Nivolumab Safety in Renal Cell Carcinoma: A Case Report

Abstract

Nivolumab is used to treat several different types of cancers. Although it is generally considered to be effective and well-tolerated, it has been associated with adverse effects requiring discontinuation of treatment, like many other drugs used for cancer. A 70-year-old male was switched from sunitinib to nivolumab for renal cell carcinoma. The patient developed persistent hypothyroidism, onycholysis, and pneumonitis at nivolumab cycle 6, 10, and 11, respectively. Using the Naranjo causality method, the likelihood of causality was deemed “probable” for pneumonitis and hypothyroidism and “possible” for onycholysis. Nivolumab was eventually discontinued due to disease progression, rather than safety concerns. Eudravigilance, the European pharmacovigilance database, was searched for all nivolumab-related individual case safety reports from Malta, up to September 4, 2023. Six reports were identified in Malta, although the 3 events identified in this case report were not reported, suggesting under-reporting in Malta. This case report identified an uncommon nivolumab adverse drug reaction (ADR), onycholysis and showed how, despite the occurrence of 3 ADRs, it was its lack of efficacy rather than its safety which led to its discontinuation in this particular patient.

Introduction

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody belonging to the class of immune checkpoint inhibitors (ICIs); it is indicated in many different types of cancers, including nonsmall cell lung cancer, renal cell carcinoma, urothelial carcinoma, melanoma, squamous cell carcinoma of the head and neck, and upper gastrointestinal malignancies. ¹ It works by binding to the programmed death-1 (PD-1) receptor and blocking its interaction with programmed death-ligand (PD-L)1 and PD-L2. Programmed death-1, PD-L1, and PD-L2 are immune checkpoints that are significantly over-expressed in neoplasms and inhibit T-cell signals. ² The presence of immune checkpoints is an adaptive response to escape detection by the immune system.^3,4 By inhibiting these immune checkpoints, nivolumab promotes the function of cytotoxic T cells to destroy neoplasm cells, selectively targeting the latter. ⁵ There are 7 ICIs licensed in Europe at the time of writing, of which nivolumab was licensed in 2015.

Although ICIs such as nivolumab have revolutionized cancer care, they also have their share of adverse drug reactions (ADRs), including immune-mediated adverse reactions. ⁶ Although ADRs occur commonly in patients taking systemic anti-cancer treatment (SACT), there is significant under-reporting in oncology. ⁷ It is therefore important to describe and understand ADRs occurring with chemotherapy as well as how they are managed in clinical practice. In the present case report, we describe a patient who developed 3 ADRs after treatment with nivolumab, which, however, did not lead to discontinuation.

Case Report

A 70-year-old retired maintenance worker, ex-smoker who stopped smoking in 2003, with a history of noninsulin-dependent diabetes mellitus, hypertension, hyperlipidemia, and splenectomy was referred to the national oncology hospital in 2020 for consideration of treatment after investigations for weight loss, anemia, and left-sided shoulder pain revealed metastatic renal cell carcinoma. Staging investigations showed a 13-cm enhancing mass in the left kidney, thrombus in the left renal vein with distal extension in the inferior vena cava, bilateral pulmonary metastatic deposits, and bone secondary metastases including L1, L2, and left scapula. His drug history included aspirin 75 mg once daily (OD), metformin 500 mg OD, simvastatin 40 mg OD, and perindopril 4 mg OD.

Initial management involved commencement of enoxaparin which was eventually switched to rivaroxaban 10 mg maintenance dose, palliative radiotherapy to the left scapula for pain relief and commencement of sunitinib 37.5 mg as first-line tyrosine kinase inhibitor, to which there was a good and sustained response. He tolerated sunitinib well with the main suspected ADR being hypothyroidism which was treated by starting 50 mcg levothyroxine. He eventually had disease progression after 18 months of treatment and was switched to nivolumab in June 2021. The patient did not have any radiotherapy while taking nivolumab. The oncology protocol used was 480 mg nivolumab once every 4 weeks.

Initial treatment with nivolumab led to a reduction in size of the left renal tumor and stable appearances of the skeletal lesions. Biochemically, the patient was tolerating treatment well but developed persistent hypothyroidism in January 2022 after 6 cycles of nivolumab. This required several dose adjustments of levothyroxine until his thyroid function tests were normalized. Interestingly, 10 cycles into nivolumab treatment, the patient complained of brittle toenails and eventually, nail dystrophy and onycholysis set in. This led to loss of 3 toenails, a potential ADR which is not commonly attributed to immunotherapy and less commonly documented in the literature.

A restaging scan performed after 11 cycles of treatment also showed new ground glass changes in the left lung and multiple consolidations and smaller foci of ground glass changes in the right lung. These changes were deemed to be drug-induced changes, likely related to nivolumab. Clinically the patient was well, his oxygen saturations were normal, and he did not express any pulmonary symptoms. Nivolumab was omitted for 1 cycle and on reviewing the patient again, there were no new symptoms. Clinically the chest was clear and saturations remained within normal limits. It was decided to proceed with nivolumab and a repeat computed tomography (CT) scan to follow-up these pulmonary changes. This showed improvement of the pneumonic changes but disease progression in bone and new lung metastases. Nivolumab was therefore stopped on the November 30, 2022, with the last cycle being cycle 17, and the patient was started on low-dose everolimus. He was continued on all his other medications. The pneumonitis resolved completely after nivolumab was discontinued. The patient was tested for COVID-19 regularly (every 1-2 months) in order to ascertain it was safe for him to take chemotherapy, from May 2020 to August 2022. COVID-19 was never detected. Therefore, changes to the lung such as ground glass opacities due to COVID-19^8,9 were excluded.

Using the Naranjo algorithm, ¹⁰ the causality assessment for pneumonitis and hypothyroidism was deemed “probable,” and for onycholysis, this was deemed “possible” (Table 1). Another causality assessment method, the French causality method, ¹¹ was also used in order to allow comparison with causality assessments in the European spontaneous reporting database, Eudravigilance. Using the French causality method, the causality for the 3 suspected ADRs was “possible” for hypothyroidism, “probable” for onycholysis, and “highly probable” for pneumonitis (Supplemental Appendix Table 1). In order to investigate whether these ADRs were previously reported in Malta, Eudravigilance, the European database of spontaneous case reports, was searched for all case reports for nivolumab in Malta on September 4, 2023. Only 6 case reports were found, none of which included the 3 ADRs identified in this article (Table 2).

Table 1.

Summary of Causality Assessment Using the Naranjo Causality Method for Nivolumab.

Criterion	Possible answers	Pneumonitis	Hypothyroidism	Onycholysis
Are there previous conclusive reports of this reaction?	Yes: +1 No: 0 Don’t know: 0	1	1	0
Did the adverse event appear after the drug was given?	Yes: +2 No: −1 Don’t know: 0	2	2	2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	Yes: +1 No: 0 Don’t know: 0	1	0	1
Did the adverse reaction reappear upon readministering the drug?	Yes: +2 No: −1 Don’t know: 0	0	0	0
Were there other possible causes for the reaction?	Yes: −1 No: +2 Don’t know: 0	2	2	−1
Did the adverse reaction reappear upon administration of placebo?	Yes: −1 No: +1 Don’t know: 0	0	0	0
Was the drug detected in the blood or other fluids in toxic concentrations?	Yes: +1 No: 0 Don’t know: 0	0	0	0
Was the reaction worsened upon increasing the dose? Or, was the reaction lessened upon decreasing the dose?	Yes: +1 No: 0 Don’t know: 0	1	0	0
Did the patient have a similar reaction to the drug or a related agent in the past?	Yes: +1 No: 0 Don’t know: 0	0	0	0
Was the adverse event confirmed by any other objective evidence?	Yes: +1 No: 0 Don’t know: 0:	1	1	1
Sum		87	6	3

≥ 9 = definite adverse drug reaction, 5-8 = probable adverse drug reaction, 1-4 = possible adverse drug reaction, 0 = doubtful adverse drug reaction.

Table 2.

Spontaneous Reports in Malta Identified From Eudravigilance.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Age	65	48	55	64	Not reported	66
Gender	Female	Female	Male	Male	Male	Male
Concomitant drugs	Not reported	Flupentixol/melitracen combination product	Amlodipine, aspirin, simvastatin	Aspirin, clopidogrel, codeine, ezetimibe, paroxetine	Amlodipine, bendroflumethiazide, levothyroxine, perindopril	Not reported
ADR(s)	Hepatitis	Lichen planus	Peripheral arterial occlusive disease	Deep vein thrombosis , thromboembolism , pulmonary embolism, respiratory failure	Acute myocardial infarction	Peripheral sensory neuropathy , scleroderma
Seriousness (as per legal definition)	Yes (caused hospitalization)	Yes (other)	Yes (other)	Yes (death)	Yes (caused hospitalization)	Yes (caused disability)
Causality	Probable	Highly probable	Uncertain	Uncertain	Uncertain	Possible
Primary source qualification	Physician	Physician	Physician	Physician	Physician	Physician

Discussion

This case report describes a patient who developed 3 ADRs after treatment with nivolumab, a biological drug placed on the European market in 2015 and currently not subject to additional monitoring with the European Economic Area. Two of the ADRs, hypothyroidism and pneumonitis were among the most common ADRs for nivolumab in the CheckMate 066 clinical trial with 1 year’s follow-up, occurring in 9 (4.4%) and 3 out of 206 (1.5%) patients, respectively. ¹² In this phase 3 trial, nivolumab was compared to dacarbazine in previously untreated melanoma. It is interesting that none of the ADRs in the present case report led to the discontinuation of nivolumab: this drug was discontinued because of disease progression. Indeed, in the CheckMate 066 trial, 111 (53.9%) of nivolumab patients did not continue treatment; however, this was much lower than for dacarbazine, where 192 (93.7%) patients discontinued treatment. ¹² The major reason for discontinuing nivolumab treatment was disease progression in this trial, occurring in 96 (46.6%) nivolumab-treated patients vs 175 (85.4%) dacarbazine-treated patients. ¹² This is consistent with our reported case. Discontinuation due to ADRs occurred in only 5 (2.4%) nivolumab-treated patients vs 7 (3.4%) dacarbazine-treated patients. ¹² Overall, nivolumab is not considered to have a significantly higher risk of serious or fatal ADRs compared to control chemotherapy or placebo, according to a meta-analysis. ¹³

The first ADR to be observed, biochemical hypothyroidism, is a known immune-mediated ADR of nivolumab. ¹ From inception to September 4, 2023, a total of 2048 case reports of hypothyroidism with nivolumab use were identified in Eudravigilance. The biological mechanism behind this is unknown but is thought to be asymptomatic destructive thyroiditis which then evolves to hypothyroidism or euthyroidism. ¹⁴ The nivolumab summary of product characteristics states that the frequency of thyroid disorders, including hypothyroidism or hyperthyroidism, was 12.5%, occurring in 516 out of 4122 persons using nivolumab as monotherapy in a trial. ¹ However, the occurrence of ADRs in clinical trials is expected to be different to that in real-world practice, where patients tend to be older and have more comorbidities, as well as taking a larger number of concomitant medications than in trials. ¹⁵ Indeed, the occurrence of hypothyroidism has been found to vary across studies which more closely resemble or are set in a real-world context. It has been found to occur in 17 out of 73 (23%) patients in a prospective study set in a Spanish oncology center. ¹⁶ A larger European study recruiting nivolumab-treated patients in Hungary, Malta, and Croatia found that 10 out of 239 (4.2%) patients developed hypothyroidism. ¹⁷ A study in Japan found that hypothyroidism developed in 67 out of 200 (33.5%) nivolumab-treated patients. ¹⁸ A study carried out in Texas recruited 657 patients treated with an ICI, of whom 43 developed thyroid dysfunction. Of these, 37 developed hypothyroidism, making the occurrence of hypothyroidism 6 patients for every 100. ¹⁹ The onset of hypothyroidism in our patient was 7 months after the start of treatment, which is approximately 28 weeks. This delayed onset is consistent with immune-mediated reactions. One study which measured the median time to onset of hypothyroidism found this to be 10.4 weeks (range = 3.4-48.7 weeks). ¹⁹ None of the medications taken concomitantly by the patient are known to be associated with hypothyroidism. Metformin has been found to be affect thyroid-stimulating hormone (TSH) levels in persons with hypothyroidism; ²⁰ a review of studies showed that this does not typically occur in persons who are euthyroid. ²¹

The second ADR to occur, brittle toenails and eventually, nail dystrophy and onycholysis, is not mentioned in the summary of product characteristics. In Eudravigilance, 4 cases of onycholysis were identified with nivolumab on September 4, 2023, when reports were not restricted to cases occurring in Malta. There is 1 published case report of nail dystrophy occurring with nivolumab, occurring after 43 cycles of nivolumab. ²² The biological mechanism behind this is unknown. The occurrence of brittle toenails and eventually, nail dystrophy and onycholysis in the present patient occurred much earlier in comparison, after 10 cycles. This ADR is uncommon, and to our knowledge, the present case report is only the fourth one to report the occurrence of nail involvement with nivolumab use, globally.^22,23

The third ADR to occur, pneumonitis, was potentially the most serious and is mentioned in the nivolumab summary of product characteristics, where specific recommendations are made on how to proceed should grade 2 or grade 3/4 pneumonitis occur. In Eudravigilance, 1641 case reports of pneumonitis were reported with nivolumab use. In our particular case, the pneumonitis was grade 1 as the patient was asymptomatic. As a result, it was decided to delay immunotherapy by 4 weeks but not give any steroids. The pneumonitis occurred after 11 cycles of nivolumab treatment, which is consistent with immune-mediated reactions. The identification of drug-induced pneumonitis can sometimes be more challenging in lung cancer patients especially in cases of hilar/bronchial obstruction which might cause atelectatic changes and recurrent chest infections and when lung radiotherapy is delivered. However, the pneumonitis changes were identified on a CT carried out on June 2, 2022. The patient started radiotherapy to the scapula on July 4, 2023, approximately 4 weeks after. It is therefore excluded that the pneumonitis changes are related to radiotherapy.

The biological mechanism behind ICI-induced pneumonitis is not clear, but it is likely due to increased T-cell reactivity to inhaled immunogenic particles after ICI-induced reversal of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and PD-1 constraints by pulmonary regulatory T cells. ²³ The risk of pneumonitis in a meta-analysis of 5 studies showed that nivolumab was significantly associated with an increased risk of all-grade pneumonitis compared to conventional chemotherapy (odds ratio = 4.75; 95% confidence interval [CI] = 1.54-14.69). ²⁴ A meta-analysis of 3 trials in renal cell carcinoma patients treated with nivolumab showed that the incidence of all-grade pneumonitis was 2.7 (95% CI = 1.9-3.6) per 100 persons; the incidence is higher in combination immunotherapy treatment. ²⁵ In a real-world cohort, pneumonitis occurred in 5 of 239 patients (2.1%) treated with nivolumab. ¹⁷ The risk factors for ICI-induced pneumonitis are exposure to tobacco smoke and higher lung tumor burden. It is not known if past thoracic radiotherapy or chronic obstructive pulmonary disease increases the risk of pneumonitis. ²⁶ A study using the Italian national pharmacovigilance reporting database found that out of 129 immune-related ADRs reported for ICIs, 59 (46%) involved nivolumab. ²⁷

There is limited information on the impact of ADRs on the discontinuing of nivolumab in a real-world setting. An Italian observational study identified patients receiving nivolumab as part of routine treatment; out of 237 patients receiving treatment in 22 oncology units, 96 (41%) stopped treatment early. ²⁸ Another observational study identified 106 patients treated with immunotherapy for advanced cutaneous melanoma who discontinued treatment in the absence of disease progression after significant tumor response. ²⁹ Overall, 60% of patients experienced toxicity leading to treatment discontinuation, although no information was available for nivolumab specifically.

Conclusions

In this case report, we identified 3 ADRs following nivolumab use for renal cell carcinoma which have not yet been reported as spontaneous reports in Malta: pneumonitis, hypothyroidism, and onycholysis. This report is only the fourth one globally to identify nail involvement with nivolumab. It is difficult to place the case in context within the national setting, since there appear to be very few reported cases. An important finding of this case report is that despite the occurrence of 3 ADRs with nivolumab, the drug was still well-tolerated and was not discontinued for drug safety reasons. The occurrence of 3 adverse events in the same patients shows the importance of drug safety monitoring among patients taking monoclonal antibodies.