Invasive melanoma represents approximately 1% of all skin cancers but accounts for the majority of skin cancer related deaths. For localized melanoma, surgical resection alone has been the standard of care with high 5-year melanoma specific survival rates for early stages. Patients with stage II and III disease are at higher risk for recurrence after resection with some cases progressing to metastatic melanoma. 5-year survival rates for melanoma metastatic regionally and distantly are 66% and 27%, respectively (1).

In melanoma, mutations in BRAF are found in approximately 40% of cases and result in constitutive activation of the MAPK pathway (2). Mutant BRAF, and downstream kinase protein MEK, have proved viable targets for melanoma therapies. Three combinations of inhibitors of mutant BRAF and MEK have been approved by the FDA for treatment of advanced unresectable melanoma (3).

A study of adjuvant combination therapy with BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib, in patients with resected stage III BRAF V600E/K-mutant melanoma showed improved recurrence free survival benefit at 3 years with overall survival rate of 86% compared to 77% with placebo. This study was published in September 2017 and led to FDA approval in April 2018. The difference in 3 year overall survival was not considered statistically significant as it did not cross the prespecified interim analysis boundary of P=0.000019 for significance (4, 5). In the aforementioned study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation of therapy in 26% of patients. Common adverse events include fevers and chills, with any grade reported in 63% of patients. These data are greater than that reported in the metastatic setting (3). Subsequent analyses suggest the rate of adverse events decreased with increased duration of therapy (6, 7). Adjuvant therapy with dabrafenib and trametinib has an intended duration of one year (4, 5).

Here we present a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition with the purpose of describing toxicities in a real-world population.

We reviewed medical records of patients treated at a single center with resected stage III melanoma who started treatment with adjuvant dabrafenib and trametinib by three independent academic medical oncologists between November 2017 and December 2019. Planned treatment was for a total of 1 year of dabrafenib and trametinib with full doses being dabrafenib 150 mg twice daily and trametinib 2 mg daily. Primary endpoint was development of toxicities. Using REDCap Data Management software, baseline patient characteristics were collected in addition to secondary endpoints including number of treatment interruptions, dose reductions, and total time on combination therapy. The study was performed according to a protocol approved by the institutional review board at the University of Michigan.

Our study offers a novel examination of a real-world population with resected stage III melanoma treated with adjuvant combination BRAF and MEK inhibition. In our experience, adjuvant combination BRAF and MEK inhibition was associated with clinically significant treatment related toxicities with the rate of adverse events exceeding what has been reported in the literature. Specifically, in the COMBI-AD trial, fevers and chills of all grades occurred in 63% of patients. Dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation of therapy in 26% of patients (4). The median time to onset of pyrexia was 23 days with median duration of 3 days. Of the patients who experienced pyrexia, 72% had recurrence (≥ 2 episodes) (8). Interestingly, there was no difference in patient reported quality of life between those receiving treatment and those receiving placebos.

In our population, 90% of patients experienced adverse effects prompting treatment interruption, 55% required at least one dose reduction, and 65% permanently discontinued therapy due to an adverse event. For the 20 patients who completed or discontinued therapy, the median total time on therapy was 148.5 days, 40.7% of the intended duration. The majority of these patients never tolerated the FDA labeled combination doses.

Our systematic approach to BRAF/MEK therapy includes obtaining baseline labs including complete blood count (CBC), comprehensive metabolic panel (CMP), lactate dehydrogenase (LDH), EKG for QTc assessment, echocardiogram to evaluate cardiac function, ophthalmologic evaluation, and standard cross-sectional imaging to assess disease at baseline. Cardiovascular testing (EKG and echocardiogram) is repeated every 3-6 months or with change in clinical status given potential cardiovascular adverse events (9). History and physical exams with laboratory testing are repeated every 4 weeks, however, additional 2 week appointments have been necessary due to symptoms and lab abnormalities. Specific attention is given to changes in liver labs which have been seen in several patients despite the relative infrequency reported in advanced melanoma patients. It is possible that use of acetaminophen could have contributed to these liver laboratory abnormalities. Combination therapy was initially started at doses of dabrafenib 150 mg BID and trametinib 2 mg daily. High rates of poor tolerance often related to pyrexia and chills leading to need for treatment interruptions, re-evaluations within days and weeks of starting treatment, some emergency department evaluations, as well as multiple dose reductions, and early termination of treatment were frequently observed regardless of disease and/or patient characteristics, or treating physician. This physician group discussed these issues and elected to decrease the starting dose of dabrafenib to 75 mg BID with the intent of minimizing initial treatment related adverse events, minimizing treatment interruptions, with the intent of uptitrating to the goal dose of 150 mg BID. This generally allowed improved adherence and fewer toxicities although uptitration was not tolerated in most cases.

Recommended management of common side effects with combination BRAF and MEK inhibition has been described in metastatic melanoma and are being used in the adjuvant setting as well (10–12). As in clinical trials, dose interruptions and dose reductions of one or both medications, as well as supportive medications, were used in the management of adverse events. In this patient cohort, premedication for pyrexia/chills with acetaminophen, ibuprofen, or low dose prednisone (n=2) were typically used for recurrent episodes of pyrexia/chills. The majority of patients used both acetaminophen and NSAIDs. This permitted some patients to tolerate the desired dose of therapy. In the two patients who received prednisone 5mg daily, this did not permit tolerance and both discontinued treatment prematurely. To date, eight of the 20 patients have relapsed with only one death. Two of these relapsed on therapy. The impact of dose interruptions and/or dose reductions on outcomes remains to be determined in the adjuvant setting. Data in advanced melanoma have shown inferior outcomes with intermittent dosing of BRAF and MEK combination therapy (13, 14).

There are few other reports of patient groups treated with adjuvant dabrafenib and trametinib. One report of 36 patients had incidences of fevers or chills of all grades of 36% and 2.8%, respectively (15). This group also reported liver adverse events in 11% as well as SAEs in 22.2% and a ‘protocol completion rate’ of 64.3%. There was no comment on cardiac side effects. Another report of 65 patients reported a discontinuation rate due to treatment related adverse events of only 9% and only one patient stopped treatment due to pyrexia (16). Forty-three patients completed treatment as scheduled. The median time to discontinuation was 9 months. The incidence of chills was very low at 1.5% and of fever at 35.4%. There was no specific comment on liver or cardiac toxicities, nor on dosages or dose reductions or interruptions. It is not known as to the reason for the differences seen in the few papers published on real world experience with dabrafenib/trametinib for melanoma in the adjuvant setting however it is possible that there is a geographical factor. Dabrafenib can cause hemolytic anemia in patients who have G6PD deficiency and it is known that there are geographic differences worldwide in percent of patients who are G6PD deficient (17, 18). While no patients at our institution experienced hemolytic anemia, this is one example of possible geographic differences in medication tolerance.

Oncologists continuously face the difficult task of balancing benefits and toxicities associated with cancer treatment. We report our findings of the side effects of adjuvant combination BRAF and MEK inhibition to demonstrate the frequency and severity of toxicities. Adjuvant combination BRAF and MEK inhibition is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.

There were some limitations to our study. First, this study was performed at a single academic center. Second, this study was retrospective and information bias must be considered. Third, practice pattern variation among physicians in dosing, management of toxicities, and decisions to hold therapy or dose reduce is probable.

Our findings indicate that adjuvant combination dabrafenib and trametinib in the treatment of resected stage III melanoma can be associated with treatment limiting toxicities. We support a comprehensive approach to adjuvant treatment including a thorough initial evaluation, close monitoring for toxicities, and prompt interventions with the goal of completing therapy with tolerable adverse events. Additional studies with larger numbers of patients are needed to validate our findings.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by University of Michigan IRB. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

MH, GW, SK, and LF contributed to conception and design and manuscript drafting. MH, GW, SK and LAF performed data collection. All authors provided substantial contribution to data analysis, editing, and final approval of the manuscript.

LF: institutional funding for clinical trials (site PI) from Array/Pfizer, Bristol Myers Squibb, EMD Serono, Kartos. Consultant for Elsevier. Array/Pfizer funding of ECOG-ACRIN clinical trial (national PI) for LAF.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.