Dabrafenib + Trametinib (Tafinlar + Mekinist)

Cancer therapies have been applied across tumor types since the advent of modern oncology practice. Chemotherapy regimens, monoclonal antibodies, and targeted therapies such as tyrosine kinase inhibitors (TKIs), for instance, have been explored first in one tumor-type setting, with expanded testing and use in other tumor types once proof of principle has been established. The wide application of bevacizumab, for example, and more recently of immune checkpoint inhibitors, illustrates how strategies that target underlying malignant processes may be useful for treating a variety of cancers.

An excellent example of this phenomenon is the discovery of BRAF V600E mutations in metastatic melanoma.¹ When dabrafenib was observed to be effective² and was approved as a monotherapy for BRAF V600E mutation–positive melanoma in January 2013 and in combination with trametinib for BRAF V600E or V600K mutation–positive melanoma in 2014,³ researchers set out to determine whether the 1% to 2% of patients with non–small cell lung cancers (NSCLCs) with the same oncogenic driver would also respond. The combination regimen was approved by the U.S. Food and Drug Administration (FDA) for patients with metastatic NSCLC with BRAF V600E mutation (as detected by an FDA-approved test) in mid-2017.⁴

The BRAF V600E Biomarker

As hypothesized, BRAF V600E is now recognized as an actionable molecular biomarker in metastatic NSCLC, joining the ranks of EGFR, ALK, and ROS1.⁷

Testing for EGFR, ALK, ROS1 is typically done in patients with NSCLC, “but BRAF is still an afterthought for a lot of physicians in this setting,” said Christina Baik, MD, of the Seattle Cancer Care Alliance/University of Washington. “My suggestion is to test for all four markers upfront, if possible. Realistically, though, by the time testing for the fourth marker is performed, there might not be sufficient tissue remaining.”

Unlike other molecular biomarkers, which are often associated with certain patient characteristics, although rare, the BRAF V.⁸ Upfront testing for the mutation as part of broad, multiplex molecular screening is ideal and recommended by the NCCN.⁹ Dr. Baik observed, however, that in real community practice, this may not be feasible because the assay may not be readily available at every facility. Moreover, results of an externally ordered test may be substantially delayed and/or the test may not be covered by third-party insurers.

“Although the presence of the mutation ideally should be confirmed by the FDA-approved test, in clinical practice, identification by a CLIA [Clinical Laboratory Improvement Amendments] laboratory–developed test is usually accurate and sufficient,” Dr. Baik said, “particularly if biopsy tissue is no longer available for further testing.”

Data supporting the combination of dabrafenib/trametinib in NSCLC derive from small, single-arm studies, with the initial studies having been conducted in second- and subsequent-line treatment settings.¹⁰ “These studies show high, durable response rates that are numerically superior to what would be anticipated with other systemic therapies in the second line and beyond,” Dr. Baik said. Whenever the regimen is started in those with the appropriate mutation, responses may be anticipated, she remarked, but tolerability can be an issue, especially in later lines of treatment, when patients are increasingly frail. Use of dabrafenib alone for NSCLC is also supported by data, although the NCCN Guidelines only recommend single-agent therapy with dabrafenib if combination therapy with dabrafenib/trametinib is not tolerated.¹¹

Use of this targeted regimen in the first-line setting¹² is controversial, Dr. Baik pointed out, because there has not been a head-to-head comparison of either chemotherapy or immunotherapy versus dabrafenib/trametinib as a first-line treatment. “Although we might predict that targeted therapy will be better than chemotherapy based on the wealth of data that exist for other actionable alterations, eg, EGFR, ALK, we don’t actually know whether this targeted therapy will be better, especially compared with immunotherapy in patients with high PD-L1 [programmed cell death ligand 1]–expressing NSCLC or versus chemoimmunotherapy,” she said. Therefore, according to the NCCN Guidelines, the decision about whether to start with chemotherapy or immunotherapy, with this targeted regimen as second line, or to start with targeted therapy, is left up to the provider.⁹ 

“For a treatment-naive patient with the BRAF V600E mutation whose tumor is also PD-L1–low or for a never smoker even if PD-L1 is high,” Dr. Baik remarked, “I would tend to select targeted therapy. Nevertheless, best practice for first-line treatment of advanced NSCLC is evolving, so my practice will likely change over time, as more data become available.”

Typical TKI Adverse Effects…Plus

When patients start on this oral combination regimen, “We instruct them to take both drugs on an empty stomach (ie, 1 hour before a meal or 2 hours after a meal) and not with any other medications,” explained Tracy A. Ruegg, MS, ARNP, AOCN, oncology nurse practitioner with the Sylvester Comprehensive Cancer Center, which is part of the University of Miami Health System. “We also ask patients to come back in 2 weeks to assess adverse effects, which usually will appear within that time frame.”

Skin Toxicity

Dr. Baik noted that in her experience, skin toxicity was more of an issue when dabrafenib was used as monotherapy. “Surprisingly, when trametinib is added, many of the dermatologic side effects of TKIs seem to be less intense. Likewise, the potential development of squamous cell carcinoma was more of a concern when dabrafenib was used alone. It appears to be less likely when trametinib is added,”^2,13 she said. 

Although skin toxicity may be somewhat less likely with the combination, Ms. Ruegg pointed out that rash is almost inevitable with TKIs in some patients. Although most patients (both those with lung cancer and those with melanoma) do very well with this combination, there is a percentage of individuals who develop a “blazing” skin reaction. “We start with a full dose. If a patient is going to develop a rash, it will happen within the first 2 to 3 weeks of starting therapy, and some break out in a week. If they develop a grade 2 to 3 rash, we hold treatment and prescribe an antibiotic, such as minocycline, to speed up the healing process. Once the rash has subsided to grade 1, we reintroduce the dabrafenib once a day. If the patient is doing well with once-daily dabrafenib, I will reintroduce trametinib, also at once daily. If and when I see the once-daily combination is well tolerated, I will reintroduce the twice-daily schedule,” she said.

Rather than wait and see whether skin rash will develop, Ms. Ruegg and her team educate patients about prevention. “We suggest patients use a thick emollient cream and cotton gloves and socks to prevent or reduce peeling of the hands and feet. We also urge patients to hydrate from the inside out by drinking 2 liters of water per day. I also recommend a fish oil supplement, which helps with skin hydration, as long as it is not taken at the same time as the dabrafenib/trametinib combination.”

Pyrexia

With the combination of dabrafenib and trametinib, “we see a good deal of mild fevers, so we need to educate both patients and medical staff about this adverse effect. In the clinical trials,^10,12 grade 1 fever was reported in 40% to 50% of patients, so it is pretty common,” Dr. Baik revealed. “The issue is that we have to be able to distinguish between drug-related fever and infection-related fever. We use a treatment algorithm for fever that combines the severity of the fever and the presence and severity of any other symptoms.” A patient with a low-grade fever and no other symptoms will probably start with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID), she said. Many times, that’s enough to bring the patient’s temperature down to a normal level. If, in contrast, the fever persists despite antipyretic treatment, “then we hold targeted therapy until the fever resolves. Usually the culprit is dabrafenib, so we might only hold that part of the regimen. It usually takes only a few days for the fever to resolve, at which point, I would rechallenge with dabrafenib at the same dose but with prophylactic acetaminophen 30 to 60 minutes before the patient takes the drug. If a patient does develop a fever, it will tend to be recurrent with treatment, so prophylaxis with acetaminophen (or an NSAID) often will have to become part of the regimen. More rarely, patients may develop a fever with rigors and even dehydration, without other symptoms or signs of infection. They can feel quite sick, so in those situations, we hold both drugs until the fever dissipates.”

We have to be able to distinguish between drug-related fever and infection-related fever. 

Ms. Ruegg has observed less pyrexia but noted fatigue and malaise are common, sometimes initially associated with a low-grade fever. NSAIDs are a mainstay of management for those joint aches and low-grade fevers. “We had a patient who just could not tolerate the full-combination doses because of fatigue and ‘not feeling well.’ We held the trametinib—because the dabrafenib is the inhibitor of the driver mutation—and finally had to reduce even the dabrafenib to just once a day. Nevertheless, even with that dose reduction, which the patient was finally able to tolerate, she derived good benefit, which was radiologically demonstrable. It was effective for controlling her lung cancer for a durable period.”

Vision Changes

Patients on this regimen also need to be seen regularly by an ophthalmologist, according to Ms. Ruegg. “During our clinical trial [of dabrafenib/trametinib] in NSCLC, patients saw the ophthalmologist at every visit,” she said. There may be changes in visual acuity, and uveitis has been reported. In clinical practice, monthly eye exams are probably not necessary, but Ms. Ruegg urges practitioners to ask about changes in vision and encourages patients to maintain visits to their eye care specialists. “We sometimes assume patients will tell us when they notice a change, but we should proactively ask. Patients may not connect eye issues with their lung cancer treatment,” she said.

Heart and Lungs

Although rare, these drugs—mostly trametinib—can be associated with cardiac dysfunction, Dr. Baik pointed out, “so we generally obtain a pretreatment echocardiogram and another one after about 3 to 4 months on treatment.” Ms. Ruegg’s team also starts with a baseline echocardiogram and periodic assessments during treatment. “Although rare, congestive heart failure has been reported with trametinib. Knowing the baseline cardiac status can help the oncology team evaluate this type of symptom, if it occurs,” Ms. Ruegg said.  

Dr. Baik described a unique toxicity that is commonly associated with this regimen: dry cough, which is usually mild. “With these drugs, adverse effects can be persistent,” she explained. “They tend not to disappear or to become milder with time nor do they become worse or cumulative.” If patients develop an annoying dry cough, Ms. Ruegg said, “we might consider prescribing benzonatate capsules, although that’s not commonly necessary.”

Duration of Treatment

Patients can stay on this regimen as long as they can tolerate it and it is controlling their disease. This is an inhibitory combination, so the benefit is usually seen as disease control. Based on trial data, Dr. Baik reported, patients may be treated for an average of 9 to 12 months, or even longer. “When we see a patient has been on therapy for 6 to 9 months and disease is stable, we might be able to offer a ‘drug holiday,’” Ms. Ruegg said. Patients are evaluated radiologically and then taken off drugs for 2 to 3 months. If the next scan also shows no tumor growth, they may prolong their drug holiday. Eventually, when the scan demonstrates some tumor growth, the regimen can be restarted. “Because disease progression occurred while they were off drug, they are still eligible for treatment,” she said.

Closing Thoughts

“I would urge clinicians to test for this actionable mutation,” Dr. Baik said. It is fairly rare, but “I don’t think patients are being tested for it on a regular basis.” [The NCCN Guidelines recommend testing for BRAF V600E mutations.⁹] When patients are identified with the mutation and start treatment, the regimen is generally well tolerated. The issue of fever can be challenging, as well as time-consuming for medical staff, because of the need to ensure that there is no underlying infectious illness. The nursing staff should have an algorithm to follow, so everyone knows what to ask about and what steps to take.

Ms. Ruegg urges practitioners to review the prescribing information for both drugs, including the less common grade 3 and 4 toxicities. “Although most of your management will be focused on the common adverse events, such as rash, when something odd occurs, you need to know which drug is the likely culprit to be able to quickly adjust or hold the drug,” she pointed out.

She encouraged practitioners to customize treatment regimens by reducing and/or holding doses, as necessary, with reintroduction of drug when symptoms resolve. “If the combination seems to cause troublesome adverse effects, we have patients start dabrafenib alone, and introduce the trametinib after the situation has stabilized. Or we can dose reduce by having patients take each drug only once a day, followed by dabrafenib twice a day and trametinib still just once a day. I tailor the dosing schedule to the grade of the side effects,” she explained.

DISCLOSURES

Christina Baik, MD, disclosed no relevant relationships.

Tracy A. Ruegg, MS, ARNP, AOCN, disclosed no relevant relationships.

References

1. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694–1703.
2. Long GV, Stroyakovsky D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomized controlled trial. Lancet 2015;386:444–451.
3. National Institutes of Health. National Cancer Institute. FDA approval for dabrafenib. Available at https://www.cancer.gov/about-cancer/treatment/drugs/fda-dabrafenib. Accessed January 9, 2018.
4. 4. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm. Accessed January 8, 2018.
5. Dabrafenib (Tafinlar) Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202806s006lbl.pdf. Accessed January 8, 2018.
6. Trametinib (Mekinist) Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204114s005lbl.pdf. Accessed January 8, 2018.
7. Riely GL. What, when, and how of biomarker testing in non-small cell lung cancer. J Natl Compr Canc Netw 2017;15:686–688.
8. Luk PP, Yu B, Ng CC, et al. BRAF mutations in non-small cell lung cancer. Transl Lung Cancer Res 2015;4:142–148.
9. Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer, Version 2.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 9, 2018.
10. Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF (V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicenter phase 2 trial. Lancet Oncol 2016;17:984–993.
11. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:642–650.
12. Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017;18:1307–1316.
13. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 2017;28:1631–1639.