ctDNA Shows Utility as Predictive Biomarker for Pembrolizumab Therapy

Results from a phase 2 trial of pembrolizumab as immune checkpoint inhibition against 5 types of solid tumors show that personalized circulating tumor DNA (ctDNA) assays may be used to accurately predict response to treatment, according to study results published this week in Nature Cancer.

As part of the ongoing INSPIRE trial, investigators at Princess Margaret Cancer Center in Toronto, Ontario, conducted a prospective study on patient response to immunotherapy with the monoclonal antibody pembrolizumab against head and neck squamous cell cancer, triple negative breast cancer, epithelial ovarian cancer, malignant melanoma, and advanced solid tumors. At the heart of their study was the need, according to the investigators, for more reliable predictive biomarkers of patient response.

“Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer,” they stated. “However, existing biomarkers do not reliably predict treatment response across diverse cancer types.” This includes considering if immunotherapy is even the right treatment to pursue.

A cohort of 74 patients provided 316 serial plasma samples at baseline and every 3 cycles of treatment with 200-mg intravenous pembrolizumab, which was given once every 3 weeks.

After a median 25 months of follow-up, 12 of the patients shown to have ctDNA clearance, or undetectable levels, during treatment remained alive.

Baseline ctDNA concentration also shared a positive correlation with progression-free and overall survival and clinical response and benefit. And at the 6-to-7 week mark post treatment, 33 patients had a decrease in ctDNA that was linked to longer survival and better pembrolizumab response.

In contrast, higher ctDNA likely meant rapid disease progression and poor survival.

The personalized ctDNA assays were developed for the patients by sequencing biopsied tissue, with attention focused on the up to tens of thousands of cancer-related mutations unique to each cancer and 16 chosen for each patient on which to base the assays.

“It’s like a molecular CT scan that gives us a molecular dimension, an added layer of information to know whether a tumour is growing or not,” said Lillian L. Siu, MD, FASCO, a senior scientist and medical oncologist at Princess Margaret, BMO Chair in Precision Cancer Genomics, and a co–senior author, in a statement announcing the results. “It helps to predict early on what may happen over time. Although important, computerized tomography (CT) and other scans alone will not tell us what we need to know quickly or accurately enough.”

The authors believe their results show ctDNA could be a useful tool to use in conjunction with immune checkpoint blockade with pembrolizumab. Additional studies, however, are needed to determine the ultimate utility of genomic and immune biomarkers regarding both response and resistance to the drug.

Reference

Bratman SV, Yang SYC, Iofalla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nature Cancer. Published online August 3, 2020. doi: 10.1038/s43018-020-0096-5