From the Journals

Neoadjuvant dabrafenib and trametinib improves event-free survival in resectable melanoma

Publish date: January 29, 2018
By
Andrew D. Bowser

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Neoadjuvant data promising, role unclear

Although results of the study by Amaria et al. are “promising,” the role of neoadjuvant therapy in treatment of stage III–IV oligometastatic melanoma in clinical practice “is unclear for now,” melanoma specialists Paolo A. Ascierto, MD, and Alexander M. M. Eggermont, MD, PhD, wrote in an editorial.

Amaria et al. have presented results of the first randomized trial to evaluate neoadjuvant therapy versus standard care in patients with high-risk resectable BRAF-mutated melanoma.

Patients who received both neoadjuvant and adjuvant treatment with the dabrafenib/trametinib combination had superior event-free survival versus standard surgery and consideration for adjuvant therapy, published results show.

However, previous studies have already shown good results on this, that adjuvant dabrafenib plus trametinib (as well as nivolumab monotherapy) in this setting, “raising the question of whether a neoadjuvant approach is really needed, especially given a possible reduction of the role of surgery in the future,” Dr. Ascierto and Dr. Eggermont wrote.

Alternatively, adjuvant therapy with newer, more effective agents may be a “better way forward,” they said, noting that three patients in the trial by Amaria et al. who progressed after neoadjuvant/adjuvant dabrafenib and trametinib relapsed at first with brain metastases, raising the question of whether the treatment “might induce a resistant phenotype predisposed to the development of CNS metastases.”

That said, effectively combining neoadjuvant with adjuvant therapy could reduce the extent of surgery, make radiotherapy redundant, or increase distant metastasis-free survival and overall survival, among other benefits.

“The next generation of adjuvant trials should aim to address these outstanding questions,” they concluded.

Dr. Ascierto is with Istituto Nazionale Tumori Fondazione “G Pascale,” Napoli, Italy, and Dr. Eggermont is with Cancer Institute Gustave Roussy, University Paris-Sud, France. This commentary is based on their editorial appearing in The Lancet Oncology (2018 Jan 17. doi: 10.1016/S1470-2045[18]30016-0). The authors reported disclosures related to Novartis, Merck Serono, Bristol-Myers Squibb, Amgen, and others.


 

FROM THE LANCET ONCOLOGY

For patients with surgically resectable, BRAF-mutated melanoma, neoadjuvant and adjuvant treatment with the combination of dabrafenib and trametinib resulted in significantly longer event-free survival compared with standard care, according to results of a randomized study.

The trial was closed early because of the “large difference” in event-free survival favoring the neoadjuvant approach, the authors wrote (Lancet Oncol. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9.

While early closure limits interpretation of results, they do provide important proof-of-concept and data for future studies, wrote the authors, led by Rodabe N Amaria, MD, of the department of medical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The clinical and translational results strongly support the rationale for further assessment of neoadjuvant therapy in patients with high-risk, surgically resectable melanoma,” Dr. Amaria and colleagues said in the report on the randomized trial, believed to be the first to evaluate the role of neoadjuvant therapy versus standard care in BRAF-mutated melanoma.

Dabrafenib and trametinib combination therapy is approved as a treatment for patients with unresectable or metastatic stage IV melanoma and a BRAFV600 mutation, which is found in about half of cutaneous melanomas, authors said.

To evaluate the combination in earlier stage disease, Dr. Amaria and coinvestigators conducted a single-center, open-label, randomized, phase 2 trial of 21 patients with surgically resectable clinical stage III or oligometastatic stage IV melanoma with BRAFV600E or BRAFV600K mutations.

Patients were randomized 2:1 to receive the neoadjuvant/adjuvant treatment or to standard of care, which consisted of standard surgery plus consideration for adjuvant therapy, the authors said. Those patients assigned to the targeted therapy arm received 8 weeks of neoadjuvant dabrafenib and trametinib followed by surgery, then adjuvant dabrafenib and trametinib for up to 44 weeks.

Event-free survival, the primary endpoint of the trial, was a median of 19.7 months for neoadjuvant plus adjuvant dabrafenib and trametinib, versus 2.9 months for standard care (P less than .0001), the investigators reported.

Dabrafenib and trametinib combination therapy was well tolerated as neoadjuvant and adjuvant therapy, with no grade 4 adverse events or treatment related deaths, according to the investigators. The most common grade 3 adverse event seen with the combination was diarrhea, occurring in 2 patients (15%).

The trial is continuing as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.

Dr. Amaria and colleagues reported individual disclosures related to Merck, Bristol-Myers Squibb, Array Biopharma, and others, including Novartis Pharmaceuticals Corp., which supplied drugs and funded clinical aspects of the study.

SOURCE: Amaria et al. 2018 Jan 17. doi: 10.1016/S1470-2045(18)30015-9

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