Possible adverse effects of immunotherapy in non-small cell lung cancer; treatment and follow-up of three cases

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Abstract

In the past decade novel agents are on the market for non-small cell lung cancer adenocarcinoma based on pharmacogenomics. The epidermal growth factor receptor mutation, anaplastic lymphoma kinase and programmed death-ligand 1 investigation is necessary in the everyday clinical practice for the oncologic patient. Immunotherapy is nowadays the novel therapy for advanced stage non-small cell lung cancer with two agents nivolumab and pembrolizumab. In the current case series we will present adverse effects from our centers and comment on the treatment and follow-up of the patients.

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Current state of immunotherapy for non-small cell lung cancer.

Jyoti Malhotra, Salma Jabbour, Joseph Aisner (2017)

Lung cancer is the leading cause of cancer mortality and non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers. Platinum-based doublet chemotherapy is the standard first-line treatment for metastatic NSCLC when genomic testing reveals no targetable alteration such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) or ROS1 translocation/re-arrangements. But, chemotherapy produces response rates ranging only between 15-30%. For patients whose disease progresses on first-line chemotherapy, second-line therapy historically consists of taxane-based salvage chemotherapy with a response rate of less than 25%. Recently, immunotherapy with checkpoint inhibitor agents have demonstrated responses in advanced NSCLC, with some patients exhibiting durable responses after discontinuing therapy. In 2015, two immune checkpoint inhibitors targeting programmed cell death-1 (PD-1), nivolumab and pembrolizumab were approved for second-line therapy of NSCLC. In 2016, another checkpoint inhibitor targeting program death-ligand 1 (PD-L1), atezolizumab was approved for the same indication. Moreover, pembrolizumab also received approval in 2016 for first-line NSCLC treatment in patients with high PD-L1 expressing tumors. Immunotherapy for NSCLC has therefore, recently evolved into a true treatment modality with the acceptance of PD-1 and PD-L1 inhibitors as the new standard of care for second-line treatment. However, it is still at the discretion of the treating physician whether to use PD-1 or PD-L1 inhibitor as data to compare these two pathways is lacking. Focus is now also on exploring their role in the adjuvant and consolidation settings for NSCLC as well as on exploring novel combinations combining these agents with chemotherapy or radiation. Research is also needed in the development of predictive and prognostic biomarkers for these agents. While vaccine therapy trials in NSCLC have so far failed to show significant clinical benefit, the demonstration of enhanced immune response in these trials suggest the vaccine therapy needs additional evaluation in combination with other therapeutic modalities especially checkpoint inhibition.

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Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer

James Godwin, Shuchie Jaggi, Imali Sirisena … (2017)

Background Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM. Case Presentation A 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy. Conclusion New onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM.

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Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy

Kalliopi Domvri, Paul Zarogoulidis, Kaid Darwiche … (2013)

Lung cancer first line treatment has been directed from the non-specific cytotoxic doublet chemotherapy to the molecular targeted. The major limitation of the targeted therapies still remains the small number of patients positive to gene mutations. Furthermore, the differentiation between second line and maintenance therapy has not been fully clarified and differs in the clinical practice between cancer centers. The authors present a segregation between maintenance treatment and second line and present a possible definition for the term “maintenance” treatment. In addition, cancer cell evolution induces mutations and therefore either targeted therapies or non-specific chemotherapy drugs in many patients become ineffective. In the present work pathways such as epidermal growth factor, anaplastic lymphoma kinase, met proto-oncogene and PI3K are extensively presented and correlated with current chemotherapy treatment. Future, perspectives for targeted treatment are presented based on the current publications and ongoing clinical trials.

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Paul Zarogoulidis

Journal

Journal ID (nlm-ta): Respir Med Case Rep

Journal ID (iso-abbrev): Respir Med Case Rep

Title: Respiratory Medicine Case Reports

Publisher: Elsevier

ISSN (Electronic): 2213-0071

Publication date PMC-release: 14 July 2017

Publication date Collection: 2017

Publication date (Electronic): 14 July 2017

Volume: 22

Pages: 101-105

Affiliations

[a ]Pulmonary Department-Oncology Unit, “Theageneio” Anticancer Hospital, Thessaloniki, Greece

[b ]Pulmonary Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

[c ]Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece

[d ]Microdiagnostics, Pathology Private Center, Thessaloniki, Greece

[e ]Surgery Department, “Interbalkan” European Medical Center, Thessaloniki, Greece

[f ]Pharmacology-Clinical Pharmacology, Department of Clinical, Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

[g ]Department of Respiratory and Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China

[h ]Sana Clinic Group Franken, Department of Cardiology / Pulmonology / Intensive Care / Nephrology, “Hof” Clinics, University of Erlangen, Hof, Germany

Author notes

[∗ ]Corresponding author. Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.Pulmonary Department-Oncology Unit“G. Papanikolaou” General HospitalAristotle University of ThessalonikiThessalonikiGreece pzarog@ 123456hotmail.com

Article

Publisher ID: S2213-0071(17)30226-5

DOI: 10.1016/j.rmcr.2017.07.004

PMC ID: 5519224

PubMed ID: 28752057

SO-VID: 0b4ccd89-4ead-4e28-82c0-72f8b5642ed4

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 1 July 2017

Date revision received : 8 July 2017

Date accepted : 11 July 2017

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Possible adverse effects of immunotherapy in non-small cell lung cancer; treatment and follow-up of three cases

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Cancer Immunotherapy

Most cited references 12

Current state of immunotherapy for non-small cell lung cancer.

Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer

Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy

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