Neoadjuvant use of immunotherapy, the administration of therapeutic agents before surgery, can be more effectively applied. The advantage may include a better immune response. This is the conclusion of Professor Christian Blank, Department of Medical Oncology, Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, in Amsterdam, The Netherlands, published The Lancet Oncology. 
Immuno-oncology offers oncologists a powerful new weapon to their arsenal of therapeutic strategies aimed at fighting their patient’ s cancer. While this strategy may works particularly well for some patients, it may not work for others.
Predicting who will respond may be a difficult puzzle to solve.
But that is what Blank and his team of researchers have been trying to accomplish. Their attempt focuses on a neoadjuvant approach: immunotherapy prior to surgery.
Such an approach could have many advantages. “You can determine whether a patient responds to a certain drug, because during surgery you can see which cancer cells have died,” Blank noted
“Also, the immune response is expected to be broader and therefore better. And if the tumor is still present, the immune system can ‘learn’ to recognize [and kill] the tumor and its variations. The neoadjuvant approach may also result in a smaller, and therefore easier to remove tumor,” Blank added.
The Netherlands Cancer Institute investigates the options of neoadjuvant therapy in patient with different types of cancers, including skin, intestine, breast, stomach, bladder, lung, renal cell, and head and neck cancer.
So far, the most advanced studies in patients with melanoma, which concluded last year, showed positive results. However, these studies also showed severe side effects among the participating patients with lymph node metastases.
That’s why the researchers initiated a new study to determine the safety and efficacy of adjusted neoadjuvant dosing schemes.
Together with colleagues in Sydney, Australia and Stockholm, Sweden they compared three different treatment schedules with ipilimumab and nivolumab in 86 melanoma patients with lymph node metastases.
Until recently, the standard treatment for patients at this stage of the disease was removal of the lymph nodes. These patients faced a poor prognosis, with more than 50% patients dying within 5 years after surgery as a result of small invisible metastases elsewhere in the body.
Blank and his colleagues published the results of the OpACIN-neo study, a multicenter, open-label, phase II, randomized, controlled trial in The Lancer Oncology. 
The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.
Of the 105 patients screened for eligibility to participate in the trial, 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups.
The participating patients were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously.
Participating patients were aged at least 18 years, had a WHO performance status of 0–1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1.
Three patients were excluded after randomization because they were found to be ineligible.
A total of 86 patients received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board because of severe adverse events).
Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C.
The difference in grade 3–4 toxicity between group B and A was −20% (95% CI −46 to 6; p=0·158) and between group C and group A was 10% (−20 to 40; p=0·591).
The most common grade 3–4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3–4 adverse events were seen in more than one patient.
In Group A one patient died 9.5 months after the start of treatment, possible as a result of treatment-related late-onset immune-related encephalitis.
Nineteen patients (63% [95% CI 44–80]) of 30 patients in group A, 17 (57% [37–75]) of 30 in group B, and nine (35% [17–56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61–92]) patients in group A, 23 (77% [58–90]) in group B, and 17 (65% [44–83]) in group C.
“The results of this study confirm that neoadjuvant therapy is effective and we have now found a schedule with acceptable side effects”, noted Lisette Rozeman, MD, first author of the publication.
After a follow-up of on average 8 months none of the patients who responded to either one of the three tested treatment schedules had relapsed (0 of 65). In 9 out of the 21 non-responders the disease did recur.
“The elegant aspect of the neoadjuvant approach is that the treatment result seems to be a good predictor for disease recurrence,” Blank explained.
“In the future it might even be possible to leave out surgery in patients who respond very well. Our studies also indicate that we might be able predict whether a patient will respond to this drug combination based on a small number of biomarkers. Although this is something we’ll have to investigate this in a larger group,” Blank added.
The phase II PRADO extension study is currently investigating the optimal treatment schedule of the OpACIN-neo study in 100 melanoma patients with lymph node metastases. After completion at the end of 2019, a larger phase III study will have give a definitive answer as to which is better – adjuvant or neoadjuvant immunotherapy.
Together with two other large melanoma centers in Australia and the US, Blank has established an international consortium to streamline the clinical development of neoadjuvant immunotherapy.
“If all future studies share the same study design, the identification of biomarkers to predict which combination is likely to be more efficient will be easier. And as a result, personalized cancer immunotherapy may come within reach.”
Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) – NCT02977052
 Rozeman EA, Menzies AM, Van Akkooi ACJ, Adhikari C, Bierman C, Van de Wiel BA, Scolyer, RA, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. The Lancet Oncology Published:May 31, 2019DOI:https://doi.org/10.1016/S1470-2045(19)30151-2 [Article]