Pembrolizumab Moves Toward EU Approval for Resected Stage IIB/IIC Melanoma

Scot W. Ebbinghaus, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of pembrolizumab (Keytruda) for use as adjuvant therapy in adult and adolescent patients aged 12 years and older with stage IIB or IIC melanoma following complete resection. Additionally, CHMP recommended expanding the indication for pembrolizumab in advanced unresectable or metastatic and stage III melanoma as adjuvant therapy following complete resection for adolescent patients aged 12 years and older.¹

The positive opinion was based on findings from the phase 3 KEYNOTE-716 trial (NCT03553836), in which pembrolizumab demonstrated a statistically significant improvement in recurrence-free survival (RFS) vs placebo in patients 12 years and older with stage IIB and IIC melanoma following complete resection (HR, 0.65; 95% CI, 0.46-0.92; P = .00658).

Additionally, pembrolizumab demonstrated significant improvements in RFS (HR, 0.57; 95% CI, 0.46-0.70; P < .001) and distant metastasis-free survival (DMFS; HR, 0.60; 95% CI, 0.49-0.73; P < .001) vs placebo in patients with stage III melanoma in the phase 3 KEYNOTE-054 trial (NCT02362594).²

The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second or third quarter of 2022.

“Based on the results of the KEYNOTE-716 trial, [pembrolizumab] has shown a significant improvement in recurrence-free survival and distant metastasis-free survival for these patients with resected stage IIB or IIC melanoma,” Scot W. Ebbinghaus, MD, vice president, global clinical development, Merck Research Laboratories, stated in a press release. “The CHMP’s positive recommendation brings us one step closer to providing patients 12 years and older in the European Union with a new option for resected stage IIB or IIC melanoma that can reduce the risk of their cancer returning.”

The multicenter, randomized, double-blind, placebo-controlled KEYNOTE-716 trial enrolled 976 patients aged 12 years and older with resected stage IIB or IIC melanoma. Following complete surgical resection, patients were randomized to 200 mg of pembrolizumab or the pediatric dose of 2 mg/kg of pembrolizumab intravenously up to a maximum of 200 mg every 3 weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. The primary end point of the trial was RFS, and secondary end points included DMFS and overall survival (OS).

KEYNOTE-054 was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma. Patients were randomized 1:1 to receive 200 mg of pembrolizumab every 3 weeks or placebo for up to one year or until disease recurrence or unacceptable toxicity. The co-primary end points were RFS in all-comers and RFS in patients with PD-L1–positive tumors. Secondary end points included DMFS and OS in all-comers and in patients with PD-L1–positive tumors.

In December 2021, the FDA approved pembrolizumab for the adjuvant treatment of adult and pediatric patients with stage IIB or IIC melanoma following complete resection based on findings from KEYNOTE-716.³ The regulatory agency also expanded the indication for the agent for adjuvant use in patients with stage III melanoma following complete resection to include pediatric patients aged 12 years and older.

In March 2022, Merck announced that KEYNOTE-716 also met its key secondary end point of DMFS at a prespecified interim analysis.² These results will be featured in a late-breaking oral presentation at the 2022 ASCO Annual Meeting on June 5.

References

1. Merck receives positive EU CHMP opinion for KEYTRUDA® (pembrolizumab) as adjuvant treatment for adult and adolescent (≥12 years of age) patients with stage IIB or IIC melanoma following complete resection. News release. Merck. May 20, 2022. Accessed May 20, 2022. https://bit.ly/38AFkw3
2. Merck’s KEYTRUDA® (pembrolizumab) demonstrated significant improvement in distant metastasis-free survival (DMFS) compared to placebo as adjuvant therapy for patients with resected stage IIB and IIC melanoma in phase 3 KEYNOTE-716 trial. News release. Merck. March 7, 2022. Accessed May 20, 2022. https://bit.ly/3G2Maqn 
3. FDA approves Merck's KEYTRUDA (pembrolizumab) as adjuvant treatment for adult and pediatric (≥12 years of age) patients with stage IIB or IIC melanoma following complete resection. News release. Merck. December 3, 2021. Accessed May 20, 2022. https://bit.ly/3DrqYal