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COMMENTARY Open Access
News from the melanoma sessions of the
European Cancer Congress 2017
Piotr Rutkowski* and Katarzyna Kozak
Abstract
During the European Cancer Congress, the melanoma sessions focused on practice changing trials. Recent developments
and approvals in immunotherapy and targeted agents have significantly changed the landscape of melanoma therapy
in the metastatic setting and provide great promise for adjuvant and neoadjuvant treatment in high-risk locoregional
disease. Perioperative (combined pre- and postoperative) strategies may be extremely beneficial for patients with bulky
stage IIIC disease. The long-term results of the European Organisation for Research and Treatment of Cancer (EORTC)
18071 adjuvant trial ipilimumab versus placebo after complete resection of high-risk stage III melanoma, demonstrating
improvement in overall survival, has established the reference bar for further trials with postoperative therapy.
Keywords: Melanoma, Ipilimumab, Adjuvant, Neoadjuvant, BRAF inhibitor, Pembrolizumab, Anti-PD-1
Background
Melanoma accounts for a small percentage of all skin
malignancies, but it is still responsible for a majority of
deaths due to cutaneous cancers. Moreover, because of
aging and an increasing population, the age at death of
melanoma patients has steadily increased, with present
predictions showing that the number of melanoma cases
will continue to increase until 2030, after which time we
may see a decrease [1]. Nevertheless, recent develop-
ments and approvals in immunotherapy and targeted
agents have significantly changed the landscape of mel-
anoma therapy in the metastatic setting and provide
great promise for adjuvant and neoadjuvant treatment in
high-risk locoregional disease [2–5].
The European Cancer Congress took place on January
27–30, 2017, in Amsterdam, The Netherlands, with a
main focus on practice changing trials and oncopolicy.
The aim of this article was to describe the highlights
from the Melanoma Sessions, which addressed mainly
present and future use of adjuvant and neoadjuvant
treatment in high-risk locoregional disease as well as
studies on immunotherapy in poorly prognostic sub-
groups of metastatic patients, which are important from
a practical point of view.
Adjuvant therapy
One of the most important issues was the debate on the
long-term results of the European Organisation for Re-
search and Treatment of Cancer (EORTC) 18071 adju-
vant trial ipilimumab versus placebo after complete
resection of high-risk stage III melanoma. It is the first
trial with an immune checkpoint inhibitor used postop-
eratively after lymph node dissection, showing significant
improvement in recurrence-free survival and overall sur-
vival (5-year RFS rates 40.8% vs. 30.3% and 5-year OS
rates 65.4% vs. 54.4%, respectively) [6]. Despite clear
benefits in reduction of risk of death, the use of adjuvant
ipilimumab remains controversial considering the sig-
nificant adverse event rates – grade 3–4 immune-related
adverse events occurred in 41.6% of patients treated with
ipilimumab as compared to 2.7% in placebo arm, result-
ing in only 42% of patients receiving more than four
doses of ipilimumab. Further dilemmas were presented
during the debate “This house believes that high-risk
stage III melanoma should NOT be treated with adju-
vant ipilimumab after complete resection” by Prof. A.
Eggermont, Dr A. van Akkooi, Prof. D. Schadendorf,
Prof. G. Long, Prof. J. Haanen, Prof. P. Nathan, concern-
ing the ipilimumab dose and duration of treatment as
well as patient selection. Over the next 2 years, the land-
scape of adjuvant therapy will likely be significantly
changed following the reporting of results of trials with
BRAF (+ MEK) inhibitors and anti-PD-1 drugs.
* Correspondence: piotr.rutkowski@coi.pl
Department of Soft Tissue/Bone Sarcoma and Melanoma; Maria
Sklodowska-Curie Memorial Cancer Center and Institute of Oncology,
Roentgena 5, Warsaw 02-781, Poland
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Rutkowski and Kozak BMC Medicine  (2017) 15:57 
DOI 10.1186/s12916-017-0826-4
Neoadjuvant treatment
Another block of presentations regarded neoadjuvant
therapy of locally advanced melanomas. Some prelimin-
ary results of trials with BRAF and MEK inhibitors were
presented.
Prof. Haanen presented the first results of the Reductor
trial on 13 patients with initially unresectable or locally
advanced (with high chance of a positive margin) BRAF-
positive stage IIIC melanoma [7]. Patients were treated
with dabrafenib and trametinib for 8 weeks; 11 patients
underwent surgery and, finally, 9 achieved R0 resection
(9/13 = 69% R0 resectability rate). Of these 9 patients
(with median follow-up of 9 months; range 3–22 months),
6 had a recurrence and 3 remain disease free.
Dr Amaria discussed a trial of neoadjuvant (8 weeks)
plus adjuvant (44 weeks) therapy with dabrafenib and
trametinib versus standard upfront surgery [8]. In 21 pa-
tients, neoadjuvant and adjuvant dabrafenib/trametinib
(14 patients) significantly improved relapse-free survival
over the standard arm (7 patients; P < 0.0001). Among
12 patients assessed after preoperative therapy, complete
pathological response was observed in 7 (58%).
Prof. Long presented the results of a trial with neoad-
juvant and adjuvant dabrafenib plus trametinib combin-
ation in BRAF-mutated stage III bulky disease resectable
melanoma patients who were treated preoperatively for
12 weeks and postoperatively up to 52 weeks [9]. In 30
assessed patients after 12 weeks of therapy, patho-
logical and PET-FDG metabolic complete response
was achieved in 50%. Nine patients (30%) recurred
during follow-up, with a median time to recurrence
of 51 weeks.
These results of neoadjuvant targeted therapy for lo-
cally advanced BRAF-mutated stage IIIC melanomas
seems promising. On the other hand, the OpACIN trial
with neoadjuvant combined immunotherapy (ipilimu-
mab + nivolumab) achieved an overall response rate of
80% in 10 patients, albeit accompanied by high toxicity.
Immunotherapy in the metastatic setting
The survival of advanced, unresectable metastatic mel-
anoma has been greatly improved over the last few years.
This unprecedented development is related to the intro-
duction of immune checkpoint inhibitors with anti-
bodies against CTLA-4 and PD-1 and targeted therapy
with BRAF and MEK inhibitors. The most important
studies presented during ECCO 2017 regarded the out-
comes of anti-PD-1 immunotherapy in poorly prognostic
subgroups of patients.
Reports from the KEYNOTE-006 study with pembroli-
zumab versus ipilimumab analyzed the outcome of pa-
tients with elevated lactate dehydrogenase (LDH) levels
at baseline [10]. Progression-free survival (PFS) was bet-
ter in patients treated with pembrolizumab compared
with ipilimumab (normal LDH, median 7.0 months vs.
2.9 months; elevated LDH, median 2.8 months vs.
2.5 months). For overall survival (OS), the median was
not reached in either group for normal LDH patients,
but in elevated LDH patients, improved survival was ob-
served with pembrolizumab (median 14.7 months vs.
6.2 months). However, the general outcomes for anti-
PD-1 monotherapy were unsatisfactory in the group
with increased LDH (especially if more than twice the
upper limit norms). Similarly, patients with advanced mu-
cosal melanoma treated with pembrolizumab in three stud-
ies (KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006
[11]) experienced a median PFS of 2.8 months and median
OS of 11.3 months, which were worse than for non-
mucosal melanoma patients, yet anti-PD-1 activity was still
observed.
Conclusions
Following the promising results of new systemic therapies
in stage IV disease, these are currently being investigated in
phase II and III trials in adjuvant and neoadjuvant settings.
Neoadjuvant therapy has several potential advantages, in-
cluding a possibility of decreased surgical morbidity, pre-
vention of micrometastases, personalization of adjuvant
therapy based on the response to neoadjuvant therapy, and
the opportunity to collect biospecimens for evaluation of
the underlying mechanisms of action and drug resistance.
In metastatic disease, new strategies are desired for patients
with poorer prognostic factors at baseline.
Funding
No external funding was provided for this study.
Authors’ contributions
Both authors prepared and approved the final version of the manuscript.
Competing interests
PR served as a member of Advisory Board for Novartis, GSK, MSD, Roche,
BMS, Amgen, and Bayer and has received honoraria for lectures from
Novartis, Pfizer, BMS, MSD, and Roche. KK has received honoraria for lectures
from Roche and BMS.
Received: 14 February 2017 Accepted: 22 February 2017
References
1. Autier P, Koechlin A, Boniol M. 1144 – Prediction of numbers of melanoma
deaths by 2050. Eur J Cancer. 2017;72 Suppl 1:S123–4. doi:10.1016/S0959-
8049(17)30484-7.
2. Rutkowski P. Introduction to the special issue of European Journal of
Surgical Oncology: New roads in melanoma management. Eur J Surg Oncol.
2016;43(3):513–6. doi:10.1016/j.ejso.2016.12.001.
3. Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, et al. Diagnosis and
treatment of melanoma. European consensus-based interdisciplinary
guideline - Update 2016. Eur J Cancer. 2016;63:201–17.
4. NCCN Guidelines. Melanoma. Version 2.2017. https://www.nccn.org/
professionals/physician_gls/f_guidelines.asp#melanoma. Accessed Feb 2017.
5. Ugurel S, Roehmel J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A, Larkin J,
Long GV, Lorigan P, McArthur GA, Ribas A, Robert C, Schadendorf D,
Garbe C. Survival of patient s with advanced metastatic melanoma:
The impact of novel therapies. Eur J Cancer. 2016;53:125–34.
Rutkowski and Kozak BMC Medicine  (2017) 15:57 Page 2 of 3
6. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD,
Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C,
Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L,
Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G,
Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab
adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.
7. Haanen J, Blank C, van Thienen H, Mallo H, Adriaansz S, ter Meulen S,
Madu M, Pronk L, van der Hiel L, van de Wiel B, Peeper D, van Akkooi A.
1146 – Downsizing of locally advanced stage III (bulky) BRAF V600E/K
melanoma with combination targeted therapy to achieve R0 resection.
Eur J Cancer. 2017;72 Suppl 1:S124. doi:10.1016/S0959-8049(17)30485-9.
8. Amaria R. Treatment with neoadjuvant and adjuvant BRAF and MEK
inhibitors is associated with improved relapse-free survival over standard-of-
care therapy in patients with high risk resectable BRAF-mutant melanoma.
Presentation at ECCO 2017. http://www.eccocongress.org/Scientific-
Programme/Searchable-Programme. Accessed Feb 2017.
9. Long G. Neoadjuvant therapy in bulky stage III melanoma: Are we there
yet? Presentation at ECCO. 2017. http://www.eccocongress.org/Scientific-
Programme/Searchable-Programme. Accessed Feb 2017.
10. Long GV, Blank C, Ribas A, Mortier L, Carlino MS, Lotem M, Lorigan P,
Neyns B, Petrella TM, Puzanov I, Richtig E, O'Day SJ, Masucci G, Lebbe C,
Steven N, Lutzky J, Hille D, Ebbinghaus S, Ibrahim N, McNeil C. 1141 –
Impact of baseline serum lactate dehydrogenase concentration on the
efficacy of pembrolizumab and ipilimumab in patients with advanced
melanoma: data from KEYNOTE-006. Eur J Cancer. 2017;72 Suppl 1:S122–3.
doi:10.1016/S0959-8049(17)30482-3.
11. Butler M, Hamid O, Ribas A, Hodi FS, Walpole E, Dauad A, Arance A,
Brown E, Hoeller C, Mortier L, Schachter J, Long J, Ebbinghaus S, Ibrahim N,
Robert C. 1142 – Efficacy of pembrolizumab in patients with advanced
mucosal melanoma enrolled in the KEYNOTE-001, 002, and 006 studies.
Eur J Cancer. 2017;72 Suppl 1:S123. doi:10.1016/S0959-8049(17)30483-5.
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