Castration-Resistant Metastatic Prostate Cancer Responds to a Combination of Immune-Control Point Inhibitors

Two Checkpoint Inhibitors Provide Promising Early Results for Immunologically Cold Disease

Some patients with metastatic prostate cancer respond to a combination of immune checkpoint inhibitors after the failure of hormone therapy and chemotherapy, according to the first Results of a clinical trial conducted by researchers at the MD Anderson Cancer Center of the University of Texas, presented today at the American Society of Clinical Symposium on Genitourinary Cancers in San Francisco.

Principal Investigator Padmanee Sharma, MD, Ph.D., professor of Genitourinary Medical Oncology and Immunology at MD Anderson, said the results of the combination of ipilimumab, a CTLA-4 blocking drug , to a PD-1 inhibitor, was an encouraging step for cancer. been very resistant to immune therapies at checkpoints.

The research conducted by Sharma and 2018 Nobel Laureate Jim Allison, Ph.D., president of Immunology, responsible for MD Anderson's immunotherapy platform, have justified the combination of the two drugs. The platform is part of MD Anderson's Moon Shots program^™, a collaborative effort to accelerate the development of scientific breakthroughs in clinical advances that save the lives of patients.

Among the castration-resistant patients who had progressed after second-generation hormone therapy (Cohort 1), 25% (8 of 32) had their tumors contracted by the combination of immunotherapy after a median follow-up of 11, 9 months. Among those who progressed after chemotherapy and hormone therapy (cohort 2), 10% (3 of 30) had a median follow-up response of 13.5 months.

"This was the first combined trial of two point-check immune therapies in prostate cancer," said Sharma. "These results support the idea that immune-control point blocking can play an important role in the treatment of these patients and provide the foundation for testing this strategy as part of the strategy." 39, a larger clinical trial. "

There were four complete responders, two in each cohort, out of the 62 patients that could be evaluated for tumor growth.

The side effects of the combination were consistent with those seen in previous trials of combinations of other cancers: 42% of patients in cohort 1 and 53% of cohort 2 had grade 3 adverse events. to 5. Among cohort 1, 33% had to discontinue their participation due to adverse events, and 35.6% had to withdraw from cohort 2. The most common adverse reactions were diarrhea, fatigue, rashes, nausea and hypothyroidism. Four patients died of treatment-related adverse events, two in each cohort.

The progression of the disease was the most common reason for leaving the trial: 51.1% of Cohort 1 and 44.4% of Cohort 2 quit for this reason.

The researchers also badyzed a number of biomarkers and found that a higher burden of tumor mutation was badociated with the response.

Combination warms the cold tumor

In previous clinical trials, neither drug had resulted in a single treatment for prostate cancer, a so-called "cold" cancer, because it did not attract the attention of the immune system. Some T cells, the target warriors of the adaptive immune system, infiltrate prostate tumors.

In a phase I trial, no patient responded to nivolumab alone, with the PD-1 inhibitor requiring an immune response before attacking tumors.

The clinical trial on the multicenter combination of Bristol-Myers Squibb, maker of both drugs, was organized as a result of research published in Nature Medicine by Sharma and Allison, who provided the scientific basis for the Association on prostate cancer.

The badysis of tumor samples before and after treatment in the course of a clinical trial on ipilimumab and the anti-hormonal drug Lupron, Sharma, Sharma, Allison and colleagues showed that l & # 39; Ipilimumab elicited an immune response to cancer reflecting significant T cell penetration into tumors.

They also found that PD-L1, a T-cell-activated PD-1 checkpoint ligand, was strongly expressed by the tumor and the surrounding tissue in response, thus ending the T-cell attack. Sharma and Allison hypothesized that combination therapy would induce an immune response with ipilimumab and then protect that response from PD-1 deactivation with nivolumab.

Sharma said the investigators and sponsor, Bristol-Myers Squibb, are designing a follow-up trial that includes changing the dosing or planning of ipilimumab in an effort to reduce side effects.

The current trial patients, CheckMate-650, will be evaluated based on overall response rate, radiographic progression-free survival as the primary endpoints, and overall survival as a secondary endpoint.

Allison has already received royalties from Bristol-Myers for the development of ipilimumab, but no longer receives such payments.