Paris — "It's not just what you give, it's when you give it," said the investigator reporting "that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence."
Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.
At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.
"Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma," Patel commented.
She suggested that the explanation for the findings was that "inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells...[and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors."
The findings were presented here during a presidential symposium at the European Society for Medical Oncology (ESMO) 2022 Annual Meeting in Paris, France.
"This trial provides us with more evidence of when one strategy may be preferred over the other," commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center, New York City. She was not involved with the trial.
"Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven 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," she told Medscape Medical News when approached for comment.
"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," she said. However, she added that "we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery."
Details of the New Results
The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.
The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.
At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).
"With a limited number of events, overall survival is not statistically different at this time," Patel said. "Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm."
The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.
Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, UK, noted that the study had "striking results" and was a landmark trial with a simple but powerful design.
However, he pointed to some questions which need to be addressed in the future. "One important question is what is the optimal duration of neoadjuvant treatment and can we individualize it?"
Another question is just how much postoperative treatment is really needed and can pathology help determine that. "Can surgery be safely be avoided altogether?" he asked. "Another issue is the need for anti-CTL4 therapy—which patients might benefit from anti-CTL4, in addition to anti-PD-1?"
"And by extension, this paradigm provides a great platform for testing new agents including combinations in cases where PD-1 is not sufficient to achieve a sufficient response," said Larkin. "In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment."
Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. "The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials," said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia, PA. "Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines."
S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck's anti-PD-1 therapy. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Olszanski has reported participation in advisory boards for BMS, Merck, and InstilBio and running trials for them.
ESMO 2022. Abstract LBA6. Presented September 11, 2022
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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Cite this: Not Just What, But When: Neoadjuvant Pembrolizumab in Melanoma - Medscape - Sep 11, 2022.