Perimyocarditis Associated with Immune Checkpoint Inhibitors: A Case Report and Review of the Literature.

Patient prognoses have been significantly enhanced by immune checkpoint inhibitors (ICIs), altering the standard of care in cancer treatment. These novel antibodies have become a mainstay of care for metastatic non-small-cell lung cancer (mNSCLC) patients. Several types of adverse events related to ICIs have been identified and documented as a result of the launch of these innovative medicines. We present here a 74-year-old female patient with a stage IV lung adenocarcinoma, treated with nivolumab plus ipilimumab, who developed perimyocarditis two weeks after receiving the third cycle of immune checkpoint inhibitor therapy. The patient was diagnosed using troponin levels, computed tomography (CT) angiography, and echocardiography. After hospitalization, her cardiac condition was successfully resolved with corticosteroids, colchicine, and symptomatic treatment. To the best of our knowledge, this is one of the rarest cases to be reported of perimyocarditis as a toxicity of immunotherapy in a patient treated for adenocarcinoma of the lung.

Radiosynthesis and preclinical PET evaluation of 89Zr-nivolumab (BMS-936558) in healthy non-human primates.

Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types. This study reports the preparation and in vivo evaluation of 89Zr labeled nivolumab in healthy non-human primates (NHP) as a preliminary study of biodistribution and clearance. The radiochemical and in vivo stabilities of the 89Zr complex were shown to be acceptable for imaging. Three naïve NHPs were intravenously injected with tracer only or tracer co-injected with nivolumab followed by co-registered by positron emission tomography (PET) and magnetic resonance imaging (MRI), acquired for eight days following injection. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis. Radioactivity in the spleen was significantly reduced by addition of excess nivolumab compared to the tracer only study at all imaging time points. Liver uptake of the radiotracer was consistent as a clearance organ with minimal signal from other tissues: lung, muscle, brain, heart, and kidney. The results indicate specific biodistribution to the spleen, which can be blocked by co-administration of excess nivolumab. Distribution to other organs is consistent with elimination pathways of antibodies, with primary clearance through the liver.

The PAZOREAL noninterventional study to assess effectiveness and safety of pazopanib and everolimus in the changing metastatic renal cell carcinoma treatment landscape.

VEGFR and mTOR inhibitors are broadly used in metastatic renal cell carcinoma (mRCC) therapy, and sequential first-line pazopanib (VEGFR inhibitor) and second-line everolimus (mTOR inhibitor) is a standard treatment option. Nivolumab and lenvatinib/everolimus combination was recently approved in Europe for use in mRCC after previous therapy. Prospective routine data on sequential therapy including nivolumab and/or lenvatinib are missing. This is a prospective, noninterventional study, which evaluates the effectiveness, tolerability, safety and quality of life following 450 patients with mRCC starting either on pazopanib as first-line therapy or third-line everolimus plus/minus lenvatinib following nivolumab. Adults with histologically confirmed mRCC of any subtype, who have a life expectancy of at least 6 months, are eligible.

A Case of Immune-Mediated Pneumonitis Associated With Dual Nivolumab and Ipilimumab Immunotherapy Treatment.

Nivolumab and ipilimumab are immunotherapy agents used in combination to treat metastatic melanoma and have proven to be efficacious. However, they have been linked to the development of immune-mediated inflammatory processes in various organ systems and tissues, including immune-mediated pneumonitis (IMP). This case report describes a 50-year-old female patient with metastatic melanoma who was treated with nivolumab and ipilimumab therapy and developed IMP as a complication. Despite treatment with steroids and infliximab, the patient's condition worsened, and she passed away due to respiratory compromise. This report emphasizes the potential for serious complications in patients receiving combination immunotherapy and highlights the importance of close monitoring and risk stratification, particularly in patients with underlying lung conditions.

Unilateral Posterior Uveitis in a Patient Receiving Nivolumab for Malignant Melanoma.

Patients using immunotherapies like immune checkpoint inhibitors (ICIs) can develop ocular immune-related adverse effects (irAEs). Nivolumab (Opdivo®;Bristol-Myers Squibb, New York, NY, USA) is a commonly used ICI used to treat malignancies. A 75-year-old woman presented to our eye clinic with sudden loss in vision in the right eye. She had started nivolumab monotherapy 10 days before the onset of symptoms for the treatment of melanoma. Examination showed low visual acuity (20/170) in the right eye with few reactive cells and macular oedema and swelling in the anterior and posterior segments, respectively. Optical coherence tomography (OCT) of the right eye showed intra-retinal and sub-retinal fluid and multiple hyperreflective inner retinal round foci in the areas of inflammation. The differential diagnoses were infectious uveitis, Vogt-Koyanagi-Harada-like syndrome or masquerade retinopathy. After a full work-up, the patient was diagnosed with unilateral posterior uveitis. The patient responded to topical steroid therapy with improved vision (20/30). Uveitis is listed as an adverse effect on the prescribing list of the drug Opdivo®. Although not reported before, our case demonstrated unilateral involvement. We thus recommend clinicians to be wary after complaints of side effects from their patients; ocular toxicities should be considered.

Nivolumab-Induced Pneumonitis in a Patient With Urothelial Cancer.

The introduction of immune checkpoint inhibitors has revolutionized cancer treatment. These drugs function by inhibiting the binding of programmed death-1 (PD-1) and its ligand, PD-L1, which inhibits the immune response against cancer cells. Nivolumab is a PD-1 inhibitor that specifically targets the PD-1 pathway. The main side effects of these drugs are unpredictable immune-related toxicities that occur when self-reactive T cells are abnormally activated and cause inflammation in various organs. The organs most often affected are the endocrine glands, lungs, skin, and gut. Recognizing and addressing lung inflammation is crucial, particularly in individuals with lung cancer. However, it can be challenging to diagnose due to the distinctive features of their disease and treatment regimen. This case report presents a 66-year-old man with a medical history of hypertension, chronic kidney disease (stage 3A), hypothyroidism, type 2 diabetes mellitus (DM), and transitional cell carcinoma of the bladder with interstitial pneumonitis secondary to nivolumab. The patient presented to the Eisenhower Medical Center, Rancho Mirage, CA, with dyspnea and cough for two weeks. He received methylprednisolone (Solu-Medrol) at 1.0 mg/kg for immune checkpoint inhibitor-induced pneumonitis and was discharged on 1 liter (L)/min home-oxygen therapy along with prednisone 50 mg twice daily (BD) for six weeks, trimethoprim-sulfamethoxazole (Bactrim) DS BD, and pantoprazole (Protonix) 40 mg once daily. Subsequently, nivolumab therapy was discontinued. At his follow-up visit two weeks later, he felt well and did not need oxygen therapy at rest.

What is the importance of difference in LCM strategy in drug development? - Learnings from Keytruda and Opdivo.

Immune checkpoint inhibitors have changed how cancer is treated. As of February 2022, six immune checkpoint inhibitors had been approved, with Keytruda and Opdivo accounting for the majority of global sales. Here, the impact of the differences in commercial success between Keytruda and Opdivo is reviewed by analyzing inter-organizational deals since their launch in 2014. Both showed a correlation between the cumulative number of indications and product sales trends, the latter crossing from 2017 to 2018. Differences in sales were due to different approaches to life cycle management by inter-organizational deals and drug development strategies, the key to commercial success.

An Unusual Etiology of Hypothyroidism and New-Onset Insulin-Dependent Diabetes: A Rare Side Effect of Nivolumab.

Nivolumab, a monoclonal antibody targeting programmed cell death 1 receptor, is prescribed for many advanced cancers like malignant melanoma, non-small cell lung cancer, renal cell cancer, etc. With the increase in the use of nivolumab like immunotherapy, the incidences of immune-related side effects are also on the rise. Immune-related endocrinopathies like hypothyroidism and new-onset type 2 diabetes mellitus associated with nivolumab use, although rare, are already documented in the literature. Here we present a case of hypothyroidism and new-onset type 2 diabetes mellitus in a renal cell cancer patient receiving nivolumab for the past six months. The patient was managed successfully with discontinuation of nivolumab, intravenous insulin, and thyroid hormone replacement therapy. These types of endocrinopathies can be fatal; hence, prompt diagnosis and management are required. Thus, not only physicians' awareness of such endocrinopathies among nivolumab-treated patients but also patients' awareness regarding warning signs and symptoms are essential.

Recent Debate over How to Tackle Rapid Increases in Pharmaceutical Expenditure in Japan.

Pharmaceutical expenditure has been rapidly increasing since 2000 in Japan mainly due to successive introduction and diffusion of high-priced new pharmaceuticals (thereafter, drugs). The share of drug expenditure in the national healthcare expenditure rose from 19.6% in 2000 to 22.3% in 2013, a 2.7% point rise in 13 years. In the same period, the share of healthcare personnel's income dropped 3.8% points from 50.2% to 46.4%. Further, in 2016 national healthcare expenditure rose for 3.8%, which is exceptionally high by Japanese standard (roughly 2%), and the main culprit was the rapid increase in drug expenditure due to successive introduction of extremely high-priced drugs. Due to these changes, drugs have become the main target in current healthcare cost containment policy. In this article, I briefly explain two debates relating to drug cost and cost control that occurred in 2016 and 2017, respectively, in Japan, based on my two articles that I wrote when I participated in these debates. Although two debates are independent, the first debate that was triggered by an introduction of extraordinary high-priced drug (Opdivo) substantially affected the second debate on how to introduce official cost-effectiveness appraisal of new drugs in Japan.

Corneal ulceration associated with Nivolumab use.

PURPOSE: To describe a case of corneal ulceration associated with Nivolumab use. OBSERVATIONS: An 80-year-old woman treated with Nivolumab for metastatic melanoma developed an intractable corneal ulcer in her left eye, refractory to all therapies - including surgery to cover the ulcer with a conjunctival flap - until topical prednisolone acetate was tried, which was curative. CONCLUSIONS AND IMPORTANCE: Nivolumab use may be associated with a form of steroid-responsive corneal ulceration.

Inflammatory Reaction Secondary to Immune Checkpoint Inhibitor Therapy Mimicking a Post-Operative Brain Abscess.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of many cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. These therapeutics increase the activity of T cells against neoplastic cells, although the immune response generated also has the potential to target normal cells, resulting in immune related adverse events (irAEs). Most irAEs occur outside of the nervous system, but cases of limbic encephalitis, hypophysitis, optic neuritis, and pseudoprogression have been reported. CASE DESCRIPTION: Here, we present a case of an intracranial irAE after neoadjuvant stereotactic radiosurgery and craniotomy for resection of a left parietal lobe metastasis. The patient presented with headache, right-sided apraxia, and a pronator drift 2 weeks after surgery. Imaging findings were suggestive of an intracranial abscess. The lack of fever, normal white blood cell count, and benign clinical appearance in the setting of combination nivolumab and ipilimumab therapy argued in favor of an irAE, however. After initiation of dexamethasone, the neurologic deficits resolved and the magnetic resonance imaging of the brain normalized over 7 weeks. CONCLUSIONS: This is the first report of an acute surgical-site irAE after stereotactic radiosurgery and craniotomy in a patient receiving nivolumab and ipilimumab. These immune-mediated responses can be treated with corticosteroids and close observation.

Checkpoint inhibitors: a cutting edge in oncology.

The checkpoint inhibitor field, and indeed the whole of immuno-oncology, is fast-paced and fascinating, with huge clinical and commercial potential. The challenge in the coming years will be to define the best type and combination of immunotherapy, and the best target population to receive it. Keytruda's ground-breaking approval for a biomarker-based rather than location-based indication is a solid step in this direction, and is likely to be followed by other such approvals. As the field develops, it is to be hoped that immuno-oncology therapeutics will continue to deliver the significant improvements in patient outcome that have been seen so far.

Precision medicine in immune checkpoint blockade therapy for non-small cell lung cancer.

Immune checkpoint blockade therapy by targeting the programmed death protein 1/programmed death ligand 1 (PD-L1) axis using antibodies has yielded promising clinical responses in patients with non-small cell lung cancer (NSCLC). However, owing to the dynamic expression of PD-L1, degree of mutational/neoantigen load, intratumoral heterogeneity, infiltrated immune cells of tumor microenvironment of NSCLC, the response rates to these agents are limited, despite several companion diagnostic assays by detecting PD-L1 in tumor cells have been introduced into clinical practice. Therefore, in this era of precision medicine, there is an urgent need for predictive biomarkers to identify NSCLC patients likely to benefit from this novel therapy.

Intellectual property issues of immune checkpoint inhibitors.

Immune checkpoint inhibitors are drugs that interfere with tumor escape responses. Some members of this class are already approved, and expected to be blockbusters in the future. Many companies have developed patent activities in this field. This article focuses on the patent landscape, and discusses key players and cases related to immune checkpoint inhibitors.

Combinatorial immunotherapy with checkpoint blockers solves the problem of metastatic melanoma-An exclamation sign with a question mark.

Results from recent clinical trials demonstrate that a combinatorial immunotherapeutic regimen based on 2 distinct checkpoint blockers, namely, the CTLA4-targeting agent ipilimumab and the PD-1-specific molecule nivolumab, causes objective responses in a majority of subjects with advanced melanoma. These findings revolutionize the treatment of a neoplasm that was considered incurable until recently. Nonetheless, announcing the defeat of melanoma appears premature. Indeed, a sizeable fraction of patients does not respond to ipilimumab plus nivolumab, and the long-term efficacy of this immunotherapeutic regimen has not yet been investigated. Moreover, many patients experience severe side effects, calling for the development of strategies that uncouple the efficacy of ipilimumab plus nivolumab from their toxicity.