Men with metastatic castration-resistant prostate cancer (mCRPC) showing evidence of active immune responses in their tumors live longer without disease progression after being treated with Yervoy (ipilimumab), a Phase 2 trial shows.
These findings demonstrate that a subset of men with this form of advanced prostate cancer may benefit from treatment with immune checkpoint inhibitors — therapies that remove the “brakes” on the immune system to better fight cancer — despite having a low number of mutations in their tumors. Better responses were linked to higher numbers of immune T-cells in tumors.
Trial findings were reported in the study, “Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer,” published in the journal Science Translational Medicine.
Certain types of malignancies, including melanoma or non–small cell lung cancer (NSCLC), tend to respond better to treatment with immune checkpoint inhibitors because they have a high number of genetic mutations, called a high tumor mutational burden. These mutations lead to the production of abnormal proteins, or neoantigens, that can easily be recognized and targeted by the immune system.
“Because tumor neoantigens can be recognized by the immune system,” the researchers wrote, “it is expected that the presence of preexisting immune [cell] infiltrates within the tumor microenvironment is also associated with clinical benefit to ICB [immune checkpoint inhibitors].”
In the case of prostate cancer, however, these neoantigens are usually found in very low numbers, limiting patients’ response to these immunotherapies.
Yet, two previous Phase 3 trials (NCT00861614 and NCT01057810) assessing the effects of Yervoy, an immune checkpoint inhibitor, in men with mCRPC found that a sub-group of patients showed durable responses following treatment.
These observations led investigators to wonder if effective immune responses to checkpoint inhibitors were possible in patients with a low tumor mutational burden.
The trial, which was carried out in collaboration with Bristol-Myers Squibb (Yervoy’s manufacturer), enrolled 30 men with mCRPC from January 2015 to May 2018. Twenty-nine of these 30 people were given at least one dose of Yervoy and eligible for the final data analysis.
During the study, Yervoy was administered at a dose of 3 mg/kg every three weeks. Eleven patients (38%) were treated with four doses of the medication.
Participants were followed for a median period of 45.5 months (nearly four years) after receiving their first dose of Yervoy.
In the overall population, median radiographic progression-free survival (PFS) — that is, the median time patients lived until showing signs of disease progression in radiographs — was three months. In turn, median overall survival (OS) was 24.3 months (about two years).
Eight patients (28%) experienced severe (grade 3) side effects, including dermatitis (skin irritation) and diarrhea. No life-threatening (grade 4) of fatal (grade 5) side effects were reported.
Results showed two distinct responses to Yervoy : nine patients responded “favorably” to Yervoy with a PFS greater than six months and OS greater than one year; and 10 who responded “unfavorably,” with a PFS of less than six months and OS of less than one year.
At the time of the analysis, more than half (67%, 6 people) of those who responded “favorably” to treatment were alive, while all 10 who responded “unfavorably” had died of their disease. Survival for those who responded to Yervoy ranged from 33 to 54 months (nearly three to four-and-a-half years).
A comparison of tissue samples from these men found that those who responded “favorably” to treatment had a higher number of immune T-cells in the tumor.
Samples from these patients also showed increased activity of the anti-tumor interferon-gamma signaling cascade, despite a low number of mutations in their tumors.
Researchers isolated some T-cells from tumors of patients who responded “favorably” to Yervoy, and found that these cells were able to recognize and react to tumor neoantigens. T-cells from patients who responded “unfavorably” to treatment, in contrast, seemed to be unable to mount such responses.
“Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in prostate cancer,” Sumit Subudhi, MD, PhD, the study’s lead author and a professor of genitourinary medical oncology at University of Texas, said in a press release.
Findings “also suggest that pretreatment tissue correlatives [markers] … may improve patient selection for treatment with ICB, particularly for those cancers with low TMB [tumor mutational burden],” the scientists wrote. “In summary, our clinical study provides data to support further testing of immunotherapy strategies in patients with metastatic prostate cancer.”
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