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Combination therapy improves survival in melanoma

Dermatology TimesDermatology Times, July 2018 (Vol. 39, No. 07)
Volume 39
Issue 7

The combination of encorafenib plus binimetinib significantly improved overall survival versus vemurafenib in patients with BRAF-mutant melanoma, updated results of the randomized, phase three COLUMBUS trial show.

Researchers reporting at the American Society of Clinical Oncology annual meeting on June 4 presented a study in which they compared the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) melanoma staging systems. The eighth edition differentiates melanoma IIIA and IIIB survival slightly worse than the previous edition, they said.

Max Fullah Madu, M.D., a physician with the Netherlands Cancer Institute in Amsterdam who led the study, sought to determine if the eighth edition offered an improvement in prognostic accuracy. Dr. Madu and colleagues focused on the expansion of stage III subgroups from three in the seventh edition (IIIA, IIIB and IIIC) to four in the eighth edition with the introduction of a new ultra-high-risk IIID subgroup.

The study is based on the treatment outcomes of 640 melanoma cases from a Netherlands Cancer Institute database. The patients were treated between 2000 and 2016 and followed for a median of 59 months.
In terms of survival discrimination, which is a measure of prognostic accuracy, both staging systems performed similarly with no statistical difference between systems. Melanoma-specific survival estimates were comparable between the seventh and eighth editions, but the eighth edition did not perform as well in differentiating melanoma-specific survival between stage IIIA and III.

Researchers analyzed prognostic factors for melanoma-specific survival and distant metastasis-free survival finding a median melanoma-specific survival rate of 138 months and 96 months for patients with distant metastases-free survival.

The findings were mixed for stage IIIA melanoma for both the 7th and 8th editions. In estimating survival, both the 7th and 8th editions were comparable, but the 8th edition failed to differentiate melanoma-specific survival between stage IIIA and IIIB. For patients with sentinel node metastasis of less than one, researchers found excellent melanoma-specific survival and distant metastasis-free survival rates.

In looking at survival differentiation between the stage III subgroups using the eighth edition, they saw an overlap in the three A and three B survival curves over the first four years of follow-up, resulting in a differentiation that reached only borderline statistical significance (P = 0.047). By contrast, the seventh edition criteria produced a clean separation in IIIA and IIIB survival curves, resulting in a significant difference (0.002).

Given the lower proportion of patients in the 8th edition IIIA group, Dr. Madu said the results should be viewed with some caution. By eighth edition classification, 12% of the Netherlands patients were considered IIIA, compared to 25% of patients using seventh edition classification.


Survival within the 8th edition IIIA subgrouping might be stratified further using European Organization for Research and Treatment of Cancer (EORTC) criteria for sentinel node tumor burden, Dr. Madu said.

In a large EORTC study, patients with a maximum diameter of the largest metastatic deposit in the sentinel node of 1 mm or less had much better survival compared with those with a maximum diameter more than 1 mm.
For the Netherlands data set, using seventh edition staging, stage IIIA patients with a maximum diameter of 1 mm or less had a 5-year survival of 89%, versus 65% for those with a maximum diameter greater than 1 mm (P < 0.001). The difference was slightly less, but still significant, using the 8th edition criteria with 5-year survival of 91% versus 72% for 1 mm or less and greater than 1 mm, respectively (P = 0.020).

The finding was corroborated by a study recently published in the European Journal of Cancer that included a multicenter cohort of more than 1,000 sentinel node-positive patients. Comparing four different prognostic models, investigators found that the combination of eighth edition AJCC staging plus sentinel node tumor burden was the best prognostic model.

“The EORTC tumor burden criteria can be a powerful adjunct to AJCC staging, especially in a post-completion lymph node dissection era where less staging information will be available,” Dr. Madu said. “I hope for a future in which AJCC criteria, combined with sentinel node tumor burden without the need for completion lymph node dissection, will allow precise and minimally invasive tumor staging in melanoma patients.”


Dr. Madu highlighted three points about the 8th edition:

1. It's more complex in clinical use.
2. It does not add any new prognostic factors.
3. And, adjuvant therapy trials have all been performed with 7th edition staging criteria.

One of the most significant changes in the eighth edition is having redefined AJCC prognostic stage IIIA groupings, including the addition of a new ultra-high-risk stage IIID subgroup.

In a presentation on re-evaluating the staging and management of stage three melanoma, April K.S. Salama, M.D., director of the melanoma program at Duke Cancer Institute, said: “The way I think of this is that it has essentially become more selective at each end of the spectrum.”

Dr. Salama said IIIA includes patients who may have a more favorable prognosis versus the previous IIIA criteria, while IIID is designated for patients who are at the highest risk of recurrence.

The AJCC melanoma expert panel also changed the TNM criteria needed to gain entry to the subgroups, making it difficult to translate between versions, Dr. Madu said.

“A patient who was stage IIIA in the previous edition can now be stage IIIC in the current edition. This raises a few questions ― especially in this time of rapidly changing melanoma treatments,” Dr. Madu said.


Rinehard Dummer, MD, provided disclosure information related to 4SC, Almirall Hermal GmbH, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline/Novartis, Incyte, Johnson & Johnson, LEO Pharma, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche/Genentech.

Dummer R, Ascierto PA, Gogas H, et al. “Overall survival in COLUMBUS: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs vemurafenib (VEM) or enco in BRAF-mutant melanoma.” American Society of Clinical Oncology 2018 Annual Meeting. Presented Monday, June 4, 2018. Abstract 9504.

Dummer R, Ascierto PA, Gogas HJ, et al. “Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.” Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6.

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