Intracranial complete response to toripalimab and anlotinib in a patient with recurrent brain metastases of small cell lung cancer after failure of second-line maintenance therapy: a case report

Introduction

Small cell lung cancer (SCLC), which accounts for approximately 13–15% of lung cancers, is a highly aggressive neuroendocrine tumor characterized by rapid growth (1). SCLC can be divided into limited and extensive stages. Chemotherapy and radiotherapy are the main treatment methods for SCLC. However, early recurrence occurred in majority of patients within the first year of treatment, leading to poor prognosis. Approximately 10–25% of patients with SCLC have symptomatic or asymptomatic brain metastases at initial diagnosis, and more than 50% will develop brain metastases during the disease course (2). Radiotherapy is commonly used for the treatment of brain metastases from SCLC, with a local control rate up to 93% (3). However, the survival was still dismal, with a 12-month overall survival (OS) rate of 39% (3). In recent years, immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for solid tumors (4). The IMpower133 and CASPIAN studies showed that ICIs combined with chemotherapy significantly prolonged OS in patients with extensive-stage SCLC compared with chemotherapy alone as first-line treatment (5,6). However, the therapeutic effect of antibody treatments like ICIs on brain metastases is limited because of the blood-brain barrier. Therefore, new treatment modalities need to be explored for SCLC patients with brain metastases.

Here, we reported a patient with multiline-treated SCLC whose primary lung tumor achieved sustained complete response (CR) throughout the treatment period, but with relapsed brain metastases. After failure of programmed cell death-1 (PD-1) inhibitor sintilimab combined with multikinase inhibitor anlotinib as second-line maintenance therapy for brain metastases, the patient was treated with another PD-1 inhibitor toripalimab in combination with anlotinib, and sustained CR for brain metastases was achieved. We present the following case in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-666/rc).

Case presentation

A 59-year-old female patient visited our hospital because of “cough with left back pain” in March 2019. Positron emission tomography-computed tomography (PET-CT) revealed a metabolically active soft tissue mass in the left lower lobe of lung, with a size of approximately 3.3 cm × 3.6 cm (Figure 1A,1B). Multiple lymphadenopathies in seven mediastinal regions and the left hilum were metabolically active, with size of approximately 1.7–2.1 cm for the larger ones, indicating metastases. No evidence of brain metastases was found. Electronic bronchoscopic biopsy results suggested SCLC. The patient was diagnosed with limited-stage small cell carcinoma of the left lower lung.

Figure 1 Positron emission tomography-computed tomography of chest (A) and brain (B) when the patient was diagnosed.

Initial chemotherapy with six cycles of etoposide and nedaplatin was given. The patient achieved CR according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by chest computed tomography (CT) and cranial enhanced magnetic resonance imaging (MRI) (Figure 2A). Then thoracic-adapted intensity-modulated radiation therapy (IMRT) (45 Gy in 30 fractions) and prophylactic brain radiotherapy (25 Gy in 10 fractions) were sequentially delivered. Approximately 3 months after the end of radiotherapy, the patient was still in CR as confirmed by chest CT and brain enhanced MRI (Figure 2B).

Figure 2 Brain magnetic resonance imaging images at different time points during treatment. Red arrows indicate the location of brain lesion.

Approximately 6 months after the end of radiotherapy, the patient was noted to have cranial enhanced MRI findings of abnormal signals in the left cerebellar hemisphere, indicating brain metastases (Figure 2C). CT and ultrasound of cervical lymph nodes, liver, gallbladder, spleen and pancreas did not show other sites of disease recurrence. After consultation with experts in the radiotherapy department, IMRT for target brain metastases were performed (40 Gy in 10 fractions). Anti-angiogenic drug anlotinib (12 mg, once daily) was given concurrently during IMRT. Irinotecan and lobaplatin were added to anlotinib after the end of IMRT. Enhanced MRI of the brain lesions showed partial response (PR) after one cycle of this regimen (Figure 2D), and showed CR after four cycles (Figure 2E).

Since grade 3 adverse reactions occurred, the patient received sintilimab (200 mg, once every 3 weeks) combined with anlotinib as maintenance therapy for three cycles. However, brain metastases relapsed again 2.5 months after achieving CR (Figure 2F). Considering the small relapsed lesions without symptoms, sintilimab combined with anlotinib was continued for another three cycles. Cranial enhanced MRI showed no changes in target lesions (Figure 2G).

After obtaining consent from the patient, sintilimab was switched to toripalimab (240 mg, once every 3 weeks). The relapsed brain metastases achieved CR after two cycles of toripalimab combined with anlotinib (Figure 2H). With another seven cycles of this regimen, CR had been maintained for 6 months (Figure 2I). The safety was manageable during treatment with toripalimab combined with anlotinib, without serious adverse reactions. Interestingly, the primary lung lesions remained in CR throughout the treatment period after the initial treatment.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Here, we reported a patient with limited-stage SCLC with recurrent brain metastases after the failure of second-line maintenance therapy and who achieved sustained CR after treatment with toripalimab in combination with anlotinib.

More than 50% of patients with SCLC will develop brain metastases during the disease course (2), leading to worse prognosis. The IMpower133 and CASPIAN studies demonstrated that ICIs combined with chemotherapy significantly improved the OS in patients with extensive-stage SCLC compared with chemotherapy alone as first-line treatment (5,6). However, no optimal treatment has been established for SCLC after failure of standard treatment, and studies on ICIs in brain metastases from SCLC are limited.

Toripalimab, a humanized anti-PD-1 monoclonal antibody, disrupts the binding of PD-1 and programmed cell death-ligand 1 (PD-L1) to programmed cell death-ligand 2 (PD-L2) and induces the endocytosis of PD-1 protein, relieving the inhibitory effect of PD-1 on T cells; this leads to complete restoration of T cells and complete immune normalization (7,8). The anti-tumor activity and safety of toripalimab monotherapy has been investigated in non-small cell lung cancer (NSCLC) (9), but data on toripalimab monotherapy in SCLC are lacking. Anti-angiogenic inhibitors that target both vascular endothelial growth factor (VEGF) and angiogenin 2 (ANG2) induce vascular normalization of abnormal blood vessels in tumors, thereby limiting the growth of tumor cells and have the advantage of regulating the tumor immune microenvironment, so they are suitable to be combined with ICIs. At the tumor site, the numbers of myeloid-derived suppressor cells and Treg cells decrease along with enhanced cytotoxic T cell infiltration, which makes the tumor immune microenvironment suitable for anti-PD-(L)1 immunotherapy (10). A phase II trial of toripalimab plus surufatinib [an inhibitor of VEGF receptor (VEGFR) 1–3, fibroblast growth factor receptor (FGFR) 1 and colony-stimulating factor-1 receptor (CSF-1R)] in 19 patients with advanced SCLC who had failed first-line systemic chemotherapy showed that the confirmed objective response rate (ORR) and disease control rate (DCR) were 10.5% and 94.7% (11), respectively. The median PFS was 3.0 months and median OS was 10.9 months (11). Another phase II trial enrolled 11 patients with extensive-stage SCLC who received toripalimab plus anlotinib as maintenance therapy after disease control with platinum-based chemotherapy (12). All patients achieved PR or stable disease, but the median PFS was not reached due to the short follow-up time (4.6 months) (12). In a phase II study of 16 patients with extensive-stage SCLC treated with first-line toripalimab combined with etoposide, carboplatin/cisplatin, and anlotinib, 100% of patients achieved objective response (1 CR and 15 PR) (13), and the median progression-free survival (PFS) was 13.3 months (14). Toripalimab combined with anti-angiogenic drug with or without chemotherapy has been investigated in SCLC. The present case supplemented the evidence on toripalimab plus anlotinib in patients with SCLC and brain metastases, which deserves further investigation.

In this case, MRI found no changes in target lesions during treatment with sintilimab plus anlotinib, indicating that PD-1 inhibitor might still have some effects on disease control. In addition, no immune-related adverse events occurred during the treatment. We speculated that switching another PD-1 inhibitor might bring more benefits and the patient could tolerate continued immunotherapy. After obtaining consent from the patient, sintilimab was switched to toripalimab. The sustained CR with toripalimab plus anlotinib indicated that this decision was correct, which also suggested the possibility of switching another PD-1 inhibitor as immunotherapy rechallenge. The differences in the molecular structure and mechanism of action among anti-PD-1 monoclonal antibodies might also contribute to the difference in efficacy, as supported by studies of various anti-PD-1 antibodies in similar populations with the same type of tumor.

Anlotinib is a small molecule multi-target tyrosine kinase inhibitor, which can effectively inhibit VEGFR, platelet-derived growth factor receptor (PDGFR), FGFR, c-Kit and other kinases with significant inhibitory activity, thus exerting anti-tumor angiogenesis and inhibiting tumor growth and metastasis through multiple pathways (15,16). The application of anti-angiogenic drug can improve cerebral edema, which is caused by brain metastases and radiotherapy (17). Some studies have also demonstrated the synergistic effect of radiotherapy combined with anlotinib for patients with NSCLC and brain metastases (18,19). In addition, angiogenesis and VEGF-VEGFR pathway play important roles in brain metastases, and the inhibition of VEGFR pathway can inhibit brain metastatic tumor growth (20,21). The subgroup analysis of ALTER 1202 study showed that third- or further-line anlotinib could bring significant survival benefit for patients with brain metastases at baseline compared with placebo (22). The combination of anlotinib with chemotherapy as first-line treatment for extensive-stage SCLC also showed promising clinical benefits (ORR: 80–89%; median PFS: 9.4–11.4 months) in previous phase II trials (23,24). Thus, anlotinib was given concurrently with radiotherapy and subsequent chemotherapy when brain metastases were found in the present patient. On the other hand, considering the synergistic effect of ICI and anti-angiogenic drug (10), anlotinib was still continued when sintilimab was switched to toripalimab.

In conclusion, the results observed from this case suggest that the combination of toripalimab and anlotinib may be an alternative promising treatment for patients with brain metastases from SCLC. Further clinical studies to evaluate this potential treatment strategy and the difference in efficacy among PD-1 inhibitors for this population are required.

Acknowledgments

The authors thank the patient and patient’s kin for agreement to publication of the report.

Funding: The study was supported by Henan Medical Science and Technology Research Joint Construction Project (No. LHGJ20190206), Key Research Projects of Henan Higher Education Institutions (No. 20A320058), and Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University (No. YNQN2017170).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-666/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-666/coif). LM reports that since the initial planning of the work, this study was funded by Henan Medical Science and Technology Research Joint Construction Project (No. LHGJ20190206), Key Research Projects of Henan Higher Education Institutions (No. 20A320058), and Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University (No. YNQN2017170). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7-30. [Crossref] [PubMed]
2. Hiddinga BI, Raskin J, Janssens A, et al. Recent developments in the treatment of small cell lung cancer. Eur Respir Rev 2021;30:210079. [Crossref] [PubMed]
3. Viani GA, Gouveia AG, Louie AV, et al. Stereotactic radiosurgery for brain metastases from small cell lung cancer without prior whole-brain radiotherapy: A meta-analysis. Radiother Oncol 2021;162:45-51. [Crossref] [PubMed]
4. Vaddepally RK, Kharel P, Pandey R, et al. Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers (Basel) 2020;12:738. [Crossref] [PubMed]
5. Liu SV, Reck M, Mansfield AS, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol 2021;39:619-30. [Crossref] [PubMed]
6. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2021;22:51-65. [Crossref] [PubMed]
7. Keam SJ. Toripalimab: First Global Approval. Drugs 2019;79:573-8. [Crossref] [PubMed]
8. Fernandes RA, Su L, Nishiga Y, et al. Immune receptor inhibition through enforced phosphatase recruitment. Nature 2020;586:779-84. [Crossref] [PubMed]
9. Wang Z, Ying J, Xu J, et al. Safety, Antitumor Activity, and Pharmacokinetics of Toripalimab, a Programmed Cell Death 1 Inhibitor, in Patients With Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial. JAMA Netw Open 2020;3:e2013770. [Crossref] [PubMed]
10. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15:325-40. [Crossref] [PubMed]
11. Cheng Y, Shen L, Yu X, et al. 157P Surufatinib plus toripalimab in patients with advanced small cell lung cancer (SCLC) after failure of first-line systemic chemotherapy. Ann Oncol 2021;32:S1448-9. [Crossref]
12. Lv D, Wu G. 468 A phase 2 study of toripalimab plus anlotinib as maintenance therapy in exten-sive-stage small cell lung cancer. J Immunother Cancer 2021;9:A497. [Crossref]
13. Luo H, Jian D, Feng Y, et al. Efficacy and safety of toripalimab with anlotinib and chemotherapy as first-line therapy in patients with extensive-stage small-cell lung cancer: Preliminary results of an open-label, single-arm, phase II study. J Clin Oncol 2021;39:e20570. [Crossref]
14. Luo H, Jian D, Feng Y, et al. 461 Updated PFS analysis of toripalimab with anlotinib and chemo-therapy as first-line therapy in patients with extensive-stage small-cell lung cancer (ES-SCLC). J Immunother Cancer 2021;9:A490. [Crossref]
15. Xie C, Wan X, Quan H, et al. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci 2018;109:1207-19. [Crossref] [PubMed]
16. Wang G, Sun M, Jiang Y, et al. Anlotinib, a novel small molecular tyrosine kinase inhibitor, sup-presses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma. Int J Cancer 2019;145:979-93. [Crossref] [PubMed]
17. Zhuang H, Shi S, Yuan Z, et al. Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues. Mol Cancer 2019;18:21. [Crossref] [PubMed]
18. He Z, Liu J, Ma Y, et al. Anlotinib Combined with Cranial Radiotherapy for Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Retrospectively, Control Study. Cancer Manag Res 2021;13:6101-11. [Crossref] [PubMed]
19. Liu J, Xu J, Ye W, et al. Whole-Brain Radiotherapy Combined With Anlotinib for Multiple Brain Metastases From Non-small Cell Lung Cancer Without Targetable Driver Mutation: A Single-Arm, Phase II Study. Clin Med Insights Oncol 2022;16:11795549221079185. [Crossref] [PubMed]
20. Pishko GL, Muldoon LL, Pagel MA, et al. Vascular endothelial growth factor blockade alters magnetic resonance imaging biomarkers of vascular function and decreases barrier permeability in a rat model of lung cancer brain metastasis. Fluids Barriers CNS 2015;12:5. [Crossref] [PubMed]
21. Boult JKR, Box G, Vinci M, et al. Evaluation of the Response of Intracranial Xenografts to VEGF Signaling Inhibition Using Multiparametric MRI. Neoplasia 2017;19:684-94. [Crossref] [PubMed]
22. Cheng Y, Wang Q, Li K, et al. P2.12-26 The Impact of Anlotinib for Relapsed SCLC Patients with Brain Metastases: A Subgroup Analysis of ALTER 1202. J Thorac Oncol 2019;14:S823-4. [Crossref]
23. Deng P, Yang H, Chen C, et al. P48.05 Anlotinib Plus Platinum-Etoposide in 1st-Line Treatment of Extensive-Stage Small-Cell Lung Cancer: A Single-Arm Phase II Trial. J Thorac Oncol 2021;16:S501. [Crossref]
24. Han B, Zhang W, Zhang B, et al. P48.09 Anlotinib Plus Etoposide and Carboplatin as First-Line Treatment for Extensive-Stage Small Cell Lung Cancer: A Single Arm Phase II Trial. J Thorac Oncol 2021;16:S503. [Crossref]