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CASE REPORT
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 1191-1195

Rechallenge of camrelizumab in non-small-cell lung cancer patients treated previously with camrelizumab and microwave ablation


1 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, Shandong Province, China
2 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China

Date of Submission14-Jun-2020
Date of Decision19-Jul-2020
Date of Acceptance06-Aug-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Xin Ye
Department of Oncology,The First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute. No. 16766, Jingshi Road, Jinan, Shandong Province, 250014
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_798_20

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 > Abstract 


Camrelizumab is a programmed death receptor-1 inhibitor originally developed in China for the treatment of refractory lymphoma. It has also been effective in non-small-cell lung cancer patients. However, the rechallenge of camrelizumab was not reported previously. We report the rechallenge of camrelizumab therapy in two patients previously treated with microwave ablation (MWA) and camrelizumab. Although objective responses were achieved, camrelizumab therapy was discontinued because of the development of immune-related pneumonia (IRP). Treatment with camrelizumab was reinitiated after the patients recovered from IRP. The reoccurrence of more severe IRP necessitated additional corticosteroid therapy. The rechallenge of camrelizumab in patients treated with MWA plus camrelizumab regimen and who developed IRP should be cautious.

Keywords: Immune-related pneumonia, microwave ablation, nonsmall-cell lung cancer


How to cite this article:
Wei Z, Yang X, Ye X. Rechallenge of camrelizumab in non-small-cell lung cancer patients treated previously with camrelizumab and microwave ablation. J Can Res Ther 2020;16:1191-5

How to cite this URL:
Wei Z, Yang X, Ye X. Rechallenge of camrelizumab in non-small-cell lung cancer patients treated previously with camrelizumab and microwave ablation. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1191-5. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1191/296447




 > Introduction Top


Immune checkpoint inhibitors (ICIs) are widely used to treat advanced non-small-cell lung cancer (NSCLC) as first-line and subsequent-line regimens.[1],[2],[3],[4],[5],[6] Camrelizumab is a programmed death receptor-1 (PD-1) inhibitor approved for treating refractory lymphoma. Camrelizumab therapy also showed a survival advantage in advanced NSCLC patients.

Microwave ablation (MWA) has been used to treat both early-stage and advanced-stage NSCLC.[7],[8]

ICI rechallenge (re-administration) because of disease progression or intolerable toxicity has not been fully evaluated for advanced NSCLC treated with ICIs. Here, we report on camrelizumab rechallenge after immune-related adverse events (irAEs) in NSCLC patients previously treated with MWA and camrelizumab.


 > Case Reports Top


Case 1

A 47-year-old woman without a smoking history underwent a lobectomy on February 23, 2017. The pathological diagnosis was left lower lobe invasive adenocarcinoma with mediastinal metastases (stage pT3N2M0, IIIB). No sensitive epidermal growth factor receptor, anaplastic lymphoma kinase fusions, and ROS proto-oncogene 1 (ROS1) mutations were identified with PD ligand-1 (PD-L1) tumor proportion score (TPS) <1% (Dako 22C3 assay). Four cycles of pemetrexed plus cisplatin were administered as adjuvant chemotherapy, followed by adjuvant irradiation (50 Gy in 25 fractions). Pulmonary metastases occurred 7 months post-surgery. Subsequently, the patient was treated with pemetrexed, gefitinib, and osimertinib at another hospital; however, disease progression continued. Thus, MWA was conducted (February 21, 2019) on three right pulmonary metastases. One week postablation, camrelizumab was administered (200 mg every 2 weeks). Four cycles later, as the MWA-treated metastases reached complete ablation, a complete response of other pulmonary metastases was achieved. Five cycles later, pulmonary imaging showed multiple patchy high-density foci in both lungs, indicating grade 2 immune-related pneumonia (IRP). No IRP-related clinical symptoms were identified. Subsequently, methylprednisolone was administered (2 mg/kg for 1 week, decreased gradually). Five days later, computed tomography (CT) scan showed IRP improvement, and 1 month later, the new foci disappeared. The patient was rechallenged with camrelizumab at the former dose. However, Grade 3 IRP recurred after three cycles of camrelizumab retreatment. Because the patient also presented with cough and shortness of breath, methylprednisolone was re-administered; 1 week later, the IRP decreased [Figure 1].
Figure 1: The image of immune-related pneumonia before and after rechallenge of immune-related pneumonia. (A1-3) Immune-related pneumonia occurred after five cycles of camrelizumab. (B1-3) 28 days after administration of methylprednisolone; (C1-4) Immune-related pneumonia recurred after rechallenge with camrelizumab for three cycles. (D1-4) Immune-related pneumonia decreased after seven days of methylprednisolone therapy

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Case 2

A 55-year-old woman presented with pulmonary nodes on CT scan. Subsequent CT showed peripheral tumors in the left lower lobe, with mediastinal and right hilar lymph node involvement and pulmonary metastases. CT-guided biopsy verified the pathological diagnosis of squamous cell lung cancer (thyroid transcription factor 1 negativity and p40 and cytokeratin 5/6 positivity), stage IVA (cT3N2M1). Genetic tests did not identify sensitivemutations. Immunohistological analysis showed 80% PD-L1 TPS. MWA was conducted on the primary tumor. One week later, camrelizumab was administered (200 mg every 2 weeks). Complete ablation was achieved in the primary tumor, and a partial response (PR) was observed in other lesions. Following IRP occurrence three cycles later, methylprednisolone was administered (2 mg/kg for 1 week, decreased thereafter). The IRP improved 5 days postmethylprednisolone treatment and disappeared 45 days later. At this stage, the patient was treated with docetaxel plus cisplatin; however, disease progression occurred. The patient was rechallenged with camrelizumab (using previous dose and intervals). Despite achieving PR after one cycle, grade 2 IRP recurred. Methylprednisolone was re-administered, and camrelizumab was discontinued again. After 1 week of methylprednisolone administration, the IRP subsided [Figure 2].
Figure 2: The image of immune-related pneumonia before and after rechallenge of immune-related pneumonia. (A1-3) immune-related pneumonia occurred after three cycles of carelizumab. (B1-3) one month after administration of methylprednisolone; (C1-4) immune-related pneumonia recurred after the rechallenge of carelizumab for one cycle. (D1-4) immune-related pneumonia decreased seven days of retreatment of methylprednisolone

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 > Discussion Top


We report two patients previously treated with MWA plus camrelizumab rechallenged with camrelizumab after camrelizumab discontinuation because of IRP. Although objective responses were achieved in both cases, a more severe IRP necessitated corticosteroid treatment.

ICIs have been approved as first-line regimens alone or in combination with platinum-based doublet chemotherapy in advanced NSCLC patients.[1],[2],[3] Furthermore, ICI alone is the first choice for subsequent treatments.[4],[5],[6] The relatively low objective response rate, the inferior progression-free survival (PFS) rate, and irAEs limit ICI application in cancer therapy. Although ICI-associated adverse events are less common than those associated with chemotherapy, their toxicities necessitate corticosteroid treatment, leading to ICI discontinuation.[4],[5],[6]

ICI rechallenge because of disease progression was first reported for malignant melanoma.[9] In that study, 51 patients were retreated with ipilimumab upon disease progression. Of these, 28 regained disease control, with a median overall survival (OS) of 21 months. Adverse events were observed in only 22% of patients, and no new toxicity was identified.[9] Another study [10] reported retreatment with anti-PD-1/PD-L1 antibodies in patients who developed serious irAEs requiring treatment interruption. Of 38 patients, 10 (26%) had recurrence of the initial irAEs, whereas 10 (26%) had new irAEs. Although most irAEs were mild and manageable, two deaths occurred. Among those without observed PR before the irAEs, PFS and OS were longer in the retreatment cohort.[10] ICI rechallenge in advanced NSCLC has been rarely described. However, Watanabe et al.[11] reported that the effect of ICI rechallenge was limited.[11] In their study, 14 patients with disease progression after the first ICI treatment underwent ICI rechallenge. The median PFS and OS values were low (1.5 months and 6.5 months, respectively). The objective response and disease control rates were also low (7.1% and 21.4%, respectively). Adverse events were not significantly different compared with those with the first ICI administration.[11] In contrast to their findings, in our study, camrelizumab rechallenge was effective in both patients.

IRP is a relatively common and potentially life-threatening adverse event. Following ICI therapy, Grade 1 and 2 IRP incidence ranges from 2% to 13.2%, whereas the incidence of IRP of ≥ Grade 3 is up to 4.2%.[12],[13] Treatment with PD-1 antibodies is more likely to trigger IRP than treatment with PD-L1 antibodies in treatment-naive patients. Furthermore, patients treated with PD-1 antibodies are more likely to develop grade 3 or 4 IRP.[14]

The expression levels of interferon (IFN) regulatory factor 5 and its related cytokines (interleukin [IL]-6, IL-10, and IFN-gamma-inducible protein 10) are significantly increased in IRP patients and positively associated with disease severity.[15]

IRP can be classified into five subtypes: cryptogenic organizing pneumonia-like (COP), ground-glass opacity (GGO), interstitial, hypersensitivity, and pneumonitis not otherwise specified.[16] Here, the IRP in the two patients mainly presented as COP and GGO subtypes.

Because most IRP patients can recover from IRP with corticosteroid intervention, they are usually the first-choice treatment. Infliximab, mycophenolate mofetil, intravenous immune globulin, and cyclophosphamide are mainly used to treat serious and steroid-refractory pneumonitis.[17],[18],[19] Here, the patients experienced Grade 2 or 3 IRP and recovered with corticosteroid treatment.

A previous study reported that poor clinical outcomes associated with pneumonitis were more frequent in current smokers and patients with underlying lung conditions.[16] In this study, 11 patients experienced recurrent pneumonitis during drug holding or corticosteroid therapy, among whom 8 experienced resolution or improvement although three died. Twelve patients were rechallenged with immunotherapy after an initial Grade 1 or 2 pneumonitis event. Three patients (25%) experienced recurrent pneumonitis that resolved with drug holding and corticosteroid therapy.[16] The study's small sample limited the conclusion, which should be further evaluated in a large sample study.

Therefore, in advanced NSCLC patients treated with MWA plus camrelizumab, camrelizumab rechallenge can be effective although should be carefully considered when IRP had occurred previously.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The study was supported by National Natural Science Foundation of China (No. 81901851) and Wu Jieping Medical Foundation (No.320.6750.19025).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65.  Back to cited text no. 6
    
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Yao W, Lu M, Fan W, Huang J, Gu Y, Gao F, et al. Comparison between microwave ablation and lobectomy for stage I non-small cell lung cancer: A propensity score analysis. Int J Hyperthermia 2018;34:1329-36.  Back to cited text no. 7
    
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Wei Z, Ye X, Yang X, Huang G, Li W, Wang J, et al. Microwave ablation plus chemotherapy improved progression-free survival of advanced non-small cell lung cancer compared to chemotherapy alone. Med Oncol 2015;32:464.  Back to cited text no. 8
    
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Chiarion-Sileni V, Pigozzo J, Ascierto PA, Simeone E, Maio M, Calabrò L, et al. Ipilimumab retreatment in patients with pretreated advanced melanoma: The expanded access programme in Italy. Br J Cancer 2014;110:1721-6.  Back to cited text no. 9
    
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Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res 2018;6:1093-9.  Back to cited text no. 10
    
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Watanabe H, Kubo T, Ninomiya K, Kudo K, Minami D, Murakami E, et al. The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer. Jpn J Clin Oncol 2019;49:762-5.  Back to cited text no. 11
    
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Nishino M, Chambers ES, Chong CR, Ramaiya NH, Gray SW, Marcoux JP, et al. Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer. Cancer Immunol Res 2016;4:289-93.  Back to cited text no. 12
    
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Cho JY, Kim J, Lee JS, Kim YJ, Kim SH, Lee YJ, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer 2018;125:150-6.  Back to cited text no. 13
    
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Khunger M, Rakshit S, Pasupuleti V, Hernandez AV, Mazzone P, Stevenson J, et al. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of trials. Chest 2017;152:271-81.  Back to cited text no. 14
    
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Wang X, Guo J, Wang Y, Xiao Y, Wang L, Hua S. Expression levels of interferon regulatory factor 5 (IRF5) and related inflammatory cytokines associated with severity, prognosis, and causative pathogen in patients with community-acquired pneumonia. Med Sci Monit 2018;24:3620-30.  Back to cited text no. 15
    
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Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol 2017;35:709-17.  Back to cited text no. 16
    
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Andruska N, Mahapatra L, Hebbard C, Patel P, Paul V. Severe pneumonitis refractory to steroids following anti-PD-1 immunotherapy. BMJ Case Rep 2018;2018:bcr2018225937.  Back to cited text no. 17
    
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Li R, Lee G, El-Sherief A. Immunotherapy causing pneumonitis in a patient with non-small cell lung cancer (NSCLC). BMJ Case Rep 2019;12:e226044.  Back to cited text no. 18
    
19.
Wei Z, Yang X, Ye X, et al. Camrelizumab combined with microwave ablation improves the objective response rate in advanced non-small cell lung cancer. J Cancer Res Ther 2019;15:1629-34.  Back to cited text no. 19
    


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