Medical Information

Pembrolizumab significantly improved distant metastasis–free survival vs placebo when used as an adjuvant treatment in patients with resected stage IIB and IIC melanoma, according to additional data from the phase 3 KEYNOTE-716 trial.

Pembrolizumab (Keytruda) significantly improved distant metastasis–free survival (DMFS) vs placebo when used as an adjuvant treatment in patients with resected stage IIB and IIC melanoma, according to additional data from the phase 3 KEYNOTE-716 trial (NCT03553836).

Previously, 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 data from the first interim analysis of KEYNOTE-716, which showed that the immunotherapy significantly improved recurrence-free survival (RFS) vs placebo, reducing the risk of disease recurrence or death by 35% (HR, 0.65; 95% CI, 0.46-0.92; P = .0132).

At this interim analysis, pembrolizumab continued to demonstrate an improvement in RFS, and no new safety signals were reported.

Full data from the trial will be shared at an upcoming medical meeting, according to a press release issued by Merck.

“Patients with melanoma that has spread to distant sites have a significantly worse prognosis and the goal of adjuvant therapy is to delay disease recurrence, especially distant metastases,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Laboratories, stated in the press release. “In KEYNOTE-716, adjuvant treatment with [pembrolizumab] first showed a significant improvement in RFS and has now demonstrated a significant improvement in the time until the first diagnosis of a distant metastasis compared with placebo. The DMFS data from KEYNOTE-716 reinforce the evidence for [pembrolizumab] as adjuvant therapy in stage IIB and IIC melanoma.”

The multicenter, double-blind, placebo-controlled, phase 3 trial enrolled 976 patients with newly diagnosed, resected, high-risk stage II melanoma who were at least 12 years of age and who had an ECOG performance status of 0 or 1.

Following complete surgical resection, study participants were randomized to receive pembrolizumab at 200 mg or the pediatric dose of 2 mg/kg up to a maximum of 200 mg, given intravenously every 3 weeks (n = 487), or placebo (n = 489) for up to 1 year. Treatment was administered until disease recurrence or intolerable toxicity.

Participants were stratified based on AJCC eighth edition T stage (> 2.0-4.0 mm with ulceration vs > 4.0 mm without ulceration vs > 4.0 mm with ulceration).

The primary end point of the trial was RFS per investigator assessment, and key secondary end points include DMFS, overall survival, and safety. Health-related quality of life served as an exploratory end point.

Earlier data presented during the 2021 Society for Melanoma Research Congress, showed that the median RFS had not yet been reached (NR) with either pembrolizumab (95% CI, NR-NR) or placebo (95% CI, 29.9-NR; HR, 0.61; 95% CI, 0.45-0.82). In the investigative and control arms, the 18-month RFS rates were 85.8% and 77.0%, respectively.

At a median follow-up of 14.4 months, the proportion of patients who received pembrolizumab and experienced distant recurrence was 4.7% vs 7.8% of those who were given placebo.

When broken down into subsets, among those with T3b disease, the median RFS had not been reached (95% CI, NR-NR) with pembrolizumab or with placebo (95% CI, NR-NR; HR, 0.40; 95% CI, 0.23-0.69). The 18-month RFS rates in the investigative and control arms were 91.1% and 77.4%, respectively.

Among those with T4b disease, again, the median RFS had not yet been reached with the immunotherapy (95% CI, 24.2-NR) or placebo (95% CI, 25.2-NR; HR, 0.82; 95% CI, 0.54-1.26). In this subset, the 18-month RFS rate with pembrolizumab was 78.9% vs 74.1% with placebo.

Additionally, 85.2% of patients who received the immunotherapy did not have a RFS event vs 76.5% of those who were given placebo; 14.8% and 23.5% of patients, respectively, experienced an event.

Among those who had an event and received pembrolizumab, 7.8% had local or regional or locoregional recurrence and 6.4% had distant recurrence. In those who received placebo, 10.2% had local or regional or locoregional recurrence and 12.3% had distant recurrence. A total of 3 patients who received pembrolizumab died vs 5 patients who received placebo.

A total of 483 patients who received pembrolizumab and 486 patients who were given placebo were assessed for safety. Data showed that 95.4% and 91.4% of patients, respectively, experienced any-grade toxicities, with 28.2% and 19.1% of patients, respectively, experiencing events that were grade 3 to 5 in severity.

Treatment-related adverse effects (TRAEs) were reported in 82.8% of those who received the immunotherapy vs 63.4% of those who were given placebo. Grade 3 to 5 TRAEs were experienced by 17.0% and 4.3% of patients, respectively.

Moreover, 16.4% of patients discontinued pembrolizumab and 2.5% discontinued placebo. Notably, no toxicities resulted in death.

References

1.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 March 7, 2022. https://bit.ly/3IQaxrH

2.FDA approves Merck's KEYTRUDA (pembrolizumab) as adjuvant treatemnt 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 March 7, 2022. https://bit.ly/3DrqYal

3.Luke JJ, Long GV, Khattak MA, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: updated results from the KEYNOTE-716 trial. Presented at: 2021 Society for Melanoma Research Congress; October 28-31, 2021; virtual.

4.Luke JJ, Rutkowsi P, Queirolo P, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741

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