KEY TAKEAWAYS
- KEYNOTE-716 is a phase 3, randomized, double-blind, placebo-controlled, crossover or rechallenge trial to evaluate the efficacy of adjuvant pembrolizumab in resected stage IIB or IIC melanoma patients.
- The primary endpoint was recurrence-free survival, while the secondary endpoint was distant metastasis-free survival.
- The intention-to-treat population revealed that pembrolizumab significantly improved distant metastasis-free survival compared to placebo (HR 0.64, 95% CI 0.47-0.88, p=0.0029).
- The median recurrence-free survival in the pembrolizumab group was 37.2 months (95% CI NR-NR). In contrast, the placebo group was not reached (95% CI NR-NR).
- The risk of recurrence was lower in the pembrolizumab group (HR 0.64, 95% CI 0.50-0.84).
- The most common grade 3 or worse adverse events included hypertension, diarrhea, rash, autoimmune hepatitis, and increased lipase.
Patients with stage IIB or IIC melanoma who underwent surgery alone are at high risk of recurrence. Therefore, a clinical trial (KEYNOTE-716) was conducted to assess the efficacy of adjuvant pembrolizumab in reducing the risk of recurrence for such patients. The study was a randomized, double-blind, placebo-controlled, phase 3 trial conducted at 160 medical centers and hospitals across 16 countries. The study results from the first interim analysis showed that pembrolizumab significantly improved recurrence-free survival compared to placebo in stage IIB or IIC melanoma.
The results from the secondary endpoint of distant metastasis-free survival, the prespecified third interim analysis, and the recurrence-free survival with longer follow-up were reported in this trial. The study included 976 patients aged 12 years and above with newly diagnosed, wholly resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in pediatric patients) or placebo, both intravenously, every three weeks for 17 cycles or until disease recurrence or unacceptable toxicity.
At a median follow-up of 27.4 months, the results showed that either group did not reach median distant metastasis-free survival. Pembrolizumab significantly improved distant metastasis-free survival compared to placebo, with a hazard ratio of 0.64 (95% CI 0.47-0.88, p=0.0029). Similarly, the median recurrence-free survival was 37.2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0.64, 95% CI 0.50-0.84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs. 17 [4%] of 486 patients in the placebo group), diarrhea (eight [2%] vs. one [<1%]), rash (seven [1%] vs. two [<1%]), autoimmune hepatitis (seven [1%] vs. two [<1%]), and increased lipase (six [1%] vs. eight [2%]).
Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) in the placebo group. However, no treatment-related deaths were reported. In conclusion, the study results indicated that adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, significantly improving distant-metastasis-free survival versus placebo and continued reduction in the risk of recurrence with an acceptable adverse event profile.
Source:https://pubmed.ncbi.nlm.nih.gov/36265502/
Clinical trial:https://clinicaltrials.gov/ct2/show/NCT03553836
Long GV, Luke JJ, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Mohr P, Dummer R, Gershenwald JE, Yoon CH, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Ascierto PA; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomized, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1378-1388. doi: 10.1016/S1470-2045(22)00559-9. Epub 2022 Oct 18. PMID: 36265502.
