Is it possible to predict who will respond well to neoadjuvant immunotherapy? Clearly, some patients do exceedingly well with immunotherapy. Other patients’ disease progresses despite neoadjuvant therapy. Additional research may uncover physiological differences between responders and non-responders.
Explore This IssueApril 2023
“Can we predict who will respond with biomarkers?” said Vasu Divi, MD, associate professor of otolaryngology–head and neck surgery at Stanford University in Stanford, Calif. Right now, the answer is no. Identification of biomarkers could help physicians personalize treatment and avoid delaying surgery in patients whose disease is likely to progress despite immunotherapy.
What is the optimal timing and dosage of neoadjuvant immunotherapy? The initial pilot study of neoadjuvant immunotherapy for locally advanced resectable cutaneous squamous cell carcinoma used two doses of cemiplimab. The subsequent phase 2 trial allowed up to four doses. The phase 3 trial may use “a set three doses for everybody,” Dr. Gross said.
No one yet knows the optimal timing or dosage of neoadjuvant immunotherapy. To date, researchers have studied only single drug neoadjuvant therapy. Would escalating patients’ doses, administering additional doses, or adding other drugs in combination improve response, particularly in patients who experience a partial response?
Is radiation necessary after neoadjuvant immunotherapy? Most patients who participated in the initial pilot study of neoadjuvant immunotherapy did not undergo radiation therapy after surgery due to their “dramatic pathologic responses.” To date, these patients seem to be doing well, but additional data are needed to determine the long-term impact of skipping adjuvant radiotherapy.
Current evidence suggests that response to neoadjuvant immunotherapy can be used to personalize adjuvant treatment. “If there is a very good response to neoadjuvant immunotherapy, adjuvant treatment can be de-escalated,” said Dr. Sadeghi. “On the other hand, a poor response would indicate that adjuvant treatment should be escalated.”
The adjuvant treatment plan was left to the discretion of each site in the phase 2 trial, and it “wasn’t studied systematically,” Dr. Divi said. “I think it really deserves a systematic study to determine if we need to be as aggressive with subsequent local treatment in patients who have a really good response to neoadjuvant therapy as compared to patients who do not.”
The PRADO trial, which assessed the impact of personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in patients with high-risk stage III melanoma, reported good outcomes after personalized response-directed treatment. Sixty-one percent of enrolled patients experienced a major pathologic response (MPR) with combination neoadjuvant immunotherapy, and 59 of the 60 patients with an MPR did not undergo therapeutic lymph node dissection, “resulting in significantly lower surgical morbidity and better quality of life.” The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with an MPR (Nature Med. 2022;28:1178-1188).