Pembrolizumab and Stage II Melanoma: KEYNOTE-716 Trial Results Will Open Path to a New Treatment Paradigm for High-Risk Tumors

Initial results from the placebo-controlled, randomized KEYNOTE-716 trial investigating the use of pembrolizumab as adjuvant treatment for stage IIB/C melanoma have shown significant efficacy versus placebo in preventing both locoregional and distant recurrence of the disease.

The principal investigator of the KEYNOTE-716 trial is Jason Luke, MD, FACP, associate professor of medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutics Center within the UPMC Hillman Cancer Center Immunology and Immunotherapy Program.

Dr. Luke presented the study findings in an abstract titled “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,” at the European Society of Medical Oncology (ESMO) Congress 2021, held virtually September 16-21, 2021.

FDA Approval of Pembrolizumab for Stage II B/C Melanoma

Based on the findings from the KEYNOTE-716 study, the U.S. Food and Drug administration granted approval for the use of pembrolizumab to treat stage IIB and stage IIC melanoma in both adult and pediatric patients after complete resection.

Summary of Key Findings

Close to 1,000 individuals were enrolled in the global trial from 150 centers. Participants were eligible if they were > 12 years of age and had newly diagnosed, resected, high-risk melanoma. Participants were further stratified by T category (3b, 4a, 4b) and if they were of pediatric age. Participants were randomized to either placebo or pembrolizumab for up to 17 cycles receiving 200mg infusions every three weeks. Pediatric patients received a lower dose of 2 mg/kg.

“Our primary endpoint for the study was recurrence-free survival, and we also investigated distant metastasis-free survival and overall survival rates, along with general safety, quality-of-life measures, and adverse events,” says Dr. Luke.

The pembrolizumab cohort experienced an overall recurrence rate of 11.1%. Locoregional recurrences accounted for 6.4% of the total. Distant recurrence or metastasis occurred in 4.7% of participants at the initial interim analysis of 12 months posttreatment (median follow-up 14.4 months).

The placebo cohort was found to have an overall recurrence rate of 16.8%, with locoregional and distant recurrence amounting to 8.4% and 7.8%.

This reduction in recurrence rates and death between the pembrolizumab and placebo cohorts – 35% – likely marks the beginning of a new treatment era for these high-risk tumors, one that, while not all patients will ultimately benefit from, will afford many the opportunity to lower their risk for recurrence. 

From a safety and adverse event standpoint, the study showed the treatment regimen to have a manageable safety profile. Grade III or higher adverse events occurred in 16.1% of the participants receiving pembrolizumab. There were no deaths associated with adverse events in the cohort. Immune-related events in the pembrolizumab cohort occurred in 36.2% of participants; most were low-grade versions of hypo-and hyperthyroidism.

“Given that a significant portion of recurrences in these melanoma patients are distant – in the lungs, or the liver, brain – and are therefore very difficult to treat successfully in the long-term, the findings from our study are magnified in this respect,” says Dr. Luke.

Perspectives from Dr. Luke on Initial Findings

“From my perspective, the most important takeaways for clinicians from our study right now are the realizations of the true high-risk nature of stage IIB/C melanoma, and that treatment with pembrolizumab significantly reduces the risk of recurrence, be it locoregional or distant,” says Dr. Luke. “Historically, these disease states have not carried with them a high-risk classification from the perspective of the treating physicians. That has been due more so to a misnomer and practice patterns than statistical evidence of recurrence and mortality rates. Traditionally, surgical resection was the only treatment option, and the one adjuvant treatment available was interferon alpha. Interferon had poor efficacy and was highly toxic leading it to subsequently be removed from national guideline recommendations for treatment. So, stage II melanoma was really looked at as low-risk only because there was nothing available outside surgery to offer these patients. Our study and its findings should definitively change this perception and future clinical practice."

An intriguing and perhaps controversial outcome of the findings from Dr. Luke’s study is the possibility that current surgical paradigms for managing stage IIB/C disease may be overly aggressive in light of this new data on pembrolizumab’s efficacy profile.

“The reason we currently perform sentinel lymph node biopsy in melanoma is to describe the risk. Clinical trials do not clearly demonstrate that lymph node surgery improves long-term outcomes, but I realize that some will argue otherwise,” says Dr. Luke. “Nevertheless, the randomized clinical trials that have been conducted to date do not support these arguments. Based on the data from the KEYNOTE-716 trial, we know stage II disease is high risk. Therefore, it is possible based on these results that in the future we may do fewer sentinel lymph node biopsies.”

While the future remains unwritten, the results from this study have potential major practice implications in terms of referral patterns affecting dermatologists, surgeons, medical oncologists, and overall surgical practice patterns.

New Follow-Up Data Presented at Society for Melanoma Research Meeting

On October 31, Dr. Luke presented additional findings from the KEYNOTE-716 trial in a lecture at the 18th International Congress of The Society for Melanoma Research (SMR), which was held virtually due to the ongoing COVID-19 pandemic October 28-31, 2021.

The title of Dr. Luke’s presentation was “Pembrolizumab (Pembro) Versus Placebo (PBO) After Complete Resection of High-Risk Stage II Melanoma: Updated Results From KEYNOTE-716.”

Dr. Luke’s presentation included an additional six months of follow-up data from the study (18 months in total), extending the findings from the study’s initial analysis presented in an abstract at the ESMO Congress 2021.

Updated Recurrence Findings

The 18-month analysis continues to support the use of pembrolizumab for stage IIB/C melanoma. Participants in the pembrolizumab cohort experienced an overall recurrence rate at 18 months of 14.8 percent, while those in the placebo group saw a 23.5% rate of overall recurrence. Distant recurrence rates were 6.4% for pembrolizumab and 12.3% for placebo, an improvement of nearly 50%. 

With the 18-month data, recurrence-free survival was further improved with longer follow-up, with the hazard ratio for recurrence-free survival now showing a 39% improvement in the patients receiving pembrolizumab as compared with placebo (0.61; 95% CI; 0.45-0.82). Recurrence-free survival also remained improved in the pembrolizumab group for all of the stratified disease subtypes. Particularly, at the 18-month interval, the T4b group showed notably further improvement over the 12-month data. Safety data remained unchanged at the 18-month analysis.

“Of course the data from our study continues to mature and we look forward to longer-term follow-up analysis. This study holds tremendous promise to better understand the longitudinal outcomes of patients in the stage II setting (receiving pembrolizumab or not) as no large clinical trials for this subset of patients has been performed in more than 15 years,” says Dr. Luke. “Still, many questions remain unknown about which patients may be optimally treated with pembrolizumab for stage IIB/C melanoma, or what an optimal duration of treatment may be. As a field we must not lose sight of the individualized patient decision weighing the risk of side effects from treatment versus the potential risk reduction associated with pembrolizumab treatment. But, KEYNOTE-716 demonstrates very important efficacy findings in terms of reduction in risk of recurrence, and how clinicians ought to approach the disease in terms of its high-risk nature. Yes, finding biomarkers that can aid in identifying ideal patients will be very helpful, and zeroing in on how long to treat are highly desirable goals, but this work could be decades in the making. Should we pursue it? Of course. However, we know now that we can, in some patients, cut their risk for disease recurrence significantly. That is huge for the field and for our patients."

References and Further Reading

ESMO Congress 2021 Presentation and Abstract

KEYNOTE-716 Study on ClinicalTrials.gov (NCT03553836)

Presentations and abstracts from the SMR 2021 Virtual Congress are forthcoming for registered attendees. Visit the website for additional information on timing.

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 December 3, 2021. https://bit.ly/3DrqYal