Checkpoint Inhibitors Induce Response, Higher Rates of Side Effects

“There has been a rapid expansion in the use of checkpoint inhibition in many solid tumor types,” lead author Emily Hinchcliff, M.D.
BY Katie Kosko
PUBLISHED March 26, 2018
The use of immune checkpoint inhibitors in women with recurrent ovarian cancer has a clinical benefit but a higher rate of adverse effects (AEs) than previously reported in other tumor types, according to study findings presented during the 49th Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancers held in New Orleans March 24-27.

Checkpoint inhibitors block certain proteins made by some types of immune system cells and some cancer cells. The proteins can keep T cells from killing cancer cells, but checkpoint inhibitors block those proteins, releasing the T cells to attack the cancerous cells.

“There has been a rapid expansion in the use of checkpoint inhibition in many solid tumor types,” lead author Emily Hinchcliff, M.D., The University of Texas MD Anderson Cancer Center in Houston, said. “The use of agents in ovarian cancer is still an area of active investigation both as monotherapy but also in combination with triple cytotoxic chemotherapy, targeted agents or other immunologic effector modulation.”

The researchers examined women with recurrent disease who were being treated with an immune checkpoint inhibitor between January 2012 through August 2017 to describe the clinical outcomes associated with this type of treatment. In particular, they investigated data on demographic, clinical and biologic factors, and, in particular, were interested in the outcomes of response to therapy and immune-related adverse event, noted Hinchcliff.

The study included 44 women, who were predominately Caucasian (70.5 percent) and a median age of 53 years. A majority of women had high-grade serous pathology and about half had platinum-sensitive disease at initial diagnosis.

The population of patients were highly treated with a median of four prior lines of therapy and as many as 10. “All patients treated in the clinical trials underwent somatic mutation testing prior to enrollment,” said Hinchcliff. “The mutation panel testing varied across the trials included, thus we analyzed a common subset of 50 genes.” The mean number of mutations was two, with a range of zero to 18.

The majority of patients (64 percent) were treated with a checkpoint inhibitor as part of combination regimen and 36 percent received checkpoint inhibition as monotherapy. The combination regimens included checkpoint-checkpoint (21 percent), checkpoint plus other immune effector (46 percent), checkpoint plus targeted therapy (18 percent) and checkpoint plus traditional cytotoxic chemotherapy or radiation (14 percent).

The checkpoint that was targeted among women varied: anti-PD-1 was most common in 50 percent of women followed by anti-CTLA-4 and the combination of anti-PD-L1 and anti-CTLA-4.

The study found that, of the 42 patients with data available, 13 patients (31 percent) progressed. Twenty patients (48 percent) had initially stable disease, meaning the cancer was not getting better or worse. A partial response was seen in six patients (14 percent), and three of them experienced pseudo-progression, which is tumor growth from treatment effect rather than true disease progression.

Overall, immune checkpoint inhibitors demonstrated a response rate of 14 percent and stable disease rate of 48 percent.

Researchers only looked at grade 3 or 4 immune-related side effects. In 21 patients (48 percent), 28 side effects occurred and 14 patients (62 percent) who experienced a side effect required a dose delay. Dermatologic, colitis, pulmonary and cardiovascular side effects occurred, but the most common side effects were elevation in hepatic (liver) or pancreatic enzymes, which was seen in six patients (14 percent). “These rates are much higher than what has been previously reported in other tumor types,” said Hinchcliff.

To understand why these side effects occurred, the researchers took a more detailed look at regimens received by patients and all, but one, received checkpoint inhibitor as part of a combination regimen.
“It is possible that there are tumor or histology-specific off-target effects of immune checkpoint inhibition that merit further investigation to aid in both prediction and prevention of such adverse events,” said Hinchcliff.
 
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