Monday, February 1, 2016

Anti-Pd1 for melanoma: skin and eye changes, LDH as predictor for outcome, and intratumoral T cells

Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort.  Hwang, Carlos, Wakade, et al.   J Am Acad Dermatol. 2016 Jan 12.
“Anti-programmed cell death (PD)-1 therapy is emerging as the backbone of new standard of care immunotherapy for metastatic melanoma. Immune-related cutaneous events are observed in these patients. We reviewed the clinical and histologic information of all patients treated with single-agent anti-PD-1 therapy for metastatic melanoma at Westmead Hospital, Sydney, Australia, from May 2012 to February 2015.  Of the 82 patients included in the study, 34 had dermatology assessments. Forty (49%) developed a form of anti-PD-1-associated cutaneous adverse events. In all, 17% developed lichenoid reactions and eczema, and 15% developed vitiligo. An estimated 25% of patients were expected to develop their first lichenoid reactions within 8.3 months, and eczema and vitiligo within 10.3 months of therapy. These adverse events tend to appear together in patients on anti-PD-1 therapy. Anti-PD-1 therapy is associated with the development of immune-related cutaneous events. Lichenoid reactions, eczema, and vitiligo are the 3 most prevalent lesions observed in our population. There is a tendency for lichenoid reactions and eczema to occur with vitiligo.”

Cyclosporine for Dry Eye Associated With Nivolumab: A Case Progressing to Corneal Perforation.  Nguyen, Elia, Materin, Sznol, Chow.  Cornea. 2016 Jan 14.
[This is a presentation of] 2 cases of severe dry eye associated with Nivolumab, with 1 case progressing to corneal perforation.
 CASE 1: A 58-year-old man with metastatic melanoma was referred for the management of severe bilateral dry eyes after undergoing his sixth cycle of Nivolumab. The right eye progressed to corneal perforation 4 weeks after referral, after which Nivolumab was discontinued. When metastatic disease recurred, Nivolumab was continued with an ocular surface stabilized with an intensive regimen that included topical cyclosporine.
CASE 2: A 46-year-old woman with metastatic melanoma was referred for severe dry eye symptoms around the timing of her third cycle of Nivolumab. Improvement of symptoms and surface staining was achieved with a regimen that included aggressive lubrication and topical cyclosporine. On follow-up after completing Nivolumab therapy, metastatic melanoma has remained regressed.
Nivolumab can cause or worsen dry eye disease to the point of corneal perforation. Given that its antitumor effect is immune-mediated, therapies targeting ocular surface inflammation can be effective for stabilizing dry eye disease in patients who continue treatment with Nivolumab.

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma.  Diem, Kasenda, Spain, et al. Br J Cancer. 2016 Jan 21.
“Treatment with programmed death receptor-1 (PD-1) antibodies is associated with high response rates in patients with advanced melanoma. Reliable markers for early response and outcome are still sparse.  We evaluated 66 consecutive patients with advanced/metastatic melanoma treated with nivolumab or pembrolizumab between 2013 and 2014. The main objectives of this study were to investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal vs above the upper limit of normal) correlates with overall survival (OS), and, second, whether the change of LDH during treatment predicts response before the first scan and OS in patients with an elevated baseline LDH.
After a median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a significantly shorter OS compared with patients with normal LDH (N=32; 6-month OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5%). In those 34 patients with elevated baseline LDH, the relative change during treatment was significantly associated with an objective response on the first scan: the 11 (32%) patients with partial remission had a mean reduction of -27.3% from elevated baseline LDH. In contrast, patients with progressive disease (N=15) had a mean increase of +39%. Patients with a relative increase over 10% from elevated baseline LDH had a significantly shorter OS compared with patients with 10% change (4.3 vs 15.7 months).
LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.”

PD-1 blockade expands intratumoral T memory cells.  Ribas, Shin, Zaretsky, et al. Cancer Immunol Res. 2016 Jan 19.

"Tumor responses to PD-1 blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated and single cell infiltrates were analyzed by multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells (moMDSCs) significantly increased in patients' biopsies taken on treatment. The percentage of cells with a T regulatory phenotype, monocytes, and NK cells did not change while on PD-1 blockade therapy. CD8+ T memory cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4+ T effector memory cells significantly decreased on treatment, whereas CD4+ T effector cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 were detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and MDSCs in tumors, with the CD8+ T effector memory subset being the major T-cell phenotype expanded in patients with a response to therapy.”

A bit of a mish-mash...but the more we know, the better we can know what to expect and how to treat side effects.  Hopefully, we will finally understand and accumulate the data such that valid blood markers will be available to evaluate patients for whom anti-PD1 therapy is most likely to work and easily assess its effectiveness while the patient is on the medication...thereby saving valuable time, finding the best treatment for the patient, and avoiding more invasive or expensive routine assessments.  That's my hope anyway. - c

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