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Patients with metastatic urothelial carcinoma have new, much-needed options in second- and third-line treatments with the recent FDA approvals of erdafitinib and enfortumab vedotin, according to a presentation at the Hematology/Oncology Pharmacy Association virtual 2021 conference.

Urothelial carcinoma is the sixth most common cancer diagnosis in the United States, with an estimated 81,400 new diagnoses in 2020 and 17,980 deaths. It largely impacts older adults, with a median age of 73 years, and men are much more impacted than women. 

Presenter Renee McAlister, PharmD, BCOP, a clinical pharmacy specialist at Vanderbilt University Medical Center, said that approximately 90% of urothelial carcinomas arise in the bladder, although approximately 10% arise in the upper tract.

Traditional second-line treatments include immunotherapy and single agent chemotherapy, such as docetaxel, paclitaxel, and gemcitabine. These treatments all have relatively low response rates, however, with approximately 13.3% of patients responding to docetaxel and 9.5% responding to paclitaxel. 

Single agent chemotherapy is traditionally the only option for third-line treatment. With the approval of erdafitinib in both the second and third lines and enfortumab vedotin in the third line, however, these options have been expanded.

Erdafitinib is a fibroblast growth factor (

) inhibitor that was approved in April 2019 for metastatic urothelial carcinoma with a susceptible 

 genetic alteration that has progressed during or following platinum-containing chemotherapy. 

 fusions are most common in bladder cancers, McAlister said, occurring in up to 20% of metastatic urothelial carcinomas. 

The BLC2001 study evaluated erdafitinib in patients with a median age of 68 years, most of whom had progressed following prior chemotherapy and 22% of whom had progressed following prior immunotherapy.

According to McAlister’s presentation, investigators found a confirmed response rate of 40%, with 3% of patients exhibiting a complete response and 37% exhibiting a partial response. Furthermore, 49% of patients with a 

 mutation responded and 16% of patients with 

 fusions responded. The overall median duration of response was 5.6 months, and the median progression-free survival (PFS) was 5.5 months. Finally, the median overall survival (OS) was 13.8 months.

Treatment-related adverse events (TRAEs) included hyperphosphatemia, stomatitis, diarrhea, dry mouth, decreased appetite, dysgeusia, alopecia, hand foot syndrome, and nail changes. McAlister noted that hyperphosphatemia is a biomarker for efficacy and can be managed by restricting dietary intake to 600 to 800 grams per day or by initiating a phosphate binder for levels greater than 7 mg/dL. Patients should also avoid vitamin D and antacids.

Next, McAlister discussed the approval of enfortimab vedotin in both the second- and third-line settings. Enfortimab, a nectin-4 monoclonal antibody, was approved in December 2019 for the treatment of locally advanced or metastatic urothelial carcinoma after platinum-based chemotherapy and a programmed cell death protein 1 (PD-1) or programmed death cell ligand 1 (PD-L1) inhibitor. The approval was based on the phase 2 EV-201 study and the phase 3 EV-301, the results of which were published about a month ago, McAlister said.

The phase 3, open-label, multicenter study consisted of mostly men (79.1%), with a median age of 68 years. About 18% of participants had a history of diabetes, 87% had received 1 to 2 previous systemic therapies, and about 70% wee non-responders to immunotherapy. According to the study results, the median OS was 12.8 months in the enfortimab group versus 8.97 months in the chemotherapy arm. Similarly, PFS was 5.5 months in the enfortimab group and 3.71 months in the chemotherapy group.

TRAEs included alopecia, peripheral sensory neuropathy, pruritus, fatigue, decreased appetite, diarrhea, ocular toxicity, anemia, and hyperglycemia. McAlister said recommended dosing is 1.25 mg/kg intravenously on days 1, 8, and 15 of a 28-day cycle. She also noted that it has a low emetic risk and added that testing for nectin-4 expression is not required.

“These approvals really have changed the landscape for metastatic bladder cancer,” McAlister concluded.

McAlister R. Targeted Therapy in Metastatic Urothelial Carcinoma. Presented at: Hematology/Oncology Pharmacy Association 2021 virtual conference; April 15, 2021. Accessed April 15, 2021.

Articles

Urothelial carcinoma is the sixth most common cancer diagnosis in the United States, with an estimated 81,400 new diagnoses in 2020 and 17,980 deaths. 

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Oncology

Erdafitinib, Enfortimab Vedotin Offer New Treatments for Metastatic Urothelial Carcinoma

A survey from Scripta Insights found that some of the first words that come to consumers’ minds when thinking of prescription drugs are “expensive,” “necessary,” and “cost(ly).”

Scripta surveyed 372 respondents between 18 and 60 years of age about American attitudes and behaviors around prescription drug pricing. All respondents have health insurance through their employer and take 1 or more prescription drugs on a regular monthly basis.

The results of the survey found that despite having health insurance, approximately 66% of the respondents think they pay too much for prescription drugs. A further analysis showed that this directly correlates to how much they spend out of pocket monthly, ranging from 45% for those spending under $15 to 86% for those who spend $50 or more.

In addition, 52% of respondents believe that pharma companies are the number 1 offender of high prescription drug prices, followed by insurance companies (17%) and the government (15%). Marketing/advertising, drug ingredients/manufacturing, and research and development were the highest 3 factors that respondents felt drove prescription drug pricing.

The survey also revealed that 71% of the respondents believe that 

 are helping to solve the high cost of prescription drugs. However, only 16% of people report looking for a coupon when they cannot afford their medications.

“Pharmacy coupon and discount services aren’t treating the condition of high prescription drug prices, they’re merely treating its symptoms; they’re not getting rid of your brain tumor, they’re just making your headache feel better today,” said Eric Levin, CEO of Scripta Insights, in the press release. “Coupon services are all promoting the same [pharmacy benefit manager]-based system that is the hidden culprit behind the high costs on the majority of drugs in the US.”

The majority (73%) of people surveyed who are on a deductible plan know where they are with their deductible and the impact it will have on their prescription costs before they go to the pharmacy. At the pharmacy counter, more than half of people (57%) have asked whether the cash price of a drug is cheaper than the price through their insurance, whereas 60% of patients have asked their physician the cost of a drug when getting a new script.

Although the survey found that the most popular action respondents take is asking their physician for a cheaper option before a pharmacist, 51% do not believe their physician knows the price they will pay for the drug they are prescribing.

“People trust their physicians and want to take the medicine their doctor prescribes, but affordability has a major impact on adherence—I’ve seen it with my own patients,” said Paul Bradley, MD, chief medical officer and head of the P&T Committee at Scripta Insights, in the press release. “Believe it or not, most physicians don’t know the cost of a drug or what the member copay is on your insurance plan when they write your prescription.”

As for changing medications to save money, more than half of people (58%) have received a recommendation to take a different less expensive drug for their medical condition, with advice coming from trusted sources, such as a physician or pharmacist (54%), or non-experts, such as a family member or friend (32%).

Further, 96% of respondents are willing to make a prescription change, such as switching their prescription, if their physician said it was allowed, to pay less for their medications. Approximately half of those surveyed (46%) are willing to switch to a new medication to save as little as $15 per month.

The most popular prescription switches people are willing to make include switching from a brand name to a generic drug (70%) and switching to a different brand name drug (52%).

In order to save on the cost of prescription drugs, approximately 25% of patients are willing to:

Get a new prescription for a higher dosage pill and split it in half with a pill splitter

Take a different form of drug (such as a gel instead of a cream)

Take the drug more frequently such as twice daily instead of once daily)

Consumers in pain over high prescription prices, ready to take action and in need of better tools, according to survey by scripta insights. Scripta Insights [email]. Accessed April 14, 2021.

Scripta surveyed 372 respondents between 18 and 60 years of age about American attitudes and behaviors around prescription drug pricing.

Retail

Reimbursement

Survey Finds Consumers in Pain Over High Prescription Prices, In Need of Better Tools

Although antihistamines are commonly used to manage hives, sneezing, and watery eyes during allergy season, many patients may be taking their medications incorrectly, according to Derek Chu, MD, PhD, a McMaster University allergy expert and clinical scholar.

“People need to rethink what they stock in their home cabinets as allergy medicines, what hospitals keep on formulary, and what policymakers recommend,” Chu said in a press release. “The message needs to get out. This publication is on time for the spring allergy season and as COVID vaccines roll out, for which rashes are common and antihistamines can be helpful.”

Co-author Gordon Sussman, MD, FRCP, FACP, DIP.ABIM, FAAAAI, said in the press release that there are new second generation antihistamines that prescribers should know about. Their new study, published in the 

, lists 5 things to know about proper antihistamine use.

Antihistamines are among the most commonly and incorrectly used medications worldwide, according to the press release. Their best use is for the management of hay fever and outbreaks of hives, and not for management of asthma, eczema, coughs, or insomnia.

Notably, first-generation antihistamines are associated with substantial and sometimes fatal adverse effects (AEs). These antihistamines are ones with diphenhydramine, chlorpheniramine, or hydroxyzine, which can cause drowsiness and affect cognitive functions, such as school performance. Overdosing with these types of antihistamines can cause death and are potentially dangerous for both young and older people.

Second-generation antihistamines are safer and just as affordable and as effective as first-generation antihistamines, according to the study authors. Later-generation antihistamines are proven to be more effective and last longer with less severe AEs, such as drowsiness, according to the study authors.

In their fourth point, the authors said antihistamines should not be used instead of epinephrine to treat anaphylaxis. Oral drugs can be used in combination with epinephrine injections to treat anaphylactic reactions, but they are not a proper substitute.

Finally, they said most antihistamines are safe to use during pregnancy and breastfeeding. Researchers have shown that antihistamines at standard doses do not harm fetuses during pregnancy and may be used during breastfeeding. Similarly, the researchers said they are safe for children to use.

“These are new modern second-generation antihistamines that are potent, specific, fast acting, and of proven safety which everyone should be using to treat allergic rhinitis and hives,” Sussman said in the press release.

Are you using antihistamines properly? [news release]. EurekAlert; April 6, 2021. 

https://www.eurekalert.org/pub_releases/2021-04/mu-ayu040121.php

Second-generation antihistamines are safer and just as affordable and as effective as first-generation antihistamines, according to the study authors.

Allergy

Note Proper Use of Antihistamines During Spring Allergy Season

A new study has found a novel biological basis for mood disorders, allowing researchers to develop a blood test for depression and bipolar disorder aimed at a precision medicine approach to treatment. This study, published in 

, builds off of previous research into biomarkers for tracking suicidality, post-traumatic stress disorder, and Alzheimer disease, according to the authors.

“Through this work, we wanted to develop blood tests for depression and for bipolar disorder, to distinguish between the 2, and to match people to the right treatments,” said Alexander B. Niculescu, MD, PhD, professor of psychiatry at IU School of Medicine, in a press release. “Blood biomarkers are emerging as important tools in disorders where subjective self-report by an individual, or a clinical impression of a health care professional, are not always reliable. These blood tests can open the door to precise, personalized matching with medications, and objective monitoring of response to treatment.”

The study was conducted over the course of 4 years and followed 300 participants. Researchers first observed these individuals in both high and low mood states and recorded changes in biomarkers in their blood between these 2 states. These results were cross-validated with large databases developed from all previous studies in the field to allow the researchers to prioritize their findings.

The top 26 candidate biomarkers were then validated in independent cohorts of clinically severe people with depression or mania, before testing in additional independent cohorts to determine their strength in predicting who is currently ill and who will become ill in the future.

The researchers developed a blood test for RNA biomarkers that can indicate the severity of a patient’s depression, their risk for developing severe depression in the future, and the risk of future bipolar disorder. They were then able to demonstrate how to match patients with medications based on these tests and found a new potential medication for the treatment of depression, according to the study.

“Blood biomarkers offer real-world clinical practice advantages,” Niculescu said in the release. “The brain cannot be easily biopsied in live individuals, so we've worked hard over the years to identify blood biomarkers for neuropsychiatric disorders. Given the fact that 1 in 4 people will have a clinical mood disorder episode in their lifetime, the need for and importance of efforts such as ours cannot be overstated.”

In addition to the diagnostic and therapeutic findings, the research team found that mood disorders are underlined by circadian clock genes, which regulate seasonal, day-night, and sleep-wake cycles. This could explain why certain patients get worse with seasonal changes, according to Niculescu.

IU School of Medicine researchers develop blood test for depression, bipolar disorder [news release]. EurekAlert; April 8, 2021. Accessed April 9, 2021. 

https://www.eurekalert.org/pub_releases/2021-04/iuso-iso040721.php

This study, published in Molecular Psychiatry, builds off of previous research into biomarkers for tracking suicidality, post-traumatic stress disorder, and Alzheimer disease, according to the authors.

Mental Health

Researchers Develop Blood Test for Depression Severity, Bipolar Disorder

The FDA has awarded a Rare Pediatric Disease Designation (RPD) to WP1066, a p-STAT3 inhibitor that treats patients with ependymoma, a rare type of tumor that develops in the brain or spinal cord.

Ependymoma forms in the ependymal cells of the brain and spinal cord, which line the passageways in which cerebrospinal fluid nourishes brain flows. The disease can occur at any age but occurs most frequently in young children.

WP1066, which appears to directly elicit tumor cell death and prompt the immune system to attack tumors, was previously 

 in diffuse intrinsic pontine glioma, medulloblastoma, and atypical teratoid rhabdoid tumors.

“The FDA’s recognition of the high prevalence and unmet needs in the treatment landscape for ependymoma, especially in pediatric patients is a significant milestone as we continue to advance and expand the WP1066 development program,” said Walter Klemp, chairman and chief executive officer of Moleculin, in a press release. “We currently have orphan drug designation for WP1066 for the treatment of brain tumors, as well as RPD designation for 3 other pediatric indications, and believe that ependymoma represents another important rare indication.”

The novel drug is an immune/transcription modulator that can directly inhibit certain key oncogenic transcription factors, which include the activated form of STAT3 known as p-STAT3, which is considered a master regulator of tumor activity. The drug can also inhibit several other signaling proteins that have been linked to tumor development and stimulates a natural immune response and memory to fight tumor progression.

WP1066 has shown antitumor efficacy across a wide variety of tumor cell lines, indicating a survival benefit in several animal models. Further, WP1066 can enhance the antitumor effects of the immune system and its response to tumor activity. Research also suggests the agent may have a dual-action mechanism that allows for the treatment of an array of resistant tumors and can be paired in novel combinations for unresponsive tumors.

Subject to FDA approval of WP1066 for ependymoma, Moleculin Biotech, the drug developer, would be eligible for a voucher that may be redeemed to receive priority review for a subsequent marketing application for a different product candidate or that could be sold or transferred.

“We continue to be encouraged by the data WP1066 has demonstrated to date and believe it has potential to be an effective therapy for pediatric patients with ependymoma,” Klemp said in the release.

Ependymoma is a rare type of tumor that develops in the brain or spinal cord and can occur at any age, but occurs most frequently in young children.


Specialty Pharmacy

FDA Grants Rare Pediatric Disease Designation to Treatment for Ependymoma

 I can hear some physicians saying, “You are infringing on my right to practice the way I want to practice. You are going to make me give out naloxone. You are going to make me counsel my patients. You are labeling these drugs in a way that I do not think is appropriate for my patients.” I’m sure there are providers that say, “I want my autonomy here.”

 Can you name 1 doctor who would say it is not a good idea to educate a diabetic about hypoglycemia?

 No one who is not in prison at the moment.

 Exactly. It goes back to understanding what is normal and what is good medical care, emphasizing that good medical care means looking at the risks involved in any treatment: the good, the bad, and the ugly. The ugly is not breathing anymore and dying, whether it is intentional or unintentional. When we prescribe opioids with the best of intentions, to people who we have done very well, there still is a risk. That risk can be somewhat mitigated by the appropriate discussions and the appropriate use of naloxone. Hopefully, that that would resonate with more people. They can appreciate that this is the best practice, as they would do in their other areas of medical care.

 What are some strategies here? In other words, we agree. I suspect if you put this in the abstract, all physicians would agree that living is better than dying. Overdoses are bad; naloxone prevents them. How do you get from here to getting physicians onboard and saying everybody should be doing this?

You have to change policy; that is the first step. Then you prescribe often. You get over your reluctance to do it, and there will still be physicians who will be reluctant, but I am sure you all know somebody who has gotten the call that said, “I’m so happy I had that naloxone, it saved my life.” Or someone may say, “I feel more secure that I have that.” These are the things happening in our state.

 It is a combination of carrots and sticks. It takes a policy to hit a certain group of folks. It comes with the reward of lowering the bar and making it easy. Or if you back up even further, we need to make folks think that this is both a good idea and with the policy, that it is required. Letting folks know that this is a good thing, making it easy, eliminating the need for a prescription when you can, and then having some antidote data to explain why it’s a good idea will all result in success.

We did a naloxone training a few years ago at 1 of the hospitals that I work at, and that night 1 of the nurses who works at the hospital saved her daughter. It does not take many cases like that to get a small microcluster of folks onboard very quickly.

It is not 1 effort that will hit everyone. Some physicians need sticks to get them moving in the right direction—maybe a lot of them do—but a mix between positive and negative reinforcement in addition to other stories that pull at folks’ heartstrings a little—a combination of all those things is the most effective.

 I also think that education starts early in our careers. If we can start educating the health care professionals in the beginning of their training, so it becomes integral to what they do, it will also help, because they’ll be coming out of their schooling with it being normal for them to do this.

One of the things that we have done is we have pharmacies that have overdose response protocols. We think there is an overdose in a pharmacy once every single day. I know many of my colleagues and students have saved people in the parking lot and in the bathrooms, just as some have said. I just heard this week that we have lots of overdoses in Rhode Island. We were in the top 10 areas for many years. We are probably going to be in it this year. But at 1 of the major hospitals’ associated primary care clinics, someone overdosed and there was no naloxone, and none of the physicians or nurses or pharmacists carried it. They had to call EMS [emergency medical services] to their primary care clinic. I ask you, do all of you have naloxone, and is all your staff trained to use it? Dr [Jeremy] Adler is. nodding yes. It’s interesting: They said we’ve got risk assessment and legal involvement. I’m like, this is a no-brainer. All of you are health professionals. You should have had it. My student was walking past a hospital and saw someone having an overdose and a nurse who was walking at the same time, had naloxone, saved the person, got them connected to care.

Theresa Mallick-Searle, MS, RN-BC, ANP-BC:

 It’s the same sort of public health initiative as CPR [cardiopulmonary resuscitation]. It is going to take more, unfortunately. People do not like to be told what to do at any level, and this needs to be a mandate. We need to work together. I’ve seen the biggest push in terms of the promotion of naloxone for patient safety recently. I’m learning about what these EDs [emergency departments] are doing, and it is a great thing you are doing in New York, but it has really been the pharmacists pushing this. I get patients who come back to clinic and educate me with all that they learned from the pharmacist about the availability of naloxone. It is working together.

 Your analogy is apt. A few years ago, it was, “Let’s get defibrillators everywhere.” A defibrillator, I must tell you, in an unexpected location, saved the life of my best friend who went down with VFib [ventricular fibrillation]. It is so much easier to do naloxone; it is silly. To involve lawyers with a drug that has no real downside, no adverse effect, and has only an upside just seems to be [saying]: It is cheap, it is available, it works, and it saves lives. So what am I missing here?

Videos

Multidisciplinary panel of clinicians discuss whether recommendations made by national, state, and local agencies infringes upon clinical practice autonomy.

Peer Exchange

Are Recommendations Infringing Upon Practice Autonomy?

 What are the challenges in adopting biosimilars in your practice? We have a great mix of panelists: Ryan has the academic perspective. Tim is in New York, where he has his own mecca of cancer center that drives decisions across the country. Brandon comes from the community side, so we’re trying to understand the various dynamics that play a role in biosimilar adoption. We’ll start with Ryan in terms of the challenges seen for biosimilar adoption in the oncology and nononcology space.

 Great question. We’ve had different stories between oncology and nononcology, and I’ll lead with that. Initially, about 3 to 4 years ago, we started having our first biosimilars really integrate the growth factor space with pegfilgrastim. A lot of discussions were coming up with biosimilars. In academic institutions, a lot of physicians and providers were very much against biosimilars initially. They had their opinions. This was for patients in curative state. The thought was, “How could we experiment with their lives with biosimilars?” Oh, has that changed.

Coming from there, we did a survey. We figured out the biggest education gaps in terms of biosimilar adoption. What are things we can focus on? Through time and familiarity, and with help from our payers forcing us to use some biosimilars, our providers got a lot more familiar with utilizing them across this space. For oncology, it’s become very accepted to utilize biosimilars. We’re also being a lot more sensitive to the financial toxicity and total cost of care of value-based contracts that our organization may join in. From that perspective, our providers are on board and have almost deferred to pharmacy at this point through a P&T [pharmacy and therapeutics] proposal to select the most appropriate biosimilar for a patient as long as it’s the same therapeutic drug. That’s been a huge lift for us, and it’s allowed us to be very adaptable and excel the practice of our pharmacy team while being good financial stewards and utilizing biosimilars by carrying costs and therapeutic selection.

But within the nononcology space, it’s been a little slower uptake. When we think of rituximab, it’s used across oncology and nononcology. Oncology providers were more receptive to uptake it, especially in the patient population for hematology. But when we have our nononcology areas, such as gastroenterology and rheumatology, there has been a little more hesitation around switching. There is a little more lack of awareness about immunogenicity data and concerns there. Now there are some rituximab products that come up that have switching data, specifically within rheumatology, and that’s been really helpful to leverage so that we can be a strong utilizer of biosimilars in the oncology area.

 That’s great. You guys are doing some amazing things, and I’m sure that there’s significant adoption across your territory.

Ryan Haumschild, PharmD, MS, MBA, provides insight on biosimilar adoption both in oncology and non-oncology practice settings.

Biosimilars

Adopting Biosimilars in Clinical Practice

 What are the recommendations the CDC put out, and are they being implemented? Are they mandatory? What’s the deal here, Jeffrey?

 This is what I said before. Everyone is a first responder, so everyone needs naloxone. My colleagues had a federal grant-funded program where you can go online, watch a training, and they will mail you naloxone. This is fantastic. Actually, in more than half the states in the country, the pharmacy-based naloxone nonprescription laws allow you to call your pharmacy, fill it, and have your insurance pay for it, and they will mail it to you.

We made these adaptations for COVID-19. This helps decrease that stigma. If an officer or off-duty officer comes to my house because my neighbor overdosed or someone is at risk in my apartment complex, they say you need naloxone, and they either drop it off or, if they do not have enough, they say you can call your pharmacy and they’ll ship it right here. Those are the things that are necessary. This report also said the majority of opioids being used illicitly are synthetic opioids, and that’s what’s killing people. There were more overdoses in the 12-month period leading into and including May 2020. There were more overdoses than ever reported, over 81,000, and the majority of those involved synthetic opioids. There is not just a rise in synthetic opioids where I live on the East Coast; it is happening in the Northeast, California, Washington, Oregon, New Mexico, Utah. In these places, the number of overdoses as a result of the misuse of synthetic opioids is still increasing.

Dr Lynch, I think, talked about making sure that naloxone gets in the hands of people after prison. I know New York has that. Rhode Island has that, and we are expanding that. Now we are expanding drug treatment for opioid use disorder treatment in prisons. Treatment is prevention as well, but we are making sure that we prescribe and dispense naloxone with people who are on pharmacotherapy for opioid use disorder. That is where that ties in with the health alert.

 Not only do we need—and I think the CDC said this—to be sure naloxone gets out there, but people have to understand naloxone and how to use it. For example, the half-life of naloxone may be shorter than the half-life of some of the opioids, so you may need another dose. People need to understand that. There needs to be a widespread education program. Nobody is jumping in on this.

 In regard to the public health aspect, we have also worked hard educating the public about good Samaritan laws. When naloxone is used, you still should call 911. When the police come, they are not hauling everybody away in most cases. It is still recommended that you call for emergency services after naloxone is used. We have partnered with some local health departments and put naloxone rescue boxes on walls. They are similar to what an AED [automated external defibrillator] cabinet would look like. At the site of an overdose, someone from the health department will usually come out within a couple of days with a box that has naloxone in it, some gloves, a little business card of instructions, and on the outside, instructions to call 911. We have colocated those with AED boxes, but we have also put them in odd spots such as bathrooms of certain places, public transportation, etc. There is no alarm or anything that goes off when you open the door. Somebody watches them, and when they are empty, the health department replenishes them.

Jeffrey Bratberg, PharmD, FAPhA, and Joshua Lynch, DO, EMT-P, FAAEM, FACEP, discuss highlights from the December 2020 CDC Health Alert and application.

December 2020 CDC Health Alert Highlights and Implementation

Although there are some important considerations for oral chemotherapies in pediatric patients with low-grade gliomas (LGGs), oral formulations can offer effective treatments in this unique patient population, according to a session at the Hematology/Oncology Pharmacy Association virtual 2021 conference.

Gliomas are the second most common childhood malignancy and the most common solid tumor in children, said presenter Kate Reichert, PharmD, BCPPS, a pediatric oncology clinical pharmacy specialist at Memorial Sloan Kettering. LGGs account for approximately 40% of all central nervous system (CNS) tumors for children under 18 years of age, and they have a wide range of histologic subtypes.

Generalizing symptoms are secondary to increased intracranial pressure from obstruction of the ventricles and can include headaches, lethargy, nausea, and vomiting, while localizing symptoms vary. Surgical resection is the mainstay of therapy and may be curative when a total resection is possible, whereas chemotherapy is utilized for incompletely resected, unresectable, or progressive pediatric LGGs with varying response rates, according to Reichert.

She said the most common chemotherapy regimen for pediatric patients with LGGs is carboplatin and vincristine, although vinblastine monotherapy has recently been extensively used. Radiation used to be a first-line therapy but has fallen out of favor because of documented risks of radiotherapy in the developing brain, according to Reichert.

The presentation reviewed 3 chemotherapies for this patient population: selumetinib, trametinib, and dabrafenib. All 3 have shown encouraging results in clinical trials.

Selumetinib is a potent, selective oral non-ATP-competitive small molecule inhibitor of MEK1/2 and was approved by the FDA in 2020 for pediatric patients aged 2 years and older for the treatment of neurofibromatosis type 1 (NF1) with symptomatic, inoperable plexiform neurofibromas. Selumetinib must be given on an empty stomach and swallowed whole, which Reichert noted can be a challenge in young children.

In a clinical trial of selumetinib in pediatric patients with 

-aberrant or NF1-associated recurrent, refractory, or progressive LGG, investigators found that selumetinib is active with the potential to be an alternative to standard chemotherapy. The findings led to the development of 2 Children’s Oncology Group (COG) phase 3 studies comparing selumetinib to standard chemotherapy in newly diagnosed pediatric LGG.

Precautions with selumetinib include bleeding risk, cardiomyopathy, CPK elevations, rash, diarrhea, ocular toxicity, and hepatic impairment. Reichert said there are currently a trio of phase 3 trials investigating its use.

Next, Reichert discussed trametinib and its potential for pediatric patients with LGGs. It is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity, and is FDA-approved for several adult indications. Findings from a retrospective, multi-center, centrally reviewed study by Selt F et al showed a 100% disease control rate with 6 partial responses, 2 minor responses, and 10 patients with stable disease.

The study had a median treatment time of 12.5 months and adverse effects (AEs) occurred in 89% of patients, with 44% experiencing severe AEs. Most of the AEs were skin rash and paronychia, Reichert said. Like selumetinib, trametinib must be administered on an empty stomach and should be administered at the same time each day. Notably, it may also enhance the AEs of dabrafenib.

Finally, Reichert said dabrafenib seems to be well-tolerated and is showing promising results in clinical trials. It is a potent, selective inhibitor of some mutated forms of the protein kinase 

 V600 mutations and is FDA-approved for several adult indications, both as a monotherapy and combination therapy.

Research published by Hargave et al evaluated the safety, tolerability, and clinical activity of dabrafenib in pediatric patients with advanced 

 V600 mutation-positive solid tumors. Of the 32 patients with pediatric LGG, 15 were continuing treatment at the data cutoff. They had an overall response rate of 44% and a 1-year progression-free survival rate of 85%. Fatigue was the most common treatment-related AE, and grade 3 or 4 AEs were reported in 9 patients.

It should be administered on an empty stomach with doses approximately 12 hours apart. When given in combination with trametinib, Reichert said the once-daily dose of trametinib should be taken at the same time each day with either the morning or evening dose of dabrafenib. Precautions for dabrafenib include febrile reactions, hemorrhage, hyperglycemia, malignancy, uveitis, and venous thromboembolism.

With any oral chemotherapy option, Reichert said it is important to consider the available formulations and their various administration schedules. Practitioners are hoping for approved oral formulations that are easier for children, although Reichert said medical professionals can contact manufacturers for dissolution information if necessary. More mature clinical trial data will also be interesting in the future, to see whether any AEs differ between pediatric patients and adults, although they seem to be well-tolerated so far in children, according to Reichert.

Reichert K. Oral Chemotherapy for Pediatric Low-Grade Gliomas. Presented at: Hematology/Oncology Pharmacy Association 2021 Virtual Conference; April 14, 2021. Accessed April 14, 2021.

Oral chemotherapies can be effective treatments for children with low-grade gliomas, although clinicians should consider available formulations and administration schedules. 

Expert: Consider Oral Chemotherapies for Pediatric Patients With Low-Grade Gliomas

The delivery of intravenous cancer therapies in the home has been a topic of great importance since the start of the COVID-19 pandemic, explained Stephanie Kang, PharmD, MS, BCPS, a clinical manager from University of North Carolina (UNC) Homecare Specialists at UNC Health, during a session at the Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference.

Currently, home infusion within the larger ambulatory infusion setting poses some specific advantages and disadvantages in relation to the other location options available. There are 3 main ambulatory infusion locations that are used for intravenous cancer therapies: hospital-based clinics, freestanding infusion clinics, and the patient’s home.

Of the 3 locations, hospital-based clinics have the advantage over the others of being held to the highest regulatory standards, especially in terms of United States Pharmacopeia compliance, according to Kang. Additionally, the hospital affiliation of these clinics provides the greatest level of access to specialized care.

The disadvantages presented in hospital-based clinics include price, as they are the most expensive location option for infusion, as well as their inconvenience for patients. Inconvenience may especially be a factor if the clinic’s hours of operations are limited, which may also contribute to longer wait times for scheduling treatments.

Alternatively, freestanding infusion clinics may be slightly more convenient because they are dispersed around the community, while also providing a lower cost than hospital-based clinics. However, if not affiliated with the patient’s primary oncology team, these location options can cause issues regarding fragmented care due to difficulties around communication between each care team involved.

Within the home infusion setting options, the lower cost of this setting in relation to hospital-based clinics poses specific advantages, although the cost remains about the same as the cost of freestanding infusion clinics. However, the convenience of the infusion location being in the patient’s home makes this option more advantageous for the patient than freestanding infusion clinics, which will still require transportation considerations.

However, if the home infusion provider is a third-party company that is external to the patient’s primary care team, the issue of fragmented care may also arise in the home infusion setting. Additionally, concerns regarding the patient’s limited access to their care team may pose problems, since removing the need to visit the clinic for each infusion limits patients' interaction with their provider. There are also other problems that may arise around the patient’s potential limited access to emergency services if a negative reaction or adverse event (AE) occurs during the infusion.

Currently, there are 2 issues that have caused a shift in focus toward the home infusion setting, according to Kang. The first issue is the payer’s side of care mandates, which has arisen as a point of interest due to the lower cost of home infusion and freestanding infusions, bringing about a shift among payers toward requiring that patients receive treatments in either of these settings, rather than in the hospital-based clinic setting.

The second issue that has caused a shift toward the home infusion setting is the COVID-19 pandemic, which led to an overall push for home infusions as a way of mitigating the spread of COVID-19 among patients and health care professionals.

In light of this, the Centers for Medicare and Medicaid Services (CMS) issued a new interim final rule during the pandemic that was intended to allow additional beneficiaries, particularly among high-risk patients, to receive home infusions to reduce COVID-19 transmission concerns. As a result of this interim final rule, CMS made it easier for patients to receive home infusions of a wider variety of medications, including cancer therapies.

Within the past 2 years, several national oncology organizations have released position statements related to home infusion of cancer therapies. For example, in the position statement of the American Society of Clinical Oncology (ASCO), the organization explained several concerns around safety, which included the lack of double checks prior to administration, the risk of life-threatening AEs, the potential for chemotherapy spills or exposure to non-cancer patients in the home, the question of liability if there was an error in the drug preparation, and the lack of oncology-trained nurses going out into the home.

However, ASCO also acknowledged some advantages to patients being able to receive infusions in the home, such as increased participation in clinical trials, as well as increased access to care, specifically for patients located in rural regions.

In light of these advantages to the home infusion setting, ASCO made 6 recommendations for administering cancer therapies in the home. The first recommendation was to use public funds to formally research the safety and efficacy of cancer therapies because there is currently not significant primary literature on this topic.

ASCO’s second recommendation was for CMS to not extend the interim final rule established during the pandemic that makes available a wide variety of therapies for infusion in the home. The third recommendation was that CMS looks to work closely with oncology experts to ensure that the provider and patient agree to the home setting as the most appropriate setting for care. 

Upon the agreement of this setting, ASCO recommended that CMS require quality reporting of oncology-specific measures to further evaluate safety and efficacy outcomes, primarily due to the lack of available data in these areas.

ASCO’s fourth recommendation was to limit cancer therapies to exceptional circumstances in which the benefit to that patient would outweigh the risk, while the fifth recommendation was to require a consultation with the oncologist before allowing any delivery of pre-prepared cancer therapies. Lastly, ASCO recommended that payers require proof of safety protocols and precautions for home infusion providers.

Conversely, the Community Oncology Alliance (COA) released a position statement stating that they fundamentally oppose the home infusion of chemotherapy, cancer immunotherapy, and supportive drugs for cancer treatment due to serious patient safety concerns.

COA’s specific reasoning for their opposition was that patient’s need face-to-face, high-touch evaluation with each treatment cycle, that the number of treatments increases incidence of AEs and interactions, that the specialty care-trained team is not available in the home, and that home infusions have limited access to emergency medications, equipment, and personnel.

Based on these observations and recommendations from prominent oncology organizations, Kang explained that there are clearly benefits for the home infusion setting, but there remain barriers to this setting that need to be addressed for this to be a successful site of care.

In light of this, the Gorski Model for Safe Home Infusion Therapy outlines 4 factors that are required for safe care in the home, although this model is more generally intended for home infusion for all medications. The requirements include appropriate patient selection, comprehensive assessment and monitoring, appropriate patient education, and interprofessional communication and collaboration.

“If I put this into my own words, I would say the safe model for home infusion therapy requires the right patient, the right regimen, the right resources to the patient, as well as the right level of communication across care teams,” Kang said during the session.

Kang S. Intravenous Cancer Therapies in the Home - Innovative or Dangerous? Presented at: Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference; April 14, 2021; virtual. Accessed April 14, 2021.

Home infusion within the larger ambulatory infusion setting poses some specific advantages and disadvantages in relation to the other location options available.

Assessing the Advantages, Disadvantages of Intravenous Cancer Therapies in the Home 

In a presentation at the virtual Hematology/Oncology Pharmacy Association (HOPA) Annual Conference 2021, Amy M. Sion, PharmD, BCOP, reviewed 4 first line clinical trials in stage IV renal cell carcinoma, all of which compared their treatment arm to sunitinib monotherapy. In each trial, overall response rate (ORR) and median progression-free survival (PFS) in the novel treatment arm showed significant improvement over the sunitinib treatment arm.

In the CheckMate-214 trial, patients with intermediate and poor risk as measured by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model were randomized into 2 treatment arms: one using a combination of ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab monotherapy, and one using sunitinib 50 mg daily. In a 42-month follow up, the results showed a 42.1% ORR for the ipilimumab and nivolumab treatment arm compared to 26.3% for sunitinib monotherapy, and a median PFS of 11.6 months compared to 8.3 months.

“The median overall survival was still not estimable at the 42 months follow-up, but our hazard ratio is statistically significant,” Sion said. “You’ll see this with all of our IO doublet trials as well—our overall survival is taking a while to get reached because the patients are living much longer on these combination therapies.”

KEYNOTE-426, a similarly designed trial, compared patients randomly assigned to either a combination of pembrolizumab and axitinib or sunitinib monotherapy. In the initial results, published in 

, the combination arm had an ORR of 59.3% compared to 35.7% for sunitinib, and median PFS was 15.1 months versus 11.1 months. As with CheckMate-214, median overall survival (OS) could not be evaluated at the time of analysis, although the 24-month OS reported at a follow up analysis was 74% for the pembrolizumab and axitinib group compared to 66% for patients on sunitinib monotherapy.

“When they broke their outcomes down by risk stratification, the overall survival and progression-free survival in the intermediate- to poor-risk groups favored pembrolizumab and axitinib, whereas in the favorable risk categories, both of these outcomes favor [pembrolizumab and axitinib], but were not statistically significant,” Sion said.

Slightly different in its design, the JAVELIN Renal 101 study focused on patients with tumor tissue available for programmed death-ligand 1 (PD-L1) testing and had primary endpoints of PFS and OS in patients with PD-L1 positive tumors. Patients were randomized into either the combination therapy of avelumab and axitinib, or sunitinib monotherapy. The results for patients with PD-L1 positive tumors showed an ORR of 55.2% for the combination arm compared to 25.5% for patients on sunitinib. The median PFS was 13.8 months for patients on avelumab and axitinib, and 7.2 months on sunitinib.

“This is only in patients with PD-L1 positive tumors. When we look at the overall population, the numbers are almost the same,” Sion said. “So, the authors concluded from this that PDL status does not appear to be predictive of whether or not these patients are going to respond to IO combination therapy.”

The CABOSUN trial compared the efficacy of cabozantinib monotherapy to sunitinib monotherapy, with a primary endpoint of PFS. ORR was 20% in the cabozantinib arm compared to 9% in the sunitinib arm, and median PFS was 8.6 months versus 5.3 months.

Though the trials each had similar focuses and conclusions, Sion warned against cross comparing the results of each study.

“We have a tendency to want to do that, because they look similar and because the therapies are similar, and the patients are similar,” Sion said. “However, there’s a lot of imbalances in the demographics and also in the trial design.”

Amy M. Sion. Updates in Renal Cell Carcinoma. Presented at: HOPA Annual Conference 2021; April 14, 2021; Virtual.

In each trial, overall response rate and median progression-free survival in the novel treatment arm showed significant improvement over the sunitinib treatment arm in patients with renal cell carcinoma. 

Study: Four Treatment Options for Renal Cell Carcinoma Prove More Effective Than Sunitinib Monotherapy

Systemic racism, implicit bias, and how they adversely affect certain patient populations were addressed in a keynote speech Wednesday at the virtual Hematology/Oncology Pharmacy Association Annual Conference 2021. Speaker Lakesha M. Butler, PharmD, BCPS, diversity and inclusion coordinator and clinical professor at Southern Illinois University Edwardsville, also discussed causes of health inequity and how pharmacists can prevent and mitigate them to improve patient outcomes during the John G. Kuhn Keynote Lecture, “Dismantling Structural Racism in Pharmacy.”

Pharmacists take an oath to consider the welfare of humanity and relief of suffering as their primary concern; however, Butler noted that some communities and patients disproportionately experience social detriments of health based on structural racism, which is often perpetrated by implicit bias as well as other behaviors and policies.

According to Butler, recent literature have discussed how health care providers have implicit biases—negative associations—but don’t necessarily know that they have them. Although individuals oftentimes go into health care fields, such as pharmacy, with the goal of helping people, she said studies are finding that “we all have implicit biases.”

“Implicit bias can result in minority patients being prescribed less pain medications or being delayed diagnostic testing, resulting in health care disparities,” Butler said.

Referring to 2020 as “the year of 2 pandemics,” Butler discussed the relationship between COVID-19 and racism as a timely example of health disparity. In addition to high-profile social justice issues centered on racism, Butler said the COVID-19 pandemic has shined a light on systemic racism and how health care is impacted.

“Racism is far from being novel or new. COVID [-19] has shown us that we have quite a way to go,” Butler said.

CDC data presented by Butler show disproportionate COVID-19 statistics for populations in the United States, comparing people of color compared to the White population. The statistics are as follows:

The Black and African American population have reportedly had 2.6 times higher cases, 4.7 times higher hospitalizations, and 2.1 times higher deaths from COVID-19 than White Americans.

The Native American and Native Alaskan population have had 2.8 times higher cases of COVID-19, 5.3 times higher hospitalizations, and 1.4 times the number of deaths from the virus.

The Hispanic and Latino population has had 2.8 times higher cases, 4.6 times higher hospitalization, and 1.1 times higher number of COVID-19 deaths.

Asian Americans have had 1.1 times higher cases, 1.3 times higher hospitalizations, and showed no increase above the White population in the number of deaths.

In her presentation, Butler addressed the history of racism in the United States, such as inequitable policies, that have negatively affected Black Americans and other non-White populations, as well as modern practices that may perpetrate racism. Racism has often led to social determinants of health.

According to Butler, social determinants of health are a set of 6 environmental conditions that have a profound impact on death rates and life expectancy for all conditions, including cancer and COVID-19. These environmental conditions are economic stability, access to a quality education, health care access and quality, neighborhoods, social and community context, and access to healthy food.

Health care providers, including pharmacists, need to dig deep to identify social determinants for each patient, Butler said. She compared each patient case to an iceberg, in which only a small portion is seen above the water.

“If we stay on the surface, we’re doing our patient a disservice. We must reflect on and examine what we don’t know below the surface,” she said.

Hundreds of years of systemic racism in the United States, including enslavement and Jim Crow laws, have led to many social determinants that may affect an individual’s health today, and may preclude a patient from obtaining prescribed medications and visiting health care providers.

Using a patient case as an example of what providers might encounter, she addressed a man with hypertension, asthma, and other medical conditions. Subpar housing, such as living near a toxic waste facility, may be contributing to his asthma, she said. The man’s hypertension could be caused by racial profiling or other social stressors that are not typically seen by the White population. Lack of access to healthy foods also plays a role in patients’ health.

According to Butler, more than 80,000 individuals die each year in the United States because of health disparities. Data have also shown that Black men have more than 30% higher risk of prostate cancer compared with White men, and Black individuals are 3 times more likely than non-Hispanic White individuals to experience kidney failure.

In closing her keynote address, Butler discussed steps for dismantling structural racism. Recognizing and believing that racism is structural and systemic, understanding how social determinants of health affect patients and how care providers can educate themselves are several steps. She said providers also need to identify and address personal biases.

Lakesha M. Butler, PharmD, BCPS, diversity and inclusion coordinator and clinical professor at Southern Illinois University Edwardsville, discussed causes of health inequity and how pharmacists can prevent and mitigate them to improve patient outcomes.

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