Long-term benefit of immunotherapy in a patient with mismatch repair deficient/microsatellite instability-high/high tumor mutational burden lung cancer: case report and literature review

doi:10.21203/rs.3.rs-2092664/v1

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Case Report

Long-term benefit of immunotherapy in a patient with mismatch repair deficient/microsatellite instability-high/high tumor mutational burden lung cancer: case report and literature review

https://doi.org/10.21203/rs.3.rs-2092664/v1

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Genetic mutations that cause defective mismatch repair, may result in microsatellite instability, which is common in colorectal carcinoma and gastric cancers as well as Lynch syndrome. Mismatch repair deficiency/microsatellite instability-high(dMMR/MSI-H) predicts the tumor response to immune checkpoint inhibitors. However, few studies have evaluated the effects of immune checkpoint inhibitors on dMMR/MSI-H non-small cell lung cancer (NSCLC). We report here a squamous lung cancer patient with dMMR/MSI-H and high tumor mutational burden(TMB-H) who obtained the long-term benefit from immunotherapy. We consider that NSCLC patient with dMMR/MSI-H can benefit from immune checkpoint inhibitors.

mismatch repair deficiency/microsatellite instability-high

high tumor mutational burden

non-small cell lung cancer

immunotherapy

case report

Lung cancer is one of the most common cancers worldwide. The World Health Organization revealed that 2.207 million new cases of lung cancer were reported in 2020, with the highest mortality rate among all cancer.^[1] Immunotherapy is one of the main treatmens for advanced non-small cell lung cancer (NSCLC). In particular, programmed cell death-protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) inhibitors are effective for the treatment of advanced NSCLC. The main biomarkers of the efficacy of immune checkpoint inhibitors are tumor cell surface PD-L1 expression level, tumor mutational burden (TMB), mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H), and tumor-infiltrating lymphocytes.

Defects in DNA mismatch repair may lead to microsatellite instability, and subsequently a high TMB (TMB-H) and PD-L1 overexpression. The presence of dMMR/MSI-H detection was first detected in patients newly diagnosed with colorectal cancer. Studies have shown that dMMR/MSI-H is closely associated with the immunotherapy responce of solid tumors, particularly colorectal cancer,^[2] hysterocarcinoma,^[3] and gastric cancer.^[4] Accordingly, pembrolizumab and nivolumab were approved for the treatment of dMMR/MSI-H tumors by the United States Food and Drug Administration (FDA) in 2017.^[1][6] Furthermore, pembrolizumab was approved as the first-line treatment of unresectable or metastasized dMMR/MSI-H colorectal cancer in 2020. However, additional evidence is required to determined whether dMMR/MSI-H can predict the effects of immune checkpoint inhibitors on NSCLC. Here, we report a case of unresectable or metastasized dMMR/MSI-H/TMB-H squamous cell lung cancer with a long-term good reponse to toripalimab treatment.

A 53-year-old non-smoker presented with an irritating cough, chest tightness, and shortness of breath for 5 months. There was no family history of tumors. Chest computed tomography (CT) showed a lesion near the right upper hilum with right upper pulmonary bronchial occlusion, and multiple lymph node metastases in the right hilum and mediastinum. Positron emission tomography-CT (PET-CT) showed that the lesion involved the adjacent pleura and bronchi of the right upper lobe. No other metastases were detected (Fig. 2A). The patient underwent fiberoptic bronchoscopy and biopsy of the tumor. Pathological examination of the tissue from the right upper lung revealed moderately differentiated squamous cell carcinoma (Fig. 1A, B). The patient was classified as T3N2M0 (Ⅲb) according to the 8th edition of the Union for International Cancer Control (UICC). Next-generation sequencing revealed MSI-H as well as mutations in MSH2 (p.E364*Exon7), MSH6 (p.F1104Lfs*11Exon5) (Fig. 1C), TP53 (p.R213*Exon6) and PTEN (p.R130QExon5) .The tumor mutational burden was 29.84 Muts/Mb. The results of the genetic test led us suspected that this patient possessed dMMR, MSI-H and TMB-H. The patient achieved stable disease (SD) after four courses of docetaxel plus cisplatin chemotherapy and 23 cycles of radiotherapy. Due to financial reasons, the patient was started on toripalimab immunotherapy on October 11, 2019. In March 2022, PET-CT showed an inactive or substantially suppressed tumor in the right upper lobe near the lung hilum (Fig. 2A). At the time of writing this report ( August 2022), the patient has been followed for 33 months and continues to maintain SD with toripalinab treatment (Fig. 2B and 3).

DNA mismatch repair genes correct base mismatch. The MMR system comprises four genes and their encoded proteins (MLH1, MSH2, MSH6, and PMS2), which identify and repair base mismatch, insertion, and deletion in the DNA damage response signal network and maintain the structural integrity and stability of DNA.^[7] Mutations in the MMR system genes occur mainly in Lynch syndrome (also called hereditary nonpolyposis colorectal cancer)^[8] and endometrial carcinoma and gastric cancers. However, lung cancer patients have an MMR gene mutation only 4–5%^[9]. MMR leads to mismatch accumulation during DNA base replication and consequently MSI-H. DeMarchiP et al.^[10] showed that the morbidity rate of MSI-H lung cancer was only 0.8% (4 cases) among 480 cases of lung adenocarcinoma, and there was only one mismatch repair defect (MLH1, PMS2) in 4 cases of highly microsatellite unstable lung cancer (MLH1, PMS2)^[10]. Furthermore, there was only 1 case of MSI-H (0.19%) among 524 cases of NSCLC^[11]. We report a rare case of a patient with dMMR/MSI-H/TMB-H squamous cell lung cancer who maintained SD during 33 months of toripalimab treatment. Therefore, dMMR/MSI-H NSCLC can benefit from immunotherapy, and dMMR/MSI-H may serve as a predictor of the response to immunotherapy for patients with dMMR/MSI-H/TMB-H NSCLC.

DMMR/MSI-H cancers are characterized by a strong mutator phenotype, high somatic mutation load, lymphocyte infiltration, and high expression of immune checkpoint markers.^[12] These cancers often produce new antigens to promote immune cell infiltration and upregulation of immune checkpoint molecules to promote tumor immune escape. PD-1 receptor inhibitors are used for immunotherapy and antagonize the aforementioned effects. The production of new antigens by MSI tumor underlies their increased immune activity. Because of the enhanced anti-tumor efficicy, patients with MSI tumors show a better prognosis and higher survival rate compared with non-MSI tumors.

Several large-scale clinical studies have demonstrated a role of dMMR/MSI-H in immunotherapy. In the KEYNOTE-177 study, patients with dMMR/MSI-H colorectal cancer were randomized to treatment with pembrolizumab or chemotherapy^[13]. The median survival times in the chemotherapy and pembrolizumab groups were 8.2 and 16.5 months, respectively. In the KEYNOTE-016 study, the objective response rate in the pembrolizumab group reached 36% in dMMR/MSI-H colorectal cancer and 46% in other cancers. As a result, pembrolizumab was approved by the FDA for the treatment of MSI-H/dMMR cancer that are unresectable and have metastasized.^[14] In the CheckMate-142 study,^[15] nivolumab alone and nivolunmab plus ipilimumab were used to treat dMMR/MSI-H colorectal cancer; the patients were followed up for a median of 21 and 25.4 months, respectively, and demonstrated objective response rates of 34% and 58%, respectively. Furthermore, the nivolunmab plus ipilimumab group had a disease control rate of 81%, 12-month progression-free survival(PFS) rate of 71%, and 12-month overall survival rate of 85%. ^[16] As a result, Nivolumab was approved by the FDA for the treatment of dMMR or MSI-H metastatic colorectal cancer patients aged ≥ 12 years who exhibit disease progression after treatment with fluorouracil, oxaliplatin, and irinotecan.

Few studies have evaluated the relationship between MMR gene mutations and immunotherapy response in NSCLC patients. Mendez et al,^[17] revealed that the PFS of patients with loss of MMR expression (8 months) was two-fold longer than that of patients who with retained MMR expression (4 months)^[17].

Previous studies have shown that the TMB is associated with a good response to immune checkpoint inhibitors.^[17] This may be due to changes in the microsatellite sequence of patients with dMMR and a large number of tumor cell mutations, resulting in TMB-H and consequently the production of new antigens and lymphocyte mobilization. As a result, tumor growth and tumor lymphocyte infiltration, may be inhibited, leading toa good effect of immunotherapy.^[18] Huang et al,^[19] found that the median PFS was longer in patients with TMB-H lung cancer versus low TMB lung cancer (10.6 months vs. 3.9 months). This suggests that TMB is a potential biomarker of the response to the PD-1 and PD-L1 inhibitors in advanced NSCLC. Additionally, Rizvi et al.^[20] revealed that a higher non-synonymous TMB in NSCLC is associated with a good long-term response to pembrolizumab treatment.

The FDA-approved immune checkpoint inhibitors for NSCLC treatment include pembrolizumab, nivolumab, and atezolizumab. In the KEYNOTE-024 study, pembrolizumab was used for untreated NSCLC without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The pembrolizumab group had a two-fold greater 5-year survival rate compared with the chemotherapy group (31.9% vs 16.3%).^[22] in the CheckMate078 trial, nivolumab treatment had greater efficacy and fewer side effects compared with docetaxel treatment for stage IIIb/IV NSCLC that progressed after platinum-containing dual-drug treatment.^[23] A growing number of immune medicines, including pembrolizumab and nivolumab, have been approved by the FDA for the treatment of NSCLC based on the positive results of clinical trials.

The PD-1 inhibitor toripalinab was approved by the National Drug Administration in China, for the treatment of advanced or metastatic melanoma that had previously failed systemic therapy. In the CHOICE-01 study, the PFS of patients with EGFR- and ALK-negative stage Ⅲb/IV NSCLC was considerably longer in the toripalinab group with the placebo group (median PFS: 8.4 vs. 5.6 months).^[24] Furthermore, in the PD-L1 positive and negative subgroups, the risk of disease progression or death was decreased by 48% and 51%, respectively. The TMB-H (≥ 10mutations/Mbp) subgroup showed a better response to combination chemotherapy containing triplizumab and a lower risk of progressive disease or mortality compared with TMB-L group(median PFS: 13.1 vs.5.5 months, HR = 0.34). Our patient treated with toripalinab maintained SD over the 33-month follow-up.

In conclusion, our patient with a rare dMMR/MSI-H/TMB-H squamous cell lung cancer showed a good response to toripalinab treatment and achieved SD. The good treatment outment may be because of the benefit of conventional treatment on dMMR/MSI-H tumors and the longer PFS achieved by toripalinab resistance in TMB-H lung cancer. Studies on dMMR lung cancer are scarce, and there is no unified standard for the selection of immunosuppressants. Toripalinab may be useful for the treatment of such cases. Additionally, dMMR/MSI-H can be used to predict the treatment response of lung cancer to immune checkpoint inhibitors.

Acknowledgements

The authors are grateful to the patient and family members for their kind cooperation.

Funding

This study was supported by funding from Project of Scientific and Technological Innovation Governance System in the Post-epidemic Period of Guangzhou China [grant number ZLY202019]

Availability of data and materials

The datasets generated during and/or analysed during the current study are included in this published article (and its supplementary information files).Further inquiries are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Written informed consent was obtained from the individual(s) for the publication of any potentially identififiable images or data included in this article.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Authors' contributions

Concept and design: NL,RC. Acquisition, analysis, and interpretation of data: NL,RC,ZW. Drafting of the manuscript: NL. Critical revision of the manuscript for important intellectual content: RC,DL,XY. Study supervision: XY. All the authors gave fifinal approval of the version to be published, and agree to be accountable for all aspects of the work.

Authors' details

† These authors have contributed equally to this work.. *Correspondence: Ruilian Chen and Xiaowei Ye.1First Clinical Medical College, Guangzhou University of Traditional Chinese, Guangzhou, China, 2Department of Oncology, The First Affilliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou,China

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Long-term benefit of immunotherapy in a patient with mismatch repair deficient/microsatellite instability-high/high tumor mutational burden lung cancer: case report and literature review

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