1. Nalley, Catlin

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Adjuvant pembrolizumab decreased the risk of disease recurrence or death by 35 percent among patients with Stage IIB and IIC melanoma when compared to placebo, according to findings presented at the ESMO Congress 2021. The researchers also reported significantly prolonged recurrence-free survival, as well as a favorable benefit-risk profile.

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"Patients with Stage IIB/C melanoma have similar risk of recurrence and melanoma-specific survival to patients with Stage IIIA/B," noted study author Jason Luke, MD, FACP, Director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center. "Despite this, only patients with Stage III disease have access to adjuvant anti-PD-1 immunotherapy, with pembrolizumab, whereas those with Stage II do not."


To address this, KEYNOTE-716, the first Phase III, double-blind, trial to evaluate an anti-PD-1 therapy (pembrolizumab) compared to placebo in patients with resected Stage IIB or IIC melanoma. The results of the first recurrence-free survival interim analysis were presented by Luke during the ESMO Congress 2021 (Abstract LBA3).


Methods, Findings

Patients in this international, placebo-controlled Phase III trial were randomized 1:1 to receive pembrolizumab at standard approved dosing (200 mg or 2 mg/kg for pediatric patients), or placebo for up to 17 cycles over the course of 1 year, according to Luke.


Eligible patients were 12 years or older with newly diagnosed, resected, high-risk, Stage II melanoma with an ECOG PS of 0 or 1. Treatment continued until disease recurrence or unacceptable toxicity. For the interim analysis, the data cutoff date was December 4, 2020. Part 2 of the KEYNOTE-716 study is not yet mature. It will assess the outcomes of patients after recurrence and crossover to pembrolizumab and subsequent treatments, according to Luke.


"Stratification factors included the T category (T3b, T4a, T4b) with a primary endpoint of recurrence-free survival (assessed by investigators) and secondary endpoints surrounding distant metastasis-free survival, overall survival, and health-related quality of life," Luke said.


Overall, 976 patients (64% Stage IIB; 34.8% Stage IIC) were randomized with 487 in the pembrolizumab group and 489 receiving placebo. At a median follow-up of 14.4 months, the researchers reported that pembrolizumab significantly prolonged recurrence-free survival when compared to placebo (HR 0.65, 95% CI 0.46-0.92; P=0.00658; median not reached for both).


Data showed that 54 (11.1%) patients had a recurrence in the pembrolizumab compared to 82 (16.8%) with placebo. Additionally, the researchers observed 23 distant recurrence events in patients treated with pembrolizumab versus 38 in patients who received placebo. The 12-month recurrence-free survival rate was 90.5 percent versus 83.1 percent, according to the study authors.


"KEYNOTE-716 met the primary endpoint of recurrence-free survival at the pre-specified first protocol assessment demonstrating a hazard ratio of 0.65 or 35 percent reduction in the risk of recurrence for pembrolizumab as compared with placebo," Luke reported. "In addition, there was a 40 percent reduction in the incidence of distant organ metastasis for the pembrolizumab arm."


In terms of safety, Luke noted that there were no new safety signals relative to the known profile of pembrolizumab, and quality of life was similar and not statistically changed from baseline for pembrolizumab or placebo throughout the trial.


"The study establishes a new standard of care for patients with Stage IIB/C melanoma such that all of these patients should be offered this treatment moving forward," Luke told Oncology Times. "The incidence of Stage IIB/C melanoma is approximately the same as that of Stage III, so the results of this study will effectively double the number of patients who should be offered pembrolizumab in the post-surgical adjuvant setting."


Next Steps, Implications

Moving forward, the investigators will observe the study data as they mature, according to Luke, who noted this will allow for a better understanding of the total impact of pembrolizumab in this setting.


"Despite meeting the primary endpoint at the first assessment, the overall study is still early in maturation," he explained. "Based on that and our understanding from prior immunotherapy clinical trials, we fully expect to see that the hazard ratio will further improve over time and suggest that adjuvant therapy in fact has an even greater impact in reducing recurrence than what we have reported here in the first study description."


Additionally, the researchers look forward to analyzing biospecimens obtained from the trial to better understand molecular correlates of treatment response and perhaps move toward a future where they may have the ability to biomarker select patients who would benefit the most.


"The data from KEYNOTE-716 emphasize that patients with Stage IIB/C are at high risk of recurrence and that these recurrences happen rapidly after surgery," Luke said. "These results highlight that factors from the primary melanoma-including depth of invasion and ulceration-are adequate to consider adjuvant therapy with pembrolizumab.


"Therefore, the role of lymph node surgery in melanoma would be expected to evolve and perhaps be reduced over time," he concluded.


Catlin Nalley is a contributing writer.