ASCO GU 2019: Initial Results from a Phase II Study of Nivolumab plus Ipilimumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer - CheckMate 650

San Francisco, CA ( Immunotherapy with checkpoint inhibitors has revolutionized the treatment paradigm of many malignancies over the past 5 years including melanoma, lung cancer, kidney cancer, and bladder cancer1-4. However, immune checkpoint inhibitors have not been met with the same success for prostate cancer. In one of the first studies evaluating nivolumab for prostate cancer, there were 0 out of 17 responders5. However, subsequent studies have shown that there may be dramatic responses to immune checkpoint inhibitors in select populations, in combination with AR targeted agents6.  Keynote 199 presented at ASCO 2018 showed that about 10% of patients may have a PSA decline of 30-100% from baseline and patients with somatic BRCA1/2 or ATM mutations were enriched for responders (12%)7. However, only 5% of all patients had an objective radiographic response. In this study, the combination of ipilimumab and nivolumab are tested in a population of patients with metastatic castration resistant prostate cancer.

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This abstract provides the initial results from Checkmate 650, a phase II study of ipilimumab/nivolumab for asymptomatic or minimally symptomatic patients with mCRPC, both before (cohort 1) and after chemotherapy (cohort 2). Patients were first treated with the combination of both checkpoint inhibitors (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) every three weeks for four doses, followed by nivolumab 480 mg every 4 weeks. The authors created a coprimary endpoint of objective response rate (ORR) and radiographic PFS per PCWG2 and safety was a secondary endpoint. Results from the first 90 patients are reported here. 

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Baseline characteristics are shown above. The median age was 69 in cohort 1 and 65 in cohort 2. Cohort 1 had more patients without bone metastases (20% vs 6.7%) and cohort 2 had greater chemotherapy exposure, with 82% of patients having received docetaxel.  

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In terms of response outcomes, the confirmed ORR was 25% in cohort 1 and 10% in cohort 2. 2 (6%) patients in each cohort achieved a complete response. Patients who responded typically achieved a response very quickly, in about 2 months in both cohorts. 

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In terms of exploratory biomarker analysis, tumor PD-L1 ≥1% appeared to enrich for responders – 4/12 patients (33%). Tumors with mutations in DNA damage repair genes also were enriched for responders (40%, 4/10). TMB status was quantified based on whether or not the tumor was above or below the median TMB in the cohort which was 74.5 mutations/pt. Of those classified as TMB high, ORR was 56% (9/16).

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In terms of safety, 40-50% of all patients experienced grade 3-5 toxicity, most common being diarrhea, fatigue, and rash, as has been seen in other tumor types. However, it is notable that 40-50% of all patients discontinued study drug due to toxicity and the median duration of therapy was 2.1 months in cohort 1 and 1.4 months in cohort 2.               

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Ipilimumab/nivolumab is an active therapy for a small proportion of patients with mCRPC, both before and after chemotherapy. TMB high, PD-L1≥1%, DDR, and HRD mutations may enrich for responders and future biomarker work is critical to identify the population of patients who will best respond to checkpoint inhibition. A significant proportion of patients discontinued treatment due to toxicity. It is unknown if a different dosing regimen (ipi1/nivo3) or dosing schedule may be more tolerable. Long term follow-up is important to see if this combination may provide a durable response, as we have seen in melanoma and renal cell carcinoma.

Presented by: Padmanee Sharma, MD, PhD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center
Discussant:  William Kevin Kelly, DO

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA


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