Neoadjuvant Shows Positive Response in Advanced Melanoma Trial

In exploratory analyses of results from the SWOG S1801 trial in patients with stage 3–4 resectable melanoma, researchers saw a major pathological response in more than half of surgical specimens taken from patients who had been treated with neoadjuvant (preoperative) pembrolizumab.

These and other results of the analyses were recently presented at the European Society of Medical Oncology (ESMO) Congress 2023 in Madrid, Spain, by Sapna P. Patel, MD, chair of the SWOG melanoma committee and associate professor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center.

“The pathologic responses seen in S1801 highlight the potential for single-drug immunotherapy to achieve results that we know are important for individual patient outcomes, namely the demonstration of a favorable pathologic response after a few doses of treatment,” said Patel, who is also the principal investigator of the trial. 

“But it is important not to over-interpret the results. The absence of a pathologic response means there is room for improvement, but those patients still likely benefitted from a neoadjuvant approach with immunotherapy where their immune system began priming with tumor in situ than if they had gone to upfront surgery. The goal of a short duration of neoadjuvant immunotherapy is to initiate tumor priming, not necessarily to shrink the tumor(s) or demonstrate a pathologic response. Even in the absence of a radiographic or pathologic response, a patient’s immune system may have a more amplified and diversified response after a few doses of preoperative immunotherapy, and then the tumor can be resected. Soon, we hope to find regimens that are safe and powerful enough where the extent of surgery may even be reduced or avoided,” added Patel.

Assessing pathological response to treatment

Primary results for S1801, published in the New England Journal of Medicine earlier this year, showed that patients with operable stage 3B through stage 4 melanoma who started immunotherapy before surgery had significantly longer event-free survival times than patients who started immunotherapy after their surgery.

The latest abstract reports the response to neoadjuvant treatment evaluated using specimens removed from these patients during surgery. Specimens were submitted for central review on 78 percent of patients who underwent surgery in the neoadjuvant arm. “This is considered a huge success for clinical trial tissue submission in the cooperative group setting,” Patel added. “We are grateful to sites and investigators for their cooperation.”

To assess pathological response to a treatment, a pathologist examines tissue removed during surgery to see whether it includes any actively growing cancer cells—known as the residual viable tumor. If no active cells are seen, the tissue is said to have undergone a pathological complete response to treatment. If active cancer cells comprise only 1–10 percent of the tumor bed, it is said to have undergone a pathological near-complete response. 

“Major pathologic response” is defined as no more than 10 percent residual viable tumor in the examined tissue. It encompasses both the complete response and the near-complete response categories.

Coexistence of different tumor phenotypes

A total of 135 patients in S1801 who received neoadjuvant pembrolizumab subsequently underwent surgery. From these patients, 105 specimens were submitted for central review for pathological response; the vast majority of these were lymph node specimens. All reviews were performed by Victor G. Prieto, MD, PhD, the Ferenc and Phyllis Gyorkey chair for research and education in pathology at the University of Texas MD Anderson Cancer Center. At the time of review, Prieto had no information on the clinical outcomes associated with each specimen.

“Particularly interesting was the observation that there was a different distribution of response to the treatment (amount of necrosis) among different lesions and even different areas in the same patient,” Prieto said. “This suggests the existence of different tumor phenotypes in the same patient.”

The research team also correlated pathological response with recurrence-free survival (RFS). They found the rate of RFS at 24 months appeared to segregate by pathological response and was at 89 percent in patients whose tumor(s) achieved a pathological complete response.

- This press release was originally published on the SWOG Cancer Research Network website