ASCO GU 2019: Immunotherapy combination generates responses against castration-resistant metastatic prostate cancer

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Some patients with metastatic prostate cancer respond to a combination of immune checkpoint inhibitors after hormonal therapy and chemotherapy have failed, according to early results presented today at the 2019 ASCO Genitourinary Cancers Symposium in San Francisco.

Principal investigator Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at MD Anderson, said the results of combining the CTLA-4 blocking drug ipilimumab with the PD-1 inhibitor nivolumab provide an encouraging step for a cancer that’s been highly resistant to immune checkpoint therapies.

Research by Sharma and 2018 Nobel Laureate Jim Allison, Ph.D., chair of Immunology, leaders of MD Anderson’s immunotherapy platform, provided a rationale for combining the two drugs.

The platform is part of MD Anderson’s Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Among castration-resistant patients who had progressed after second-generation hormonal therapy (cohort 1), 25 percent (8 of 32) had their tumours shrink from the immunotherapy combination at a median follow-up of 11.9 months.

Among those who progressed after chemotherapy and hormonal therapy (cohort 2) 10 percent (3 of 30) had a response at median follow-up of 13.5 months.

“This was the first combination trial of two immune checkpoint therapies in prostate cancer,” Sharma said.

“These results support the idea that immune checkpoint blockade can play an important role in the treatment of these patients and provide the foundation to test this strategy in a larger clinical trial.”

There were four complete responders, two in each cohort, among the 62 patients who could be evaluated for tumour growth.

Side effects from the combination were consistent with those experienced in previous combination trials for other cancers, with 42 percent of patients in cohort 1 and 53 percent in cohort 2 experiencing grade 3 to 5 adverse events.

Among cohort 1, 33 percent had to discontinue participation due to adverse events, with 35.6 percent having to withdraw from cohort 2.

The most common adverse events were diarrhoea, fatigue, skin rash, nausea and hypothyroidism.

Four patients died from treatment-related adverse events, two in each cohort.

Disease progression was the most common reason to leave the trial, with 51.1 percent of cohort 1 and 44.4 percent of cohort 2 discontinuing for that reason.

The researchers also analysed a number of biomarkers and found that higher tumour mutational burden was associated with response.

In previous clinical trials, neither drug succeeded as single therapy against prostate cancer, a so-called “cold” malignancy because it does not attract the attention of the immune system.

Few T cells, the adaptive immune system’s targeted warriors, infiltrate prostate tumours.

In a phase I trial, no patients responded to nivolumab alone because the PD-1 inhibitor requires an immune response to be under way in order to attack tumours.

The multi-centre combination clinical trial by Bristol-Myers Squibb, maker of both drugs, was organised after research published in Nature Medicine by Sharma and Allison, provided scientific underpinning for the combination in prostate cancer.

Analysing tumour samples before and after treatment in a clinical trial of ipilimumab and the anti-hormonal drug Lupron, Sharma, Allison and colleagues found that ipilimumab caused an immune response to the cancer reflected by major T cell penetration of tumours.

They also found that PD-L1, a ligand that turns on the PD-1 checkpoint on T cells, was heavily expressed by the tumour and surrounding tissue in response, shutting down the T cell attack.

Sharma and Allison hypothesised that combination treatment would induce an immune response with ipilimumab and then protect that response from deactivation by PD-1 with nivolumab.

Sharma said investigators and sponsor Bristol-Myers Squibb are designing a follow-up trial that includes altering either the dosing or scheduling of ipilimumab with the goal of reducing side effects.

Patients in the current trial, CheckMate-650, will be assessed for overall response rate and radiographic progression-free survival as primary endpoints and overall survival as a secondary endpoint.

Source: MD Anderson Cancer Center


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