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CheckMate 650: Nivolumab and Ipilimumab in Metastatic, Castration-Resistant Prostate Cancer


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Padmanee Sharma, MD, PhD

Padmanee Sharma, MD, PhD

SOME PATIENTS with metastatic prostate cancer may respond to a combination of immune checkpoint inhibitors after treatment with hormonal therapy and chemotherapy is not successful, according to early results from the phase II CheckMate 650 trial. Principal Investigator Padmanee Sharma, MD, PhDpresented data from CheckMate 650 at the 2019 Genitourinary Cancers Symposium in San Francisco.1 Dr. Sharma is Professor of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center in Houston.

About CheckMate 650

IN CHECKMATE 650, combination therapy with nivolumab plus ipilimumab demonstrated activity in patients with advanced metastatic castration-resistant prostate cancer and even better activity in patients who had not received prior chemotherapy. The main drawback of treatment was toxicity, since only 40% to 50% of patients were able to receive the full planned 4 cycles of treatment.

“In a malignancy where immune checkpoint monotherapy has shown limited activity, nivolumab plus ipilimumab demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer,” Dr. Sharma said.

“Deep and durable objective responses, as well as falls in prostate-specific antigen (PSA) levels (PSA < 2 ng/mL) were observed in a subgroup of patients,” Dr. Sharma said. “Although the numbers were small, preliminary data suggest that biomarkers (ie, tumor mutational burden, programmed cell death ligand 1 [PD-L1] ≥ 1%, homologous repair defects, and DNA  damage and repair) may have a role in identifying patients with metastatic castration-resistant prostate cancer likely to respond to immunotherapy,” she noted, adding that further study of the combination was warranted.

CheckMate 650 was organized after research published by Gao et al in Nature Medicine provided scientific underpinning for the combination in prostate cancer.2

“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.”
— Padmanee Sharma, MD, PhD

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CheckMate 650 Findings

AMONG PATIENTS with castration-resistant prostate cancer whose disease progressed after second-generation hormonal therapy (cohort 1), 25% (8 of 32) experienced a response from the immunotherapy combination at a median follow-up of 11.9 months. Among those patients whose disease progressed after chemotherapy and hormonal therapy (cohort 2), 10% (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,” Dr. Sharma said in a statement. “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 patients who experienced a complete response—two in each cohort—among the 62 patients who could be evaluated for tumor growth.

Safety and Toxicity

SIDE EFFECTS from the combination were consistent with those experienced in previous combination trials for other cancers, with 42% of patients in cohort 1 and 53% in cohort 2 experiencing grade 3–5 adverse events. Among cohort 1, 33% had to discontinue participation due to adverse events, with 35.6% having to withdraw from cohort 2. The most common adverse events were diarrhea, 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 for patients leaving the trial, with 51.1% of cohort 1 and 44.4% of cohort 2 discontinuing as a result of disease progression.

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

Dr. Sharma said investigators 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.

DISCLOSURE: Dr. Sharma has stock and other ownership interest in BioAtla, Constellation Pharmaceuticals, Evelo Therapeutics, Jounce Therapeutics, Kite Pharma, Neon Therapeutics, and Oncolytics. She has served in an advisory or consulting role with Amgen, Astellas Pharma, AstraZeneca, BioAtla, Bristol-Myers Squibb, Constellation Therapeutics, Evelo Therapeutics, GlaxoSmithKline, Jounce, Neon Therapeutics Oncolytics, and Pieris Pharmaceuticals. Dr. Sharma owns patents licensed to Bristol-Myers Squibb, Jounce, and Merck.

REFERENCES

1. Sharma P, Pachynski RK, Narayan V, et al: Initial results from a phase II study of nivolumab plus ipilimumab for the treatment of metastatic castration-resistant prostate cancer (CheckMate 650). 2019 Genitourinary Cancers Symposium. Abstract 142. Presented February 14, 2019.

2. Gao J, Ward JF, Pettaway CA, et al: VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nature Medicine 23:551-555, 2017.


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