799P - A pilot study of the neo-adjuvant use of vemurafenib plus cobimetinib in patients with BRAF mutant melanoma with palpable lymph node metastases

Background

Melanoma patients with palpable nodal metastases have a very poor prognosis with the majority recurring within the first 2-3 years with survival ranging from 20-50% at 5 years. We aimed to ascertain that patients with a BRAF V600 mutation that receive vemurafenib and cobimetinib before surgery (neoadjuvantly) will have a higher probability of resectability, pathologic complete response, a lower risk of local recurrence and a longer DFS, PFS and OS.

Methods

This was a single arm, prospective, multi centre phase II study in patients with confirmed BRAF V600 mutated Stage IIIB and IIIC melanoma ( AJCC 7^th Edition) with palpable nodal disease. Patients received vemurafenib 960mg PO BID and cobimetinib 60mg PO OD for 4 months prior to resection followed by 8 months of adjuvant therapy post-surgery. CTscans were performed at baseline and before resection and every 6 months for the first 3 years and yearly in year 4 and 5. Biopsies for correlative studies and diagnosis were performed at baseline prior to starting therapy. The primary outcomes were the proportion of patients achieving resectability, radiologic response as per RECIST and the proportion of patients achieving a pathological response. Secondary objectives were local-regional recurrence rates, DMFS, DFS and OS.

Results

Twenty-four patients were enrolled and received neoadjuvant vemurafenib and cobimetinib and 21 underwent resection. At time of surgery 1 (20%; 95% CI 0.15-24.87) had a complete response, 16 (80%; 95% CI 56.34-94.27) had a partial response, and 2 (10%; 95% CI 1.23-31.70) had stable disease. One patient progressed as per RECIST but had a partial response upon resection. Following resection and pathological evaluation 12 (57%; 95% CI 34.02-78.18)) patients achieved a complete pathologic response, 8 (38%; 95% CI 18.11-61.56) had a partial pathologic response. Treatment related Grade 3-4 events occurred in 10 patients with no deaths due to AEs. Only 2 patients had a local recurrence. OS at 60 months was 63.9% (95% CI 43.5-93.8).

Conclusions

Neoadjuvant vemurafenib and cobimetinib led to all patients being resectable with a high response rate, pathologic response rate and low local recurrence rate in melanoma patients with palpable lymph nodes.

Clinical trial identification

NCT02036086.

Editorial acknowledgement

Legal entity responsible for the study

Sunnybrook Research Institute.

Funding

Roche.

Disclosure

T. Petrella: Financial Interests, Personal, Research Grant, For this study: Roche; Financial Interests, Personal, Advisory Board: Novartis, BMS, Merck, Pfizer, Sanofi. C. Mihalcioiu: Financial Interests, Personal, Advisory Board: Roche. C. Nessim: Financial Interests, Personal, Advisory Board: Merck, Sanofi, Novartis, EMD Serono. A. Spatz: Financial Interests, Personal, Advisory Board: Roche, Pfizer, AstraZeneca, BMS, Jansen, Merck. F. Wright: Financial Interests, Personal, Other: Merck; Financial Interests, Personal, Research Grant: Roche. All other authors have declared no conflicts of interest.