Adding Pembrolizumab to Chemo Provides Little or No Benefit in Urothelial Cancer

NEW YORK (Reuters Health) – Patients with locally advanced, unresectable, or metastatic urothelial cancer may not derive extra benefit from the addition of pembrolizumab to chemotherapy or from pembrolizumab monotherapy, according to an open-label phase-3 trial.

“The reasons for this are unclear,” Dr. Thomas Powles of Queen Mary University of London told Reuters Health by email. “Single-agent pembrolizumab was associated with long-term remissions, but again it did not clearly beat chemotherapy even in the biomarker-positive subset.”

In a paper in The Lancet Oncology, Dr. Powles and colleagues note that there is increasing evidence to support cancer treatment combining immune-checkpoint inhibitors with chemotherapy. For example, they say, pembrolizumab plus platinum-based chemotherapy is a standard of care for metastatic non-small-cell lung cancer.

Although the programmed cell death ligand-1 (PD L1) inhibitor avelumab has been approved for treatment of patients with locally advanced or metastatic urothelial carcinoma, there’s a scarcity of data on chemoimmunotherapy in patients with previously untreated, advanced disease.

To investigate, the researchers studied 1,010 such patients who were randomized to receive pembrolizumab plus chemotherapy, pembrolizumab monotherapy, or chemotherapy alone.

After a median follow-up of 31.7 months, the researchers say there was no significant improvement in median progression-free survival with pembrolizumab plus chemotherapy (8.3 months) compared with chemotherapy alone (7.1 months). This was also true of median overall survival (17.0 months vs. 14.3 months).

Overall survival was similar between pembrolizumab and chemotherapy treatment groups in the total population (15.6 months with pembrolizumab vs. 14.3 months with chemotherapy). It was also the case when restricted to the population with a biomarker combined positive score of at least 10 (16.1 months vs. 15.2 months).

Six patients (two in each group) died due to an adverse events attributed to study treatment. The most common grade-3 or -4 adverse event was anemia, seen in 30% of the pembrolizumab-plus-chemotherapy group and 33% of those given chemotherapy alone.

In light of these findings, the researchers observe that addition of pembrolizumab to first-line platinum-based chemotherapy “should not be widely adopted for treatment of advanced urothelial carcinoma.”

Dr. Powles concluded, “We will look at different combinations in the future, including non-chemotherapy-containing regimens to try improve the outcome of patients with this devastating disease.”

In an accompanying editorial, Dr. Sumanta K. Pal of the City of Hope Comprehensive Cancer Center, in Duarte, California, and colleagues stress that “the use of concurrent chemoimmunotherapy is only experimental, whereas induction platinum-based chemotherapy followed by switch maintenance avelumab remains the standard frontline therapy in advanced urothelial carcinoma.”

The study was funded by Merck Sharp and Dohme, a subsidiary of Merck, which sells pembrolizumab under the brand name Keytruda. Dr. Powles has relationships with the company, as do several of his coauthors.

SOURCE: and The Lancet Oncology, online May 26, 2021.

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