Pembrolizumab Not Active Against Cisplatin-Refractory Testicular Cancer

Pembrolizumab immunotherapy is not clinically active against treatment-refractory testicular cancer, indicate phase II study findings published in the Annals of Oncology.

“This is the first reported trial evaluating immune checkpoint inhibitors in GCT [germ-cell tumors],” reported lead study author Nabil Adra, MD, of the Melvin & Bren Simon Cancer Center, Indiana University School of Medicine in Indianapolis, Indiana, and co-authors. “Single-agent pembrolizumab did not demonstrate clinical benefit in this cohort of patients with refractory GCT.”

Research should now turn to understanding the mechanism of resistance, the authors suggested.

Anti-programmed cell death protein 1 (PD-1) immune checkpoint inhibition with the humanized antibody has shown promising antitumor effects with manageable toxicity in other types of cancer after tumors become refractory to the standard of care.

Between March and October 2016, the authors enrolled 12 men with relapsed nonseminoma GCT in a single-arm phase II trial evaluating the clinical activity of pembrolizumab (intravenous 200 mg every 3 weeks until disease progression). The primary tumor site was testis for 11 patients and mediastinum for one patient. The cancer had progressed in all 12 men following first-line cisplatin-based chemotherapy and at least 1 salvage chemotherapy treatment. The men received a median of 2 doses (range, 1-8 doses) with no partial or complete responses.

Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively, but alpha-fetoprotein levels continued to rise for both men during treatment despite radiographic stability, the authors noted.

“Ten patients had progressive disease as their best response,” the authors reported. “None of the patients on study had tumor marker decline while on treatment with pembrolizumab.”

Six patients experienced grade 3 adverse events, 4 of which were deemed “possibly related” to disease or study treatment. No grade 4 or 5 toxicities were reported and the patients did not experience any immune-related adverse events.

The small number of patients studied limited generalizability; in addition, the short duration of the study might mean that the tolerability findings are not representative of adverse event risks for patients on treatment for longer periods of time, the authors cautioned. Other trials continue to investigate immune checkpoint inhibition as monotherapy or combination regimens among patients with metastatic GCT.

Study eligibility criteria did not include PD-L1 expression levels, which have been associated with melanoma and lung cancer response to immune checkpoint inhibition, they added.

“Immunohistochemistry staining for PD-L1 was carried out on archival tumor tissues which may not represent the current immune status or the tumor microenvironment at the time of treatment with checkpoint inhibitor,” they reported. “In addition, PD-L1 expression from tumor metastatic sites was not carried out and this might also be informative. The expression of PD-L1 is known to be dynamic and is regulated by extrinsic signaling such as release of interferon-c by immune cells, loss of expression of tumor suppressor genes or activation of the AKT-mTOR pathway.”

The study was funded by Merck.