Biomarker Might Predict Metastatic Melanoma Response to Pembrolizumab Therapy

Patients whose metastatic melanoma responded to pembrolizumab (Keytruda) immunotherapy had higher baseline frequencies of circulating immune T cells positive for CD8, programmed cell death protein 1 (PD-1), and Bim (CD8+PD-1+Bim+), than did patients who later suffered disease progression, according to findings from a small study involving 38 patients presented at the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference in New York City (abstract A007).¹

“Our results indicate that measuring the frequency of CD8+PD-1+Bim+ T cells in peripheral blood of patients with metastatic melanoma may provide a way to predict or monitor responses to pembrolizumab,” said study coauthor Roxana S. Dronca, MD, assistant professor of oncology at the Mayo Clinic in Rochester, Minn.

Baseline blood analysis showed higher CD8+PD-1+Bim+ T-cell frequencies among patients who experienced RECIST v1.1 complete response, partial response, or stable disease after 4 cycles of treatment, than those who did not experience clinical benefit, as determined by radiographic tumor evaluation, Dronca reported.

“A great advantage of the approach lies in the ease of serial peripheral blood testing compared with repeated invasive tissue biopsies,” she said.

Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 protein to allow antitumor immune response. It is currently indicated in the United States following progression of unresectable or metastatic melanoma following treatment with ipilimumab (and a BRAF inhibitor in patients whose tumors harbor a BRAF V600 mutation).

Bim is a downstream signaling molecule involved in the PD-1 signaling pathway. “Levels of Bim reflect the degree of PD-1 interaction with its ligand PD-L1,” said senior study author Haidong Dong, MD, PhD, associate professor of immunology at the Mayo Clinic. “We hypothesize that the increased frequency of CD8+PD-1+Bim+ T cells in responders reflects and increased number of target T cells for PD-1 blockade with pembrolizumab, which may explain the positive clinical outcomes in these patients.”

“The discovery of a biomarker predictive of response to pembrolizumab would inform clinical decision-making,” Dronca said. “Not only would it help to identify those patients with metastatic melanoma, and possibly other malignancies, who are most likely to benefit from the immunotherapy, but it would also potentially help to identify those patients who are acquiring resistance to the agent during the course of treatment.”

That would result in fewer patients being exposed to “inadequate treatments and their associated toxicities and costs,” Dronca noted.

The findings are undergoing validation testing with serial peripheral blood samples and standardized tumor assessment in a larger prospective patient cohort that includes people diagnosed with metastatic melanoma and lung cancer, Dronca said.

The International Cancer Immunotherapy Conference is jointly sponsored by the Cancer Research Institute (CRI), Association for Cancer Immunotherapy (CIMT), European Academy of Tumor Immunology (EATI), and the American Association for Cancer Research (AACR), and will be held every other year in lieu of each member organization’s individual meetings, and will alternate between the United States and Europe.

References:

• American Association for Cancer Research. (2015).Frequency of Certain Immune Cells in Blood May Predict Metastatic Melanoma Response to Pembrolizumab.