November 04, 2014
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Ipilimumab plus sargramostim prolonged OS, decreased toxicity in metastatic melanoma

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The addition of sargramostim to ipilimumab significantly extended OS and decreased toxicity in patients with advanced melanoma, according to results of a phase 2 study.

However, the combination of sargramostim (Leukine, Sanofi-Aventis) — a granulocyte–macrophage colony stimulating factor — and the CTLA-4 blockade ipilimumab (Yervoy, Bristol-Myers Squibb) was not associated with prolonged PFS, results showed.

F. Stephen Hodi

“The addition of an immune signaler to ipilimumab both improved patient outcomes regarding better survival as well as decreased the severe side effects,” F. Stephen Hodi, MD, director of the Melanoma Treatment Center and Center for Immuno-Oncology at Dana-Farber Cancer Institute, told HemOnc Today. “Specifically, severe lung and gastrointestinal side effects were decreased. These are the organs we are concerned about the most with regard to treatment with immune checkpoint agents.”

The analysis included 245 patients with unresectable stage III or IV melanoma who had received at least one prior therapy. Researchers randomly assigned 123 patients 10 mg/kg ipilimumab on day 1 plus 250 micrograms subcutaneous sargramostim on days 1 to 14 of a 21-day cycle. The other 122 patients received ipilimumab alone.

Median follow-up was 13.3 months (range, 0.03-19.9).

Patients who received ipilimumab plus sargramostim demonstrated a median OS of 17.5 months (95% CI, 14.9-not reached), whereas patients who received ipilimumab alone demonstrated a median OS of 12.7 months (95% CI, 10-not reached).

Significantly more patients in the combination arm achieved 1-year OS (68.9% vs. 52.9%; P=.01), and the combination also was associated with a significant reduction in the risk for death (HR=0.64; 95% CI, not applicable-0.9).

Although the combination extended OS, median PFS was 3.1 months in both arms (P=.37).

Current data do not elucidate why a difference existed with OS but not PFS, Hodi said.

“It could be that the treatment is causing inflammation that looked like early disease progression, but we won’t know without further studies,” Hodi said in a press release.

Researchers evaluated safety data from 118 patients assigned the combination and 120 patients assigned ipilimumab alone.

Overall, significantly fewer patients in the combination arm experienced a grade 3 to grade 5 adverse event (44.9% vs. 58.3%; P=.04). Significantly more patients who received ipilimumab alone experienced grade 3 to 5 gastrointestinal toxicities (26.7% vs. 16.1%; P=.05) and pulmonary toxicities (7.5% vs. 0%; P=.003).

Seven patients assigned ipilimumab alone died due to a treatment-related adverse event, whereas two treatment-related deaths occurred in the combination arm.

“[The combination] reveals the possibilities of combining an immune signaling molecule with taking the brakes off at the same time,” Hodi said in the release.

Disclosure: Hodi reports research funding, nonfinancial support and personal fees from and patents licensed to Bristol-Myers Squibb, the Cancer Therapy Evaluation Program/NCI, Eastern Cooperative Oncology Group and Sanofi/Genzyme. See the study for a list of the remaining researchers’ relevant financial disclosures.