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Published on: April 12, 2017
A Pilot Study of the CD38 Antagonist Daratumumab in Patients with Metastatic Renal Cell Carcinoma or Muscle-Invasive
Matthew T Campbell1, Amishi Y Shah1, Pavlos Msaouel1
1Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC).
Experimental Design:
Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity.
Results:
In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low.
Conclusion:
Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC.
Significance:
In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.
Insights
Daratumumab treatment was safe for muscle-invasive bladder cancer (MIBC) and metastatic renal cell carcinoma (mRCC) patients. While CD38 targeting was observed, limited efficacy was detected in this pilot study.
Area of Science:
- Oncology
- Immunology
Background:
- Muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC) represent significant clinical challenges.
- CD38 is a target expressed on various immune cells and tumor cells.
Purpose of the Study:
- To evaluate the safety and preliminary efficacy of daratumumab, an anti-CD38 monoclonal antibody, in patients with MIBC and mRCC.
- To explore the immunomodulatory effects and target engagement of daratumumab in these cancer types.
Main Methods:
- A pilot study involving two cohorts: MIBC patients receiving neoadjuvant daratumumab before cystectomy, and mRCC patients undergoing biopsies before and after treatment.
- Primary endpoint: safety. Secondary endpoints: pathologic complete response (MIBC), objective response rate, and progression-free survival (mRCC).
- Exploratory analyses included immune monitoring and tissue analysis via immunohistochemistry (IHC).
Main Results:
- Daratumumab was safe and well-tolerated in both MIBC (n=8) and mRCC (n=8) cohorts, with no toxicity events reported.
- One patient in the MIBC cohort achieved a pathologic complete response. No objective responses were observed in the mRCC cohort, with a median progression-free survival of 1.5 months.
- Immune monitoring revealed significant reductions in circulating NK cells. IHC confirmed CD38 presence diminished in mRCC post-treatment, while baseline CD38 was low in MIBC.
Conclusions:
- Daratumumab demonstrated a favorable safety profile in patients with MIBC and mRCC.
- Limited efficacy signals were observed, particularly in the mRCC cohort.
- Daratumumab effectively engaged its target, CD38, on immune cells in circulation and within the tumor microenvironment of both MIBC and mRCC.
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