The first anti-PD-1 drug to clear FDA, Merck & Co. Inc.’s Keytruda (pembrolizumab) bears labeling that demonstrates the attractive safety profile of the class, especially relative to the immune checkpoint pioneer Yervoy – which could fuel off-label use in the first-line setting.

FDA granted accelerated approval Sept. 4 for Keytruda for patients with unresectable or metastatic melanoma who no longer responded to treatment with Bristol-Myers Squibb Co.’s CTLA-4 inhibitor Yervoy (ipilimumab) and – for those who are BRAF-mutation positive – a BRAF-inhibitor.

Pembrolizumab is the first of the PD-1 immunotherapy family to gain approval in the U.S., ahead of its closest rivals – Bristol’s anti-PD-1 nivolumab and Roche’s MPDL-3280A, an anti-PD-L1 candidate. Nivolumab became the first PD-1 inhibitor to win a world approval following clearance in Japan in July. Bristol partner Ono Pharmaceutical Co. Ltd. announced the drug’s launch in Japan on Sept. 2 and has reportedly set a price of $143,000 annually, which is higher than expectations for the global market.

Merck said that it plans to launch Keytruda within a week at an estimated price of $12,500 per month (cost varies depending on factors such as the weight of the patient). Keytruda is given at a dose of 2 mg/kg every three weeks as an intravenous infusion until disease progression or unacceptable toxicity. In the Phase I single arm study supporting approval, the median number of months of treatment was 6.2, which translates into a cost of $77,500. At the time of study analysis, 51% of patients received Keytruda for more than 6 months and 21% got it for more than a year.

“The cost of Keytruda is consistent with other innovative oncology medicines, including the standard of care in advanced melanoma,” the company said in a statement.

Labeling for Keytruda accentuates the milder safety profile of inhibitors of PD-1 relative to CTLA-4 that has been noted at recent medical meetings, though direct comparisons are not available yet and there were differences in the trial populations represented in the supporting data for the filings.

Keytruda’s approval was supported by the Phase I single arm KEYNOTE-001 study, which tested a 2 mg/kg dose and a 10 mg/kg dose in advanced melanoma. Labeling notes safety results for all 411 patients in the study and efficacy for a cohort of 173 patients who received the 2 mg/kg dose that was ultimately approved. The trial excluded patients who had severe immune-mediated reactions with Yervoy.

Yervoy is approved broadly for unresectable or metastatic melanoma, a clearance supported by Phase III data showing an overall survival benefit. But the CTLA-4 inhibitor’s label has a boxed warning for severe and fatal immune-mediated adverse reactions. These may involve any organ system, but the most common reactions are enterocolitis, hepatitis, dermatitis, neuropathy and endocrinopathy. In a Phase III, three-arm study that tested the drug after failure of a range of chemotherapies, 12% and 15% of those in the cohorts containing the approved dose of Yervoy had a severe-to-fatal immune-mediated adverse reaction.

Pembrolizumab’s label notes immune-mediated adverse reactions, but in the warnings and precautions section and not in a black box. In its statement announcing the Keytruda approval, FDA said that severe immune-mediated side effects “occurred uncommonly” in the lung, colon, hormone-producing glands and liver.

According to labeling, the most common immune-mediated side effect was pneumonitis, which occurred in 2.9% of the 411 melanoma patients in the trial, including Grade 2 cases in eight (1.9%) patients and one Grade 3 case (0.2%).

“The most common adverse reactions (reported in ≥20% of patients) included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia and diarrhea,” labeling states.

As for efficacy, the objective response rate for the 173 patients taking the 2 mg/kg dose was 24%; there was one complete response and 20 partial responses.

At the American Society of Clinical Oncology annual meeting in June, investigators presented data showing higher response rates in those who were Yervoy-naïve and the approval of Keytruda raises the question of whether patients and prescribers will look to use the more tolerable Keytruda instead of Yervoy as a first-line therapy, though it is only indicated for Yervoy failures Also see "Yervoy/Nivolumab May Need Stronger Survival Data To Be First Choice In Melanoma" - Pink Sheet, 2 June, 2014..

Merck is testing Keytruda head-to-head against Yervoy in first-line melanoma in the Phase III KEYNOTE-006 study.

It’s also possible that the combination of Yervoy and a PD-1 inhibitor will emerge as the best first-line regimen. Bristol presented strong efficacy data for Yervoy plus nivolumab at the ASCO meeting, though the benefit came with a high rate of severe side effects.

Approved With Time To Spare

Keytruda was designated a “breakthrough therapy” by FDA, which allows a faster approval process. Merck announced the submission of a rolling filing early this year and the drug’s approval came almost eight weeks ahead of its user fee date of Oct. 28.

Per FDA’s current style, labeling notes the caveats of the accelerated approval: “This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.”

In its statement announcing approval of pembrolizumab, the agency noted that this is the sixth new melanoma treatment approved since Yervoy’s clearance in March 2011 Also see "Yervoy Approval Has Shifted Development Landscape For Melanoma" - Pink Sheet, 4 April, 2011.. Subsequently, Schering AGSylatron (peginterferon alfa-2b), Roche’s BRAF inhibitor Zelboraf (vemurafenib), and two drugs from GlaxoSmithKline PLC– the BRAF inhibitor Tafinlar (dabrafenib) and MEK inhibitor Mekinist (trametinib) – got the green light in the U.S.

Hopes are particularly high for drugs in the checkpoint inhibitor family, including CTLA-4 and PD-1, due to improved survival and long-term response. Bristol has started a rolling submission of nivolumab with FDA in third-line squamous cell lung cancer, which it plans to complete by the end of the year, and has announced plans to file in melanoma in the third quarter.

Safety Profile Of Merck’s Anti-PD-1 Keytruda Shines In FDA Labeling

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