Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy.

Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder. Thyrotoxicosis as the initial presentation occurred in the majority of patients (93% and 56% of the patients receiving combination therapy and monotherapy, respectively). The onset pattern of the thyroid disorder was significantly different between the two groups (P = 0.01). Subsequently, 76% and 90% of the patients with thyrotoxicosis evolved to develop hypothyroidism in the combination and monotherapy groups, respectively. In the combination therapy and monotherapy groups, the median times to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either anti-PD-1 or combination anti-PD-1 and anti-CTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and evolution of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Cancer Immunol Res; 5(12); 1133-40. ©2017 AACR.

Diagnostic Comparison of CT Scans and Colonoscopy for Immune-Related Colitis in Ipilimumab-Treated Advanced Melanoma Patients.

Colitis can be a life-threatening toxicity for patients treated with immune checkpoint blockade antibodies. With the anticipated widespread use of these reagents, the timely and accurate diagnosis of immune-related colitis becomes increasingly important. To better understand the clinical presentation of colitis from ipilimumab and to assess the use of CT scans of the abdomen/pelvis as a diagnostic tool, we retrospectively analyzed patients with advanced melanoma who received ipilimumab at our institution. Ninety nine (33%) of 303 patients developed diarrhea during therapy, and 46 patients (15%) received corticosteroids for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46 (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and biopsy, CT was highly predictive of colitis on biopsy (positive predictive value 96%), and the absence of CT findings was predictive of a negative biopsy (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (positive predictive value 92%, positive likelihood ratio 7.3). We conclude that CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas colonoscopy and biopsy may not be needed to establish that diagnosis. Cancer Immunol Res; 5(4); 286-91. ©2017 AACR.

Single Institution Experience of Ipilimumab 3 mg/kg with Sargramostim (GM-CSF) in Metastatic Melanoma.

Ipilimumab, 10 mg/kg with sargramostim (GM-CSF; GM), improved overall survival (OS) and safety of patients with advanced melanoma over ipilimumab in a randomized phase II trial. The FDA-approved dose of ipilimumab of 3 mg/kg has not been assessed with GM (IPI-GM). Consecutive patients treated with IPI-GM at a single institution were reviewed. Treatment included ipilimumab every 3 weeks × 4 and GM, 250-µg s.c. injection days 1 to 14 of each ipilimumab cycle. Efficacy, clinical characteristics, toxicities, and blinded radiology review of tumor burden were evaluated. Thirty-two patients were identified with 25 (78%) having immune-related response criteria (irRC) measurable disease and 41% with central nervous system metastases. A total of 88.6% of GM doses were administered. Response rate by irRC and disease control rate at 12 weeks were 20% and 44%, respectively (median follow-up 37 weeks). Immune-related adverse events (irAE) were observed in 10 (31.3%) patients, with 3 (9.4%) grade 3 events. Patients with grade 3 irAEs had prior autoimmunity, advanced age, and poor performance status. The median OS from first dose of ipilimumab was 41 weeks. Ipi-GM treatment is feasible and in this poor-risk advanced melanoma population, efficacy appeared similar but safety appeared improved relative to historical ipilimumab alone.

Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study.

PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier. RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. CONCLUSION: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given.

Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade.

IMPORTANCE: Ipilimumab, a human monoclonal antibody targeted against cytotoxic T-lymphocyte antigen 4, has shown promise in the treatment of metastatic melanoma. However, given its mechanism of action, immune-related adverse effects have been reported with this therapy. Despite increasing reports of immune-related adverse effects related to ipilimumab therapy, dermatomyositis associated with this agent has not previously been reported. OBSERVATIONS: We describe a woman undergoing treatment with ipilimumab for metastatic melanoma who developed classic cutaneous findings of dermatomyositis along with proximal muscle weakness and elevated muscle enzymes. CONCLUSIONS AND RELEVANCE: This case adds to the expanding literature regarding immune-related adverse events associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from ipilimumab has not previously been reported. Physicians should be aware of these potential immune-related adverse events and consider drug-associated dermatomyositis in the differential diagnosis in patients receiving ipilimumab who present with a cutaneous eruption or muscle weakness.