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Giving the anti-PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda) at a higher dose but less often was safe and effective in patients with unresectable or metastatic melanoma, interim data from KEYNOTE 555 showed.

Among 44 previously untreated patients with stage III/IV disease, 38.6% responded to the 400-mg dose every 6 weeks, which was comparable to a 35.1% response rate in historical controls involving over 1,000 patients treated with other dosing schedules, reported Mallika Lala, MD, of Merck, at the American Association for Cancer Research virtual meeting.

At a median follow-up of 6.7 months, 9.1% experienced a complete response, with partial responses in 29.5% and stable disease in 22.7%. Progression-free survival is consistent with historical data, said Lala, though the analysis is still immature.

"Data from KEYNOTE 555 cohort B support that pembrolizumab administered at 400 mg every 6 weeks is a safe and efficacious dosing regimen," said Lala.

And the FDA agreed, as hours after her presentation, the agency , citing pharmacokinetic modeling and exposure-response analyses, as well as the clinical data from KEYNOTE 555.

Modeling data, which were validated in the trial, correctly predicted that trough and peak concentrations for the 6-week dosing schedule would be comparable to the 200-mg every-3-week schedule, as well as weight-based dosing schedules investigated in earlier clinical trials (2 mg/kg every 3 weeks and 10 mg/kg every 2 weeks).

At 6 weeks, the geometric mean of observed trough concentration in patients treated at the 400-mg dose was lower than with 200 mg (14.5 ug/mL vs 18.1 ug/mL, respectively), but higher than the 2-mg/kg weight-based schedule (13.4 ug/mL).

Directly following an infusion, average peak concentrations were 136 ug/mL with the 400-mg dose, which was higher than the 200-mg dose but lower than the highest clinically tested weight-based dose of 10 mg/kg every 2 weeks (220 ug/mL).

And pharmacokinetic data from past trials have shown no significant differences in pembrolizumab clearance across patients with 12 different tumor types.

"These high flat doses can bring down the number of visits of patients to the outpatient facilities of hospitals, or even will further open up home-care schedules," said AACR Session Chair Alexander Eggermont, MD, PhD, of Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands. "The pharmacokinetics are very consistent across different tumor types so it's all very encouraging."

AACR-invited discussant Siwen Hu-Lieskovan, MD, PhD, of Huntsman Cancer Institute in Salt Lake City, said that "with the promise of prolonged survival associated with checkpoint inhibitors, convenience, quality of life, and reducing healthcare costs become important issues."

She noted that dosing schedules have also evolved for nivolumab (Opdivo), going from weight-based dosing to a 240-mg every-2-week schedule to a 480-mg every-4-week schedule.

While pembrolizumab every 6 weeks demonstrated convincing short-term safety and suggested noninferior efficacy, Hu-Lieskovan said she would like to see the adverse event (AE) profile in greater detail and said the "long-term impact of lower minimum concentration and higher maximum concentration on efficacy, safety, and overall survival remain to be determined."

Nearly all patients (97.7%) experienced an AE of any grade, and grade 3/4 events occurred in one-fourth of the cohort. But treatment-related AEs of any grade occurred in only two-thirds of the cohort, said Lala, and just 2.3% of the grade 3/4 events were deemed to be treatment related.

The interim analysis of KEYNOTE 555 cohort B represented data on the first 44 patients enrolled. Patients in the international, open-label trial had a median age of 64 years, about 60% were men, and most had metastatic disease (91%). The study currently has 101 patients enrolled, with more data expected to be presented at a later date.

Historical controls used as a comparator included 313 melanoma patients from KEYNOTE-001, 556 patients from KEYNOTE-006, and 352 patients from KEYNOTE-252, which tested multiple investigational dosing regimens, as well as the approved every-3-week 2oo-mg dosing regimen.

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