Keytruda Granted sBLA for Melanoma Treatment

The FDA has accepted a supplemental biologics license application (sBLA) for the use of Keytruda (pembrolizumab) as an adjuvant treatment for patients with resected, high-risk stage 3 melanoma, according to Merck (MSD), the manufacturer of the PD-1 inhibitor.

The sBLA is supported by results from the phase 3 EORTC 1325-MG/KEYNOTE-054 trial presented at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine. In the study, adjuvant Keytruda reduced the risk of recurrence or death by 43 percent in patients with resected, high-risk stage 3 melanoma.

At a median follow-up of 15 months, the one-year recurrence-free survival (RFS) rate was 75.4 percent with the PD-1 inhibitor versus 61 percent with placebo. The RFS benefit was observed regardless of PD-L1 or BRAF mutation status. The FDA is scheduled to make its decision on the sBLA by Feb. 16, 2019.

“EORTC1325/KEYNOTE-054 was the first trial with Keytruda to demonstrate a recurrence-free survival benefit in the adjuvant setting, and we continue to actively investigate Keytruda in the adjuvant or neoadjuvant setting across our broad clinical development program,” Scot Ebbinghaus, M.D., vice president, clinical research, Merck Research Laboratories, said in a statement.

“Earlier intervention with adjuvant therapy has proven to be an important factor in reducing the risk of recurrence following surgery for patients with high-risk stage III melanoma. We look forward to working with the FDA on the review of this application, with the goal of bringing Keytruda to patients with advanced melanoma earlier in their treatment,” added Ebbinghaus.

The EORTC 1325/KEYNOTE-054 trial enrolled 1019 patients with stage 3 melanoma who were at high risk of recurrence after complete resection of their tumors. Patients had stage 3A (if N1a, at least one metastasis larger than 1 mm), stage 3B, or stage 3C (no in transit meta) disease. No prior systemic therapy for melanoma was allowed and randomization had to occur within 12 weeks of surgery.

Patient were randomized to 200 mg of Keytruda (514 patients) or placebo (505 patients) intravenously every three weeks for a total of 18 doses (approximately one year) or until disease recurrence or unacceptable toxicity. Except in the case of brain metastases, patients on placebo with recurrence were unblinded and could cross over to receive Keytruda. Additionally, patients randomized to Keytruda who had recurrence more than six months following completion of one year of initial treatment could rechallenge with Keytruda.

Patient characteristics were well balanced between the two arms. In the Keytruda arm, 63.0 percent of patients were male, and the median age was 54 years (range 19-88). The breakdown of disease stage at randomization was 15.6 percent with stage 3A, 46.1 percent with stage 3B, 18.5 percent with stage 3C with one to three positive lymph nodes, and 19.8 percent with stage 3C with at least four positive lymph nodes.

Also in the Keytruda arm, 83.3 percent of patients were PD-L1 positive (melanoma score, 2 or higher), 11.5 percent were PD-L1 negative, and the status could not be determined for 5.3 percent of patients. Regarding BRAF status, 40.9 percent had a V600E or V600K mutation, 6.8 percent had another mutation, 45.3 percent were wild-type and the status was unknown for 7.0 percent.

The primary endpoint was RFS in the overall population and in PD-L1—positive patients. The 18-month RFS rate was 71.4 percent with Keytruda versus 53.2 percent with placebo. An RFS benefit with the PD-1 inhibitor was observed across patients with either stage 3A, 3B or 3C disease.

In the PD-L1—positive group, the one-year RFS rate was 77.1 percent in the Keytruda group and 62.6 percent in the placebo group. The 18-month RFS rates were 74.2 percent versus 54.5 percent, respectively.

Among PD-L1—negative patients, the one-year RFS rates were 72.2 percent in the Keytruda arm versus 52.2 percent in the placebo group. The 18-month RFS rates were 60.6 percent versus 52.2 percent, respectively.

In BRAF 600E/V—positive patients, the one-year RFS rate was 72.5 percent with pembrolizumab versus 58.6 percent with placebo. The 18-month RFS rates were 69.2 percent versus 52.4 percent, respectively.

Among BRAF wild-type patients, the one-year RFS rate was 73 percent with Keytruda versus 59.7 percent with placebo. The 18-month RFS rates were 66.7 percent versus 48.8 percent, respectively.

Grade 3 to 5 treatment-related adverse events (AEs) occurred in 14.7 percent of the Keytruda arm versus 3.4 percent of the placebo group. In the Keytruda arm, there was one treatment-related death due to myositis.

All-grade immune-related AEs were reported in 37.3 percent of the Keytruda group and 9 percent of the placebo group. The incidence of endocrine disorders was higher with Keytruda (23.4 percent vs 5.0), with the most common endocrine disorders being hypothyroidism (14.3 percent vs 2.8 percent) and hyperthyroidism (10.2 percent vs 1.2 percent). The incidence of these 2 AEs was mostly grade 1 or 2, except for 1 case of grade 3 hyperthyroidism. Sarcoidosis also occurred at a low rate (1.4 percent vs 0 percent), with all cases being grade 1 or 2.

Grade 3/4 immune-related AEs occurred in 7.1 percent versus 0.6 percent of patients in the Keytruda versus placebo arms respectively. Events occurring at rates over 1 percent included colitis (2 percent vs 0.2 percent), pneumonitis (0.8 percent vs 0 percent) and hepatitis (1.4 percent vs 0.2 percent).

“The EORTC 1325 trial will continue to its secondary end points, distant metastasis-free survival and overall survival. We recently found that the effects of treatment on recurrence-free survival correlate very well with the effects on overall survival in trials of adjuvant therapy with interferon alfa and with ipilimumab in high-risk melanoma,” Eggermont et al wrote in the NEJM publication of their findings.

“Therefore, one may reasonably expect that the benefit of pembrolizumab for relapse-free survival that we have found in our trial will translate into an overall survival benefit, unless effective post-relapse treatments compensate for the initial disadvantage; this is a question that may be answered by the crossover design of the trial,” continued Eggermont et al.