Recent Drug Approvals

FDA Approves First Anti–PD-1: Pembrolizumab Indicated for Advanced Melanoma

The FDA approved the first ­­anti–programmed death receptor-1 (PD-1) therapy, pembrolizumab (Keytruda; Merck), for patients with unresectable or metastatic melanoma and disease progression after treatment with other melanoma therapy, such as ipilimu­mab, or, for a patient with BRAF V600 mutation, after BRAF inhibitor therapy.

The FDA accelerated its approval for pembrolizumab based on early clinical data from the KEYNOTE-001 phase 1b trial showing a high tumor response rate and long durability of response rather than on actual improvements in survival or in disease progression. Ongoing phase 2 and 3 clinical trials are being conducted to provide confirmatory information that is expected to demonstrate clinically meaningful improved outcomes, including potential im­­provement in survival and/or reduction in disease progression.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is the first-ever anti–PD-1 therapy to re­ceive FDA approval. The FDA also granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the positive early results from the phase 1b trial in 173 patients with unresectable or metastatic melanoma whose disease progressed after previous therapy, reflecting an unmet medical need for this patient population.

The FDA approval was based on early results from the ongoing mul­ticenter, open-label, randomized, dose-­comparative KEYNOTE-001 phase 1b trial. A total of 89 patients received the 2-mg/kg dose every 3 weeks; other patients received different doses, including a 10-mg/kg dose, which was just as effective. Overall, 411 patients were included in this trial.

The overall response rate in the ­­89 patients receiving the 2-mg/kg dose was 24% (95% confidence interval, 15-34), including 1 complete response and 20 partial responses. At the time of the analysis, 86% of patients with objective responses had ongoing responses, with the duration of response ranging between 1.4 and 8.5 months. In addition, 8 of these patients are still showing ongoing responses of ≥6 months.

All patients had received previous treatment with ipilimumab or a BRAF inhibitor in patients with a BRAF V600 mutation; the patients had disease progression within 24 weeks after the last dose of previous therapy. Patients were randomized to receive 2 mg/kg (N = 89) or 10 mg/kg (N = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or until disease progression. The major efficacy outcomes analyzed were confirmed overall response rate and duration of response.

The most common serious adverse events reported in ≥2% of patients who received pembrolizumab include renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse events (reported in ≥20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. (September 4, 2014)

Bortezomib Receives New FDA Indication

Bortezomib (Velcade; Millennium/Takeda Oncology), which is already approved by the FDA as an intravenous (IV) or subcutaneous treatment for patients with multiple myeloma, recently received a supplemental new indication for the retreatment of adults with myeloma whose disease had previously responded to bortezomib therapy and had relapsed (ie, progressed) at least 6 months after the last treatment with bortezomib.

Retreatment with bortezomib can be restarted at the last dose the patient had tolerated previously. The new indication includes a labeling update with dosing guidelines and safety and efficacy data related to the use of bortezomib as a single agent or in combination with dexamethasone.

The new supplemental indication was based on the results from a phase 2 clinical trial, RETRIEVE, as well as other supportive data. The single-arm, open-label, international RETRIEVE trial included 130 patients with myeloma (aged ≥18 years) who had previously responded to bortezomib-based therapy and whose disease relapsed at least 6 months after previous therapy.

The overall response rate was 38.5%; 1 patient achieved a complete response and 49 patients achieved a partial response. The median duration of response was 6.5 months (range, 0.6-19.3 months).

The safety of retreatment with bortezomib was consistent with the known safety profile of IV bortezomib in patients with relapsed myeloma; no cumulative toxicities were reported with retreatment.

The most common adverse event was thrombocytopenia, which was reported in 52% of patients. The incidence of grade ≥3 thrombocytopenia was 24%. Peripheral neuropathy was observed in 28% of patients, and the incidence of grade ≥3 peripheral neuropathy was 6%. The incidence of serious adverse reactions was 12.3%. The most common serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Overall, 13% of patients discontinued bortezomib retreatment because of adverse events. (August 8, 2014)

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