In two papers published recently in The Lancet Oncology, melanoma researchers report results from the NeoCombi trial of neoadjuvant BRAF-targeted therapy with dabrafenib and trametinib and OpACIN-neo study with combined neoadjuvant immune checkpoint inhibitors, ipilimumab and nivolumab, in patients with high-risk resectable melanoma. The treatment in both studies showed acceptable safety and encouraging antitumour activity. In particular, a high number of patients achieved complete pathological response (pCR).
However, the results from these studies open-up critical questions in the field of neoadjuvant melanoma treatment, including efforts to explore optimal dosing and schedules of combined immune checkpoint inhibitors, as well as a critical assessment of patterns of relapse in relation to pCR. In particular, no relapse was observed in patients achieving a pCR on neoadjuvant immune checkpoint blockade in OpACIN-neo, although it should be noted that follow-up was short. But, a higher risk of relapse was found with neoadjuvant BRAF-targeted therapy in NeoCombi, even in the setting of achieved pCR.
NeoCombi results
The authors explained in study background that one year of adjuvant therapy with dabrafenib plus trametinib improve relapse-free and overall survival in patients with resected, stage III melanoma. It led NeoCombi researchers to study a proportion of patients who will achieve pCR and a response according to RECIST to neoadjuvant treatment with dabrafenib plus trametinib in resectable stage IIIB–C, BRAFV600-mutated melanoma.
The NeoCombi is a single-arm, open-label, single-centre, phase II study performed at Melanoma Institute Australia. Lead author is Prof. Georgina Long. In total, 40 patients were screened, of whom 35 eligible patients were enrolled in the study. Median follow-up was 27 months.
At resection, 30 (86%) patients achieved a response according RECIST; from whom 16 (46%) had a complete response and 14 (40%) had a partial response. Five patients (14%) had stable disease, and no patients progressed. After resection and pathological evaluation, 35 patients achieved a pathological response, of whom 17 (49%) patients had a pCR and 18 (51%) had a non-complete pathological response.
Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3–4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.
Overall, the results show that a high proportion of patients achieved a pCR with neoadjuvant dabrafenib plus trametinib. Neoadjuvant treatment was tolerable, with no relapses during the 12-week neoadjuvant period. All patients were able to undergo surgery.
The authors concluded that this treatment could be a feasible in a subset of patients in whom neoadjuvant anti-PD-1 therapy might not be suitable.
OpACIN-neo results
Prof. Christian U. Blank of the The Netherlands Cancer Institute in Amsterdam, Netherlands and colleagues reported the results of the OpACIN-neo study that aimed to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective to standard dosing schedule.
OpACIN-neo is a multicentre, open-label, phase II, randomised, controlled trial. Patients are eligible patients if they have resectable stage III melanoma involving lymph nodes only, and measurable disease according to the RECIST v1.1. Enrolled patients from three medical centres in Australia, Sweden, and the Netherlands were randomly assigned to one of three neoadjuvant dosing schedules. The primary endpoints are the proportion of patients with grade 3–4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks.
In total, 105 patients were screened, of whom 89 (85%) eligible patients were enrolled in the study and 86 patients received at least one dose of study drug. The arm C was closed early 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 most common grade 3–4 adverse events were elevated liver enzymes in group A and colitis in group C; in group B, none of the grade 3–4 adverse events were seen in more than one patient. One patient in group A died 9.5 months after the start of treatment due to late-onset immune-related encephalitis, which was possibly treatment-related.
In total, 19 (63%) of 30 patients in group A, 17 (57%) of 30 patients in group B, and 9 (35%) of 26 patients in group C achieved a radiological objective response, while pathological responses occurred in 24 (80%) patients in group A, 23 (77%) in group B, and 17 (65%) in group C.
OpACIN-neo identified a tolerable neoadjuvant dosing schedule that induces a pathological response in a high proportion of patients. When more mature data confirm early findings, this schedule should be tested in the randomised phase III studies against adjuvant therapy, the current standard-of-care in patients with stage III melanoma.
OpACIN-neo was funded by Bristol-Myers Squibb.
Beth Helmink and Jennifer A. Wargo of the MD Anderson Cancer Center, Houston, TX, US, who elaborated the results from both trials in an accompanied editorial article, wrote that it is timely to embrace a concept of neoadjuvant therapy for melanoma, although its adoption should be in the context of carefully planned clinical trials.
References
Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019 Jun 3. pii: S1470-2045(19)30331-6. doi: 10.1016/S1470-2045(19)30331-6. [Epub ahead of print]
Rozeman EA, Menzies AM, van Akkooi ACJ, 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. Lancet Oncol. 2019 May 31. pii: S1470-2045(19)30151-2. doi: 10.1016/S1470-2045(19)30151-2. [Epub ahead of print]
Helmink B, Wargo JA. Neoadjuvant therapy for melanoma: is it ready for prime time? Lancet Oncol. 2019 Jun 3. pii: S1470-2045(19)30377-8. doi: 10.1016/S1470-2045(19)30377-8. [Epub ahead of print]