Thursday, March 31, 2016

More serious side effects with Anti-PD1!

Just as we learned with ipi, as more folks take anti-PD1 products, we are learning how serious some of the immune related side effects can be.  First there was this:  Fasciitis and encephalopathy after Keytruda.  And more recently, this:  Immune reactions with anti-pd1 can be serious! 
Now these reports have been published:

Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy.  Goldinger, Stieger, Meier, et al.  Clin Cancer Res. 2016 Mar 8. 

Immunotherapy experienced impressive progresses in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes and vitiligo are reported. Although frequent, they are have not been further characterized yet. In this analysis we aimed to systematically assess and characterize the adverse cutaneous reactions observed in melanoma patients treated with anti-PD-1 antibodies.

Melanoma patients were treated with anti-PD-1 antibodies within clinical trials and early access program. Adverse cutaneous eruptions emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison to maculopapular drug rash, cutaneous graft versus host disease and the severe drug eruption toxic epidermal necrolysis.

Between Feb 2013 and Sept 2015, 68 stage IV melanoma patients were treated at the University Hospital Zurich; 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes without signs of epidermal involvement to severe maculopapular rashes including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as toxic epidermal necrolysis-like reactions.

As predicted by the PD-1 knock out mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases to a toxic epidermal necrolysis-like pattern suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions.

Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study.  Koelzer, Rothschild, Zihler, et al. Immunother Cancer. 2016 Mar 15.

Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been recently approved for treatment of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). Despite important clinical benefits, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that are typically transient, but occasionally severe or even fatal.

This autopsy case illustrates that clinically overt irAEs may represent only a fraction of the total spectrum of immune-related organ pathology in patients treated with immune checkpoint inhibitors. We report a comprehensive analysis of systemic irAE pathology based on the autopsy of a 35-year-old female patient with metastatic melanoma treated first with ipilimumab and then nivolumab. The clinical course was characterized by a mixed tumor response with regression of skin and lung metastases and fatal progression of metastatic disease in the small bowel, peritoneum and brain. During therapy with ipilimumab, radiographic features of immune-related pneumonitis were noted. The autopsy examination established a sarcoid-like granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar damage. Importantly, a clinically unapparent but histologically striking systemic inflammation involving the heart, central nervous system, liver and bone marrow was identified. Severe immune-related end-organ damage due to lymphocytic myocarditis was found.

Autopsy studies are an important measure of quality control and may identify clinically unapparent irAEs in patients treated with immunotherapy. Pathologists and clinicians need to be aware of the broad spectrum of irAEs for timely management of treatment-related morbidity.

Anti-PD1-induced collagenous colitis in a melanoma patient.  Baroudjian, Lourenco, Pagès, et al.  Melanoma Res. 2016 Mar 17. 

Targeted immunotherapy has markedly improved the survival of melanoma patients. We report the case of a melanoma patient who developed a collagenous colitis under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a thickened apical subepithelial collagen layer with irregular collagen deposition of more than 25 µm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to a decrease in the number of stools to grade 2. Because of the prognosis of the disease, the efficacy of pembrolizumab in this patient and the lack of other efficient treatments, pembrolizumab was restarted, with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type of drug-induced colitis has emerged because of monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract immune-mediated adverse effects are now well described with ipilimumab. To the best of our knowledge, this is the first report of a collagenous colitis in a patient treated with pembrolizumab, thus suggesting a new mechanism of toxicity. Classically, collagenous colitis first-line treatment is based on discontinuation of the suspected treatment. However, there may be a strong benefit to maintaining an anti-PD1 regimen in our patients. In this case, symptomatic management associated with budesonide and cholestyramin enabled continuation of pembrolizumab.

New-onset toxicity with programmed death-1 inhibitor rechallenge.  Ludlow, Andrews, Pasikhova, Hill.  Melanoma Res. 2016 Mar 15. 

Immunotherapy has become a mainstay in the treatment of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1 (PD-1) inhibitors, which have been added more recently, represent two of the main classes of immunomodulating agents. PD-1 inhibitors are well tolerated and are known to have a decreased rate of occurrence of adverse effects compared with CTLA-4 inhibitors. However, the risk remains for serious immune-mediated adverse reactions. Given their long half and extended efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor may increase the risk of adverse effects. In addition, caution should be exercised when rechallenging grade 3 or 4 adverse effects with the same agent or a different agent of the same class. The re-emergence of a previous toxicity may occur or, as found in this case, a new severe effect may arise. This article will present a case of fatal immune-related hepatoxicity in a patient treated with a CTLA-4 inhibitor, followed by treatment with a PD-1 inhibitor.

Nivolumab-induced thyroid dysfunction.  Tanaka, Fujisaw, Maruyama, et al.  Jpn J Clin Oncol. 2016 Mar 23.

Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5°C after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible.

Limbic encephalitis following immunotherapy against metastatic malignant melanoma.  Salam, Lavin, Turan.  BMJ Case Rep. 2016 Mar 23.

Novel immunotherapies are increasingly being used to treat malignant melanoma. The use of such agents has been associated with triggering autoimmunity. However, there has been a paucity in reports of limbic encephalitis associated with these immunotherapies. Pembrolizumab, a monoclonal antibody against programmed cell death antigen (PD-1), is currently being trialled in the UK to treat malignant melanoma. We report a unique case of antibody-negative limbic encephalitis presenting 1 year after starting pembrolizumab, in the context of malignant melanoma. The patient presented with progressive cognitive decline. MRI of the brain revealed signal change within the limbic structures. Cerebrospinal fluid studies confirmed evidence of inflammation with raised white cell count and protein. We were able to prevent further progression of symptoms by stopping pembrolizumab and treating the patient instead with steroids. We advocate considering autoimmune neuroinflammation as a differential for neurological disorders presenting in patients receiving PD-1 antagonist treatment and immunotherapy in general.

I don't want to frighten anyone with all the crazy events documented here.  Overall, anti-PD1 products have minimal side effects compared to many other cancer treatments.  However, I published these so that should any "strange" things start happening to you after, or during, anti-PD1 therapy, you can speak with your doctor and get them checked out as quickly as possible.  After all, as Dr. Weber mused YEARS ago, 'This stuff is weird!" - c


  1. My son is on synthroid after his thyroid stopped working. We are now dealing with pancreatic symptoms. They are currently testing him for diabetes type 1. He completed treatment in January.