ACCORDING TO DATA from a small prospective study presented at the 2019 Society of Surgical Oncology Annual Cancer Symposium,1 neoadjuvant immunotherapy significantly prolonged relapse-free survival vs adjuvant immunotherapy in patients with stage III or oligometastatic stage IV melanoma intended for surgical resection. Moreover, patients who had a complete response remained recurrence-free regardless of whether they underwent surgery. Neoadjuvant immunotherapy had acceptable toxicity, authors of the study reported, when using immune-profiling to decrease toxicities from the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade by limiting its use to select patients.
Kelly M. Mahuron, MD
“The results of our study suggest that there may be a role for nonsurgical management in this patient population with careful selection,” said Kelly M. Mahuron, MD, a general surgery resident at the University of California, San Francisco. “By using immune profiling, we were also able to stratify treatment, decreasing the use of anti-CTLA agents and their associated adverse effects.”
Potential Benefits
AS DR. MAHURON explained, surgery plus adjuvant immunotherapy remains the current standard of care for locally advanced melanoma, but it’s associated with both a high risk of recurrence (up to 70%) and significant drug toxicities. Because of these risks, there has been an increased interest in neoadjuvant immunotherapy.
Although the role of neoadjuvant therapy is currently undefined in this patient population, said Dr. Mahuron, there are many potential benefits including the ability to assess patient response to therapy and examine the biology of the tumor. In addition, it’s believed that increased tumor burden and neoantigen load lead to more efficient T-cell priming and, perhaps, better T-cell killing in this setting. Finally, neoadjuvant immunotherapy may be able to eliminate postsurgical systemic therapy, which could shorten the overall duration and exposure to the latter.
“Results of our study suggest that there may be a role for nonsurgical management in this patient population with careful selection.”— Kelly M. Mahuron, MD
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Despite these potential benefits, said Dr. Mahuron, clinicians must exercise caution before utilizing neoadjuvant immunotherapy in this patient population, as surgery and adjuvant therapy are potentially curative. There are also significant drug toxicities associated with immunotherapies, especially with the use of anti–CTLA-4 agents in combination with programmed cell death protein 1 (PD-1) inhibitors.
“When weighing these risks, providers have to consider that they are delaying the definitive surgery that can cure patients,” Dr. Mahuron emphasized.
Immune Profiling to Stratify Treatment Regimens
GIVEN THESE RISKS, Dr. Mahuron and colleagues have looked for a biomarker cell population to help stratify treatment regimens and reduce immunotherapy-associated adverse events. After biopsying either the primary tumor or metastatic lesion in patients with metastatic melanoma prior to the initiation of immunotherapy, the researchers used flow cytometric analysis to see if any markers correlated with response. They found that tumor-infiltrating lymphocytes (TILs) having both CTLA-4 and PD-1 expression can predict response to anti–PD-1 monotherapy. Patients with more than 20% of TILs expressing both markers are likely to respond, said Dr. Mahuron, whereas those with fewer than 20% expressing both markers are unlikely to respond.
For this study, investigators enrolled 24 anti–PD-1 treatment–naive patients with stage III or oligometastatic stage IV melanoma intended for surgical resection. All patients had pretreatment tumor biopsies collected, with flow cytometry used to measure TIL percentages. Patients either received neoadjuvant immunotherapy or went straight to surgery followed by adjuvant immunotherapy. Patients receiving neoadjuvant immunotherapy were stratified to anti–PD-1 monotherapy or combination PD-1/CTLA-4 blockade according to immune profile.
Key Findings
AS DR. MAHURON reported, of the 17 patients who received neoadjuvant immunotherapy, 11 had a complete response, 5 had a partial response, and 1 had stable disease. Of those 17 patients, 11 agreed to undergo the recommended surgery, and none have had a recurrence. On the other hand, said Dr. Mahuron, of the seven patients who went straight to surgery, six agreed to the recommended adjuvant immunotherapy, and three of these patients have since relapsed.
“Median relapse-free survival was significantly prolonged in the neoadjuvant cohort compared to the surgical cohort,” said Dr. Mahuron. “All patients who underwent neoadjuvant immunotherapy with a complete response have remained recurrence-free at a median follow-up of 27.6 months, regardless of whether they underwent surgery.”
Dr. Mahuron added, “Although this group is too small and the follow-up is too short to make any definitive conclusions at this point, it is something to keep in mind.”
Finally, Dr. Mahuron reported that neoadjuvant immunotherapy was well tolerated, with only 1 patient in each group experiencing a grade 3 or 4 adverse event. As expected, however, more adverse events were observed in patients receiving anti–CTLA-4 agents (87.5%) in combination with anti–PD-1 therapy, and half of these patients had to transition to anti–PD-1 monotherapy.
“[T]he toxicities of such a regimen are significant….Nevertheless, the efficacy signals from these trials are compelling, and further work defining the appropriate role of neoadjuvant therapy in melanoma is necessary.”— Richard Carvajal, MD
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Data Support Neoadjuvant Immunotherapies
ACCORDING TO Richard Carvajal, MD, Director of Experimental Therapeutics and Director of the Melanoma Service at Columbia University Medical Center and NewYork-Presbyterian Hospital, the recent emergence of data supporting the use of both targeted and immunologic therapies in the neoadjuvant setting has been “truly remarkable.”
“The study presented by Mahuron et al adds to these data and demonstrates a notable 64% complete pathologic response rate with neoadjuvant immunologic checkpoint blockade in patients
with stage III or oligometastatic stage IV melanoma,” Dr. Carvajal told The ASCO Post. “These results are consistent with what has been previously reported by the group at MD Anderson Cancer Center by Amaria et al,2 where neoadjuvant checkpoint blockade also achieved complete pathologic responses in 45% of patients treated with combination therapy.”
He continued, “However, the toxicities of such a regimen are significant. The MD Anderson trial was stopped early on the basis of 2 of 12 patients treated with neoadjuvant nivolumab developing disease progression precluding surgical resection. Nevertheless, the efficacy signals from these trials are compelling, and further work defining the appropriate role of neoadjuvant therapy in melanoma is necessary.” ■
DISCLOSURE: Drs. Mahuron and Carvajal reported no conflicts of interest.
REFERENCES
1. Mahuron K, Levine L, Daud A, Alvarado M: Treatment outcomes of neoadjuvant immunotherapy in patients with locally advanced melanoma. 2019 Society of Surgical Oncology Annual Cancer Symposium. Abstract 8. Presented March 29, 2019.
2. Amaria RN, Reddy SM, Tawbi HA, et al: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 24:1649-1654, 2018.
