Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in Patients with Advanced Nonsquamous NSCLC Previously Treated with Chemotherapy

Abstract

Purpose: Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade via alleviating hypoxia, increasing infiltration of CD8+ T cells and reducing recruitment of tumor-associated macrophages. We hereby conducted a clinical trial to evaluate this combination in pretreated patients with advanced non–small cell lung cancer (NSCLC). Patients and Methods: The study included phase Ib apatinib dose-escalation and phase II expansion cohorts. Patients received apatinib at doses of 250–500 mg orally once daily, in combination with camrelizumab 200 mg intravenously every 2 weeks. Results: From March 2017 to October 2018, 105 chemotherapy-pretreated patients with nonsquamous NSCLC were enrolled and received apatinib 250 mg (recommended phase II dose) and camrelizumab. Among them, one (1.0%) complete response, 28 (26.7%) partial responses, and 48 (45.7%) stable diseases were observed. In the efficacy-evaluable population (n = 94), objective response rate (ORR) was 30.9% [95% confidence interval (CI), 21.7–41.2]. The median progression-free survival was 5.7 months (95% CI, 4.5–8.8) and overall survival was 15.5 months (95% CI, 10.9–24.5). Efficacy of combination therapy was evident across all PD-L1 and tumor mutation burden subgroups, and appeared to be improved in patients with STK11/KEAP1 mutation (mutant vs. wild-type, ORR: 42.9% vs. 28.1%; 1-year survival rate: 85.1% vs. 53.1%). No unexpected adverse events were observed. Conclusions: Combined apatinib and camrelizumab showed encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. Patients with STK11/KEAP1 mutation might derive more benefits from this combination. We will validate these results in an ongoing phase III trial (NCT04203485).

The Application of Combined Immune Checkpoint Inhibitor Modalities in Previously Treated Non-Small Cell Lung Cancer Patients and the Associations Thereof With the Lung Immune Prognostic Index

“…However, the OS curves of the three groups overlapped extensively. Several studies have shown that anti-angiogenic agents act synergistically with PD-1/ PD-L1 inhibitors to improve the low efficacy of ICI monotherapy, with an ORR of~30% (21,22). The combination treatments increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages, reversed inhibition of DC maturation, and promoted the development of an angiostatic and immune system-activating tumor microenvironment (23,24).…”

Real-World Data on Apatinib Efficacy - Results of a Retrospective Study in Metastatic Breast Cancer Patients Pretreated With Multiline Treatment

“…A prospective study reported that apatinib had encouraging clinical activity with a median PFS of 5.4 months and a median OS of 10.0 months in extensive-stage small-cell lung cancer patients who had more than two prior chemotherapy treatment failures with manageable toxicity ( 26 ). The combination of an anti-PD-1 antibody (SHR-1210) and apatinib (250 mg) treatment showed promising efficacy with acceptable toxicity in patients with hepatocellular carcinoma, gastric cancer, esophagogastric junction cancer, and advanced non-squamous NSCLC by modulating tumor immune microenvironment ( 27 , 28 ). A retrospective study of 23 metastatic colorectal cancer patients demonstrated that the combination of apatinib with chemotherapy was more effective treatment than apatinib monotherapy ( 29 , 30 ).…”

Study protocol: A single‐arm, multicenter, phase II trial of camrelizumab plus apatinib for advanced nonsquamous NSCLC previously treated with first‐line immunotherapy

“…A phase III trial has shown that camrelizumab plus chemotherapy as first‐line treatment can bring benefit to advanced or metastatic nonsquamous NSCLC 10 . Pilot studies have demonstrated that the combination treatment enhanced the anticancer capability as higher‐line therapy in advanced NSCLC patients previously treated with chemotherapy 11,12 . Additionally, for advanced hepatocellular carcinoma and cervical cancer, camrelizumab plus apatinib is also a potential option.…”

“…Promising anticancer activity has also been observed in pretreated advanced NSCLC patients. Another phase II trial has also shown the efficacy of camrelizumab in combination with apatinib on NSCLC after failure of first‐line chemotherapy, with an objective response rate (ORR) of 30.9%, median PFS of 5.7 months, and median OS of 15.5 months 12 …”