Exploratory analysis of clinical benefit of ipilimumab and nivolumab treatment in patients with metastatic melanoma from a single institution

8032 Background: Ticilimumab therapy has demonstrated anti-tumor activity in pts with metastatic melanoma. Its indirect, immune-mediated antitumor effects pose unique challenges for dose/regimen selection. Methods: It was our original intention to select the clinical dose/regimen of ticilimumab based on (1) clinical safety and tolerability and (2) attainment of target plasma concentrations derived from pre-clinical work using an ex vivo assay of ticilimumab-induced enhancement of cytotoxic T-cell function. Because numerous pts with metastatic melanoma experienced clinical benefit (i.e., durable objective responses [OR] and/or long-term survival) in early clinical trials of ticilimumab, we are using (1) safety and tolerability and (2) clinical benefit to guide dose/regimen selection. Data for evaluating these criteria come from a single-dose Phase 1 trial (0.01, 0.1, 1, 3, 6, 10 and 15 mg/kg) and an ongoing multiple-dose Phase 1/2 trial in pts with melanoma (Phase 1 portion: 3, 6 and 10 mg/kg Q1M; Phase 2 portion: 10 mg/kg Q1M and 15 mg/kg Q3M). Results: In the single-dose Phase 1 trial, 10 mg/kg was the Protocol-defined MTD but a high rate of clinical benefit was seen in the 15 mg/kg dose cohort (6/6 pts). Because the DLTs seen at 15 mg/kg (Gr 3 diarrhea, Gr 3 rash) were moderate and resolved completely within 3 months of dosing, 15 mg/kg Q3M was proposed as a safe and tolerable dose and is being studied in the Phase 2 portion of the multiple-dose Phase 1/2 trial. The Phase 1 portion of the multiple-dose Phase 1/2 trial revealed that 10 mg/kg is safe and tolerable with monthly dosing so 10 mg/kg Q1M is also being studied in the Phase 2 portion of the trial. At the end of the Simon Optimum-defined Stage 1 of the Phase 2 portion of the ongoing trial, the OR rate (3/18 pts) is the same for both dosing regimens. However, with 15 mg/kg Q3M, Gr 3/4 adverse events were less frequent (6% versus 34%). Conclusions: 15 mg/kg Q3M is proposed as the clinical dose/regimen for ticilimumab in metastatic melanoma. This dose/regimen appears to have anti-tumor activity approximately equal to 10 mg/kg Q1M but it appears to have a superior safety profile. [Table: see text]

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Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab at 10mg/kg to predict for overall survival in patients with metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2518 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2518-2518 ◽

Cited By ~ 14

Author(s):

Shigehisa Kitano ◽

Michael Andrew Postow ◽

Czrina Cortez ◽

Teresa Rasalan ◽

Humilidad F. Gallardo ◽

...

Keyword(s):

Cell Proliferation ◽

Overall Survival ◽

T Cell ◽

Metastatic Melanoma ◽

Peripheral Blood ◽

Clinical Benefit ◽

Stage Iv ◽

T Cell Proliferation ◽

Pre Treatment

2518 Background: Ipilimumab, an antibody that blocks the function of the immune inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4), significantly prolongs survival in patients with metastatic melanoma. Approximately 30% of patients derive clinical benefit from therapy. Defining biomarkers of response to ipilimumab therapy would enable selection of patients more likely to respond and is relevant for both practicing clinicians and for clinical trial design. We performed a pilot correlative study evaluating myeloid derived suppressor cells (MDSC), a population of immune suppressive monocytic cells, as a biomarker of clinical outcome. Methods: Peripheral blood from 26 patients with stage IV melanoma treated with ipilimumab 10mg/kg every 3 weeks for 4 doses at our center, as part of an expanded access program (BMS CA184-045) was assessed for MDSC quantity (%CD14+,HLA-DRlow/- cells) pre-treatment, at week 7, week 12, and week 24 by flow cytometry. MDSC ability to inhibit T cell proliferation was tested using an in vitro suppression assay. Results: We found that lower MDSC quantity pre-treatment predicted for improved overall survival (Hazard ratio 1.07 (1.03, 1.11) p=0.002) and trended toward associating with clinical benefit measured at week 24 imaging (p=0.09). This effect was independent of pre-treatment or week 7 absolute lymphocyte counts (ALC) and pre-treatment LDH when evaluated in a multivariate model with ALC and MDSC quantity HR 1.10; 95% CI 1.04, 1.17 p=0.0006 and LDH and MDSC quantity HR 1.06; 95% CI 1.01, 1.11 p = 0.013. Furthermore, a general trend of increasing MDSC number by week 24 from the pre-treatment baseline was associated with patients that did not achieve clinical benefit. MDSC suppressed peripheral blood T cell proliferation as measured by CFSE dilution in response to anti-CD3 antibody stimulation. Conclusions: Pre-treatment MDSC quantity may predict clinical response following ipilimumab therapy. Further studies evaluating MDSC as a biomarker of ipilimumab therapy are warranted both retrospectively and prospectively in a broader group of patients.

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