Personalizing neoadjuvant combination immunotherapy schemes may be possible through interferon signatures and RNA signatures, Dr Blank said. The reasons to attempt neoadjuvant therapy in this setting include the potential to reduce tumor burden before surgery, or even to replace surgery; the use of pathologic response data as surrogate outcome measures for relapse-free survival (RFS) and overall survival; and to induce broader tumor-specific immune responses.
A potential risk of such neoadjuvant therapy is a nonresponding patient whose condition deteriorates clinically and rules out potentially curative surgery, Dr Blank said. Furthermore, neoadjuvant therapy may require more patient management, timing scans, day clinic appointments, and surgery planning.
Neoadjuvant Combination Immunotherapy: OpACIN
The phase 1b OpACIN clinical trial randomized 20 patients with high-risk stage III palpable melanoma to adjuvant or neoadjuvant immune checkpoint inhibitor combination therapy. Patients received either 4 courses of ipilimumab (Yervoy) 3 mg/kg plus nivolumab (Opdivo) 1 mg/kg (the adjuvant arm) or 2 courses of ipilimumab plus nivolumab at the same doses, followed by surgery and 2 additional courses of combination immunotherapy (the neoadjuvant arm).
A comparison of T-cell receptor clones from baseline to week 6 showed that the neoadjuvant approach expanded T-cell receptors to a greater degree than the adjuvant approach. At 6 weeks, clones were detected that had not been detectable in the peripheral blood at baseline.
Neoadjuvant ipilimumab plus nivolumab induced a pathologic response rate of 78%, and 8 of the 10 patients in the neoadjuvant arm had a complete response or near-complete response.
“This response translated into excellent outcomes,” Dr Blank observed. After a median follow-up of 31.6 months, none of the 8 patients who achieved a pathologic response in the neoadjuvant arm relapsed, for an estimated 30-month RFS rate of 80%. In the adjuvant arm, 4 patients relapsed, for an estimated 30-month RFS rate of 60%.
At the time of the analysis, 16 of 20 patients were still alive; the 4 patients who had distant metastasis died.
Dr Blank noted that tumor mutation burden (TMB) did not correlate with response—the patient with the lowest TMB had a very good response and the patient with a high TMB did not have a response.
The ipilimumab plus nivolumab combination was associated with significant adverse events, regardless of its use in the adjuvant or neoadjuvant setting. Approximately 90% of patients had grade 1 to 4 adverse events.
Preserving Efficacy with a Lower Dose: OpACIN-neo
The follow-up multicenter trial OpACIN-neo investigated whether the efficacy of the neoadjuvant immunotherapy combination could be preserved with lower dosing to reduce toxicity.
The OpACIN-neo trial randomized 86 patients with resectable macroscopic stage III melanoma to standard therapy comprising 2 doses of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks (arm A); to 2 doses of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg every 3 weeks (arm B); or to 2 doses of ipilimumab 3 mg/kg every 3 weeks, followed immediately by 2 doses of nivolumab 3 mg/kg every 2 weeks (arm C). Complete lymph node dissection was scheduled at week 6.
At a median follow-up of 7.7 months, the Data Safety Monitoring Board recommended that arm C be closed because of excessive toxicity.
Grade ≥3 adverse events were 40%, 20%, and 50% in arms A, B, and C, respectively. “We achieved our goal to reduce the toxicity in the cycles-reduced arm,” said Dr Blank (he first reported these findings at ESMO 2018).
The radiologic response rates were identical (60%) in arms A and B versus 42% in arm C. As in the earlier study, the radiologic response underestimated the pathologic response rates, which were 80% in arm A, 77% in arm B, and 65% in arm C. The rates of pathologic complete response in the 3 arms were 47%, 57%, and 23%, respectively.
“The event-free survival seems to plateau at 80%, being a really promising treatment for this high-risk population,” said Dr Blank.
Disease relapse occurred in 9 of 21 patients who did not respond to treatment, but no relapses occurred in patients with a pathologic response.
Personalized Strategies on the Horizon
The high response to ipilimumab plus nivolumab should be confirmed, with a second goal of challenging the need for complete lymph node dissection, Dr Blank said. “Do we really need surgery in patients achieving these deep responses?” he asked. A clinical trial called PRADO is currently recruiting patients to address these questions.
The use of genetic signatures and PD-L1 expression could help to personalize combinations of neoadjuvant immunotherapy, Dr Blank said. In translational studies, patients with a “cold” tumor or negative interferon signature are prone to relapses, he said. These patients also tend to have low PD-L1 expression.
A phase 1b clinical trial showed that the combination of nivolumab and pegylated interleukin-2 (NKTR-214) induced an objective response rate of 42% in patients without PD-L1 expression.
In these ongoing clinical trials, neoadjuvant immunotherapy treatments are selected based on a patient’s RNA signature, followed by assessment of response and re-signature analysis—this may usher in an era of personalized therapy for advanced melanoma, Dr Blank concluded.
