Utilization Challenges Hold Back the Adoption of Bispecific Therapies

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FOR OVER 20 years, the use of monoclonal antibodies has been a consistent option in the treatment armamentarium for patients with cancer. It remains so with the addition of therapies like daratumumab (Darzalex), but the next evolution of these monoclonal antibodies to bispecific antibody therapy has opened a wider array of targeted treatment options. Still, with any major innovation in therapy come the challenges of applying it in the practice setting.

There are currently 9 FDA-approved bispecific antibodies with 8 focusing on cancer, including amivantamab-vmjw (Rybrevant), blinatumomab (Blincyto), epcoritamab-bysp (Epkinly), glofitamab-gxbm (Columvi), mosunetuzumab-axgb (Lunsumio), tebentafusp-tebn (Kimmtrak), teclistamab-cqyv (Tecvayli), and talquetamab-tgvs (Talvey).^1,2 According to the FDA, what makes bispecific antibodies a landscape-changing therapy that will potentially lead to a large number of new treatments is that bispecifics target 2 antigens in the cancer that can be independent of each other.¹ This allows for a number of targeted approaches in a single therapy to bridge cancer cells to cytotoxic immune cells. Now over 100 bispecific antibodies are in development.¹

In comparison, chimeric antigen receptors (CAR) T-cell therapies require the patient’s own cells to make the treatment. Bispecific antibodies do not require anything from the patient and are an off-the-shelf option; thus, they can be accessed more quickly than CAR T-cell therapy. These therapies do not eliminate the need for CAR T-cell therapy, but the excitement for bispecific therapies comes from the potential of its wider accessibility.

For example, for patients with B-cell lymphoma, the CD20 antigen is present for all patients with malignant B cells, and bispecifics that target the mature antigen can lead to less severe adverse events (AE) when targeting just these mature B cells.³ Though the data are exciting for these therapies, the process of delivering them is one that requires careful consideration at all levels of care.

“One thing we are realizing now in the community setting is that bispecifics have come to stay,” said Ayodele Ayoola, MD, at a live virtual Case-Based Roundtable event on the operationalization of these therapies. “We know that you can refer all these patients to an academic center, but depending on where they live...some patients don’t want to go too far. So, we’ve [concluded] that we need to learn [about these therapies], we need to know them and do a lot of teaching.”

HURDLES TO ADOPTING BISPECIFIC CARE

With any advancement in oncology, the use of a novel therapy differs in the community setting compared with the academic setting. The drug doesn’t change, but facilities and capabilities of community institutions are different from those of academic centers, and not all patients have the same access to academic centers that may be able to handle the burden and cost of these medicines more easily.

According to a 2020 survey from the Association of Community Cancer Centers on the use of blinatumomab, an early bispecific antibody, fewer than half of the medical oncologists and hematologists in the survey were familiar with it and 41% cited transitioning patients from the inpatient to outpatient setting as their most common challenge when using the bispecific antibody.⁴ Further, managing patients in remote areas (33%), securing insurance coverage (28%), managing AEs (27%), assisting patients with costs (24%), and lacking in-house expertise with the drug (22%) were cited as the other common barriers to implementing bispecific anitbodies.⁴ In polls conducted at 2 separate live virtual Case-Based Roundtable events, the answers provided by the attendees highlighted how these challenges are even holding some practices back from administering bispecific therapy.

In an event moderated by Maribel Pereiras, PharmD, BCPS, BCOP, 46% of attendees said they do not administer bispecifics at all, while 8% do not administer these therapies but are in the process of establishing a program to administer continued dosing of these therapies. Thirty-eight percent said they would send patients to an academic center for initial step-up treatment and then continue therapy at a community center. Comparatively, in a live virtual event led by Justin LaPorte, PharmD, BCOP, 43% said they would send the patient to an academic center first, but 57% of the attendees were in an institution where they could give the treatment in the inpatient setting and would consider moving patients to the outpatient setting afterward.

“I think a lot of institutions are also struggling with that financial piece as to how you incorporate [bispecific therapy] and who’s going to assume the cost of it.… I can tell you that there are different strategies, depending on which bispecific that you’re looking at or utilizing,” said Pereiras, a clinical oncology specialist at Hackensack University Medical Center in New Jersey, when explaining some of the other barriers that come with bispecific therapies. “Some of [the companies behind the drugs] do provide a new technology payment given on the back end where they will be reimbursed better than [with] traditional medications. Another one is providing free product for the inpatient administration, and then once the patient gets to the outpatient setting…you would have to purchase the supply.”

According to Pereiras, this is an attempt by the companies to try to meet providers in the middle as the finances change in the inpatient vs the outpatient settings. However, not all practices are part of a large system that can weather these prices indefinitely, which is why Pereiras recommends that while the package label for these therapies may suggest admitting the patient regardless, physicians can make that judgment as they set up the procedures for evaluating patients on these therapies.

“When we come to this point, we do not have experience using these drugs and we do not have protocols in place yet,” said Mukesh Kumar, MD, a medical oncologist and hematologist at the John B. Amos Cancer Center in Columbus, Georgia. “We are still [referring the patient to] either Northside Hospital or the Winship Cancer Institute [in Atlanta], and we have quite a few patients with myeloma that we share with Northside. So, we end up sending patients there and then after step-up dosing, when they are able to come back, we are able to handle it here. We’ll have a mutual conversation with the patient as well, and then we try to jump in and take it from that position.”

CONSIDERATIONS TO DEVELOPING PROCEDURES FOR BISPECIFIC THERAPY

LaPorte, a pharmacist at Northside Hospital and part of the Blood and Marrow Transplant Group of Georgia, has the benefit of being a part of a major hospital. Centers like these can give patients inpatient step-up treatment, then allow them to move on to the outpatient setting to receive maintenance therapy, sometimes within their own system. However, the fundamentals of continuing to educate the staff to then educate the patient and caregiver apply in any cancer center, and creating a standard operating procedure is a step any group can take.

“To get to the point to treat patients with CAR T-cell therapy, when that was new, we had to go through the same type of protocol development that [those in the community setting] might with the bispecifics. This includes talking with the emergency department and intensive care unit [ICU] staff, developing treatment protocols to treat cytokine release syndrome [CRS] and immune cell–associated neurotoxicity syndrome [ICANS] with these therapies...and educating the staff,” explained LaPorte. “We had to develop all those things [initially], so it was easy for us to transition to bispecific therapy...and our clinic is basically connected to the hospital, so we have an easy way to admit patients.”

According to LaPorte, management in any center needs to let the nursing staff know about a patient coming in who will be treated with a bispecific therapy so they can coordinate with the pharmacy staff to educate the patient on what to expect from treatment. Further, he suggested developing wallet cards for the patient if these medicines do not already come with their own. Patients and their caregivers will have to be able to identify signs of AEs like CRS and report them, regardless of where the practice is located.

According to the Academy of Oncology Nurse & Patient Navigators, education of the patient and their caregiver is a fundamental mandate for patient navigators and most likely to be carried out by them anyway.⁵ The academy cited results from a survey-based analysis for the management of patients with lung cancer that highlighted that across various types of practice settings, nurse navigators would be more likely than oncologists to give the patient and caregiver educational materials.⁶

This shows the vital role oncology nurses play in any practice and how important it is for them to be at the forefront of a practice’s use of bispecifics. The academy also wrote about how navigators would be imperative to the coordination of care for patients. Using the example of administering teclistamab to treat patients with multiple myeloma, oncology nurses were labeled the liaison between various groups working with the patient but also the ones to make sure testing, continuing treatment, and follow-up appointments are carried out, which is crucial for the use of bispecific therapies in this patient population, as they can continue for some time. Moreover, advanced practice providers and oncology nurses can end up being the ones ensuring the safe delivery of treatment in some cases; thus, having a standard operating procedure (SOP) for all staff to understand is crucial to make sure care is always delivered to the patient. LaPorte recommends assembling a team dedicated to developing these protocols, but SOPs won’t be agreed upon overnight, as every practice’s situation is different and guidelines centering around bispecifics are not as detailed due to the recent development of the drug.

“At our institution, we are in the process of developing SOPs for these, as we start to see more agents that are approved. By and large, up to this point, it has all been protocol driven, and I don’t necessarily mean an SOP that we have developed, but a research study protocol that has provided guidance on how to manage these patients,” explained Haley Cowan, PharmD, an oncology pharmacist at Children’s Healthcare of Atlanta. “Our approach to this is multifaceted, where we’re working with the physicians, the entire research team, the ICU staff, and the bone marrow transplant staff. We rely pretty heavily on our bone marrow transplant staff from their experience with CAR T-cell therapy, simply just for developing the different algorithms.”

Important to developing these procedures is considering some of the guidelines already in place for addressing AEs like CRS and ICANS. These include the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) guidelines, developed by the Mayo Clinic for addressing CRS and ICANS stemming from the use of teclistamab. Physicians can follow these guidelines depending on the grade of AE they encounter.⁷

For example, if a patient has a fever but does not have hypotension or hypoxia, the guidelines recommend starting with either 10 mg of dexamethasone given intravenously or 1 dose of tocilizumab (Actemra), which can also be given if there is no improvement with dexamethasone after 4 hours. But if there is no improvement, or it is apparent that the patient has a grade 2 to 4 CRS event, then tocilizumab is recommended for up to 3 doses before methylprednisolone at 1000 to 2000 mg every 6 hours is given for 3 days and tapered over 2 to 3 days.

Pereiras also explained that along with the mSMART guidelines, there are the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines for managing these AEs, and they somewhat differ.⁸ For example, in managing teclistamab-associated ICANS, the ASTCT guidelines call for the use of 10 to 20 mg of dexamethasone every 6 hours and then moving on to either 2 mg/kg or 1000 to 2000 mg of methylprednisolone given intravenously daily. The mSMART guidelines call for the same process of elimination if the patient starts at grade 1 and worsens, but if the patient’s AE is grade 2 to 4 by the time it’s caught, the mSMART guidelines call for methylprednisolone alone.⁷ Small changes like this are why Pereiras suggests practices consider both guidelines and see what works for them and the patient they’re treating.

“You have to think of the AEs in the short term, which is CRS and ICANS, which is heavily focused up front in the step-up doses and that first treatment dose in the long term,” Pereiras added. “On the back end, what you have to think about is what you’re going to do in terms of managing and preventing infections.”

_REFERENCES

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_{2. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. August 10, 2023. Accessed January 23, 2024. http://tinyurl.com/mwbhzxde}

_{3. Carter D. Bispecifics antibodies: the next big thing in lymphoma treatment. MD Anderson Cancer Center. June 2, 2022. Accessed January 23, 2024. http://tinyurl.com/yk6w5mf6}

_{4. Atembina L, Boehmer L, Terrell K, et al. Multidisciplinary provider insights to promote adoption of bispecific antibodies to treat cancer in the community. Blood. 2021;138(1):4033. doi:10.1182/blood-2021-153794}

_{5. Optimizing bispecific antibody therapy in multiple myeloma: a resource guide for nurse and patient navigators. Academy of Oncology Nurse & Patient Navigators. October 13, 2022. Accessed January 23, 2024. http://tinyurl.com/z8a97npv}

_{6. Roy UB, Ferris A, Jacobson M, Haskins K. Are lung cancer patients receiving education materials? the healthcare provider perspective on distribution gaps and possible solutions. J Thorac Oncol. 2018;13(10):S994. doi:10.1016/j. jtho.2018.08.1885}

_{7. mSMART: a clear and simple guide for treating patients with multiple myeloma. Mayo Clinic. January 23, 2021. Accessed January 23, 2024. http://tinyurl. com/5yad3bsa}

_{8. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j. bbmt.2018.12.758}