Pembrolizumab Does Not Improve Outcomes in Medullary Thyroid Carcinoma

A phase 2 trial (NCT03072160) investigating the efficacy of pembrolizumab (Keytruda) in patients with recurrent or metastatic medullary thyroid cancer (MTC) failed to demonstrate therapeutic responses, regardless of whether patients had received prior treatment with the yeast-based immunotherapy GI-6207, according to an article published in The Oncologist.

Researchers aimed to determine if sequencing an antigen-directed immunotherapy before an immune checkpoint inhibitor could prime the tumor microenvironment for a response in a disease traditionally resistant to such therapies. Because MTC is generally considered a "cold" tumor, investigators sought to evaluate whether the carcinoembryonic antigen (CEA)-targeting vaccine GI-6207 could enhance the clinical activity of pembrolizumab. However, the study was terminated early due to a lack of efficacy observed in the initial cohorts.

Main Data That Support the Findings

Among the 17 patients enrolled in the study, no radiographic responses occurred. In the cohort of 13 patients who had previously received GI-6207, the median progression-free survival (PFS) was 210 days. For the 4 patients who did not receive previous immunotherapy, the median PFS was 55 days. At the time of data cutoff, the 2-year overall survival (OS) was 100% for the prior-immunotherapy group and 50% for those with no prior immunotherapy.

Biochemical markers further supported the lack of efficacy. No patients in either cohort experienced a confirmed 50% or greater decline in serum CEA or calcitonin levels. Furthermore, an analysis of peripheral blood mononuclear cells (PBMCs) at 3 months did not reveal significant changes in immune cell subsets or activation markers, suggesting pembrolizumab did not induce a systemic immune impact in this patient population.

“Ever since the emergence of immune checkpoint inhibitors on the therapeutic stage of oncology, there has been a stark contrast between the responders and non-responders. This has fueled a desire in oncology to turn the proverbial “cold tumor hot” and bring clinical benefit to patients who do not respond to immune checkpoint inhibitors,” Jaydira Del Rivero, MD, associate research physician in Developmental Therapeutics at the National Cancer Institute Center for Cancer Research, and colleagues wrote in the article.

Trial Details

The open-label, non-randomized, phase 2 study was conducted to evaluate the activity of pembrolizumab in 2 distinct cohorts of patients with MTC. Cohort 1 included patients who had previously participated in a trial of GI-6207. Cohort 2 included patients with no prior history of GI-6207 treatment.

All participants received the standard-of-care dose of pembrolizumab at 200 mg administered intravenously every 3 weeks. Treatment continued for up to 2 years or until disease progression or unacceptable toxicity. The primary end point was 50% or greater decline in calcitonin levels or experience partial/complete response on imaging. Secondary end points included the impact of previous immunotherapy, immune responses, changes in CEA and calcitonin kinetics, and safety.

Patients were eligible if they had histologically confirmed MTC that was metastatic or unresectable, with evidence of disease progression within the prior 12 months. In the prior-immunotherapy cohort, the median age was 52.4 years, and 61.5% of patients were male. In the immunotherapy-naive cohort, the median age was 58.8 years, and 75% were male.

Safety

Adverse effects (AEs) in the study were between grades 2 and 3. AEs that were grade 2 included alanine aminotransferase increase (n = 1), decreased neutrophils (n = 1), hearing impairment (n = 1), fatigue (n = 2), and rash (n = 3).Grade 3 AEs included acute kidney injury (n = 1), headache (n = 1), and rash (n = 1). There were no grade 4 or 5 toxicities.

Reference

Del Rivero J, Donahue RN, Marte JL, et al. Pembrolizumab in recurrent or metastatic medullary thyroid cancer. Oncologist. 2025;31(1):oyaf348. doi:10.1093/oncolo/oyaf348