Despite Benefits, Extended-Interval Pembro Uptake Remains Low

M. Alexander Otto, PA, MMS

September 27, 2022

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the US Food and Drug Administration (FDA) approved extended dosing for stand-alone pembrolizumab — 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient healthcare encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the healthcare system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect "brisk adoption" of extended-interval dosing, said Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Michigan, and colleagues in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is "a real-world measure of clinical effectiveness," the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is "reassuring" and helps make the case for considering it "as a best practice" for single-agent pembrolizumab, the investigators write.

Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

"I was frankly surprised by the small number of patients who received the extended-interval regimen," Strohbehn told Medscape Medical News.

"Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small," at least in the VA system.

In addition, the authors note, there is no direct financial incentive for more frequent dosing in the VA system.

It's possible that low uptake could stem from clinicians' doubts about switching to an extended-interval dose, given that the FDA's approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings — which represent the first health system–level, real-world comparative effectiveness data for standard vs extended-interval pembrolizumab — should help address these concerns, the team says.

"This observational dataset lends further credence to [the dosing] regimens being clinically equivalent," said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Strohbehn and his team suggest "clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab."

Riechert also suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs "end up on the market with dosing regimens that haven't necessarily been optimized."

Across the world, investigators are conducting clinical trials "to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome," Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA's Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Reichert and Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

JAMA Oncol. Published online September 22, 2022. Abstract

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com

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