patients were screened for eligibility, among whom 57 patients were available for efficacy and safety analysis. The objective response rate (ORR) was 14.3% and disease control rate (DCR) was 79.6%. The median PFS was 5.6 months [95% confidence interval (CI): 3.3–8.0 months] and the median overall survival (OS) was 11.2 months (95% CI: 7.5–24.0 months). Among the participants who received apatinib as second-line treatment, the median PFS and OS were 6.1 months (95% CI: 2.6–7.6 months) and 12.0 months (95% CI: 7.9 months to not reached), respectively. The most common AEs of all grades were anemia (36.8%), hypertension (33.3%), fatigue (31.6%), blood bilirubin increased (22.8%), elevated transaminase (19.3%), and hand-foot syndrome (17.54%). Grade 3 AEs included 2 (3.5%) cases of hypertension and 1 (1.8%) case of fatigue. No grade 4/5 AEs were observed.
Conclusions: Apatinib showed encouraging anti-tumor activity in pretreated ES-SCLC patients with tolerable toxicities. Further larger scale studies are warranted to demonstrate the efficacy of apatinib.
Lung cancer is the most common malignancy worldwide, with more than 787,000 new cases diagnosed and 631,000 deaths in China in 2015. Small cell lung cancer (SCLC) accounts for approximately 15–20% of total lung cancer cases, of which more than two thirds are extensive stage (ES) at the time of diagnosis. As a recalcitrant malignancy, the 2-year survival rate of ES-SCLC is less than 5% attributable to the elusive pathophysiology, aggressive biology, and stagnated therapeutic progress of ES-SCLC in the past decades. The combination of platinum and etoposide was the cornerstone of therapy for first-line SCLC, until the Phase III IMpower133 and CASPIAN trials demonstrated remarkable superiority of chemoimmunotherapy in extending overall survival (OS) by adding programmed cell death protein 1 (PD-1) axis inhibitors to platinum-based chemotherapy. Based on these pivotal Phase III data, the American Food and Drug Administration (FDA) and the National Medicine Products Administration (NMPA) of China approved the combination of carboplatin, etoposide, and the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab as a first-line treatment, which was a pivotal advance for SCLC treatment.
Despite the fact that SCLC is sensitive to initial therapy, up to 80% of patients will experience relapse and eventually die from systemic metastases. However, until 2020, topotecan was the only recommended second-line therapy with an objective response rate (ORR) not exceeding 25% and OS of 6–9 months. It held this status based on its ability to prolong OS compared with best supportive care and noninferiority in controlling symptom versus cyclophosphamide, doxorubicin, and vincristine in patients relapsing from front-line chemotherapy. Therefore, it is urgently necessary to develop more effective therapeutic strategies for chemotherapy-refractory SCLC.
Emerging evidence has demonstrated that angiogenesis is a vital facilitator during the growth, invasion, and metastasis of SCLC, during which vascular endothelial growth factor (VEGF) is one of the most important mediators of tumor angiogenesis, whose high-level expression was also shown to be associated with inferior prognosis for SCLC.[12,13] Therefore, the anti-VEGF/vascular endothelial growth factor receptors-2 (VEGFR-2) axis is an attractive target for the treatment of SCLC, which underlines a convergence with non-small-cell lung cancer (NSCLC). Furthermore, this concept has been verified in several anti-angiogenic clinical trials of ES-SCLC. However, the clinical trials of bevacizumab (an anti-VEGF antibody) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) in previously untreated SCLC patients demonstrated that the results do not meet expectations, despite some improved progression-free survival (PFS) and/or OS.[15–17] It follows then that the magnitude of benefit from anti-angiogenic therapy in SCLC patients is limited. Therefore, additional studies of novel anti-angiogenesis agents and strategies for ES-SCLC are warranted.
Apatinib is an orally administered small molecular tyrosine kinase inhibitor (TKI) that selectively inhibits VEGFR-2. It has been approved for the third-line or beyond treatment of advanced gastric cancer in China and the second-line or later-line treatment of hepatocellular carcinoma. Furthermore, apatinib has shown efficacy in other solid tumors with a high level of safety, such as in NSCLC, breast cancer, gestational trophoblastic neoplasia, cervical cancer, esophageal squamous cell carcinoma, chordoma, and osteosarcoma, in monotherapy or combined therapy.
Apatinib has been demonstrated to exert an active anti-tumor effect on SCLC, not only in vitro and in vivo research, but also in several clinical trials in ES-SCLC.[29–32] When used alone, apatinib achieved an ORR of 17.5% in per-protocol population with a median PFS of 3.0 months and a median OS of 5.8 months in third-line or beyond treatment of ES-SCLC. Meanwhile, apatinib monotherapy was well tolerated with manageable toxicity, as that the incidence of the most common grade 3 or greater adverse events (AEs) were hypertension (25%), hand-foot syndrome (10%), L-gamma glutamyltransferase increased (10%), aspartate aminotransferase increased (7.5%), and thrombocytopenia (7.5%). Besides, dose reduction occurred in 37.5% of patients in safety analysis during treatment. Additionally, long-term efficacy of adding low-dose apatinib, during the chemotherapy interval and maintenance therapy following chemotherapy in the first-line treatment of ES-SCLC, increased median PFS by 2.9 months (7.8 vs. 4.9 months) and median OS by 3.9 months (12.1 vs. 8.2 months). When apatinib was combined with camrelizumab, an anti-PD-1 antibody, the confirmed ORR reached 34.0% with the median PFS and OS of 3.6 and 8.4 months, respectively, in patients who had progressed on platinum-based first-line chemotherapy. Together, though apatinib has been demonstrated to have promising anti-tumor activity with a good safety profile in third-line or beyond treatment of ES-SCLC, it is not clear about the efficacy and safety of apatinib monotherapy in ES-SCLC patients with progression after first-line chemotherapy. Thus, we designed this prospective study to evaluate the efficacy and safety of apatinib in the second- or third-line treatment of ES-SCLC patients. We present the following article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-313/rc).
Transl Lung Cancer Res. 2022;11(5):832-844. © 2022 AME Publishing Company