Defining a Role for Immunotherapy in mCRPC

— Ipilimumab active in subgroup with favorable pretreatment tumor characteristics, robust T-cell response

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The packaging and vials of Yervoy 200 mg and 50 mg

A small clinical study of checkpoint inhibitors for metastatic castration-resistant prostate cancer (mCRPC) identified favorable and unfavorable subgroups that might help inform use of the drugs in a disease that generally has proven unresponsive to immunotherapy.

Six of nine patients whose tumors had favorable characteristics -- defined by pretreatment levels of two immune-cell parameters and/or robust antigen-specific T-cell responses -- remained alive 33 to 54 months after treatment with ipilimumab (Yervoy). All nine of the patients had either radiographic or clinical progression-free survival (rcPFS) exceeding 6 months and overall survival (OS) greater than 12 months. Two of the patients had low tumor mutational burden (TMB), which is often associated with lack of response to immune therapy.

In contrast, all 10 patients with unfavorable tumor characteristics died within 10.3 months of treatment and had rcPFS less than 6 months, as reported in Science Translational Medicine.

"Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in prostate cancer," lead study author Sumit Subudhi, M.D., PhD, of the University of Texas MD Anderson Cancer Center in Houston, said in a statement. "We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade."

Immune checkpoint inhibitors, such as CTLA-4 inhibitor ipilimumab and PD-1/L1 inhibitors, have revolutionized cancer therapy with their ability to induce durable T cell-mediated responses in a variety of tumors. However, the clinical benefits remain limited to a subset of patients with cancer, Subudhi and coauthors noted in their introduction.

Some of the most impressive results with immune checkpoint blockade have occurred in patients with melanoma and non-small cell lung cancer, diseases associated with high TMB and tumor neoantigen frequency. Because the human immune system can recognize tumor neoantigens, the presence of preexisting immune infiltrates in the tumor microenvironment might also predict clinical benefit from immune checkpoint blockade, the authors continued.

Compared with melanoma and NSCLC, prostate cancers have a low TMB and frequency of mutant neoantigens. Two phase III trials of ipilimumab showed no survival benefit for patients with mCRPC, although a subgroup of men had durable clinical responses. Investigators continued to explore immune checkpoint blockade in mCRPC in a phase II trial to determine whether ipilimumab could elicit antigen-specific T-cell responses in cancers that have a low TMB.

The study involved a total of 30 men who had radiographic evidence of metastatic disease and tumor progression while on hormone therapy despite castrate serum testosterone levels. All but one of the patients received at least one dose of ipilimumab, and 27 were evaluable for safety, efficacy, and translational analyses. The patients had a median follow-up of 45.5 months from administration of the first dose of ipilimumab.

The group had a median PSA-PFS of 1.7 months, median radiographic PFS of 3.0 months, and median OS of 24.3 months. The best radiographic response was stable disease, and the treatment led to a disease control rate of 37%.

A total of 18 patients did not meet the outcome criteria used to define the favorable subgroup. All 18 p had rcPFS less than 6 months, and 10 of the 18 also survived less than 12 months. Those 10 constituted the unfavorable group included in the correlational analyses.

The 27 patients had a median TMB of 76 nonsynonymous somatic mutations, considerably less than the TMB of melanoma and NSCLC (about 200), but consistent with other studies of mCRPC, the authors said. TMB did not differ between samples from the primary tumor or metastases.

Of the 27 patients, 17 had sufficient peripheral blood mononuclear cells to evaluate T-cell responses to tumor associated antigens and neoantigens, including eight of nine patients in the favorable subgroup and four of 10 in the unfavorable subgroup. The analyses showed that the favorable cohort increased CD8 T-cell density and increased expression of the interferon-γ response gene prior to starting treatment. Additionally, treatment with ipilimumab led to increased antigen-specific T-cell responses.

The findings from this study and others have guided additional research in several directions, including combination immune checkpoint inhibition in mCRPC.

"We published a study several years ago showing that when you give anti-CTLA-4, interferon-gamma is produced by the T cells and then PD-1 and PD-L1 are upregulated," said senior author Padmanee Sharma, MD, PhD, also of MD Anderson. "That suggests that coming in with a combination might be better, and we actually have a larger ongoing study evaluating anti-CTLA-4 and anti-PD-1. We're also looking at predictive biomarkers."

A next step would be a prospective study to evaluate immune checkpoint inhibition in patients who have biomarker-positive results, she added. Research to date has shown that tumor mutation types vary from patient to patient, providing a rationale for evaluating neoantigen vaccines with immune checkpoint inhibitors.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The study was supported by Bristol-Myers Squibb, Stand Up to Cancer, the Prostate Cancer Foundation, and the National Institutes of Health/National Cancer Institute.

Sharma disclosed relationships with Achelois, Apricity Health, BioAtla, Codiak BioSciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lava Therapeutics, Lytix Biopharma, Marker Therapeutics, Neon Therapeutics, Oncolytics, and Polaris, as well as patent/royalty/intellectual property interests.

Primary Source

Science Translational Medicine

Source Reference: Subudhi SK, et al "Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer " Sci Transl Med 2020; DOI: 10.1126/scitranslmed.eaaz3577.