A new phase III clinical trial has demonstrated sustained benefits of adjuvant pembrolizumab therapy in patients with resected stage IIB or IIC melanoma. The KEYNOTE-716 study, published on March 7, 2024 in the Journal of Clinical Oncology, provides final analysis results for distant metastasis-free survival (DMFS) along with updated recurrence-free survival (RFS) data.
This double-blind, placebo-controlled study was conducted across multiple international sites and funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. The primary aim was to evaluate the efficacy and safety of pembrolizumab as adjuvant therapy compared to placebo in patients with completely resected stage IIB or IIC melanoma.
A total of 976 patients were enrolled and randomized 1:1 to receive either pembrolizumab (n=487) or placebo (n=489). Key inclusion criteria were patients aged 12 years or older with newly diagnosed, resected, histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma without regional lymph node involvement. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no previous melanoma treatment beyond complete resection.
The study population had a median age of 60-61 years, with approximately 60% of patients under 65 years old. The majority of participants were male (about 60%) and white (around 90%). Most patients had an ECOG status of 0 (over 90%). In terms of disease staging, about 63-65% had stage IIB melanoma, while 34-35% had stage IIC.
Patients received either pembrolizumab 200 mg (or 2 mg/kg up to 200 mg for pediatric patients) or placebo intravenously every 3 weeks for up to 17 cycles. Treatment continued until disease recurrence, unacceptable toxicity, or withdrawal of consent.
The primary endpoint was investigator-assessed RFS, with DMFS as a key secondary endpoint. Safety and tolerability were also assessed. The current analysis was conducted after a median follow-up of 39.4 months (range 26.0-51.4 months).
Results showed that pembrolizumab continued to demonstrate significant improvements in both DMFS and RFS compared to placebo. For DMFS, the median was not reached in either group. The estimated 36-month DMFS rate was 84.4% for pembrolizumab versus 74.7% for placebo (hazard ratio [HR] 0.59, 95% CI 0.44-0.79). This translates to a 41% reduction in the risk of distant metastasis with pembrolizumab.
Similarly for RFS, the median was not reached in either group. The estimated 36-month RFS rate was 76.2% for pembrolizumab compared to 63.4% for placebo (HR 0.62, 95% CI 0.49-0.79), representing a 38% reduction in the risk of recurrence or death.
Subgroup analyses showed consistent benefits across most predefined subgroups, including disease stage. For stage IIB melanoma, the 36-month DMFS rate was 86.7% with pembrolizumab versus 78.9% with placebo (HR 0.62, 95% CI 0.42-0.92). For stage IIC, the rates were 80.9% versus 68.1% respectively (HR 0.57, 95% CI 0.36-0.88).
Regarding safety, treatment-related adverse events (TRAEs) occurred in 82.6% of pembrolizumab-treated patients (17.2% grade 3-4) compared to 63.6% of placebo patients (5.1% grade 3-4). The most common TRAEs with pembrolizumab were pruritus (24.6%), fatigue (21.5%), and diarrhea (18.6%). Immune-mediated adverse events and infusion reactions occurred in 37.9% of pembrolizumab patients (11.0% grade 3-4) versus 9.5% of placebo patients (1.2% grade 3-4).
TRAEs led to treatment discontinuation in 15.9% of pembrolizumab patients compared to 2.5% of placebo patients. Importantly, no treatment-related deaths were reported.
The study authors concluded that these results continue to support the use of pembrolizumab as adjuvant therapy in patients with resected stage IIB or IIC melanoma. The sustained DMFS and RFS benefits, along with the manageable safety profile, reinforce the positive benefit-risk balance of this treatment approach.
This study has several strengths, including its large sample size, randomized controlled design, and extended follow-up period. The consistency of results across subgroups adds robustness to the findings. However, there are also some limitations to consider. The study population was predominantly white, which may limit generalizability to other racial groups. Additionally, overall survival data are not yet mature and will be reported in a future analysis.
The potential clinical impact of these findings is significant. Patients with stage IIB and IIC melanoma have a similar prognosis to those with stage III disease and are at considerable risk of recurrence and distant metastasis. The sustained benefits observed with adjuvant pembrolizumab in this population could lead to improved long-term outcomes and potentially prevent progression to more advanced disease stages.
These results have already influenced clinical practice, with pembrolizumab receiving approval from regulatory authorities including the US Food and Drug Administration and European Medicines Agency for adjuvant treatment of adult and pediatric patients with stage IIB or IIC melanoma following complete resection.
Moving forward, it will be important to continue follow-up to assess long-term outcomes, including overall survival. Additionally, further research may be needed to identify biomarkers that could help select patients most likely to benefit from adjuvant immunotherapy in this setting.
The KEYNOTE-716 trial also highlights the evolving landscape of melanoma management, with a shift towards earlier intervention with systemic therapies in high-risk patients. This approach aims to improve cure rates and prevent metastatic disease, potentially changing the natural history of melanoma for many patients.
However, the increased use of adjuvant therapy also raises important considerations. The financial implications of treating a broader patient population with costly immunotherapy drugs need to be weighed against the potential long-term benefits and healthcare cost savings from preventing recurrences and metastatic disease. Additionally, exposing patients with surgically cured disease to the risk of immune-related adverse events requires careful patient selection and counseling.
In conclusion, the final DMFS analysis of the KEYNOTE-716 trial provides compelling evidence for the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. The sustained efficacy benefits and manageable safety profile support the integration of this treatment approach into standard clinical practice. As with any advance in cancer therapy, ongoing research and real-world data will be crucial to further refine patient selection and optimize long-term outcomes in this high-risk melanoma population.
References
Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol. 2024;42(14):1619-1624. doi:10.1200/JCO.23.02355
