Drug development in melanoma has never been more exciting. In this year’s European Society for Medical Oncology (ESMO) Congress, unprecedented advances in two distinct drug classes were presented during the presidential session. Specifically, immune checkpoint inhibitor nivolumab has led to better recurrence-free survival as compared to standard-of-care ipilimumab in patients with surgically resected stage III/IV melanoma, according to results from the Checkmate-238 trial.1 Concurrently, exciting results were also reported from the COMBI-AD trial, in which combined BRAF and MEK inhibition with dabrafenib/trametinib has dramatically reduced the risk of relapse or death in patients with stage III BRAF-mutant melanoma in the adjuvant setting.2 The results of these two trials were published simultaneously in the New England Journal of Medicine.3,4
For patients with fully resected lymph node metastases and in-transit metastases, the risk of relapse is still high.5 Yet, the development of adjuvant therapy for melanoma has been hampered by the lack of effective drugs. Until recently, interferon is the only approved adjuvant treatment in both US and Europe,6,7 but its efficacy has been shown to be modest at best, based on >20 years of clinical trials.5 Due to its marginal benefits, adjuvant therapy is not used consistently in clinically setting.5
In the US, high dose anti-CTLA4 ipilimumab, along with interferon, has recently become the ‘preferred’ adjuvant regimen in resected stage III melanoma, based on a higher rate of recurrence-free survival, and a 11% improvement in 5-year overall survival (OS) as compared to placebo.6,8 Nonetheless, its use has been associated with serious adverse events (AE) that have led to early treatment discontinuation in over half of the patients and a death rate of 1.1%.8 As for BRAF inhibitors, while these agents have dramatically improved the outcome of metastatic melanoma patients from historic norms, the clinical benefit was usually transient and their use in adjuvant setting is still under active investigation. Thus, the unmet need for a safe and effective treatment for stage III patients is still very high.
Checkmate-238: Adjuvant nivolumab is superior to ipilimumab in both efficacy and safety in resected stage III or IV melanoma
In this phase III trial, 906 patients with stages IIIB/IIIC/IV resected melanoma who had >50% risk of relapse over 5 years were randomized 1:1 to either nivolumab (3mg/kg every 2 weeks) or active ipilimumab control. The primary endpoint was recurrence-free survival.9
The trial was stopped early due to clear evidence of benefit for nivolumab. At a minimum follow-up of 18 months, nivolumab showed a significantly higher rate of recurrence-free survival as compared to ipilimumab (66.4% vs. 52.7%; HR=0.65; 95% CI: 0.51-0.83; p<0.0001).4 Recurring-free survival according to disease stage can be seen in Figures 1.4
Lead investigator Dr. Jeffrey Weber, Deputy Director, Perlmutter Cancer Center, NYU Langone Health, US, said: “The majority of patients had higher-risk disease than in most prior adjuvant melanoma trials, which makes the findings even more encouraging.”9
Fewer treatment-related grade 3 or 4 adverse events were reported in the nivolumab arm (14% vs. 46%, respectively), with only 10% of patients taking nivolumab discontinued treatment due to side effects compared to 43% of patients taking ipilimumab.9
“So you can’t lose – nivolumab is a much more effective drug than in active control of ipilimumab and it’s less toxic,” concluded Dr. Weber.10
COMBI-AD: Adjuvant dabrafenib/trametinib doubles relapse-free survival in stage III BRAF-mutant melanoma
In this trial, 870 patients with completely resected, stage III melanoma with BRAF mutation (91% harbored a V600E mutation; 9% had a V600K mutation) were randomized 1:1 to receive oral dabrafenib/trametinib (150mg b.i.d/2mg q.d) or two matched placebo tablets for 12 months. The primary endpoint was relapse-free survival.11
At a median follow-up of 2.8 years, the combination therapy was reported to provide a 53% lower risk for 3-year relapse or death as compared with placebo (58% vs. 39%; HR=0.47; 95% CI: 0.39–0.58; p<0.001; Figure 2).3
“This is the best Kaplan-Meier survival curve for relapse-free survival we have ever seen for malignant melanoma,” said Dr. Axel Hauschild, Professor of Dermatology, University of Kiel, Germany, during his presentation at the ESMO meeting.12
The combination treatment also showed a benefit in secondary endpoints including OS (HR=0.57), distant metastases-free survival (HR=0.51) and freedom from relapse (HR=0.47).11
Treatment-related grade 3 or 4 adverse events were reported in 41% of patients on combination therapy, and 26% of them had to discontinue treatment due to adverse events, in contrast to 14% and 3% of patients with placebo respectively.
“That’s a bit more than we expected in advance but this is in the adjuvant setting so the pressure of the patients on the drug may be not the same as for the stage 4 melanoma setting,” explained Dr. Hauschild.12 “But there were no new toxicities compared to those already seen in stage IV disease and overall we can say the treatment was well tolerated.”11
Comparing apples to oranges: Immunotherapy vs. targeted therapy in advanced melanoma patients
Commenting for ESMO, Dr. Alexander M.M. Eggermont, Professor of Oncology Surgery, Gustave Roussy Cancer Campus, France, said,” The 2017 outcomes are practice changing and put an end to the use of interferon and ipilimumab.”13
While patients with BRAF wildtype disease will obviously become a candidate for nivolumab adjuvant therapy, one major question to clinicians will be how immunotherapy or targeted therapy should be selected and prioritized in patients with BRAF V600–mutant melanoma.
Dr. Dummer Reinhard, Professor and vice-chairman of the Department of Dermatology, University Hospital of Zürich, Switzerland believed that this is a matter of comparison between apples and oranges. “A direct comparison of these two studies is very challenging [because] we have different inclusion and exclusion criteria. … so just stay with the facts, no speculation.”
His opinion was echoed by Dr. Weber. “If you do a non-kosher statistical analysis, you come up with a hazard ratio of nivolumab versus placebo that’s at least as good as what was seen in the COMBI-AD trial… It comes down to whether you believe there will be a tail on the curve for immunotherapy with relapse free survival in the adjuvant mode, as you see in metastatic patients, compared to a lesser tail on the curve for BRAF/MEK drugs in the metastatic mode” he said.14
Toxicity profile, as pointed out by Dr. Reinhard and other melanoma experts, would be the critical factor influencing the clinical decision-making.14,15 “Since surgery is a curative option for most patients with stage III melanoma, drug toxicities will be more relevant in the adjuvant setting.”15 It is noted that dabrafenib/trametinib appeared to have a higher rate of adverse events than nivolumab did. Given that the prognosis of stage III patients is quite heterogenous, Dr. Eggermont believed that risk information and risk/benefit discussion with patients would be crucial.13,15
Meanwhile, Dr. Hauschild pointed out that the equation may be different from a patient’s perspective, as the decision may be affected by practical considerations, such as convenience of administration. “One is an immunotherapy which needs to be given as infusion in every two weeks, the other one is an oral therapy. So that’s two differences,” he said, noting that the former treatment would be less practical for patients living further away from the clinic.14
In Dr. Hauschild’s opinion, whether patients can be rechallenged with the same drugs on recurrence is also an important element of decision making, and it is the “burning question for the future.” He indicated that responses were seen when patients are rechalleng ed with dabrafenib/trametinib, but the analysis was not yet ready.14,16
To conclude, new standards for treating melanoma patients with or without BRAF mutations in the adjuvant setting has been established by Checkmate-238 and COMBI-AD trial. Dr. Hauschild may say this at best: “This day, September 11, will make a change in our textbooks and in our current guidelines because we have at least two new treatment options and this is a very good new treatment opportunity for our patients and a good day for melanoma patients.”12
1. Weber J. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238). European Society for Medical Oncology; 2017; Madrid, Spain. Abstract LBA8_PR.
2. A H. COMBI-AD: Adjuvant Dabrafenib (D) Plu.
s Trametinib (T) for Resected Stage III BRAF V600E/K–Mutant Melanoma. European Society for Medical Oncology; 2017; Madrid, Spain. Abstract LBA6_PR.
3. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017 [Epub ahead of print].
4. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 [Epub ahead of print].
5. Eggermont AM, Spatz A, Robert C. Cutaneous melanoma. Lancet 2014;383:816-27.
6. Coit DG, Thompson JA, Algazi A, et al. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14:450-73.
7. Dummer R, Hauschild A, Lindenblatt N, et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v126-32.
8. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapyh16;375:1845-55.
9. ESMO 2017 Press Release: Adjuvant Nivolumab Superior to Ipilimumab in Surgically Resected Stage III/IV Melanoma. ESMO. 2017. (Accessed October 3, 2017, at http://www.esmo.org/Press-Office/Press-Releases/Adjuvant-Nivolumab-Superior-to-Ipilimumab-in-Surgically-Resected-Stage-III-IV-Melanoma.)
10. Checkmate 238: Adjuvant checkpoint therapy after melanoma resection. ecancertv, 2017. (Accessed October 3, 2017, at http://ecancer.org/video/6262/checkmate-238–adjuvant-checkpoint-therapy-after-melanoma-resection.php.)
11. ESMO 2017 Press Release: Combination Targeted Adjuvant Therapy Doubles Relapse-free Survival in Stage III Melanoma. ESMO, 2017. (Accessed October 3, 2017, at http://www.esmo.org/Press-Office/Press-Releases/Combination-Targeted-Adjuvant-Therapy-Doubles-Relapse-free-Survival-in-Stage-III-Melanoma.)
12. Dabrafenib plus trametinib for stage III mutant melanoma. ecancer, 2017. (Accessed October 3, 2017, at http://ecancer.org/video/6266/dabrafenib-plus-trametinib-for-stage-iii-mutant-melanoma.php.)
13. Eggermont AMM, Dummer R. The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients. Eur J Cancer. 2017;86:101-5.
14. Expert commentary on melanoma immunotherapy latest. ecancer, 2017. (Accessed October 3, 2017, at http://ecancer.org/conference/722-esmo-2017/video/6268/expert-commentary-on-melanoma-immunotherapy-latest.php.)
15. New Adjuvant Option for BRAF Melanoma. Medscape, 2017. (Accessed October 4, 2017, at www.medscape.com/viewarticle/885541_print.)
16. Clear Benefit With Adjuvant Nivolumab in Resected Melanoma. Medscape, 2017. (Accessed October 3, 2017, at www.medscape.com/viewarticle/885539_print.)