Παρασκευή, 13 Νοεμβρίου 2015

CHARACTERISTICS OF RENAL CANCER PATIENTS RESPONDERS TO IMMUNOTHERAPY

MIAMI — Patients with renal cell carcinoma (RCC) who achieve a durable response to immunotherapy with programmed cell death (PD) inhibitor drugs have distinct pathologic, genomic, and RNA expression profiles, according to new data presented here at the 14th International Kidney Cancer Symposium (IKCS).
The expression profiles are quite different in the "exceptional" patients compared with those with primary refractory disease, explained Mark W. Ball, MD, a urology resident at Johns Hopkins Hospital, Baltimore, MD.
Immune checkpoint inhibitors that disrupt PD-1 pathway signaling, such as nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co), represent a major breakthrough in the treatment of an increasing number of tumor types, including RCC. The efficacy of PD-1 and PD-LI blockade in RCC has been demonstrated in multiple trials with objective response rates of about 20% to 30%, said Dr Ball, who presented the findings to attendees here.
Although the overall response rate may be rather low, some patients are able to achieve durable complete responses with these agents. As an example, Dr Ball pointed to a patient treated at his institution who had a durable response rate for 3 years. "He had a partial response that converted to an ongoing complete response. The question is, What predicts these complete responses?"
Previous studies have correlated response to PD-1 blockade with PD-L1 overexpression, as well as cell-mediated immune transcripts, but none of them have examined patients with long-term durable responses.
To better understand the underlying mechanisms of durable responses, Dr Ball and colleagues at Johns Hopkins conducted a study to characterize the two extremes of response to therapy: exceptional responders who achieve durable, complete response and patients who have primary refractory disease.
There were four patients at their institution with formalin-fixed paraffin-embedded archival tissue available who could be designated as exceptional. They were then compared with three patients who also had tissue available and who had shown signs of progression on their first follow-up imaging.
"Our exceptional responders had responses over 40 months, and some over 60 months, in contrast to refractory patients who progressed quite rapidly," he said.
The researchers looked at a number of factors, and immunohistochemical staining for PD-L1, CD8, and FOXP3; whole-exome sequencing; and quantitative RNA expression profiling were performed and correlated with clinical outcomes.
More Mutations and Inflammatory Cytokines
There were not any real differences in PD-L1 expression between the two groups, Dr Ball reported. However, the exceptional responders had trends toward greater CD8+ lymphocyte infiltrate (126.7 vs 28.8), both in the tumor and in the surrounding stroma.
In terms of mutational burden, exceptional responders had a higher median number of somatic mutations (67 vs 35 somatic mutations/genome) compared with those with primary refractory disease. They also had a higher number of predicted mutation-associated neoantigens than primary refractory patients (44 vs 8), and expression analysis demonstrated acute phase and immune tolerance signatures in primary refractory patients, whereas exceptional responders had higher expression of T-cell and innate immune signatures and signatures for inflammatory cytokines.
"As far as clinical characteristics, the time from nephrectomy to local recurrence was slightly longer in exceptional responders, and there was also a higher number of prior therapies in that group," said Dr Ball.
Larger studies are needed, of course, to fully elucidate the basis of response to PD-1 blockade in patients with RCC, he concluded. "And future directions include collaborating with other centers and validation of these signatures in a prospective trial."
Sabina Signoretti, MD, an associate professor of pathology at Harvard Medical School in Boston, Massachusetts, agrees that more study is needed, and with a larger cohort. "There were very few patients, but it was still very interesting and exciting," she told Medscape Medical News. "It really needs to be confirmed with more patients."
Dr Signoretti, who was approached for an independent comment, explained that it is impossible to move forward without learning more about the biomarkers, so that the treatments can be administered to the patients who are most likely to derive a benefit.
"In this study, we learned more about the patients who have achieved durable responses to these drugs," she said. "These drugs are not without toxicity, and we don't want to give them to patients that are unlikely to be helped by them."
14th International Kidney Cancer Symposium (IKCS). Presented November 6, 2015.

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