Timing of pembrolizumab makes a difference in resectable melanoma
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Neoadjuvant pembrolizumab extended event-free survival compared with adjuvant-only administration of the anti-PD-1 therapy among patients with resectable melanoma, according to phase 2 study results presented at ESMO Congress.
Background
“Several pilot studies in melanoma have suggested neoadjuvant immunotherapy is safe and feasible [in patients with resectable melanoma],” Sapna P. Patel, MD, director of the uveal melanoma program and program director of melanoma fellowship at The University of Texas MD Anderson Cancer Center, told Healio. “SWOG S1801 was designed as a head-to-head comparison between neoadjuvant immunotherapy and the traditional approach of surgery followed by adjuvant immunotherapy,” she said.
The randomized phase 2 study included 313 patients with histologically confirmed, measurable, clinically detectable and resectable stage IIIB to stage IV cutaneous, acral and mucosal melanomas without brain metastases.
Investigators randomly assigned patients 1:1 to surgery (n = 159) followed by 18 doses of 200 mg pembrolizumab (Keytruda, Merck) once every 3 weeks or three doses of neoadjuvant pembrolizumab (n = 154) followed by surgery and 15 doses of pembrolizumab once every 3 weeks. Radiation therapy could be performed after surgery.
EFS assessed from the date of randomization to the date of first documented progression that rendered a patient unable to receive planned protocol surgery, failure to begin adjuvant therapy within 84 days of surgery, relapse after surgery or death due to any cause served as the primary endpoint.
Median follow-up was 14.7 months.
Key findings
Researchers reported longer EFS with neoadjuvant pembrolizumab compared with adjuvant pembrolizumab (HR = 0.58; 95% CI, 0.39-0.87), as well as a higher 2-year EFS rate (72% vs. 49%).
They observed more deaths in the adjuvant pembrolizumab group (22 vs. 14), which corresponded to an HR for OS of 0.63 (95% CI, 0.32-1.24), although survival data had not yet matured. A complete pathologic response occurred in 28 out of 132 patients (21%) with submitted pathology reports who received neoadjuvant pembrolizumab.
The neoadjuvant therapy benefit appeared consistent across key subgroups based on age, stage, sex, performance status, levels of lactate dehydrogenase, ulceration and BRAF status.
In addition, the same number of patients made it through surgery to adjuvant pembrolizumab in both treatment groups, according to the researchers.
The groups had similar rates of adverse events, with no new safety signals identified.
Implications
“Based on these findings, clinicians can now consider upfront immunotherapy for patients with resectable stage III to stage IV melanoma before sending them for surgical resection,” Patel said.
“Correlative studies on SWOG S1801 tumor and blood specimens are currently underway to describe pathologic response rates and to evaluate antitumor T-cell populations from the neoadjuvant and adjuvant study arms,” she continued. “Future studies can explore de-escalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy.”
References :
- Neoadjuvant IO boosts high-risk melanoma EFS (press release). Available at: http://www.swog.org/news-events/news/2022/09/11/neoadjuvant-io-boosts-high-risk-melanoma-efs. Published Sept. 11, 2022. Accessed Sept. 12, 2022.
- Patel SP, et al. Abstract LBA6. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
Perspective
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Maya Dimitrova, MD
The role of adjuvant vs. neoadjuvant immunotherapy in high-risk melanoma has yet to be fully elucidated. This trial provides us with more evidence of when one strategy may be preferred over another.
Neoadjuvant immunotherapy has elicited impressive complete pathologic responses that thus far have proved to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy.
This study contributes to existing evidence that neoadjuvant immunotherapy may be more effective than when given adjuvantly. In melanoma, we can see impressive complete responses even in the metastatic setting, but the optimal timing in resectable disease is still debated. Although we don’t have that answer yet, the authors provide ongoing evidence of the activity and utility of neoadjuvant therapy in patients with high-risk disease. They add to the list of benefits that may be seen with the immediate use of checkpoint inhibitors prior to surgery and while there is still bulky tumor. As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy.
This is a well-designed study seeking to answer a difficult question regarding the sequence of systemic therapy and surgery. However, we will need long-term survival data to determine the true advantage of one sequence of therapy over the other. This study will be an important stepping stone in identifying biomarkers and characteristics of patients and tumors that respond well to checkpoint inhibitors, and may help to identify patients who can avoid prolonged exposure to the drug and the subsequent risk for immune-related adverse events.
We will need further survival data to change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.
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Patel SP, et al. Abstract LBA6. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
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