Jason Luke, MD, FACP (Assistant Professor of Medicine, The University of Chicago Medicine)
The number of available therapies for the treatment of unresectable or metastatic melanoma has dramatically increased over the past five years. Major improvements in targeting of the oncogene BRAF have led to the United States Food and Drug Administration (FDA) approval of combination BRAF and MEK inhibitor approaches, including dabrafenib and trametinib as well as vemurafenib and cobimetinib. At the same time, insights into the immune system have led to the approval of the cytotoxic T-lymphocyte antigen 4 (CTLA4) blocking antibody ipilimumab as well as the programmed death 1 (PD1) receptor blocking antibodies pembrolizumab and nivolumab. Each of these approaches has strengths and weakness which need to be adapted to the individualized care plan of each patient undergoing treatment for melanoma.
With these new drugs, perhaps the most outstanding clinical question in the field of melanoma may be which agent(s) are optimal to use after surgery (adjuvant) to avoid recurrence after resection of the primary melanoma. Dating back two decades, interferon-α in various forms has been the only adjuvant therapy approved for melanoma however it’s use has and continues to be controversial given the quite modest impact on survival and substantial toxicity profile1. For reference purposes, the major cancer guideline group known as the National Comprehensive Cancer Network has previously recommended that clinical observation was the standard of care and that physicians could “consider” the use of interferon. On a physician level, opinions about the drug range from a suggestion it should be given to every high-risk patient all the way to not being carried on the formulary (thus never given to anyone) in some major institutions.
The explosion of new therapies changes the game entirely in the adjuvant discussion of melanoma however and raises the possibility that a much higher percentage of patients may be “cured” after their initial diagnosis. The first evidence to support improvement in adjuvant care was report of The European Organisation for Research and Treatment of Cancer (EORTC) study 18071. This study evaluated patients with stage III (lymph node involved) melanoma investigating whether the drug ipilimumab would improve recurrence as well as survival of patients. Initial reports suggested that ipilimumab did improve recurrences by approximately 25%2 and more recently the final report of the study showed 28% improvement in survival at five years for patients who received ipilimumab3. In this study, most of the benefit was in the sub-population of patients who had ulcerated primary melanomas or involvement of multiple lymph nodes. Overall, this was a very important clinical trial result as it cemented ipilimumab as the first drug to very clearly confer a survival advantage after surgery for melanoma.
Treatment with ipilimumab in the adjuvant setting is not entirely straight forward however. In the EORTC 18071 study the incidence of high grade (potentially hospitalization level) immune-related side effects was 54.1% (compared with 26.2% in the placebo). These include diarrhea, shortness of breath, rash and abnormalities in hormones, among others. Therefore this treatment needs to be considered carefully in patients who might otherwise not be of great health or possibly of advanced age. An additional caveat to the study that has caused confusion in the community was that the dose of ipilimumab used in the study (and now approved by the FDA for adjuvant therapy) was 10 mg/kg every 3 weeks for 4 doses and then every 3 months for 2 years. This is in contrast to the FDA approved dose for advanced melanoma of 3 mg/kg every 3 weeks for 4 doses (then stop). The reason for this discrepancy stems from a few factors but likely most important was that in the 2010-2011 timeframe it was thought in the melanoma community, and by the maker of ipilimumab Bristol-Myers Squibb, that the FDA would approve the 10 mg/kg dose. In the end however the FDA suggested that, at that time, there wasn’t enough safety data for 10 mg/kg to approve the dose. Importantly in 2011, none of the modern medicines used to treat melanoma were available and there was an urgency to get ipilimumab available to as many patients as possible. Therefore the dose that was approved as 3 mg/kg and hasn’t been changed subsequently. However, the EORTC 18071 clinical trial had already been started using the 10 mg/kg dose and it wasn’t possible to change it.
Moving forward then, we are now in the situation in which the dose of ipilimumab used after surgery is 3.3x times higher than the dose used if melanoma becomes advanced. This has consequences as the higher dose does appear to have more side effects. Interestingly however, another clinical trial (CA184-169) has recently been reported which suggests that in patients with advanced melanoma, the 10 mg/kg dose of ipilimumab improves overall survival of patients relative to the 3 mg/kg dose, albeit with higher side effects4. Given all of this, at the current time evidence based practice in melanoma only supports giving 10 mg/kg of ipilimumab in the adjuvant setting. Further, sub-set analysis would suggest that emphasizing use of the drug in patients with ulcerated primary melanomas or multiple involved lymph nodes should be encouraged while use in non-ulcerated melanomas or those with only 1 lymph node involved should be deprioritized.
Adjuvant therapy for melanoma is on the verge of becoming even more complicated however as the results from several other clinical trials are on the horizon. These include evaluations of BRAF targeted agents as well as other immunotherapies (notably including PD1 antibodies). As shown in Table 1 these studies are testing several different approaches. Looking at this, it is immediately obvious how quickly the field of melanoma is moving given the different control or comparator arms (placebo, ipilimumab, interferon). This is a great thing for patients who are diagnosed with melanoma but can lead to confusion in understanding the overall landscape.
Broadly speaking these studies fall into two categories: BRAF targeted therapies and immunotherapy. For the BRAF trials, both BRIM8 and COMBI-AD are being compared to pill placebos. Given that BRAF targeting has improved overall survival in advanced melanoma it is thought that perhaps this approach can eliminate residual microscopic melanoma after surgery. In these trials the medicines or pill placebo are given for a year. Both of these BRAF approaches are compared with placebo given that when the studies were started it was felt that observation (as opposed to interferon) was the most clinically relevant comparison.
In the immunotherapy space, the Eastern Cooperative Oncology Group (ECOG) has fully accrued a study evaluating interferon with both high and low doses of ipilimumab. This will be an important result to prove whether or not ipilimumab is superior to interferon. It will also give a first comparison of high and low dose ipilimumab in the adjuvant setting. Notably, this was not the original intention of the clinical trial so evaluation of the statistical design for comparison between those two arms will be nuanced.
Following ECOG1609, a host of adjuvant clinical trials are evaluating PD1 antibodies. These include EORTC-1325/KEYNOTE-054 and CHECKMATE 238, which are both fully accrued pending maturation of data, and Southwestern Oncology Group (SWOG) 1404 which is actively accruing patients as of December 2016. These studies will inform several hypotheses and allow for better comparisons between PD1 immunotherapy and the standards of care including ipilimumab or intravenous placebo (clinical observation). Similar to the EORTC18071 and BRAF targeted trials, the control arm comparators for these immunotherapy studies is based on what was considered the standard of care at the time the trial began.
The field of melanoma therapeutics is clearly evolving very rapidly as drugs that are known to be active are moved from the metastatic setting to the potentially curative adjuvant setting. Many questions remain and will unfortunately not be answered by the on-going studies. For example, no comparison between BRAF targeted therapies and immunotherapy will be made in any of these studies. Further, it is possible that the 3 mg/kg dose of ipilimumab could be observed to be similar to the 10 mg/kg dose in the ECOG1609 study. That could then blur the meaning of any results from the CHECKMATE 238 and SWOG1404 studies. Even further, pilot clinical trials are beginning to suggest that there may be a tremendous benefit to giving these drugs even before surgery (neo-adjuvant) with exciting results being reported at the Society for Melanoma Research 2016 meeting5,6.
Given all of the activity above, it is a truly exciting time in melanoma oncology. An improved understanding of molecular science and immuno-biology has catapulted the field forward and many more treatment approaches beyond what have been discussed here are in development. As a field, many important issues still need to be addressed regarding patient selection for treatment (biomarkers) and extending the benefits of these therapies to earlier stages of melanoma (stage II) in a safe manner. In this context, it cannot be stressed enough that continued participation by patients and physicians in clinical trials is essential in order to continue the unparalleled success that has been seen in the past 5 years.
Table 1. High profile on-going adjuvant clinical trials in melanoma
|Trial Name||Drugs / Molecular Type||Clinicaltrials.gov Identifier|
|BRIM8||Vemurafenib vs. Placebo in patients with BRAF mutant tumors only||NCT01667419|
|COMBI-AD||Dabrafenib + Trametinib vs. Placebos in patients with BRAF mutant tumors only||NCT01682083|
|ECOG1609||Interferon vs. Ipilimumab 10 mg/kg vs. Ipilimumab 3 mg/kg||NCT01274338|
|SWOG1404||Pembrolizumab vs. Ipilimumab 10 mg/kg or Interferon||NCT02506153|
|EORTC-1325/KEYNOTE-054||Pembrolizumab vs. Placebo||NCT02362594|
|CHECKMATE 238||Ipilimumab 10 mg/kg vs. Nivolumab||NCT02388906|
- Mocellin, S. et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010 Apr 7;102(7):493-501
- Eggermont, A.M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16, 522-30 (2015).
- Eggermont, A.M. et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375, 1845-1855 (2016).
- Ascierto, P.A. et al. Overall survival (OS) and safety results from a phase 3 trial of ipilimumab (IPI) at 3 mg/kg vs 10 mg/kg in patients with metastatic melanoma (MEL), Abstract 1106O. European Society of Medical Oncology Meeting, Copenhagen, Denmark 2016.
- Blank CU, van Akkooi A, Rozeman L, et al. (Neo-)adjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage 3 melanoma – the OpACIN trial. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016.
- Amaria RN, Prieto P, Tetzlaff M, et al. Treatment with neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016.