PD-L1 expression predicted response to immunotherapy in melanoma

Patients with advanced melanoma whose tumors expressed programmed death ligand-1 demonstrated improved immune responses and longer PFS after treatment with the investigational immunotherapy MK-3475 than patients whose tumors were PD-L1 negative, according to study results presented at the American Association for Cancer Research Annual Meeting.

“This is an extraordinarily active antibody in melanoma,” researcher Adil I. Daud, MD, co-director of the UCSF Melanoma Center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, said during a press conference. “Although the objective response rate was higher in patients with PD-L1–positive tumors, the quality of response was just as good in patients with PD-L1–negative tumors.”

Adil I. Daud

The binding of PD-1 — a protein present on T cells — with the PD-L1 protein present on some melanoma tumors prevents T cells from attacking cancer cells.

MK-3475 (Merck) — a humanized monoclonal antibody — is designed to block PD-1, allowing the T cells to attack cancer cells.

Daud and colleagues evaluated tumor samples from 125 patients with late-stage melanoma.

All patients had participated in a clinical trial designed to evaluate MK-3475 at three doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks.

Some patients had undergone prior treatment with the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb). Those who had not undergone prior ipilimumab were only eligible if they had undergone two or fewer prior therapies.

All patients had ECOG performance status of 0 or 1. Patients on systemic steroids, or those with active autoimmune disease or untreated CNS metastases, were excluded.

Of the 125 tumor samples, 89 (71.2%) were PD-L1 positive, meaning at least one of every 100 tumor cells expressed the protein. The other 36 samples were PD-L1 negative.

Overall, median PFS was 36 weeks, with OS rates of 89% at 6 months and 81% at 12 months. Median duration and median OS were not reached.

Patients whose tumors expressed PD-L1 demonstrated significantly longer median PFS (10.6 months vs. 2.9 months; HR=0.54; 95% CI, 0.28-1.05). Researchers also reported higher rates of 6-month PFS (57% vs. 35%), 6-month OS (93% vs. 75%), 12-month PFS (45% vs. 18%) and disease control (65% vs. 37%) among patients with PD-L1–positive tumors.

Although median OS was not reached, researchers calculated an HR of 0.67 (95% CI, 0.25-1.83) for OS in favor of patients with PD-L1–positive tumors.

The results suggest PD-L1 is a “robust marker” for determining which patients may benefit from treatment with MK-3475, Daud said.

“The clinical utility of PD-L1 expression in melanoma is not clear, just because unselected patients have such a high level of response,” Daud said. “We think this is a good foundation to build on. Ongoing studies and larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response.”

Among patients with PD-L1–positive tumors, overall response rates were similar between those who had undergone prior ipilimumab treatment and those who had not (44% vs. 47%). Among patients with PD-L1–negative tumors, response rates were 14% for those who underwent prior ipilimumab treatment and 17% for those who had not.

“This suggests that prior treatment with … ipilimumab does not impact the ability of these tumors to respond to MK-3475, nor does it affect the viability of PD-L1 as a marker of response to MK-3475,” Daud said.

Among all patients treated with MK-3475 for at least 6 weeks, researchers reported a 24% increase in CD8-positive T-cells and a 17.5% increase in CD4-positive T cells. The finding suggests MK-3475 treatment improved the immune response in these patients at all doses, according to researchers.

For more information:

Daud AI. Abstract #CT104. Presented at: AACR Annual Meeting; San Diego; April 5-9, 2014.

Disclosure: The study was funded by Merck. Daud reports research support from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck and Pfizer, as well as advisory board roles with Merck and GlaxoSmithKline.