INTRODUCTION
Lung adenocarcinoma is one of the most common diseases observed in the clinic. Although surgery is main treatment, most patients are diagnosed in the late stage and become unresectable. Platinum-based chemotherapy has been considered as the first-line standard treatment for lung adenocarcinoma. However, tumor cells can gain resistance to multiple types of chemotherapy as the number of chemotherapy cycles increases; moreover, the treatment effect is not ideal. The emergence of molecular targeted therapeutic drugs has brought new hope to patients with lung adenocarcinoma. Unfortunately, it is difficult for patients with negative driver genes to benefit from molecularly targeted therapy. It is worth mentioning that the emergence of immune checkpoint inhibitors (ICIs), of which programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) are representative, has led to new therapeutic options in patients with lung adenocarcinoma with negative driver genes. Studies have found that camrelizumab , as a single agent or combined with chemotherapy for the first-line treatment of patients with non–small cell lung cancer (NSCLC) with negative driver genes, can improve the disease response rate, progression-free survival (PFS), and overall survival (OS).[ 1 , 2 ] Although camrelizumab can produce positive clinical efficacy, some patients develop resistance to immunotherapies and experience reactive cutaneous capillary endothelial proliferation (RCCEP).[ 3 ]
Based on research findings, apatinib , as an antiangiogenic tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2, can improve the antitumor immune response and relieve RCCEP.[ 4–6 ]
Here, we report a case in which a patient with advanced lung adenocarcinoma with negative driver genes has obtained benefit from treatment with camrelizumab combined with a small dose of apatinib .
CASE HISTORY
A 70-year-old female presented with cough and bloody sputum in January 2020. Computed tomography (CT) showed 4 × 4 cm lesions in the left lung and mediastinal adenopathy [Figure 1a ]. The patient was diagnosed with left lung adenocarcinoma classified by the pathological analysis as cT2cN2M0, stage IIIa. The patient and her family refused an operation because of the patient’s advanced age. After discussion, a multidisciplinary team decided to start the patient on ICIs combined with chemotherapy as the initial treatment regimen. Between January 2020 and February 2020, the patient received two cycles of carboplatin (400 mg intravenously, 3 weeks/cycle) plus pemetrexed disodium (1000 mg intravenously, 3 weeks/cycle) chemotherapy. Simultaneously, a gene sequencing study was performed. The results of the gene sequencing studies were negative for EGFR wild-type, ALK arrangement, and ROS1 gene fusion. The expression of PD-L1 was 90%. In February 2020, the patient received camrelizumab (200 mg intravenously) combined with pemetrexed disodium (1000 mg intravenously) chemotherapy, repeated every 3 weeks. After two cycles of treatment, CT revealed lung lesions, indicating a partial response (PR) by modified RECIST 1.1. criteria [Figure 1b ]. After six cycles of treatment, the response was maintained at stable disease (SD) [Figure 1c ]. Unfortunately, the side effects of chemotherapy were worse than before common terminology criteria for adverse events (CTCAE grade 3), and RCCEP was caused by camrelizumab (RCCEP grade 2) [Figure 2a ]. In June 2020, the treatment regimen was adjusted to camrelizumab (200 mg intravenously) combined with a low dose of apatinib (250 mg qd orally) repeated every 3 weeks. After six cycles of camrelizumab (200 mg) plus apatinib (250 mg), the curative effect achieved was complete response (CR) [Figure 1d ] and the symptoms of RCCEP were milder than before [Figure 2b ]. At the time of end of follow-up (March 2021), the efficacy evaluation revealed that CR was reached, as shown by the CT scan, and the symptoms of RCCEP disappeared [Figure 2c ]. The patient remained on treatment with this camrelizumab (200 mg intravenously) combined with apatinib (250 mg qd orally) regimen without interruption. The response of SD was maintained until the date of publication.
Figure 1: (a) Before therapy, CT scan showed a left lung mass, mediastinal adenopathy. (b) After two cycles of camrelizumab combined with pemetrexed disodium, CT revealed lung lesions indicating a PR. (c) After six cycles of camrelizumab combined with pemetrexed disodium, the response was maintained at SD. (d) After six cycles of carboplatin plus apatinib , the curative effect achieved a CR. CR = completed response, CT = computed tomography, PR = partial response, SD = stable disease
Figure 2: (a) RCCEP during treatment with camrelizumab and pemetrexed disodium. (b) After six cycles of carboplatin plus apatinib , the symptom of RCCEP was better than before. (c) The last follow-up time was March 2021, when the symptoms of RCCEP disappeared. RCCEP = reactive cutaneous capillary endothelial proliferation
DISCUSSION
The above case report demonstrates that camrelizumab combined with a low dose of apatinib resulted in remarkable clinical benefits in a patient with advanced lung adenocarcinoma with negative driver genes. Camrelizumab has been proven to be effective for a variety of cancers in Chinese studies.[ 7 , 8 ] The mechanism of action is through the inhibition of the binding of PD-1 to PD-L1 to achieve an antitumor effect.[ 9 ] In recent years, studies have found the efficacy and safety of camrelizumab plus chemotherapy in patients with advanced lung cancer with negative driver genes.[ 10–12 ] In our study, the lesions in the patient’s lung were significantly smaller after six cycles of camrelizumab combined with pemetrexed disodium. However, ICIs may cause immune-related adverse events (irAEs) such as RCCEP, colitis, and pneumonitis because of the overactivation of the body’s immune system.[ 13 ] In addition to the above irAEs, RCCEP is the most common adverse reaction related to camrelizumab . Several studies have found that camrelizumab monotherapy can cause a higher incidence of RCCEP.[ 14 ] A potential reason for this is that the dynamic balance between pro- and antiangiogenic factors may be damaged by the reactivation of immune responses, causing the abnormal proliferation of skin capillary endothelial cells.[ 10 ] Apatinib is a selective VEGFR2 inhibitor that has been approved in China for patients with a variety of solid tumors.[ 15–17 ]
Studies have demonstrated that the combination of apatinib with camrelizumab can effectively reduce the incidence of RCCEP.[ 18 ] The mechanism of action may be that apatinib blocks the VEGF/VEGFR2 signal transduction pathway and inhibits the development of RCCEP.[ 19 ] In addition, studies have found that a low dose of apatinib can induce an enhanced therapeutic effect by optimizing the tumor microenvironment in patients with lung adenocarcinoma treated with camrelizumab .[ 20 ] In conclusion, camrelizumab combined with a low dose of apatinib can effectively inhibit not only the tumor growth, but also the incidence rate of irAEs. In this case, the patient experienced RCCEP grade 2 after six cycles of camrelizumab combined with pemetrexed disodium. Treatment was continued after it was adjusted to camrelizumab combined with apatinib . In the follow-up treatment, the efficacy evaluation revealed a CR, and the symptoms of RCCEP disappeared.
CONCLUSION
This case report provides a rationale for camrelizumab combined with a low dose of apatinib for the treatment of patients with lung adenocarcinoma with negative driver genes. However, owing to the limited number of patients studied, this regimen requires further large-scale clinical testing.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her names and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Shan Q, Wang H, Han X, Guo J, Wang Z. Duration of immunotherapy in patients with
advanced lung adenocarcinoma with negative driver genes:Case report and literature review. Thorac Cancer 2020;11:3001–6.
2. Huang W, Zhang Q, Da L, Shen Y, Xiong F, Zhang C. Effectiveness and safety of
camrelizumab combined with chemotherapy in nonsquamous nonsmall cell lung cancer as the second-line therapy:A retrospective analysis. J Cancer Res Ther 2022;18:576–80.
3. Huang J, Xu B, Mo H, Zhang W, Chen X, Wu D, et al. Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res 2018;24:1296–304.
4. Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, et al.
Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma:Results from two single-arm, phase 1 trials. Lancet Oncol 2018;19:1338–50.
5. Li W, Wei Z, Yang X, Huang G, Han X, Ni Y, et al. Salvage therapy of reactive capillary hemangiomas:
Apatinib alleviates the unique adverse events induced by
camrelizumab in non-small cell lung cancer. J Cancer Res Ther 2019;15:1624–8.
6. Yang C, Feng W, Wu D.
Apatinib for advanced nonsmall-cell lung cancer:A retrospective case series analysis. J Cancer Res Ther 2018;14:159–62.
7. Zhang X, Chen J, Liu N, Wang Q, Wu Q, Gao F, et al.
Camrelizumab (SHR-1210) with carboplatin and albumin-binding paclitaxel in patients with metastatic or recurrent cervical cancer:An open-label, phase 2 trial. J Cancer Res Ther 2022;18:482–7.
8. Li Y, Li HL, Hu HT, Shao S-S, Chen C-S, Guo C-Y, et al. Clinical observation of local intervention combined with
camrelizumab and
apatinib in the treatment of metastatic soft-tissue sarcoma. J Cancer Res Ther 2021;17:1718–24.
9. Niu M, Yi M, Li N, Luo S, Wu K. Predictive biomarkers of anti-PD-1/PD-L1 therapy in NSCLC. Exp Hematol Oncol 2021;10:18.
10. Chen X, Ma L, Wang X, Mo H, Wu D, Lan B, et al. Reactive capillary hemangiomas:A novel dermatologic toxicity following anti-PD-1 treatment with SHR-1210. Cancer Biol Med 2019;16:173–81.
11. Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, et al.
Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL):A randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med 2021;9:305–14.
12. Yi M, Zheng X, Niu M, Zhu S, Ge H, Wu K. Combination strategies with PD-1/PD-L1 blockade:Current advances and future directions. Mol Cancer 2022;21:28.
13. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immunerelated adverse effects of
immune checkpoint inhibitors :A review. JAMA Oncol 2016;2:1346–53.
14. Wang F, Qin S, Sun X, Ren Z, Meng Z, Chen Z, et al.
Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with
camrelizumab :Data derived from a multicenter phase 2 trial. J Hematol Oncol 2020;13:47.
15. Li Y, Li H, Hu H, Yuan H, Zhao Y. Efficacy and safety of transcatheter arterial chemoembolization combined with either 125I seed implantation or
apatinib in hepatocellular carcinoma with portal vein tumor thrombosis:A retrospective comparative study. J Cancer Res Ther 2020;16:1691–7.
16. Liu S, Zhao G, Yu G, Guo N, Zhang Y, Li Q, et al. Transcatheter arterial chemoembolization combined with low-dose
apatinib in the treatment of unresectable hepatocellular carcinoma in elderly patients:Efficacy and safety. J Cancer Res Ther 2020;16:1165–70.
17. Tian Y, Cheng X, Li Y. Chemotherapy combined with
apatinib for the treatment of desmoplastic small round cell tumors:A case report. J Cancer Res Ther 2020;16:1177–81.
18. Scott AJ, Messersmith WA, Jimeno A.
Apatinib :A promising oral antiangiogenic agent in the treatment of multiple solid tumors. Drugs Today (Barc) 2015;51:223–9.
19. Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with
apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer:Anopen-label, dose escalation and expansion study. Clin Cancer Res 2019;25:515–23.
20. Zhao S, Ren S, Jiang T, Zhu B, Li X, Zhao C, et al. Low-dose
apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer. Cancer Immunol Res 2019;7:630–43.
