A variety of other trials evaluating pembrolizumab combination treatments are underway, including combinations with BRAF and MEK inhibitors, other unique immune-checkpoint inhibitors, vaccines, cytotoxic therapies, and radiation therapy Table 2. To view a larger version of Table 2, click here. Highly effective adjuvant therapy for high-risk resected stage II and III melanoma has been lacking for decades. In the s, interferon was FDA approved based on improvement in recurrence-free survival RFS compared to placebo; however, no OS advantage has been seen with the drug. Additionally, interferon has a high toxicity profile with poorly tolerated flu-like symptoms being common.
A PEGylated form of interferon was FDA approved in based on improved RFS compared to placebo, but still there was no improvement survival; however, this new formulation is more convenient to administer. Given the apparent superiority of the PD-1 inhibitors nivolumab and pembrolizumab over ipilimumab in trials of patients with metastatic melanoma, a series of new studies evaluating PD-1 inhibition in high-risk resected melanomas have been undertaken. Pembrolizumab is being evaluated in two separate randomized Phase III trials. RFS in all the subjects and in the subset of subjects with PD-1 ligand expression in the resected tumor is the primary endpoint.
Immunotherapy for Melanoma: Finding a Response to an Unstoppable Disease - Cancer Patient Resources
Secondary endpoints include distant metastatic-free survival and OS. This study has completed accrual and is awaiting data maturation for publication. Baseline PD-1 ligand testing of the tumor is being performed, and patients are being stratified by expression status. The techniques of preparation of these products are often delegated to pharmacy technicians or technical assistants.
Their tasks are delegated tasks under the supervision of an oncology pharmacist: they must well understand their responsibilities, use the most current techniques of preparation which are validated, evaluated periodically and controlled by the oncology pharmacist. Education is an important role of the oncology pharmacist.
It can be towards other healthcare professionals or residents or even students.
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But the most important educational role is towards the patient. Each patient starting antimelanoma therapy should be met with and have the chosen treatment explained. Issues of appropriate dosage and how to take the medication the most efficiently e. The dosing schedule should be clear for the patient and so should be the treatment plan. It is important to discuss side effects of the chosen therapy and what can be done either to prevent, if possible, or to control them; this issue is very important with anti-CTLA-4 or anti-PD-1 therapy where the side effects are more frequent with combination therapy, they may also present at any given time and sometimes even after the treatment has stopped.
All of this information should be reinforced with a written handout and clear information on where to call about any questions, issues, or worries. During the patient counseling described above, it is essential to do a complete medication history and medication reconciliation to detect any contraindications or discrepancies with regards to the current medication list or potential drug interactions, and to validate if the patient is taking or seeking any CAM.
The oncology pharmacist is an important player in the multidisciplinary approach to optimizing treatment of the patient with metastatic melanoma; he may bring his expertise to the healthcare team and be of value to others by his skills in education, communication of knowledge to others and his thorough and keen knowledge about current therapies and how to maximize their therapeutic benefit and minimize toxicities and how to best manage them [ 4 , 34 , 35 ].
There has also been a trend to develop oral therapies in order to simplify therapies for patients and to try to decrease the number of patients being treated in ambulatory oncology clinics [ 36 , 37 ]. This is also true for the treatment of metastatic melanoma. Yet, this brings on issues of potential drug—drug interactions which need to be challenged because they are a major concern in oncology, due to a narrow therapeutic index of molecules and toxicity of anticancer therapies.
This is at the heart of what an oncology pharmacist does on a daily basis whether it be during prescription validation, medication reconciliation or patient counseling [ 38 , 39 ]. Drug—drug interactions happen when two drugs that are either inducers, inhibitors or substrates of the same metabolic enzyme are administered together and could lead to an unexpected metabolism of one or the two drugs.
This could lead potentially to a lack of efficacy or severe toxicity [ 40 , 41 ].
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Pharmacokinetic interactions happen when one drug alters another drug by affecting either its absorption, distribution, metabolism or excretion. Pharmacodynamic interactions occur when drugs influence each other's effect directly due to competing at a receptor site on the same physiological system.
Pharmaceutical interactions take place when drugs are combined in solution or admixed during infusion that is issues of physical or chemical compatibilities [ 40—43 ]. Pharmacokinetic drug—drug interactions altering drug metabolism are common. The CYP is a metabolic enzyme system whose purpose is to eliminate drugs from the body. Many enzyme families have been identified within this entity; yet, the CYP3A4 is the most common involved in the metabolism of current medications. A drug that inhibits the CYP enzymes will generally decrease the metabolism of a given drug, thus leading to potentially higher drug concentrations and therefore potential increased toxicity.
This phenomenon happens quickly. The opposite phenomenon, where a drug induces the CYP system, would result in an increased clearance of the other drug, decreasing its serum concentration and potentially its efficacy.
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This phenomenon presents itself in a slower fashion. If a drug is metabolized to an active drug via the CYP system and is given with an inducer, we would see an increased serum concentration of the active metabolite, which could cause potentially serious toxicities [ 40 , 44—46 ]. We will try to address this issue in a practical fashion and try to offer tools that may help out oncology pharmacists in their current practice. Ipilimumab is a monoclonal antibody and is not metabolized by the CYP enzyme system. A Phase I combination trial of ipilimumab and vemurafenib had been stopped prematurely due to hepatotoxicity; this association is therefore not recommended [ 11 , 47 ].
No formal drug interaction trials have been conducted with regard to nivolumab or pembrolizumab. The risk of drug interactions for these monoclonal antibodies is considered very low [ 48 , 49 ]. The question that arises frequently with immunotherapy is whether immunosuppression with corticosteroids renders the immunotherapy less effective [ 20 ]. Some authors believe that the use of prior or concomitant immunosuppression can make this happen [ 26 ].
Immunosuppression is often used to treat immune-related adverse events and studies so far have demonstrated that the use of immunosuppression has not had a negative impact on response rates or on time to response compared with patients treated with immunotherapy not requiring at any given time immunosuppression [ 20 , 24 ]. Recommendations from the manufacturers are that immunotherapy should not be started if the patient is on active immunotherapy with corticosteroids because of the potential interference with the pharmacodynamic activity of the immunotherapy [ 47—49 ].
Therefore, drugs that are either strong inducers or inhibitors of CYP3A4 see Table 4 should be avoided if to be used concomitantly with vemurafenib; or an alternative to the inducer or inhibitor should be considered [ 36 , 51—55 ] Strong inducers may decrease the serum concentration of vemurafenib and have an effect on the efficacy of the molecule.
Strong inhibitors would increase the serum concentration of vemurafenib and may put the patient at risk of significant toxicity see Figure 1 [ 36 , 52 , 55]. Data taken from [ 36 , 51 ]. Data taken from [ 36 , 55 , 52 ]. Vemurafenib is also known for causing inhibition of the metabolism of drugs that are substrates of the CYP1A2 e.
Vemurafenib can also inhibit CYP2C9 e. An alternative should be considered or the substrate should be avoided if it has a narrow therapeutic index [ 36 46 52 , 55 ].
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Dabrafenib is a BRAF V inhibitor which is metabolized to hydroxy-dabrafenib, desmethyl-dabrafenib and carboxy-dabrafenib. The clinical activity is essentially defined by the parent molecule and the first two metabolites; the role of carboxy-dabrafenib is considered to be minimal with regard to clinical activity [ 56—58 ]. Drug interactions have the potential to affect the serum concentrations of dabrafenib and its metabolites [ 58 ]. Drugs that are either strong inhibitors or inducers of CYP2C8 should not be used concomitantly with dabrafenib see Table 4 [ 36 , 46 , 52 , 56 ].
Strong CYP3A4 inducers may decrease the serum concentration of dabrafenib and one should monitor therapy closely; strong CYP3A4 inhibitors should be avoided because the may cause increased serum concentration of dabrafenib and exacerbate toxicities [ 52 , 56 ]. Dabrafenib may decrease the serum concentration of CYP2C8, CYP2C9 and CYP3A4 substrates; alternative therapies should be considered to the given substrate and concomitant therapy should be avoided; if this is not feasible, patients should be monitored closely for efficacy of the substrate [52,56].
Dabrafenib is known to decrease serum concentrations of warfarin, hormonal contraceptives and dexamethasone; substitution should be considered see Figure 2 [ 58 ]. Data taken from [ 36 , 52 , 55 , 58 ]. Trametinib is an inducer of CYP3A4 in vitro but at a low level. Therefore, interactions with substrates are not anticipated [ 46 , 52 , 56 , 59] , Cobimetinib is another anti-MEK molecule which is a known major substrate for CYP3A4; inducers should be avoided because they may decrease the serum concentration of cobimetinib and potentially have an impact on therapeutic efficacy.
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CYP3A4 inhibitors should be avoided if used concomitantly with cobimetinib because they may increase the serum concentration of cobimetinib and may lead to increased toxicity. Data taken from [ 36 , 46 , 52 , 60 ]. Cobimetinib has been shown in vitro to be an inhibitor of CYP3A and CYP2D6 but this effect has not been seen at clinically relevant doses in clinical practice [ 46 , 60 , 46 ].
The above recommendations should be considered and individualized to the patient and his clinical condition, co-morbidities and other medications or CAM he may be taking. We recommend using the following tools in helping the oncology pharmacist in his decisional process see Box 1. This is a very large definition and for the sake of the oncology pharmacist's interest, we will limit this definition to that of natural products that encompass herbs, vitamins and minerals, probiotics, homeopathic products [ 62 , 63 ].
A newer concept which is growing in popularity is that of integrative medicine where alternative therapies are integrated to science-based medicine and offer the patient the integration of two very different approaches to their treatment.
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The use of CAM is on the rise in the oncology population and this is probably also true in patients with metastatic melanoma [ 64—66 ]. Studies have shown that CAM use is higher in patients of the female sex, patients with a higher level of education, in non-Hispanic white race patients, in patients with diminished functional status and patients of a younger age [ 67 ]. A survey has demonstrated that fewer than half of oncologists engage discussions with their patients about herbs and supplements because of a lack of knowledge and education that inhibits an open discussion about the topic.
Oncologists are yet worried about herbs and supplements interfering with the efficacy of a patient's chemotherapy treatment or increasing the risk of toxicities or unwanted complications. The oncology pharmacist is the ideal healthcare practitioner to deal with this issue because of his knowledge in pharmacotherapy, his interest in optimizing the cancer treatment and his focus on patient care [ 68 , 69 ].